More than 65 million people around the world have epilepsy. Each year, one in 20 children and one in 100 adults will develop the seizure disorder caused by electrical misfiring in the brain. The fourth most common neurological disorder in the United States after migraine, stroke and Alzheimer’s disease, epilepsy can cause profound cognitive and physical disabilities, poor quality of life and, sometimes, sudden death.
Despite being described as a “sacred disease” by Hippocrates around 400 BC, epilepsy care has progressed slowly due, in part, to a lack of research funding and focus. In recent years, though, the momentum has shifted. Nationwide, parent advocacy groups have raised awareness and research dollars at the grassroots level. The latest insights from biology as well as cutting-edge technology have allowed investigators from all disciplines to shed light on the basic understanding of this genetically complex disease. In March 2012, an Institute of Medicine (IOM) report highlighted a serious gap of knowledge about epilepsy and recommended increased research efforts.
Now, in 2015, Northwestern Medicine’s Institute for Translational Neuroscience has launched an epilepsy research center. This exciting initiative will bring together the academic medical center’s top clinical and research minds in the area of epilepsy, taking full advantage of Northwestern’s nationally prominent clinical services for pediatric and adult epilepsy patients to pursue ultra-modern breakthroughs in care.
“In the past 15 years, we’ve built a strong clinical team at Lurie Children’s,” says Douglas R. Nordli Jr., MD, head of the Epilepsy Center at Ann & Robert H. Lurie Children’s Hospital of Chicago and professor of pediatrics and neurology at the Feinberg School of Medicine. “However, everything we currently do is a therapeutic Band-Aid. We can blunt seizures with medication, but usually we can do nothing to correct the underlying problem. Conspicuously absent had been the presence of high-profile, world-renowned research capabilities that now exist right next door at the medical school and precisely align with our clinical research interests.”
Dr. Nordli has teamed up with Alfred L. George Jr., MD, Magerstadt Professor and chair of pharmacology at the Feinberg School, to lead the development of the new epilepsy research center at Northwestern Medicine. A renowned authority on ion channel proteins, Dr. George, a recruit from Vanderbilt University, published with Australian colleagues in 1998 the discovery of the first identified mutation in a brain sodium channel gene associated with epilepsy. At Northwestern, he continues this important work. To build the center, George is in the process of reaching out to diverse faculty members―clinicians and investigators from neurology and physiology to genetic medicine and medicinal chemistry―across Northwestern’s two campuses to “catalyze the convergence” of their expertise in epilepsy research.
“If we keep stirring the pot just right, we can stimulate a unique blend of research in this emerging field of study,” explains George. “Then we can exploit this expertise to advance the science of epilepsy, and ultimately, improve clinical care.”
More than 40 different forms of epilepsy exist in individuals of all ages. However, children and older adults are among the fastest growing segments of the population today with new cases of the disease, according to the Institute of Medicine. Seizures occur for a variety of reasons, including traumatic brain injury, tumors and genetic factors that are not necessarily inherited. It’s the latter that can cause the disorder to appear in kids before their first birthday.
Says George, “Most cases of early onset epilepsy tend to be genetic and about two-thirds of them are due to mutations in ion channel genes, conditions referred to as channelopathies.”
Zeroing in on severe childhood epilepsy, George works in close collaboration with epilepsy researcher and mouse geneticist Jennifer Kearney, PhD, associate professor of pharmacology. Dr. George focuses on the functional consequences of ion channel mutations, while Kearney investigates the genetics of epilepsy. Together, they endeavor to develop novel, more targeted medications for the disorder, which in children, can lead to devastating irreversible developmental and behavioral problems.
“Our animal models allow us to mimic the whole physiology of epilepsy in mice,” explains Kearney. “By studying genetic modifiers, we can better understand genetic factors that influence how the epilepsy appears in humans.” She recently described a new mutation linked to severe childhood epilepsy in the Oct. 2014 issue of Annals of Neurology. Her Northwestern Medicine team found an anomaly in the KCNB1 potassium channel gene that causes neurons to misfire and leads to seizures and disrupted development.
Northwestern’s technological capabilities in high-throughput drug screening of ion channels will give the new center a distinct advantage in the study of epilepsy. The Department of Pharmacology recently installed a state-of-the-art automated electrophysiology platform, the first of its kind in North America. This equipment allows for large-scale functional and pharmacological annotation of human ion channel variants, not just for epilepsy but other diseases as well, according to George.
Sodium channel genes are activated in the brain, influencing the normal firing of neurons. Mutations of this channel family have been correlated with severe childhood epilepsy. In particular, the SCN1A gene has more than 1,100 mutations, most of which have been identified in Dravet syndrome—a rare form of epilepsy that begins in infancy and often does not respond well to therapy.
George and Kearney have long studied SCN1A. Coincidentally, Lurie Children’s epilepsy expert Linda C. Laux, MD, ’01 GME, assistant professor of pediatrics and neurology, cares for one of the largest groups of children with Dravet syndrome in the nation. Lurie Children’s has diagnosed and treated more than 175 patients since 2000. This bit of serendipity allows for Northwestern Medicine investigators to make an even greater contribution to advancing care. Says Dr. Laux, “We can provide clinical information and patient samples vital in making the most accurate phenotype/genotype correlations to better understand the disorder and tailor treatment for individual patients.”
Currently available epilepsy drugs work well in some people but not in all. Finding the right match often involves trial and error. Not only may a medication ultimately fail to alleviate symptoms but it may also cause unnecessary adverse side effects. The emerging area of “reprogramming” offers a revolutionary method for delivering treatment that precisely addresses each patient’s distinctive genetic makeup. Using blood samples or simple skin biopsies, investigators can generate patient-specific induced pluripotent stem cells to create cell-based models of epilepsy for particular individuals.
“We are essentially gaining access to each patient’s brain. Generating their stem cells, we then create brain cells with their unique genetic constellation. This process allows us to study their disease in a culture dish,” says Evangelos Kiskinis, PhD, assistant professor of neurology and physiology. “By testing cells in the laboratory, we hope to better predict the benefits of available and novel drug therapy, which will be a huge advantage in clinical care.” Most recently a faculty member at the Harvard Stem Cell Institute, Kiskinis brings to Northwestern and the epilepsy research center his experience in this leading-edge technology. He is currently working on modeling Dravet syndrome in collaboration with epileptologists at Lurie Children’s Hospital.
Improvements in DNA sequencing technology continue to offer new insights into a variety of diseases, helping to link genetic anomalies with clinical outcomes. Applying the latest genomic tools to obtain a bigger, more comprehensive picture is the next logical step for genetically based epilepsies such as Dravet syndrome and seizure disorders in general, according to Elizabeth M. McNally, MD, PhD, director of the Feinberg School’s Center for Genetic Medicine. Another key collaborator in the new epilepsy center, she says, “If we can start organizing the wide variety of genes and variants underlying epilepsy and identify pathways, we can then develop a more rational approach to treatment to address the disease in its many forms.”
Given the rich source of clinical and research experience available at Northwestern, the recently launched Northwestern Medicine epilepsy research center will initially focus on Dravet syndrome. While it only affects one to three percent of children with epilepsy, this rare disease offers a perfect jumping off point for treating other seizure disorders.
“By better understanding the genetics of hyperexcitability in the brain of a specific population, we can begin to find clues that may help us to treat all patients with epilepsy,” says Stephan U. Schuele, MD, MPH, director of the Comprehensive Epilepsy Center based at Northwestern Memorial Hospital and associate professor in neurology and physical medicine and rehabilitation. “The knowledge gained about children with congenital channelopathies such as Dravet syndrome could one day be applied to the many adults who develop acquired, non-genetic forms of epilepsy and drug resistance.”