Editorial
Finally, a Randomized, Controlled Trial of Epilepsy Surgery
N Engl J Med 2001; 345:365-367August 2, 2001
- Article
In all of modern medicine, few generally accepted therapeutic interventions are as underutilized as surgical treatment for epileptic seizures. More than 2 million people in the United States have epilepsy, and 400,000 to 600,000 of them have seizures that cannot be controlled by antiepileptic drugs.1 As many as one quarter to one half of these people are potential candidates for surgical treatment, yet a 1990 survey revealed that only 1500 therapeutic surgical procedures for epilepsy were performed in the United States in that year and that the rate of use of surgery for epilepsy was equally low in other industrialized countries.2 Surgical treatment for epilepsy was essentially nonexistent in the developing world 10 years ago,2 although it is now offered in some developing countries.3 Even if the rate of surgical treatment had doubled in the past decade, however, it would have had only a small effect on the health care burden imposed by epilepsy.4
It is difficult to understand why physicians, as well as patients, remain reluctant to choose surgical treatment for epilepsy, since this therapeutic intervention has offered the only chance of cure for this disorder for more than a century.5 Furthermore, thousands of published reports have documented its safety and efficacy. True, brain surgery is invasive, but neurosurgical techniques have improved greatly in recent years, whereas uncontrolled epileptic seizures still present a substantial risk of disability and death.6,7 Although presurgical evaluation can be expensive, modern neurodiagnostic techniques have markedly reduced the need for costly, invasive studies,8 and the cost of surgery for epilepsy remains a small fraction of the cost of a lifetime of disability. Certainly, an important obstacle to surgery's taking what many believe to be its rightful place in the therapeutic armamentarium for epilepsy has been our failure to apply the gold standard for the evaluation of therapeutic efficacy — the randomized, controlled trial.
Why has there never been a randomized, controlled trial of surgery for epilepsy? In this regard, surgery for epilepsy has been a victim of its own success. The construction of an ethical randomized, controlled trial requires equipoise — honest doubt about the outcome. Most epilepsy centers currently report rates of freedom from seizures of 70 to 90 percent among patients with surgically remediable epileptic syndromes.8 Given that uncontrolled epileptic seizures may increase the risk of death by a factor of almost five,6 how can a patient with drug-resistant epilepsy who is referred for surgical treatment ethically be randomly assigned to continued pharmacotherapy? Equipoise certainly does not exist in the minds of those who are asked to perform the surgical intervention.
Finally, however, in this issue of the Journal, Wiebe and his colleagues report the results of a randomized, controlled trial of surgical treatment for epilepsy that they were able to justify ethically because the waiting list for surgery at their institution already exceeded one year.9 Consequently, they could randomly assign 40 patients with temporal-lobe epilepsy to a medical-treatment protocol during the one year of expected delay without introducing additional risk and assign another 40 to immediate surgery. This clever protocol design required the authors to make two concessions that might have compromised their ability to obtain significant results: the follow-up time had to be limited to one year, which is short for demonstrating the beneficial effects of successful surgery on the quality of life and social functioning; and randomization took place before presurgical evaluation, so that patients were not definitively identified as appropriate candidates for surgery at the time they were randomly assigned to the surgical group. Nevertheless, the study did yield statistically significant differences in outcome with respect to both seizures and quality of life, as well as a trend with respect to social functioning. More important, perhaps, this study has also demonstrated that a well-designed randomized, controlled trial of surgery for epilepsy can be completed successfully.
Even though four patients assigned to the surgical group did not undergo surgery, 58 percent of the patients in the group were free of disabling seizures at one year, as compared with only 8 percent of those assigned to receive medical treatment.9 Of the patients assigned to the surgical group who actually underwent surgery, 64 percent were free of disabling seizures. This figure is somewhat lower than those reported recently for carefully selected patients with mesial temporal-lobe epilepsy,10,11 but the surgical group in the study by Wiebe et al. included several patients with complicated epilepsy, as evidenced by the fact that six required invasive presurgical investigations. Overall, the seizure-related outcome was similar to previously published results for the surgical treatment of unselected patients with temporal-lobe epilepsy.12 Furthermore, in all patients in the surgical group who continued to have seizures, the frequency of seizures decreased. In contrast, only 34 percent of those in the medical group had such a decrease.
The quality of life for patients with epilepsy is clearly related to the recurrence of seizures,13 but it takes some time for lifestyle to improve after seizures have been eliminated by surgery. That patients in the surgical group in the study by Wiebe et al. had significantly higher scores on a quantitative measure of the quality of life at the end of one year than patients in the medical group is impressive.9 The strong trend toward higher rates of employment and school attendance in the surgical group9 is also meaningful.
This randomized, controlled trial should help alleviate residual doubt about the efficacy of surgical treatment for temporal-lobe epilepsy, but it is not the end of the story. This definitive demonstration that randomized, controlled trials comparing surgery for epilepsy with medical therapy are feasible should stimulate many more studies involving patients with other forms of drug-resistant epilepsy that are surgically remediable.
For surgically remediable syndromes that begin early in life, before the acquisition of essential social and vocational skills, the question of when to consider surgical intervention is particularly important. Properly timed, successful surgery can avert irreversible psychosocial consequences of disabling seizures.14 Since the number of available antiepileptic drugs has doubled in recent years, it could literally take a lifetime to prove that a patient's seizures are unresponsive to all medications in every conceivable combination. However, recent evidence suggests that drug-resistant epilepsy may be predicted after only one or two appropriately chosen pharmaceutical agents have been proved ineffective.15 Thus, for many patients, it may be reasonable to consider surgical treatment within a year or two after the onset of disabling epileptic seizures, when eliminating seizures should offer the best chance for a return to a full and productive lifestyle.
Even if referrals for surgery for epilepsy increase, successful outcomes with respect to seizures may not have a maximal beneficial effect on patients' lives until referring physicians stop considering surgical intervention for seizures a last resort. True equipoise exists with regard to the timing of surgical intervention. Therefore, to establish surgery as the treatment of choice for epileptic syndromes such as mesial temporal-lobe epilepsy, randomized, controlled trials must now be conducted to evaluate the potential benefits of early surgical intervention for these conditions.
Jerome Engel, Jr., M.D., Ph.D.
UCLA School of Medicine, Los Angeles, CA 90095-1769- References
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Jerzy P. Szaflarski, Scott K. Holland, Lisa M. Jacola, Christopher Lindsell, Michael D. Privitera, Magdalena Szaflarski. (2008) Comprehensive presurgical functional MRI language evaluation in adult patients with epilepsy. Epilepsy & Behavior 12:1, 74-83
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Anne T. Berg. (2004) Stopping Antiepileptic Drugs after Successful Surgery: What Do We Know? and What Do We Still Need to Learn?. Epilepsia 45:2, 101-102
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