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IS TEMPORAL LOBE EPILEPSY A SURGICAL DISEASE?
Philadelphia—The first randomized controlled trial to compare surgical treatment of epilepsy with medical treatment has been completed—and the results are striking. At one year, the cumulative proportion of temporal lobe epilepsy patients free of complex partial seizures was 58% in the surgical group compared with 8% in the medical group. In fact, the study found that surgically treated patients benefited more than medically treated patients on several outcome measures: quality of life, employment or school enrollment, and freedom from any seizures (including auras). Except for the difference in employment or school enrollment, these differences were highly statistically significant.
ROBUST EVIDENCE
Samuel Wiebe, MD, MSc, Associate Professor at the Departments of Clinical Neurological Sciences and Epidemiology and Biostatistics at the University of Western Ontario, Canada, designed the study and was its principal investigator. The study was a single-center, pragmatic, parallel-group, randomized, controlled trial with external, blinded outcome assessment, and it used an intention-to-treat analysis.
Patients with refractory temporal lobe epilepsy (having failed at least two anticonvulsant drugs in the past) were randomized either to a one-year waiting list for further medical treatment or to immediate temporal lobectomy. Forty patients were randomized to each treatment group, giving 90% power to detect a 40% difference in freedom from seizure at the 5% significance level. All patients were followed for one year.
Dr. Wiebe presented the study results at the 53rd Annual Meeting of the American Academy of Neurology in Philadelphia. “We believe that this randomized controlled trial provides robust evidence to support the view that surgery in a highly selected group of patients with temporal lobe epilepsy is more effective than medical therapy,” he said.
Following Dr. Wiebe’s presentation, Susan S. Spencer, MD, Professor of Neurology and Director of the Epilepsy Fellowships, Electrophysiological Monitoring, and the Clinical Epilepsy Service at Yale University, served as discussant. Dr. Spencer welcomed the advent of randomized controlled trials for comparing the outcomes of medical and surgical treatment of temporal lobe epilepsy—especially because previously published literature on the topic is limited by variable outcome categorization, selection criteria, and surgical approaches; by small sample sizes; and by lack of medically treated control subjects with whom to compare surgical results.
INTERPRETING THE RESULTS IS NOT STRAIGHTFORWARD
But Dr. Spencer noted that the interpretation and extrapolation of Dr. Wiebe’s findings are “not straightforward.” One limitation she adduced is the one-year follow-up used in the trial; it may not be adequate for assessing long-term outcomes. Previously published literature includes a retrospective parallel longitudinal cohort study of 185 medically treated and 200 surgically treated uncontrolled-epilepsy patients, featuring a mean follow-up of nine years.
“Indeed, the surgical group had significantly fewer seizures than did the medically treated group—but the surgical group also had significantly more neurologic compromise,” Dr. Spencer said. “And interestingly, over this extended follow-up, there was no significant difference between the medically and surgically treated groups in activities of daily living and other measures of quality of life.”
A prospective temporal lobectomy series that included a comparison group of non-operated patients showed significant improvements in both seizures and quality of life, but the latter observation was made only in patients who had more than 90% seizure reduction, and only after two years’ follow-up.
Another limitation imposed by the design of the randomized controlled trial is its small patient population, which Dr. Spencer said limits adequate multivariable analyses of predictors of outcome.
Dr. Spencer noted that the results of Dr. Wiebe’s study may not be generalizable to the usual temporal lobectomy patient at the current time in view of the study’s particular selection criteria, surgical approach, and outcome parameters. “Surgery in this study differed in the dominant and nondominant hemispheres … and included only partial hippocampal resection in many patients; yet most institutions at the current time favor predominantly mediotemporal resection, including most of the hippocampus, and perform similar resections in the two hemispheres,” Dr. Spencer said.
One of the primary outcomes in the randomized controlled trial was freedom from complex partial and generalized seizures, but not from simple partial seizures. Dr. Spencer noted that this is at odds with most current series, which also specify freedom from simple partial seizures (other than those with fairly subjective aura).
Dr. Spencer noted, too, that temporal lobe epilepsy is not always refractory. Depending on the composition of the population reported, complete seizure control has been attained with initiation or modification of medical treatment in 11% to 42% of patients with medial temporal lobe epilepsy—including up to 25% of so-called refractory patients.
THE IMPORTANCE OF LONG-TERM FOLLOW-UP
Dr. Spencer underscored some of her reservations about the randomized controlled trial by sharing some preliminary results of her own ongoing, prospective, observational study—the Multicenter Study of Epilepsy Surgery. Among the first 200 temporal lobectomy patients in her study, 55% achieved remission within the first year, and another 20% did so during the next year. But by one year after remission, 15% of those patients had a relapse, and by two years the relapse rate climbed to 20%.
In all 200 patients, quality-of-life scores improved dramatically within three months after surgery, but then they leveled off after one year in seizure-free patients and dropped rapidly back to their baseline levels in those patients with continued seizures. Anxiety scores followed this same pattern, whereas depression scores rose even higher (indicating worse depression) than their presurgery baseline levels in patients with continued seizures. Employment in both the entire group and the seizure-free group showed only a very modest improvement, and only after two years’ follow-up.
According to Dr. Spencer, the first randomized controlled trial to compare surgical treatment of epilepsy with medical treatment proves the efficacy of temporal lobectomy for seizures and for quality of life, but only at one-year follow-up and only with its particular protocol. She said one cannot conclude from Dr. Wiebe’s study that temporal lobe epilepsy is a primary surgical disease—especially because temporal lobe epilepsy is not always refractory and the prior literature raises significant concerns about seizure relapse and about long-term outcome in the spheres of anxiety, depression, neurologic status, and quality of life.
Whether surgery is an appropriate early or primary treatment for temporal lobe epilepsy is a question not answered by the randomized controlled trial, the prior literature, or the ongoing multicenter study. “To accurately approach this question, what we really need is information about the natural history of medically treated temporal lobe epilepsy—that is, we need control groups over the long term,” Dr. Spencer said.
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—John Schneider
Suggested Reading
Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal lobe epilepsy. N Engl J Med. 2001;345:311-318.
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