Early Surgery Deemed Best for Drug-Resistant Epilepsy

Surgery was clearly superior to pharmacotherapy at relieving seizures in a study of patients with intractable mesial temporal lobe epilepsy who were no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs.

Though the study sample was small, with only 38 subjects, surgery also proved to be better at improving quality of life, allowing patients to drive vehicles, and increasing their socialization, according Dr. Jerome Engel Jr. of the University of California, Los Angeles, and his associates, whose report was published March 7 in JAMA.

“We found that the benefit of surgery in newly intractable epilepsy is very large (allowing it to be demonstrated in a small randomized trial),” and that patients who avoid surgery are very unlikely to improve with further pharmacotherapy. This probably raises their risk of death and of adverse psychological and social consequences, the investigators noted.

Surgery for epilepsy is often delayed for years or avoided altogether, in part because many consider it a last resort. “There is concern that surgery early in the course of mesial temporal lobe epilepsy could produce cognitive deficits in otherwise cognitively intact patients,” Dr. Engel and his colleagues wrote.

In fact, this trial was terminated early solely because so few patients were being referred to the participating epilepsy centers for possible surgery that subject accrual was deemed inadequate.

But earlier surgery could prevent significant morbidity and even premature death. The American Academy of Neurology has recommended surgery as the treatment of choice for medically intractable epilepsy since 2003, but the excess lag time before surgical referral hasn’t decreased since then and still remains at more than 10 years.

The Early Randomized Surgical Epilepsy Trial (ERSET) was designed to compare the outcomes of surgery with those of continued pharmacotherapy, focusing on patients no more than 2 years beyond the point where they failed to respond to adequate trials of two brand-name antiepileptic drugs. This interval was considered “a time when adverse psychological and social consequences of disabling seizures might be minimal, and seizures might conceivably still respond to further trials of AEDs [antiepileptic drugs],” the researchers wrote.

In all, 38 patients aged 12 years and older (mean age 34 years) with intractable, disabling seizures were referred from 16 medical centers and randomly assigned to continue pharmacotherapy (23 subjects) or to undergo en bloc resection of the anterior 3.5-4 cm of the lateral temporal lobe, sparing the superior temporal gyrus, followed by removal of the mesial structures (15 subjects). The patients were followed every 3 months for 2 years.

Despite efforts to include adolescent patients in this trial, only two were ultimately recruited, and both were randomly assigned to the pharmacotherapy group. Therefore it remains unknown whether the study results apply to adolescent patients.

Eleven (73%) of the 15 patients who underwent surgery were free from disabling seizures during the second year of follow-up (the primary outcome of the trial), but none of the patients taking only AEDs reached that end point (JAMA 2012;307:922-30).

Moreover, “the 2 participants in the surgical group who continued to have seizures in year 2 experienced substantial improvement in seizure frequency,” the investigators noted.

Patients who became seizure free also reported that they no longer experienced auras.

The mean number of AEDs used by patients in each group did not change appreciably in either group from baseline to 2 years.

The surgical group had significantly greater increases in health-related quality of life than did the pharmacotherapy group at all time points during follow-up. Twelve (80%) were able to drive vehicles at 2 years, compared with 5 (22%) in the pharmacotherapy group. And the surgery group reported a median increase of 7 days per month in socializing with friends, compared with a median decrease of 1 day per month with pharmacotherapy.

There were no differences between the study groups in employment status, hours worked per week, sick days, or days socializing with family.

Thirteen serious adverse events occurred, seven in the medical group and six in the surgical group. Events in the medical group were related to continuing seizures, including three cases of status epilepticus. Events in the surgical group included postoperative vomiting that required a gastrostomy, bleeding into the subarachnoid space that required placement of a shunt, and a mild cerebral infarction that fully resolved during follow-up.

Patients in the surgery group had substantially lower performances than did those in the medical group on immediate and delayed recall, but not on any nonmemory measures. “Verbal memory deficits are to be expected following resection of the language-dominant mesial temporal lobe of participants with normal presurgical memory,” the investigators wrote.

Nevertheless, the sample size in this study “was too small to permit a definitive conclusion that early surgery does not present a greater risk for cognitive disturbances than continued pharmacotherapy,” they added.

Overall, the ERSET results “reinforce the view that surgery soon after failure of two antiepileptic drug trials offers the best chance of preventing a lifetime of disability,” Dr. Engel and his colleagues said.

The findings also remind clinicians that “all patients with epilepsy should be referred to an epilepsy center as soon as trials of 2 antiepileptic drugs fail, and surgery should be performed,” they added.

The ERSET study was supported by the National Institute of Neurological Disorders and Stroke and the National Institutes of Health. Several of the authors reported receiving consultancy fees, lecture or speakers bureau fees, or travel expense fees from manufacturers of devices and drugs to treat epilepsy.

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