ARRA Investments in Epilepsy
Public Health Burden
Epilepsy refers to a broad range of neurological conditions associated with repeated unprovoked seizures, which can result from genetic or congenital disorders, brain tumor, infection, stroke, or traumatic brain injury, among other causes. Together, the epilepsies affect an estimated one percent of people in the U.S., and available treatments fail to control seizures in about one third of cases.
Many forms of epilepsy have genetic causes. Knowing the genes that influence susceptibility for epilepsy yields insights into disease mechanisms and strategies to treat and prevent epilepsy in people at risk:
An ARRA Grand Opportunity grant is supporting genome-wide sequencing to identify rare gene variants in 50 families in which multiple individuals have epilepsy. This study will also determine if such variants are associated with epilepsy in a larger sample of unrelated patients and controls.
An ARRA supplement will accelerate enrollment into the Epilepsy Phenome/Genome Project by adding new personnel and recruitment centers. This multi-institutional project to identify the genetic basis of some of the most common epilepsies is collecting DNA and clinical information from over 6,000 epilepsy patients and controls that will be available for broad research use.
Epileptogenesis is the process by which brain tissue acquires the ability to generate spontaneous seizures. A better understanding of this process could enable intervention before chronic epilepsy develops.
NIH ARRA funds are supplementing an ongoing prospective study of 200 children to understand the consequences of prolonged febrile seizures, which are associated with fever in children. The study will determine the relationship between these seizures, damage to the brain’s temporal lobe, and the later development of temporal lobe epilepsy (TLE).
Another NINDS study is using an animal model of febrile seizures to look for biomarkers of epileptogenesis. With supplemental ARRA funds, this study will determine whether diffusion tensor imaging (DTI), a type of imaging that can also be used in humans, can detect changes in the brain’s white matter that may predict the subsequent development of TLE.
Although several medications are available for the treatment of seizures, none are known to prevent the development or progression of epilepsy. Treatment fails to control seizures in about 30% of patients, and many experience adverse side effects from medications or surgical intervention. NIH ARRA funds are supporting efforts to develop new ways to treat and prevent epilepsy. For example:
Vigabatrin is the only approved anticonvulsant for a type of epilepsy called infantile spasms and is also used in adults with refractory seizures, but it can cause irreversible vision loss and damage to the brain in many patients. A preclinical study supported by an ARRA Challenge Grant will determine if coadministering the diuretic bumetanide can prevent adverse effects of vigabatrin.
Over 30% of patients with moderate or severe traumatic brain injury (TBI) develop epilepsy. A Challenge Grant funds a study to test whether a novel compound targeting a newly described cell death mechanism will prevent epilepsy and improve functional outcomes in a TBI animal model.
ARRA funds are supplementing an ongoing project to develop and validate an animal model of epileptogenesis for quick and effective screening of emerging antiepileptogenic drugs on a large scale. The supplemental support will be used to screen four potential treatments in the model.
A Challenge Grant-funded project will use a novel imaging technique in a rodent brain slice model of TLE. The method can simultaneously record activity in up to 100 neurons and support cells called astrocytes, and is a new tool for assessing TLE mechanisms and potential treatments.
Toward a goal to develop devices that can predict seizures before they occur and deliver electrical stimulation to the brain to counteract epileptic activity, ARRA-funded grants are developing new techniques for recording brain activity, predicting seizures, and delivering stimulation.
Cognitive, behavioral, and emotional impairments often accompany epilepsy, but the causes of such co-morbid conditions are poorly understood. ARRA funded projects are focused on better understanding these causes as well as on strategies to limit or prevent comorbidities in epilepsy, including:
A prospective study in children with epilepsy is characterizing cognitive development, brain maturation, and structural abnormalities associated with behavioral comorbidities.
Another study with an ARRA supplement is following over 600 children into adulthood to assess the relationship between seizure history and psychiatric, behavioral, and educational outcomes.
An ARRA grant
are supporting studies in mice to investigate how seizures early in life disrupt the development and growth of neurons in the hippocampus, a brain region often involved in epilepsy that is critical for learning and memory. These studies will help determine if such disruptions contribute to cognitive deficits in children with recurrent seizures.
A Challenge Grant is supporting a pilot trial of an intervention program combining home-based treatment with group cognitive therapy for the prevention of depression in people with epilepsy.
-- Whole-genome sequencing in multiplex epilepsy families -- Goldstein, David; Ottman, Ruth (NC)
-- The Epilepsy Phenome/Genome Project (EPGP) -- Lowenstein, Daniel (CA)
-- Consequences of Prolonged Febrile Seizures in Childhood -- Shinnar, Shlomo (NY)
-- Febrile Seizure Model -- Neuronal Injury and Mechanisms -- Baram, Tallie Z (CA)
-- Attenuating the Retinal and CNS Adverse Effects of Vigabatrin with NKCC1 Inhibitors -- Jensen, Frances E (MA)
-- Efficacy of Necrostatins on Posttraumatic Epilepsy -- Dietrich, W Dalton (FL)
-- Validation of High-Throughput Screening of Candidate Antiepileptogenic Drugs- Mazarati, Andrey M (CA)
-- Calcium Signaling in Astrocytes -- White, John A; Wilcox, Karen S (UT)
-- Towards a Behavioral Index of Seizure Susceptibility -- Sunderam, Sridhar (PA)
-- Single Unit Based Seizure Prediction -- Chang, Jing-Yu (PA)
-- Anticonvulsant effects of novel concentric ring electrode electrical stimulation -- Besio, Walter G (NC)
-- Neuropsychological Progression of New Onset Epilepsy -- Hermann, Bruce P (WI)
-- Long-term outcomes of childhood-onset epilepsy -- Berg, Anne T (IL)
-- Short and long-term impact of neonatal seizures on hippocampal granule cell integration -- Danzer, Steve C (OH)
-- Immature Hippocampus: Epileptogenic Properties -- Swann, John W (TX)
-- Preventing Depression in People with Epilepsy: An Extension of Project UPLIFT -- Thompson, Nancy J (GA)
Page Last Updated on June 30, 2018
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