Fast Ripples Making Waves as First Reliable Biomarker for Epilepsy

Caroline Cassels
Medscape Medical News 2006. © 2006 Medscape

December 12, 2006 (San Diego) — Fast ripples — brief, high-frequency, interictal oscillations — are showing promise as the first reliable biomarker for epilepsy, says a leading expert.

Here at the First North American Epilepsy Regional Congress, Jerome Engel, MD, PhD, whose group at the David Geffen School of Medicine at the University of California, Los Angeles, first described fast ripples in 1999, told delegates attending the presidential symposium that fast ripples not only may provide clinicians with an accurate diagnostic tool but also may have the ability to predict epilepsy, assess treatment efficacy in a timely manner, and aid in the development of rapid screening methods to identify new antiepileptic compounds.

"Currently, there are no reliable surrogate markers for epilepsy, which is one of the holy grails in all diseases. Right now we use interictal EEG spikes [to diagnose epilepsy], but they tend to be nonspecific and don't indicate where seizures originate, so they are less than ideal," Dr. Engel told Medscape.

Animal models of temporal lobe epilepsy (TLE), as well as human data, show that fast ripples are specific to the area of the brain that generates seizures. Furthermore, said Dr. Engel, research has also shown fast ripples correlate with the severity of epilepsy and are able to predict which animals will develop seizures following brain injury.

If fast ripples ultimately turn out to be a reliable biomarker, and particularly if a method to record them noninvasively can be found, this could revolutionize epilepsy diagnosis, treatment, and research, particularly in TLE, the most common and most treatment-resistant form of the disease, he said.

Dr. Engel noted that medical treatment of epilepsy currently consists of a trial-and-error strategy. "We give a drug and we don't know whether it works or not until it is confirmed by the presence or absence of another seizure. This approach can take months or even years. In the meantime, another seizure could be devastating and even result in death," he said.

A study conducted by Anne Berg, PhD, from Northern Illinois University, in DeKalb, and published in Neurology in 2003 (Berg AT et al. Neurology. 2003;60:186-190) found that among patients with intractable epilepsy, it took an average of 9 years to prove medical therapy was ineffective.

Furthermore, the same study found that among patients who eventually received surgical treatment, it took an average of 22 years before they were referred.

According to the American Epilepsy Society, 60% to 70% of theUS epilepsy population has good seizure control with medication. Of the remaining 20% to 30%, half are potential surgical candidates. Even though surgical success rates are in the range of 70% to 90%, only a very small percentage of these patients are ever referred for surgery.

Surgery Underutilized

Right now, said Dr. Engel, surgery is greatly underutilized. Part of the reason for this is that presurgical evaluation is time consuming, expensive, and due to the fact that electrodes have to be placed directly into the brain to record seizures, is frequently associated with considerable risk.

He estimated there are probably "a few hundred thousand patients" in the United States alone who are potential surgical candidates but maybe only 3000 a year actually receive this form of treatment.

"A good biomarker that could accurately detect the presence and severity of epilepsy would allow us to make a definitive diagnosis and localize the area of the brain that needs to be resected with a single test. This would greatly increase the number of patients who would receive and benefit from surgery," he said.

In addition, Dr. Engel noted, there is a great deal of ongoing research investigating ways of preventing epilepsy in individuals who are at high risk because they have suffered traumatic brain injury or had an intracranial infection. Although such treatments are still in the experimental stages, it is feasible that in the future an accurate biomarker could help identify which patients would be most likely to benefit from epilepsy prophylaxis.

Next Challenge

Finally, said Dr. Engel, if fast ripples live up to their expected potential, it would provide scientists with a rapid, inexpensive method of identifying new drug compounds.

"Testing drug compounds in animal models of epilepsy is time consuming and expensive. If we had a cheap surrogate marker of temporal lobe epilepsy, we could screen thousands of drugs very quickly and cheaply," he said.

However, before any of this can occur, researchers' face the challenge of finding a noninvasive method of measuring fast ripples.

"Right now, fast ripples can be recorded only with electrodes implanted directly into the brain. Obviously, it is not practical or desirable to do this in large numbers of patients," he said.

One possible method is to use magnetoencephalography, which has the capability of recording signals deep within the brain that cannot be picked up with EEG. Another possible method he said is to use a combination of functional MRI and EEG testing.

First North American Epilepsy Congress: 60th Annual Meeting of the American Epilepsy Society: Presented December 3, 2006.