By Ann Poduri, M.D., M.P.H., Deputy Director, NINDS, and Walter J. Koroshetz, M.D., Director, NINDS
In honor of National Epilepsy Awareness Month, we would like to highlight the state of epilepsy research and the role of NINDS in supporting research to better understand, diagnose, treat, and ultimately prevent epilepsy.
Epilepsy is a neurological disorder that is characterized by recurring seizures that result from abnormally synchronized brain activity. Epilepsy affects people of all ages, and the lifetime prevalence of epilepsy worldwide is 1 in 26, meaning that 1 in 26 of us will be affected. Epilepsy often starts in childhood, and an estimated half a million children (0-17 years old) in the U.S. have epilepsy, making it one of the most prevalent childhood neurological disorders. We refer to the “epilepsies” due to many underlying causes and associated conditions. For around half of diagnosed people, their epilepsy has been linked to infection, head trauma, genetic causes, injury before birth, and other causes. For everyone else, they continue with seizures and related conditions without an identified cause and are presumed to have some degree of genetic susceptibility.
The most common way to treat epilepsy is with antiseizure medications. A study published today, supported by NINDS, indicates that two common antiseizure medications (lamotrigine and levetiracetam) used during pregnancy do not harm neurological development in children. Treating epilepsy during pregnancy is challenging and complex, but this long-running study offers valuable insight for pregnant women with epilepsy.
While antiseizure medications are effective for many people with epilepsy, about 1 in 3 of people with epilepsy have “drug-resistant” seizures that continue despite trying multiple medications. Further, many anti-seizure medications have marked side effects. To address the unmet need for effective and tolerable anti-seizure medications, NINDS created the Epilepsy Therapy Screening Program in 1975. The program’s current focus is on finding drugs for drug-resistant epilepsy and for disease prevention and modification.
Surgery is also considered when medication is unsuccessful at controlling seizures and when doctors have identified a clear “seizure focus” in the brain. NINDS-supported research, including studies funded by the Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative®, continues to improve methods for mapping seizure activity in the brain that can guide surgical interventions. In the NINDS Division of Intramural program, Sara K. Inati, M.D., runs the Neurophysiology of Epilepsy Unit. Her lab uses noninvasive imaging approaches in individuals undergoing evaluation for epilepsy surgery to identify where seizures start and model how these spread in the brain.
To support better treatments and the prevention of epilepsy, we must know more about its causes, including genes and pathways associated with epilepsy. In 2010, NINDS launched the Centers Without Walls (CWoW) for Collaborative Research in the Epilepsies to bring together multi-disciplinary teams from around the country to tackle hurdles in epilepsy research. Following the enrollment of 4,000 individuals with epilepsy through the Epilepsy Phenome/Genome Project, the Epi4K Consortium began efforts to analyze DNA sequences of these 4,000 individuals. The first major discovery was new “candidate genes” for childhood epilepsy that continue to be studied today in depth. Thanks to the work of the Epi4K Consortium, other NINDS-supported laboratories, and a broad network of international collaborators, we have moved from a handful of epilepsy genes twenty years ago to hundreds today. Epi4K efforts have now expanded into the worldwide Epi25 Collaborative with support from the National Human Genome Research Institute.
Early in my [Poduri’s] career, I discovered that epilepsy could result from “somatic mutation,” which refers to genetic variants that arise after conception and leave a fraction of cells in an individual with genetic variants. For example, if a mutation occurs early in prenatal development in a single precursor cell to a subset of brain cells, the mutation will be replicated across all cells that descend from the affected precursor cell, which could lead to localized areas of brain malformation associated with epilepsy and intellectual disability. These areas of abnormality contain some genetically normal cells and some cells with a genetic variant disrupting brain function, leading to a “mosaic” pattern. We found mosaic somatic variants in hemimegalencephaly, a malformation of half of the brain that is associated with severe intractable epilepsy. Specifically, we found somatic variants involving genes in a particular signaling pathway involving a protein called the mammalian target of rapamycin, or mTOR.
Today, researchers and clinicians can use deep sequencing techniques to find somatic variants in surgically resected brain tissue. The rate of identifying specific genetic causes for epilepsies associated with brain malformations has increased from 0% to 50% for small lesions, like focal cortical dysplasias that are seen routinely in an epilepsy clinic, and from 0% to 80% for large but rarer malformations, such as hemimegalencephaly.
While we have identified many epilepsy-associated genes, we still have more to discover. Moreover, we now have an opportunity to bridge the gap between scientific discovery and delivery of precise diagnoses to individuals with active epilepsy. In my [Poduri’s] own research and through partnerships with other pediatric hospitals, we have seen that close to half of infants with new-onset epilepsy, whether they are seen in the neonatal intensive care unit or the neurology clinic, have a rapidly identifiable genetic cause, with immediate effects on diagnosis, prognosis, and clinical care. With partial funding from NIH, my group and many others have engaged with family-led foundations to create registries for individuals with pathogenic variants. These registries critically inform people with lived experience about opportunities to contribute to research and share discoveries that impact decisions about their care. NINDS values and will continue to incorporate the perspectives of people with lived experience with epilepsies into our epilepsy research priorities.
Recognizing that there are many important unmet research needs in epilepsy, and that the field is rapidly evolving, NINDS has long partnered with the epilepsy research community, the American Epilepsy Society (AES), and the broader community to evaluate the current state of epilepsy research and develop Benchmarks for Epilepsy Research. NINDS hosts Curing the Epilepsies conferences, where interested groups—researchers, clinicians, people with epilepsy and their families, advocates, and representatives from non-profit foundations—convene to identify future research priorities to incorporate in the Benchmarks. Through this work, the epilepsy community has identified the continued need for basic research into the molecular and network abnormalities underlying epilepsy as well as research on the impacts of comorbidities, side effects of anti-seizure medications, and sudden unexpected death in epilepsy (SUDEP).
In addition to the Epi4K and Epi25 collaborative efforts noted above, NINDS has supported the following CWoWs for Collaborative Research in the Epilepsies: 1) the Center for SUDEP Research, which studies the incidence, biomarkers, and risk identification and prevention of SUDEP; 2) the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx), which identifies biomarkers to predict who is likely to develop epilepsy following a traumatic brain injury; 3) the Channelopathy-Associated Epilepsy Research Center, which used high-throughput technologies (such as stimulating and recording from hundreds of neurons simultaneously) to identify the consequences of identified genetic variants in ion channels; and 4) the Epilepsy Multiplatform Variant Prediction (EpiMVP) project, which focuses on variants in non-ion-channel epilepsy genes that have unknown significance. These large-scale studies have seeded new collaborations, training, and research that continues well beyond the 5-year funding periods for these Centers. NINDS also supports a broad portfolio of investigator-initiated epilepsy research, including basic, translational, and clinical studies.
NINDS is deeply committed to improving health equity for neurological disorders including epilepsy and to understanding how social determinants play a role in disease prevalence, access to care, and health outcomes. The latest research from Rebecca Gottesman, M.D., Ph.D., senior investigator at NINDS, shows that self-reported sexual and gender minorities (SGM) are twice as likely to report active epilepsy than their non-SGM peers. These findings highlight the importance of collecting SGM status in studies and the need for targeted research on SGM populations. In addition, NINDS Senior Investigator and current AES President William Theodore, M.D., has fostered the efforts of the AES/International League Against Epilepsy – North America Joint Task Force for Epilepsy Health Care Disparities. This task force was established in 2023 to explore the health care disparities experienced by people with epilepsy and develop recommendations to address these disparities. At NINDS, we want to ensure that the exciting epilepsy research efforts we support are inclusive and available to individuals with epilepsy regardless of their age, sex, race, income, or geographical location.
We are proud of NINDS’s historical and continued support of epilepsy research and look forward to building on these past successes to better understand, diagnose, treat, and ultimately prevent epilepsies. Through our continued partnerships with scientists, clinicians, and people with lived experience, we are committed to a better future for those with epilepsies.