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Abstracts & Commentary
Sources: Wiebe S, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. 2001;345:311-318; Engel J Jr. Finally, a randomized, controlled trial of epilepsy surgery. N Engl J Med. 2001;345:365-367.
With an innovative study design, Wiebe and colleagues raise the level of discussion about epilepsy surgery from reports of surgical case series to the standard of the randomized, controlled trial. Wiebe et al accomplished this by randomly assigning 80 patients with temporal lobe epilepsy to surgery (n = 40) or treatment with antiepileptic drugs (AEDs) for 1 year (n = 40). A critical feature of the protocol was randomization prior to initiation of a presurgical evaluation. Selection and other biases were therefore eliminated. The primary outcome measure was freedom from seizures that impair awareness of self and surroundings (ie, complex partial and secondarily generalized seizures). They report that cumulatively 58% of the surgical group but only 8% of the medical group (P < 0.001) achieved this end point after 1 year. Of the secondary outcome measures, there was a statistically significant difference favoring surgery for frequency and severity of seizures and for quality of life.
In an accompanying editorial, Engel emphasizes the need for a similar trial that will address the question of when to intervene, noting that: "Properly timed, successful surgery can avert irreversible psychosocial consequences of disabling seizures."
Neurology Alert focuses this commentary upon the results of the medically treated group in Wiebe et al’s study. This is the "treatment group" of the practicing neurologist. This emphasis also serves to highlight the frustrations of AED management and provides further justification for surgical referral.
Only 3 patients of 40 in the medical group were seizure free at 1 year follow-up. Why did even epilepsy specialists fare so poorly in controlling seizures with AEDs? One suspects that most of the 80 epilepsy patients enrolled in this study were already refractory to medical treatment. The mean duration of epilepsy was about 20 years, a typical duration reported for nonrandomized surgical series. Moreover, these patients had a mean of 5 seizures per month after trials of 6 AEDs on average. Actually, the seizure-free outcome in the medically managed group is a testament to Wiebe et al’s skill in spite of the patient demographics. Finally, one should recognize that the outcome of "seizure freedom" has been recognized by neither general neurologists nor the Food and Drug Administration as the standard for epilepsy therapy. The former tend to use a rather flexible definition of "adequate" control while the latter focuses on the "50% responder rate" (the proportion of patients who have ³ 50% reduction in seizure frequency) in evaluating the efficacy of new AEDs. Such therapeutic end points do not lead to meaningful changes in quality of life, employability, et cetera.
On the other hand, perhaps one should be less pessimistic about a seizure-free outcome rate of 8% among the medically managed patients. Is it appropriate for Wiebe et al to say that "prolonged trials of anticonvulsant drugs are futile [our emphasis]" when so many patients in the medical group became seizure free? In this trial, 32 of 40 medically treated patients had a change in the AEDs prescribed and all 40 had a switch in AED or dose increase over 1 year. Wiebe et al do not specify the therapeutic maneuvers required to produce seizure freedom. (It would be enlightening if the 3 patients who became seizure free merely needed an increase in dosage of their baseline AED(s) at randomization or were patients with a shorter duration of illness.) If one assumes that it takes at least 3 months to conduct an adequate therapeutic trial of a new AED in patients with 3-5 seizures per month, serial trials of add-on therapy with the 8 novel AEDs recently available in the United States would require at least 2 years. These are 2 years that these patients can ill afford. There is sufficient evidence to show that seizure freedom will usually not be achieved with AEDs alone after only 1 or 2 drugs have failed (Kwan P, Brodie MJ. N Engl J Med. 2000;342:314-319) and that the probability of benefit from surgery is inversely proportional to the duration of epilepsy (Hennessy MJ, et al. J Neurol Neurosurg Psychiatry. 2001;70:450-458).
The popular media have been quick to report accounts of this study. It is disheartening to read a neurologist’s comment: "I think the surgery is effective, but the potential side effects worry me" (Blakeslee S. The New York Times. August 2, 2001:1). Such a comment ignores the fact that the secondary outcome measures of the study suggest that the total "side effect" burden of medical treatment is higher than for temporal lobectomy. Neurology Alert believes that in patients with medically refractory epilepsy the sword (ie, neurosurgical intervention) is mightier than the pen that prescribes AEDs. Neurologists should refer temporal lobe epilepsy patients (after 1-2 AEDs have failed) for evaluation of their surgical candidacy with little hesitation, rather than subject such patients to the excess morbidity and mortality of endless AED trials and continued seizures (Sperling MR, et al. JAMA. 1996;276:470-475). While randomized, controlled trials still need to be performed to address the timing (Engel J Jr. Arch Neurol. 1999;56:1338-1341) of temporal lobectomy, the efficacy of extratemporal surgery, or the role of vagus nerve stimulation vs. surgical resection, the data of Wiebe et al remove any lingering doubt about the relative benefits and risks of medical vs. surgical management of temporal lobe epilepsy. —Andy Dean
Dr. Dean is Assistant Professor of Neurology and Neuroscience, Weill-Cornell Medical College, Attending Neurologist, New York Presbyterian Hospital, New York, NY.