ARTICLE IN BRIEF
Investigators reported that in a randomized trial none of the epilepsy patients assigned to receive antiepileptic drugs alone became seizure-free, but 85 percent for whom data was collected were seizure-free at the end of the two-year follow-up. Nine of the 11 had no seizures at all after surgery.
Surgical removal of a portion of the temporal lobe, widely regarded as a last-resort treatment for epilepsy, appears to control seizures so effectively it should be tried as soon as a patient has failed to respond to two antiepileptic medications, according to a new study.
“This confirms what we have known all along — that surgery is a powerfully effective treatment and there's no reason to wait,” said Jerome Engel Jr., MD, PhD, lead author the research published in the March 7 issue of the Journal of the American Medical Association (JAMA). “Evidence shows that if patients fail two trials of drugs, their chances of leading a seizure-free life are 3 percent or less. Yet, less than 1 percent of pharmacoresistant epilepsy patients are referred to an epilepsy center where they can be evaluated.”
Dr. Engel, the Jonathan Sinay Distinguished Professor of Neurology, Neurobiology, and Psychiatry and Biobehavioral Sciences, and director of the Seizure Disorder Center at the David Geffen School of Medicine at University of California, Los Angeles, said the findings support the practice parameter issued by the AAN Quality Standards Committee in 2003.
The AAN parameter concluded that anteromesial temporal lobe resection for disabling complex partial seizures provides greater benefits than continued treatment with antiepileptic drugs (AEDs). The subcommittee, led by Dr. Engel, also recommended that patients with drug-resistant seizures should be referred to an epilepsy center early in order to avoid irreversible disability, but lacked data to determine how early would be appropriate.
Two “remarkable” things stand out in the current study, said study author Samuel Wiebe, MD, MSc, FRCPC, head of the Division of Neurology at the University of Calgary, and director of clinical research for the Hotchkiss Brain Institute. “First, that surgery is effective early after patients are deemed refractory to medication,” he said. “Patients should not wait for surgery as long as they are waiting now. Second, that the size of the benefit of surgery is astoundingly large — so large, in fact, that with only a handful of patients statistically significant results were obtained.”
The Early Randomized Surgical Epilepsy Trial (ERSET) was a controlled, parallel-group clinical trial conducted at 16 epilepsy surgery centers in the US. The study, led by Dr. Engel, randomized 38 patients who had experienced disabling seizures originating in the temporal lobe for up to two years despite treatment with antiepileptic medications. Twenty-three continued treatment with antiepileptic drugs, and 15 were assigned to have temporal lobe surgery followed by continued treatment with AEDs.
None of the patients assigned to receive AEDs alone became seizure-free, but 11 of the 13 surgery patients (85 percent) for whom data was collected were seizure-free at the end of the two-year follow-up. Nine of the 11 had no seizures at all after surgery.
Surgery also improved quality of life, according to scores on the Mental Health, Epilepsy-Targeted, and Cognitive Subscales of the Quality of Life in Epilepsy-89.
While the surgery disrupts the hippocampus and can impair memory if the epilepsy itself has not already done so, an editorial in the same issue of JAMA pointed out that the study's small enrollment provides insufficient data to determine whether the memory decline observed in some surgical patients “is equal to, greater than, or less than memory decline that might occur during the long-term medical management.”
By the end of the two-year follow-up some members of the surgical group performed slightly worse than the medication group on immediate (p=.01) and delayed (p=.02) recall tests, but the memory deficits were modest and not always noticeable, according to Dr. Engel. “Verbal memory deficits from surgery in the language-dominant hemisphere are most likely to be noticed by the patient, but for most there are ways to make accommodations,” he said. “The statistically significant improvement in quality of life means that patients who have this problem consider this a good tradeoff for not having seizures anymore.”
The authors of the editorial, Donald L. Schomer, MD, of Harvard University, and Roger J. Lewis, MD, PhD, of the University of California, Los Angeles, also pointed out that the 38 patients enrolled fell far short of the goal of 200, but conceded that “the observed treatment effect was so large that the benefit of AMTR (anteromesial temporal resection) seems unequivocal.”
Dr. Engel contends that the small enrollment represents a symptom of the problem: “It is tragic that less than 1 percent of patients with pharmacoresistant epilepsy are referred to epilepsy centers,” he said, “and even more disturbing that referrals are made an average of 22 years after onset, when it is too late to reverse disability.”
SURGERY: SOONER OR LATER?
Later surgery for epilepsy can also be effective, but the JAMA study demonstrates that earlier may be better for many patients, said Shlomo Shinnar, MD, PhD, Hyman Climenko Professor of Neuroscience Research, and director of the Comprehensive Epilepsy Management Center at Montefiore Medical Center of Albert Einstein College of Medicine in New York. Dr. Shinnar was not involved with the study.
“For many years the thinking among the general neurologists has been, if the patient has had epilepsy for 20 years, I'll send him for surgery, but if it's been only two or three years, I'll try two or three more drugs first,” Dr. Shinnar said. “This paper is saying that if medical therapy isn't working, then epilepsy surgery should be considered fairly early in the course of treatment. That's what's new here. In 2003 the AAN practice parameter said we should do surgery earlier, but practice parameters don't always change practice. That's why it was important to get this out.”
Patients with temporal lobe epilepsy may have a 70-80 percent chance of achieving freedom from seizures, according to Dr. Shinnar, while those with extra-temporal non-lesional epilepsy may face poorer prospects and, if not good candidates for surgery, may want to keep trying antiepileptic drugs. But all patients who have failed two AEDs should be referred for evaluation to a comprehensive epilepsy center, according to Dr. Shinnar.
“That doesn't mean they'll all go to surgery,” he said. “They may have the wrong diagnosis; they may need to try a different drug or different dose. But at the end of the day the majority will be evaluated for surgery, and the argument in this paper is that if early surgery is effective, and will save the patient 15 years of uncontrolled seizures, then it makes sense. I think this is an important study because it demonstrates the efficacy of epilepsy surgery, and shows why people should get it early.”
The JAMA study may help soften the resistance among many physicians to referring seizure patients to an epilepsy center for possible surgery, according to Orrin Devinsky, MD, professor of neurology, neurosurgery and psychiatry, and director of the Comprehensive Epilepsy Center at the New York University Langone Medical Center.
“Many neurologists and non-neurologists think brain surgery is very dangerous, even potentially life threatening, while having a complex partial seizure in which the patient stares for a minute or two twice a month is not terribly disabling,” Dr. Devinsky said.
“The problem is that having one or two seizures a month places limitations on life, and taking moderate to eventually high doses of several medications is associated with side-effects. I think surgery is a real option for patients with difficult-to-control medial temporal lobe epilepsy who have failed at least two appropriate medications, and have seizures localized to one temporal lobe. I think it's a physician's duty to present that option and tell patients that is their best chance for seizure freedom, their best chance to drive a car.”
• Engel J, McDermott MP, Kieburtz K, et al, for the Early Randomized Surgical Epilepsy Trial (ERSET) Study Group. Early surgical therapy for drug-resistant temporal lobe epilepsy: A randomized trial. JAMA 2012;307(9):922-930.
• Engel J, Wiebe S, Enos B. Practice parameter: Temporal lobe and localized neocortical resections for epilepsy. Neurology 2003;60:538-547.
• Schomer DL, Lewis RJ. Stopping seizures early and the surgical epilepsy trial that stopped even earlier. JAMA 2012;307(9):966-968.
• Wiebe S. Outcome patterns in epilepsy surgery – The long-term view. Nature Rev Neurol 2012;8:123-124.