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.

“We have a lot to learn about each part of the process,” Scharfman notes. “We have gaps in understanding what it is that sets apart people who suffer an initial insult but do not get epilepsy; we have gaps in understanding [the middle phase] of epileptogenesis and how we would block it, and we have gaps in understanding the chronic phase, in terms of how dynamic it is.”

Still, she adds, “There is an enormous amount that we’ve learned. I actually feel a lot of excitement because my colleagues [in epilepsy research] are making great progress all the time.”

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.

“Right now we treat epilepsy by trial and error: we give a patient a drug, then wait and see if they’re going to have another seizure,” says Engel. “What we need is some way to tell if a drug is going to work without having to wait for another seizure.”

New drug discovery could also be greatly enhanced if there were surrogate markers for epileptogenicity, Engel says. “There are hundreds of thousands of compounds that are potential anti-epileptic drugs, and it’s very difficult to screen them for potential efficacy,” he says. “If we had surrogate markers for specific seizure types, we could identify drugs that would be useful in the seizure types that aren’t easily treated by current drugs.”

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.

“We are beginning to chip away at this,” says Jensen. “But it requires an orderly approach, and a way that researchers can share their data and try to stage the epileptogenic process. It’s slowly happening.”

Close, ongoing collaboration and cross-talk between clinicians and basic researchers is essential to further progress, experts say. “It’s the only way advances are going to be made,” says Engel.

Brenda Patoine is a freelance science writer who has been covering neuroscience for more than 15 years. She can be reached at bpatoine@aol.com.

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