Early Surgery for Refractory Epilepsy Beneficial

Megan Brooks

March 07, 2012

March 7, 2012 — For patients with drug-resistant temporal lobe epilepsy, surgery soon after failure of 2 antiepileptic drug (AED) trials is more effective than continued medical management in controlling seizures and improving quality of life, according to results of the Early Randomized Surgical Epilepsy Trial (ERSET).

"Despite reported success, surgery for pharmacoresistant seizures is often seen as a last resort," the study team notes in a new report published March 7 in the Journal of the American Medical Association. "Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death."

First author Jerome Engel Jr., MD, PhD, from the David Geffen School of Medicine, University of California, Los Angeles, told Medscape Medical News that surgery "should be considered early to avoid irreversible disabling social and psychological consequences of recurrent seizures. All patients with refractory epilepsy should be referred to an epilepsy center to determine if they might be surgical candidates, and for additional advanced diagnostic and therapeutic support if they are not," he added.

Dr. Jereome Engel Jr.

The results of this study "support the conclusions of the American Academy of Neurology practice parameter, namely that all patients with epilepsy should be referred to an epilepsy center as soon as trials of 2 AEDs fail, and surgery should be performed if patients meet criteria for an AMTR [anteromesial temporal resection]," the authors note in their paper.

Most Seizure-Free After Surgery

ERSET was a controlled, parallel-group clinical trial performed at 16 epilepsy surgery centers in the United States. It included 18 males and 20 females aged 12 years and older with mesial temporal lobe epilepsy (MTLE) and disabling seizures for no more than 2 consecutive years after adequate trials of 2 AEDs. Planned enrollment was 200, but the trial was halted prematurely because of slow accrual.

Patients were randomly allocated to continued AED treatment (n = 23) or to standard AMTR plus AED treatment (n = 15) and observed for 2 years. In the medical group, 7 patients underwent AMTR before the end of follow-up and 1 patient in the surgical group never had surgery.

In the primary analysis, which included patients who did not have complete follow-up data during year 2, freedom from disabling seizures during the second year of follow-up was achieved in 11 of 15 patients who had surgery (73%) and none of the 23 patients who continued on medical therapy (P < .001).

An analysis of only patients who provided complete data in year 2 (or reported seizures in year 2) found that 11 of 13 in the surgical group (85%) were seizure free compared with 0 of 19 in the medical group. Nine of the 11 participants in the surgical group who became seizure free never experienced a seizure after surgery.

Surgery also improved quality of life (QOL) as well as ability and access to driving and socialization, "despite the small number of participants," the researchers report. They say the effect on surgery on overall QOL was reflected in the Mental Health, Epilepsy-Targeted, and Cognitive Subscales of the Quality of Life in Epilepsy-89 (QOLIE-89).

"We were pleased to see such robustly positive results with respect to quality of life, as well as seizures, with such a small sample," Dr. Engel told Medscape Medical News.

Yet, freedom from seizures and improved QOL did not predict return to work, Donald L. Schomer, MD, from the Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts, and Roger J. Lewis, MD, PhD, from Harbor-UCLA Medical Center, Torrance, California, and David Geffen School of Medicine at University of California, Los Angeles, point out in a commentary published with the study.

"Employment activities did not seem to show a group difference even though measures of social engagement did show a positive effect," they write.

"This matter is especially troublesome in terms of the ultimate effect of either treatment approach on the total medical and social burden and costs of MTLE," they note. "Patients with MTLE need ongoing counseling and access to work-related training whether they receive surgery or not."

Memory May Decline

In terms of cognitive function, there were no significant treatment group differences with respect to the primary memory and nonmemory measures, although participants in the medical group tended to perform better on memory tests, particularly at 24 months (P = .08).

When individual tests were examined, the surgical group performed worse than the medical group on immediate (P = .01) and delayed (P = .02) recall tests at 24 months. Also, a higher percentage of patients in the surgery group than the medical group showed a decline at 12 months in delayed verbal recall (36% [4 patients] vs 0%; P = .03) and naming (55% vs 7%; P = .02), "consistent with postsurgical rates reported in a recent meta-analysis," the investigators write.

"Verbal memory deficits are to be expected following resection of the language-dominant mesial temporal lobe," the investigators say. They also point out that continued epileptic seizures can also have a negative effect on cognitive function. The current sample was too small to permit definitive conclusions on the effects of surgery on cognitive function.

"What is not known from this study is whether the surgically induced memory decline is equal to, greater than, or less than memory decline that might occur during the long-term medical management," Dr. Schomer and Dr. Lewis write in their commentary.

Thirteen serious adverse events (7 in the medical group and 6 in the surgical group) occurred in 9 study patients (4 in the medical group, 5 in the surgical group) during the study. Of the 7 serious adverse events in the medical group, 2 were unrelated to the study or to seizures and 5 were related to seizures, including 3 cases of status epilepticus in the medical group.

Of the 6 serious adverse events in the surgery group, 3 were findings on postoperative magnetic resonance imaging suggestive of ischemic changes, but only 1 was a cerebral infarction with clinical manifestations (transient mild impairment in naming and receptive language).

Two others were postoperative complications; 1 was vomiting due to worsening of a preexisting esophageal dysmotility that required gastrostomy and the other was a communicating hydrocephalus attributed to resection-related bleeding into the subarachnoid space that resulted in placement of a ventriculoperitoneal shunt. The other serious adverse event in the surgery group was a shoulder dislocation and fracture due to a seizure during video-electroencephalography monitoring.

Confirmatory Data

John Duncan, MA, DM, FRCP, FMedSci, professor of neurology, University College London, United Kingdom, who was not involved in the study, agrees with the conclusions put forward by the researchers. "This paper confirms the utility of anterior temporal lobe resection early in the course of temporal lobe epilepsy that is not controlled with AEDs."

"All too often," he told Medscape Medical News, "individuals are only referred for epilepsy surgery when they have endured epilepsy for 2 decades. This study had the opportunity to make definitive statements and it is very regrettable that it was closed prematurely by the funding agency."

The study was supported by the National Institutes of Health. Dr. Engel has disclosed receiving consultancy fees from Medtronic, Valeant, Acorda, the US Food and Drug Administration, and Best Doctors; fees to his institution for expert testimony; lecture/speakers bureau fees from Esai, Johnson & Johnson, Novartis, and Lippincott; royalties from Wolters Kluwer, Wiley Blackwell, Elsevier, and MedLink; and fees for travel accommodations/meeting expenses from UCB Pharma. A complete list of disclosures for study and commentary authors are listed with the original article. Dr. Duncan has been consulted by and received fees to his institution for lectures from Eisai, GE Healthcare, Pfizer, GlaxoSmithKline, sanofi-aventis, and UCB, as well as departmental and grant support from Medtronic, Cyberonics, and VSM MedTech.

JAMA. 2012;307:922-930, 966-968. Abstract Commentary

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