Unraveling Epileptogenesis: Research Yields Clues to How Epilepsy Develops, Progresses

adapted from an article by Brenda Patoine, a freelance science writer, for Epilepsy USA magazine, Sept/Oct 2007

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.

A Cascade of Brain Changes
At the Cure Epilepsy conference held last spring at the National Institutes of Health, Scharfman outlined three general phases along the time course of epileptogenesis: a rapid phase that ensues in the first minutes and hours following an insult to the brain; an intermediate phase measured in days, and a third phase that lasts weeks to months. Each stage is characterized by distinct events that unfold in a cascade of brain changes, first at the cellular and molecular level, then at the level of nerve cell connections and networks, to ultimately create a brain that is prone to spontaneous seizures.

These phases represent the broad strokes that are framing the picture of epileptogenesis, not unlike the early pencil sketches of an artist painting a complicated landscape. But at this point, many of the fine details that will complete the picture remain elusive.

What is clear is that an epileptogenic insult sets off an immediate chain reaction in affected brain cells. Glutamate, a brain transmitter that is integral to normal learning and memory but toxic at high levels, floods neural circuits, disrupting brain function and wounding or killing brain cells. This triggers the immune system to step up to battle, which paradoxically causes inflammation and a cascade of changes that further damage brain cells, similar to what happens in stroke or head trauma. Throughout the process, different genes are switched on and off in a dynamic dance that alters signaling pathways within and among nerve cells.

In response to these initial changes, the brain appears to try to recapitulate its early development, as if a “repair and rebuild” program has been switched on. New neurons and blood vessels are generated, and existing neurons grow new branches (axons and dendrites) and form new connections with other cells. But for reasons still unclear, the repair job is faulty, and the end result is a heightened predisposition to further seizures.

In Search of Control Points
A better understanding of epileptogenesis is a top priority in epilepsy research, because this fundamental knowledge will likely unlock the keys to better diagnosis and treatment, as well as ways to prevent and cure epilepsy. A critical step in applying what is being learned is to identify specific biological hallmarks, or “biomarkers,” that can help determine where in the epileptogenic process an individual is at a given time, so that clinical decisions can be made accordingly. The idea is to uncover “control points” along the process at which specific interventions can be used to counteract the events underlying a particular stage and interrupt the development of full-blown epilepsy.

Identifying biomarkers for epileptogenesis and for epileptogenicity – defined as the presence, location and severity of epileptic abnormalities – “is one of the Holy Grails in epilepsy research right now,” says Engel. “The development of surrogate markers would significantly facilitate progress in clinical research. We are stagnated to a certain extent because we don’t have a good surrogate marker.”

Reliable markers for epileptogenesis would not only make it possible to predict who would develop epilepsy following an insult to the brain or in the presence of some genetic risk factor, but would also make it possible to identify people who have a type of disorder that is unlikely to respond to anti-epileptic medications and might be candidates for early surgical remediation.

Markers for epileptogenicity would also have immediate practical applications, including answering the fundamental question of who has epilepsy and who doesn’t. For example, in a baby who has a fever-induced seizure (a common epileptic trigger), a marker could tell whether the baby has a persistent abnormality that is going to cause more seizures later on, or if the seizure was a transient, isolated response in an otherwise normal brain. These kinds of markers could also be used to identify what part of the brain is affected by epilepsy in order to guide surgical removal, and to determine whether therapeutic interventions would be effective in a particular individual.

Scientists are making progress in developing markers for epilepsy on several fronts, notably in efforts to apply brain imaging methods and techniques for recording patterns of electrical signals from the brain to help define critical time points in the epileptogenic process.

Close, ongoing collaboration and cross-talk between clinicians and basic researchers is essential to further progress, experts say.