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Epilepsy
Seizure disorders are common in children. Nearly 8 percent of all children will experience a seizure before their 16th birthday; with epilepsy affecting 1 percent of the pediatric population. During the past ten years there have been significant advances in our understanding of the effect of epilepsy on brain structure and function resulting in large part from revolutionary advances in imaging technology. These studies demonstrate that epilepsy causes progressive brain injury. Furthermore, there have been great advances elucidating the developmental, molecular and physiological mechanisms underlying epilepsy. The Comprehensive Pediatric Epilepsy Program (CPEP), under the direction of William Davis Gaillard, MD, is one of the largest multidisciplinary epilepsy programs in the country. CPEP is designed to provide clinical care and conduct clinical research into the origins, impact and treatment of epilepsy in children.
This multidisciplinary team has active research in:
- neuroimaging of seizure disorders
- seizure predication and control
- neurotransmitter diseases and mechanisms or epileptogensis
- mood and anxiety disorders in epilepsy populations
- identification and evaluation of recent onset epilepsy
- drug trials
- development of coping and socialization skills in children with epilepsy
- improving access to care and improved outcomes
Children's has more than 12,000 patient-related epilepsy visits every year, and Children's maintains the nation’s largest database of children with new onset seizures. Children’s CPEP is an innovative, multidisciplinary clinical and research program that evaluates and cares for children from the onset of seizures, through novel therapeutic interventions, and epilepsy surgery. We serve as a regional and national resource for epilepsy evaluation and care. We have a multi-disciplinary team with seven pediatric neurologists who have expertise in epilepsy and board certification in clinical neurophysiology, two pediatric neurosurgeons, one pediatric neuroradiologist, two pediatric neuropsyhologists, a child psychiatrist, a social worker, and specialty nursing.
Development and application of advanced imaging technology is a primary focus of CPEP clinical research. Dr. Gaillard’s lab pioneered the use of fMRI cognitive studies in children and has helped establish fMRI as a viable alternative to replace invasive methods of language localization (intra-carotid amobarbital test) for planning and conducting epilepsy surgery. Children's is the lead site in an American Epilepsy Foundation supported initiative to establish an international consortium of pediatric epilepsy centers to conduct structural and functional imaging investigations. As epilepsy affects brain function during critical periods of brain development for higher ordered cognitive functions, epilepsy populations offer an opportunity to study neural plasticity and provide potential interventions to spare function. Current studies in Dr. Gaillard’s laboratory are directed to delineate the normal development of brain systems that underlie language processing and elucidate the effect of epilepsy on those and other higher ordered cognitive systems. The neurocognitive aspects of our experimental and clinical program are conducted in collaboration with Gerard A. Gioia, PhD, chief of Neuropsychology, and Chandan Vaidya, PhD, developmental and cognitive psychologist. Experimental methods include paradigm design; fMRI acquisition, processing, and analysis; and brain behavior correlations. Madison Berl, PhD, is piloting fMRI studies of working memory and language in children with epilepsy under a CReFF award.
The CPEP pharmacology program has played a leading role in conducting intervention and neuroprotection trials along with innovative pharmacokinetic, and pharmagogenomic studies. Joan A Conry, MD, is conducts industry supported studies to evaluate the efficacy of leveteracitam, topiramte and clobazam in childhood epilepsy. Dr. Conry plays a lead role in the NINDS multi-center study of Absence Epilepsy. Phillip L. Pearl, MD, is conducting a pilot study of Leveteracitam to prevent epilepsy in traumatic brain injury. Drs. Conry and Gaillard, with James M. Chamberlain, MD, (PI) and PICARN are investigating the kinetics Ativan in the treatment of childhood seizures. John N. Van Den Anker, MD, PhD, head of the PPRU, is participating in a pharmacogenetic study of idiopathic adverse reactions to carbamazepine and valproate.
Jay A. Salpekar, MD, is exploring mood and anxiety disorders in children with epilepsy supported by pharmacutical industry grants. The study should lead to the development of new models for the inter-relationship of epilepsy and mood/anxiety disorders, to new treatment intervention strategies. Sandra Cushner-Weinstein, MSW, studies family coping skills and their effect on children with epilepsy; she has produced an educational DVD for children and families of children with epilepsy, and has, with Mark Weisman, MD, recently secured federal NICHQ funding to improve access to epilepsy medical care by underserved populations. Phillip L. Pearl, MD, and Maria Acosta, MD investigate GABAergic mechanisms of epileptogenicity in the inborn error of metabolism, succinic semialdehyde dehydrogenase deficiency.
In addition to multiple clinical studies, active basic and translational investigations in childhood epilepsy are ongoing in the Children's epilepsy program in conjunction with our collaborators at Georgetown University (GU) and George Mason University (GMU). Studies in the laboratory of Vitorio Gallo, PhD, are focused on defining the developmental and physiological properties of hippocampal GABAergic interneurons, a class of cells that die in temporal lobe epilepsy. Loss of inhibitory GABAergic neurons is implicated in initiating and sustaining epileptogenesis, and whose replacement may offer a therapeutic target. Dr. Gallo’s laboratory recently established a transplantation paradigm aimed at regenerating GABAergic interneurons in the hippocampus from grafted postnatal neural stem cells. Dr. Gallo’s laboratory expertise in glial cell development allows for studies to elucidate the role of developmental glial-neuron interactions in epileptogenesis. Experimental methods include immunohistochemistry, neural cell culture techniques, confocal laser scanning microscopy, optical imaging, and a variety of molecular techniques.
Studies in the laboratory of Margaret L. Sutherland, PhD are focused on the role of glutamate transport in the seizure sequelae. Through the use of transgenic models of glutamate transport overexpression, Dr. Sutherland’s laboratory has demonstrated that enhance glutamate uptake can inhibit seizure activity and cell loss in experimental models of temporal lobe epilepsy, as well as in an in-vivo model of glioblastoma. She has also used transgenic methodologies to demonstrate that over expression of the Akv1.1 K+ channel gene during critical periods of postnatal development can lead to spontaneous absence-type seizures in the adult animal. Dr. Sutherland’s recent arrival at CRI facilitates a new translational component of her research, which combines her interests in ion channel and transporter biology with SNP analysis of these critical genes in childhood epilepsies. Experimental methods include EEG analysis, transgenic animal biology, electrophysiology, molecular biology, glial cell biology, SNP analysis, promoter analysis, behavioral analysis (Morris Water Maze, elevated Y maze, non-spatial recognition touch screen analysis), stucture-function analysis, and receptor and transporter kinetics.
Understanding neuronal population behavior is critical to novel translational studies targeting seizure prediction and control. Studies in the laboratory of Steven Schiff, MD, PhD, at GMU, conducted in collaboration with Steven Weinstein, MD, vice chair Children's Division of Neurology, are aimed to elucidate organizing principles of neuron population activity using linear and non linear methods of neuron interaction and modulation. He has pioneered seizure onset prediction in humans and in experimental animal models. Current studies examine the interaction between 2-3 identified neurons to characterize excitatory and inhibitory neuron behavior as seizures arise, and to determine how their synaptic current inputs and spike outputs determine the onset, persistence, and termination of seizures. An ongoing focus of this research is to investigate and develop methods of neuron population control using electrical fields in brain slice and whole animal epilepsy models. Experimental methods include patch clamp, cell slice intracellular recordings, whole animal chronic extra-cellular recording, linear and non-linear methods of analyzing neuron dynamics, and electrical field modulation of neural activity.
Children's epilepsy program has longstanding collaboration with the Clinical Epilepsy Section (William H Theodore, MD) and EEG lab (Susumu Sato, MD) at NINDS, NIH. These studies include the use of novel PET ligands to map serotonin receptor binding abnormalities in patients with non-lesional neocortical epilepsy, and in patients with depression and epilepsy. Phillip L. Pearl, MD, is imaging a population with a GABAergic disorder SSADH with Flumazanil PET, a selective benzodiazepine receptor ligand. Other studies include advanced imaging modalities to identify the seizure focus and consequence of epilepsy on brain structure and function (MRS, MEG). Pathological studies are performed with brain tissue to examine the role of childhood HHV6 infection as a cause of mesial temporal sclerosis. These studies include human pathological studies (Steven Jacobson, PhD, NINDS, and Tammy Tsuchida, MD), mechanism studies form human brain cell cultures (Dr. Jacobson) and mouse models (Margaret L. Sutherland, PhD).
Related Links
American Epilepsy Society
www.aesnet.org
Promotes research and education for professionals dedicated to the prevention, treatment and cure of epilepsy.
Epilepsy Foundation (formerly Epilepsy Foundation of America)
www.efa.org
Provides programs of information and education, advocacy, support of research, and the delivery of needed services to people with epilepsy and their families.
International League Against Epilepsy
www.ilae-epilepsy.org
Global nonprofit organization that disseminates knowledge about epilepsy and fosters research, education and training, and improved services and care. Has official working relationship with the World Health Organization.
Medline
www.ncbi.nlm.nih.gov
Contact Information:
William Davis Gaillard, MD
Children’s Research Institute
Center for Neuroscience Research
Children's National Medical Center
111 Michigan Avenue, NW
Washington, DC 20010
202-476-5224
202-476-4988 fax
wgaillard@cnmc.org
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Watch Dr. Gaillard explain his research findings on epilepsy and its effects on brain structure and brain function.