The role of surgery to relieve seizures in patients with medically refractory epilepsy has always been controversial. “Traditionally, when there weren’t a lot of epilepsy drugs, there was still a prejudice on the part of neurologists as well as other physicians against epilepsy surgery. There were reservations about removing brain tissue that may look normal to the neurosurgeon—despite the fact that such surgery was clearly effective. Even those who were convinced that epilepsy surgery was effective in well-selected cases were using it as a last resort,” said Jerome Engel, Jr, MD, PhD. Dr. Engel, Chief of the Division of Epilepsy and Clinical Neurophysiology at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA), is the lead investigator of the Early Randomized Surgical Epilepsy Trial (ERSET), a multicenter randomized controlled study based on the belief that “the best treatment for epilepsy is to stop seizures as soon as possible in order to avoid irreversible social and psychological consequences.”

The question then becomes whether early intervention by surgical measures or by antiepileptic drugs provides the best opportunity to stop seizures without side effects. “We don’t know,” Dr. Engel admitted. “That’s why we’re doing the study.”

WHY SURGERY?

The genesis of ERSET has been lengthy, according to Dr. Engel. “Around 1990, it became clear that there were already so many new drugs that if you tried every drug in every possible combination, it could take a lifetime.” For example, he commented that a study by Anne Berg, PhD, which looked at the time it takes to determine whether someone with epilepsy is medically refractory, found it was an average of nine years before the patients failed the second drug. “Seizures don’t start and become refractory, they go through periods of remission or rare seizures, so it takes doctors a long time to decide that the drugs aren’t working,” Dr. Engel said. “There needed to be a better way to decide when to stop drugs.”

The idea of intervention for surgically remediable syndromes provided an alternative. A surgically remediable syndrome, Dr. Engel explained, is a disorder such as mesial temporal lobe epilepsy with hippocampal sclerosis, for which the pathophysiologic basis is well known, and in which the response to medication is considered poor if one or two appropriate drugs fail. The natural course of such syndromes usually includes disease progression—infants and small children show developmental delay; adolescents have memory deficits and psychological and social compromise—and surgery is successful in 70% to 90% of patients, depending on the syndrome.

Despite these success rates, however, the traditional view of epilepsy surgery as “a last resort” remained. “There have been several observations, one published by Selim Benbadis, MD, and one unofficially reported by Susan Spencer, MD, showing that the average time between epilepsy onset and surgery is close to 20 years,” Dr. Engel said. “Gary Mathern, MD, one of our neurosurgeons, just carried out an unpublished review of UCLA surgical patients since 1961 and found that there’s been a progressive increase in time between epilepsy onset and surgery. From 1961 to 1970, the average time to surgery was 12.5 years. From 1996 to 2000 it was 18 years, and that’s despite hundreds of publications about the safety and efficacy of surgery, and more than 20 textbooks and tremendous advances in neuroimaging and microsurgical technique that greatly improved safety and efficacy over that period of time.”

Dr. Engel attributed the reluctance of physicians to refer patients for surgery in part to the increase in antiepileptic drugs and other alternatives such as vagus nerve stimulation. “Many patients are referred for vagus nerve stimulation who should be referred for surgery,” he noted. “This is because surgery is not promoted as aggressively as most of the proprietary alternatives.”

A RANDOMIZED CLINICAL TRIAL

Another point against epilepsy surgery was that until recently there had never been a randomized controlled trial of epilepsy surgery. “That made a lot of physicians a bit skeptical about whether surgery really works or whether the people reporting the surgery—the performing neurosurgeons and neurologists—were biased,” Dr. Engel said. During the past three years, however, two studies have put this issue somewhat to rest, and in the process laid the direct groundwork for ERSET. In 2001, Samuel Wiebe, MD, and colleagues in the Effectiveness and Efficiency of Surgery for Temporal Lobe Epilepsy Study Group published the results of the first randomized controlled trial to assess the safety and efficacy of surgery for epilepsy, which concluded that “in temporal lobe epilepsy, surgery is superior to prolonged medical therapy.”

Subsequently, the American Academy of Neurology, in cooperation with the American Epilepsy Society and the American Association of Neurological Surgeons, published evidence-based practice parameters on localized neocortical resections for temporal lobe epilepsy. The parameter was based on the review of Dr. Wiebe’s study as well as 24 Class IV studies, all of which indicated that “the benefits of anterior mesial temporal resection for disabling complex partial seizures is greater than continued treatment with antiepileptic drugs,” while the risks were “at least comparable.” The committee determined that further studies of the subject were warranted, particularly to determine whether early surgical intervention should be the treatment of choice—and ERSET was born.

STRINGENT CRITERIA, OPTIMIZED APPROACH

The ERSET protocol will randomize 200 patients who meet the following basic criteria: 12 or older; failure of two antiepileptic drugs, one of which must be the brand name Dilantin, Tegretol, Carbatrol, or Trileptal; and disabling seizures (defined as six seizure days or more per year) for no more than two consecutive years. “If the patient had a remission of more than six months, then that clock starts ticking after seizure recurrence, and that’s really important because a lot of people who’ve had seizures for a while that haven’t been bad will still be candidates for ERSET, and they need to know that,” Dr. Engel noted.

Those patients who meet the criteria and have seizures compatible with the diagnosis of temporal lobe epilepsy will be screened at one of 19 sites around the United States. If it is determined that they likely have mesial temporal lobe epilepsy, they will undergo a detailed neurodiagnostic evaluation that includes psychological and psychiatric testing, and neuroimaging. If testing indicates that they are candidates for surgery, Dr. Engel said, they will undergo inpatient video EEG monitoring.

Patients who are candidates for surgery will be randomized to either surgery and medication or two more years of medication. The medication protocol is designed by a panel of experts in clinical pharmacology for the optimal use of available antiepileptic drugs. “If the medication fails after those two years and they still want surgery, they’ll get the surgery at the end of two years as part of the study. So one way to look at it is surgery now or surgery in two years,” Dr. Engel clarified.

“One misconception that needs to be dispelled is that this trial pits medicine against surgery, and that patients in the surgical arm aren’t going to be treated with drugs. The patients in the surgical arm will be treated with drugs just like the patients in the medical arm. Usually we don’t consider taking surgical patients off drugs until they’ve been seizure-free for two years, and this is a two-year follow-up protocol. So it’s comparing an optimized, tailored medical protocol alone with an optimized, tailored medical protocol plus surgery. It’s important that that’s clear.”

ERSET is a National Institute of Neurological Disorders and Stroke– sponsored trial, organized as a result of a National Institutes of Health planning grant. Dr. Engel also applauded the spirit of collegiality in the epilepsy community when he noted that “the money that was used to bring people together to write the planning grant was provided by the pharmaceutical companies and Cyberonics.”

WHY NOT SURGERY?

In preparation for ERSET, Dr. Engel and his colleagues conducted a focus group to determine obstacles to patient participation. “The number one reason cited by patients for not wanting surgery is that their physicians have advised them against it because of the risk of surgery. And this is unfortunate, because the risk of recurrent seizures is much greater than the risk of surgery,” Dr. Engel said.

“Mike Sperling, MD, published a paper showing that the mortality rate in continuing seizures is about five times greater than the risk of death from surgery. The risk of death from surgery for mesial temporal lobe epilepsy is close to zero, and the morbidity is also minimal. In the practice parameters paper, only 3% of patients had any type of morbidity that was permanent. Six percent had some neurologic deficits, but in half of those it was transient and gone by the end of the year.” One patient died in the Wiebe trial, and this patient was in the medical arm.

Additionally, Dr. Engel remarked that there are reports for well-defined mesial temporal epilepsy with hippocampal sclerosis that say the seizure-free outcome “should be close to 90%, not the two thirds that are in the Wiebe study or the practice parameter paper. Those series are older studies, and the Wiebe study is based on randomizing patients before evaluation, before it was determined whether the patients were good surgical candidates or not. So they had several difficult patients, and some patients who didn’t even have surgery who were in the surgical arm.”

Another problem Dr. Engel addressed with respect to the risks of surgery was memory loss. “Patients who have mesial temporal lobe epilepsy with hippocampal sclerosis almost always have some memory loss already because that part of their brain is damaged,” he said, “and if they don’t have it, they will develop it if they continue to have seizures. However, if you take that area out, you run the risk of causing memory loss.” To account for this possibility, patients randomized to the surgical arm of ERSET must undergo a Wada test to confirm that the contralateral hemisphere supports memory. “If it doesn’t, we can’t do the surgery,” he said. “We don’t expect that to happen, however, because the criteria are so stringent it’s highly unlikely these patients will be bilaterally impaired.”

RECRUITMENT

The major challenge for the successful completion of the study, however, is expected to be recruitment. “The problem is going to be getting the patients to the epileptologists,” Dr. Engel said. Most of the patients who would be candidates for the study are held by primary care physicians or general neurologists for long periods of time, he explained. “They’re certainly not in the epilepsy centers. So we need to get the word out so that these patients get referred to epilepsy centers so we can have the experts decide whether they are candidates.

“We’re hoping to get cooperation from all of the epilepsy centers around the country who understand the importance of this.... We hope that all epilepsy centers will help us to identify potential candidates, and when they find potential candidates will refer them to the 19 ERSET centers, which is not usually done. But in this case, again, there seems to be considerable collegiality among the epilepsy community.”

More information about ERSET is available on the Web at www. erset.org. Once recruitment is under way, there will also be a Web site for patients and a hotline, Dr. Engel noted.

THE FUTURE IMPACT

Asked whether he believed ERSET might be a turning point in the case for early surgery for epilepsy, Dr. Engel responded, “I think physicians are very much aware of the facts ... but they’re busy people and it depends on how it’s packaged. There are a lot of randomized controlled trials on vagus nerve stimulation and antiepileptic drugs, and those are constantly being published and being brought to the attention of physicians by drug reps, and they’re right to do that—they have something that works and they should do it. But there was typically no money available to do the same sort of promotion for surgery.

“The fact that we have funding for ERSET to do promotion means that we can bring this to the attention of the public and to physicians. Once the study is completed and the results are clear—if they are, and we don’t know whether they will be—then this will be promoted through societies and literature in a way that is more acceptable to physicians. I think the entire epilepsy community is working together to make this happen because we all believe that this study is in the best interest of patients with epilepsy.”

NR

—C. Justin Romano

Suggested Reading
Benbadis S, Heriaud L, Tatum WO, Vale FL. Epilepsy surgery, delays and referral patterns—are all your epilepsy patients controlled? Seizure. 2002;770:1-4.
Berg AT, Langfitt J, Shinnar S, et al. How long does it take for partial epilepsy to become intractable? Neurology. 2003;60:186-190.
Engel J Jr, Wiebe S, French J, et al. Practice parameter: temporal lobe and localized neocortical resections for epilepsy. Neurology. 2003;60:538-547.
Engel J Jr. Surgery for seizures. N Engl J Med. 1996;334:647-652.
Sperling MR, Feldman H, Kinman J, et al. Seizure control and mortality in epilepsy. Ann Neurol. 1999;46:45-50.
Wiebe S, Blume WT, Girvin JP, Eliasziw M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345:311-318.

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