Unraveling Epileptogenesis

Research Yields Clues to How Epilepsy Develops, Progresses

What causes epilepsy to develop in some people but not others? Why is it that an isolated seizure in one person can be just that — a one-time aberration — while in another person it triggers a worsening progression of symptoms? What’s going on in the brain during this measured march toward the brain state of over-activation that we call epilepsy?

Recent collaborations between clinical and basic research scientists to understand “epileptogenesis” — how epilepsy develops and progresses — have yielded important clues to what is happening at each stage of the epileptogenic process. Their findings are now fueling the first real attempts to prevent the onset of epilepsy, or at least to stop it from worsening. At the same time, there is a renewed appreciation for just how complex the scientific questions are.

Epileptogenesis refers both to how a normal brain becomes epileptic in the first place and to how a mildly epileptic brain can worsen — or not. "When someone has an epileptogenic insult, such as head trauma or an infection in the brain, that's not epilepsy; they may never have epilepsy, even if they have seizures initially," explains Jerome Engel, M.D., Ph.D., a neurologist and epilepsy researcher at the University of California at Los Angeles. Yet in some cases, he adds, "There are changes that occur in the brain over a period of say, six months to a year or more, that create a persistent abnormality that is capable of generating spontaneous seizures."

What is currently known about the genesis of an epileptic state has been gleaned from human studies that follow people with epilepsy to track disease progression, from animal studies in which researchers try to induce epilepsy and then observe what happens in the brain, and from laboratory studies that examine epileptogenic changes at the level of single cells and groups of cells. A vanguard group of researchers are now attempting to synthesize these findings and piece together a picture of what epileptogenesis looks like and how the process unfolds over time. This, it turns out, is no simple feat.

“The good news,” says Helen Scharfman, Ph.D., a neurologist at the Nathan Kline Institute for Psychiatric Research in Orangeburg, N.Y., “is that the research has revealed some really interesting parallels that we can build on to develop anti-epileptogenic agents. The bad news is that it is complicated."

One major complicating factor is that epilepsy is not a single disorder. In fact, some experts are pushing to rename epilepsy "epilepsy spectrum disorder," much like autism is now called autism spectrum disorder, to reflect the wide range of associated symptoms and severity. “There are multiple ways to become epileptic and there are multiple symptoms involved, not just seizures,” says Frances Jensen, M.D., a Harvard neurologist and researcher. Its severity can range from “the occasional seizure,” she adds, to extreme, frequent seizures coupled with severe mental retardation, developmental delays or autism.

This wide spectrum makes it difficult to nail down the epileptogenic process, as it likely progresses differently and at different time courses across individuals. Still, some commonalities are being unearthed.

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