Curing Epilepsies: NIH Conference Examines State of the Art

Pauline Anderson

April 25, 2013

New findings on the genetic contribution to epilepsy and a better understanding of neurologic pathways this condition shares with other disorders were among the highlights of the most recent epilepsy conference hosted by the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health (NIH) within the Department of Health and Human Services.

One of the most exciting new developments in the field is the identification of several de novo mutations involved in infantile spasms and Lennox-Gastaut syndrome (LGS), devastating childhood epileptic encephalopathies (EEs).

Conference delegates also shared research advances in the areas of deep-brain stimulation, brain mapping, and sudden unexpected death in epilepsy (SUDEP).

This year's conference, "Curing the Epilepsies 2013: Pathways Forward," which took place April 17 to 19, was the third focusing on state-of-the-art epilepsy research. The first conference, in 2000, was something of a turning point as the research goal shifted from merely controlling seizures to preventing and curing them. That conference resulted in the first set of research "benchmarks," or goals that directed research efforts toward clinically meaningful advances.

At the second conference, in 2007, participants evaluated progress made in the original benchmark areas and added comorbid conditions such as SUDEP as a new benchmark, which has since sparked increased research interest in this area.

This conference is sponsored by NINDS in collaboration with the American Epilepsy Society, Citizens United for Research in Epilepsy, Epilepsy Foundation, Finding a Cure for Epilepsy and Seizures, International League Against Epilepsy, National Association of Epilepsy Centers, Tuberous Sclerosis Alliance, and Vision 2020.

New Goals

One of the goals of the 2013 conference, said Story C. Landis, PhD, director, NINDS, in her opening remarks, was to help set the research agenda for future years. Changing the name to "Curing the Epilepsies" from "Curing Epilepsy" recognized the diversity of syndromes and diseases associated with spontaneous recurrent seizures, she said.

"Elucidating the mechanisms responsible for the epilepsies, and developing interventions to alter or prevent them, is likely to require an equally diverse set of approaches and perspectives."

At this year's conference, genes were "one of the big splashes," said Dan Lowenstein, MD, professor, neurology, and director, Epilepsy Center, University of California at San Francisco. While the genetics of epilepsy has been "hotly pursued" since the mid-1990s, with dozens of gene mutations for various forms of epilepsy now identified, almost all of them have been from patients with other affected family members, he said.

Dr. Dan Lowenstein

Now, with initiatives such as Epilepsy Phenome/Genome Project (EPGP), an international consortium of 27 clinical centers in the United States, Canada, and Australia, and Epi4k, a series of 4 projects that use modern genetic technologies to screen patient genomes for relevant mutations, important information on the genetic basis of EEs that generally don't run in families are being uncovered.

The theory is that these EEs occur on the basis of de novo mutation, Dr. Lowenstein explains. Funding from the NIH has allowed researchers to find affected patients, acquire DNA from these patients and their parents, and carry out whole-exome and whole-genome sequencing to explore whether de novo mutations might be the basis for the disease.

"The hypothesis of de novo mutations provides us with a really powerful window into identifying these genes," said Dr. Lowenstein, who is the principal investigator for EPGP.

Researchers at this most recent conference presented findings from the first Epi4K project. In sequencing 222 probands (117 with infantile spasms and 105 with LGS) and their parents, they have identified 247 de novo mutations. Analysis showed a significant excess of de novo mutations among these patients in the 4000 or so genes that are the most intolerant to functional genetic variation in the human population (P = 2.36 × 10 -5), said David Goldstein, PhD, from Duke University, Durham, North Carolina, who presented the data.

The list of gene mutations identified by the researchers as the basis of LGS is the largest to date, commented Dr. Lowenstein.

Other Epi4k projects will use genome sequencing to help identify genes that might determine responsiveness to drug therapy and other facets of the role of genetic mutations.

Researchers are also finding an overlap with genes that have been identified in patients with intellectual disabilities and with fragile X syndrome, a condition linked to autism.

"What we're thinking is that there are these semi-overlapping pathways that, depending on other as yet unidentified genetic effects, as well as very important environmental effects, may lead to a person either having just autism or just epilepsy, or in many cases both because autism is a comorbidity with epilepsy," said Dr. Lowenstein.

Brain Mapping

Delegates to the conference were also updated on where research stands in the area of brain mapping. "There have been significant strides in terms of neuroimaging techniques that allow more and more refined identification of abnormal architecture of the brain, and diffusion tensor imaging that is starting to map out the actual connections in networks between neurons," commented Dr. Lowenstein.

There has also been interesting work in the field of electroencephalography (EEG), which provides a "spatial map" of where seizures may be occurring in the brain, he said. However, he noted that "a lot of work needs to be done" still to better understand from where seizures emanate, how networks are involved in generating seizures, and the mechanisms of seizure spread.

At this meeting, researchers reported "modest but encouraging results" from recent trials that investigated 2 forms of brain stimulation, said Dr. Lowenstein. "They emphasized that these are just first-generation approaches or technologies. Clearly, there's the hope of finding more precise ways of targeting a seizure focus or network, and ablating it with neurostimulation or maybe focal methods of local drug delivery."

In the area of SUDEP, there has been "some progress" in understanding this comorbidity, especially with the help of NIH-sponsored projects, said Dr. Lowenstein.

SUDEP is the most common cause of death for people with epilepsy, who have a much higher mortality rate than those without epilepsy. In addition to SUDEP, epilepsy can coexist with depression, migraines, sleep disorders, autism, and nonepilepsy seizures.

However, in terms of new drug development for epilepsy, there was not much to report. About a dozen new drugs have been introduced in the last 20 or so years, and some of these may lead to fewer drug interactions and have a milder adverse effect profile compared with some traditional antiepileptic drugs, especially phenobarbital, he said. Still, about 30% of patients with epilepsy remain refractory, a statistic that hasn't changed in 50 years, noted Dr. Lowenstein.

"Overall, the percentage remains about same," he told Medscape Medical News. "There are a couple of specific syndromes in which drugs have been identified that seem to be preferable, and drugs that should be avoided, but unfortunately, we still don't have any remarkable progress that we can report."

Wrong Tools?

What might explain some of this lack of progress is that scientists are using the wrong tools. "We may not have the best animal models for identifying drugs that could be useful in humans," said Dr. Lowenstein.

The only good model for epilepsy may be humans themselves, he added. "But in order for human to be a usable model, we need breakthroughs in technology that allow us to measure the function of the living human brain," said Dr. Lowenstein. As it stands now, science just doesn't have the appropriate biomarkers to identify activity in the brain or develop drugs that target that activity.

As a clinician as well as a researcher, he finds this discouraging. "I'm incredibly disappointed and frustrated, but that pales in comparison with what I see in the eyes of patients and family members every day."

One in 26 people will have epilepsy in their lifetime. More than 2 million Americans have a form of epilepsy, and about 150,000 new cases are diagnosed annually. Epilepsies result in approximately $15.5 billion in direct and indirect medical costs each year.

Some of the other research presented at the meeting in the form of abstracts included the following:

  • A survey of 18 parents of children with refractory epilepsy taking cannabidiol (CBD), a nonpsychoactive compound found in the cannabis plant, determined that the children had improved seizure control and that the drug was extremely well tolerated. Overall, 83% of the parents reported a reduction in their child's seizure frequency, in some cases up to 80%. Notably absent were such adverse effects as vomiting, diarrhea, insomnia, and aggressive behavior. The survey provides support for a placebo-controlled, double-blind trial to investigate the efficacy of CBD in this challenging pediatric population, concluded the researchers, led by Catherine Jacobson, PhD, postdoctoral fellow, Department of Neurology, Stanford University, California.

  • A study showing that infantile spasms and Ohtahara syndrome, 2 EEs that begin during a critical period of brain development, are associated with excessive and aberrant hippocampal and cortical neurogenesis. Researchers performed fluorescence immunohistochemistry studies on brain sections from 6 infants with these EEs and from 5 age-matched controls. The results suggest a potential mechanism for poor developmental outcomes in children with these EEs despite successful control of their spasms, according to the researchers, headed by Laura A. Jansen, MD, PhD, Pediatric Neurology, University of Virginia, Charlottesville.

  • An investigation at the University of Minnesota and the Mayo Clinic demonstrates the ability of a novel dynamic seizure imaging technique to precisely and accurately image seizure activity from noninvasive measurements. The approach is based on high-resolution EEG recordings and was designed to image the dynamic changes of ictal rhythmic discharges that evolve through time, space, and frequency. The results, which have implications for surgical evaluation, suggest the need for a prospective clinical trial, the researchers report.

  • Research from Indonesia shows that adding caffeine to phenytoin increases the effectiveness of phenytoin in general seizures. The study included 48 patients; all of them took phenytoin, 5 mg/kg, and some also took caffeine, 2.5 mg/kg. At 6 months, both groups had a significant reduction in seizure frequency (70.8% for the phenytoin-only group; 90.6% for those also taking caffeine). Patients taking caffeine had 92% terminal remission, which was significantly different (P = .00) from the other group (78.6%). In addition, 96% of the caffeine users achieved 50% or greater seizure reduction compared with 82% of the phenytoin-only group (P = .00). Adding caffeine did not change the adverse effect profile.

Curing the Epilepsies 2013: Pathways Forward. Held at the Natcher Conference Center, NIH Campus, Bethesda, Maryland, April 17-19, 2013.