ARTICLE IN BRIEF
Investigators reported that over time — up to 10 years — 50 percent of patients were seizure free, whether or not they continued to take antiepileptic drugs post surgery.
Should all patients continue to take antiepileptic drugs (AEDs) after surgery to reduce their risk for surgery? That was the question underlying a new large retrospective study from investigators at the Cleveland Clinic, presented here in December at the annual meeting of the American Epilepsy Society meeting in Washington, DC.
Neurology fellow, Ruta Yardi, MD, and her mentor, Lara Jehi, MD, director of the Cleveland Clinic's outcomes research program, who designed the study and carried out the analysis, said their findings suggest that the answer to that question is “no.”
In designing the current study, said Dr. Jehi, “we really needed to know whether the seizures post-surgery were occurring because medication was withdrawn or reduced, or whether patients would have had them anyway, even if they continued on their same medications.”
Candidates for surgical resection have failed two or more AEDs and continue to have seizures, she explained. The goal of the surgery is freedom from seizures but neurologists have always taken precautions and kept their patients on their baseline dose for a year or two, and often longer. The investigators wanted to know more about what happens with medications over time — and whether seizures return once medication is lowered or stopped.
Dr. Yardi and colleagues reviewed medical records of 609 patients who had surgery between 1996 and 2011 and had detailed information on their medications before and after surgery and a history of their pre-and-post surgical seizures. About 20 percent of the patients had stopped their medication altogether. They also had a group of patients whose medications were not changed, which allowed the research team to answer questions that could help resolve the controversy about how much medication to use and for how long. Other retrospective studies did not have a defined control group of patients who remained on their pre-surgical medications, so were limited in their ability to draw reasonable comparisons.
The investigators reported that withdrawing AEDs increased the risk of breakthrough seizures during the first few months — 40 percent of them had breakthrough seizures. But more than two-thirds of these patients who were put back on their pre-surgical doses did not have further seizures.
That 60 percent of the patients whose medication was lowered or stopped did not have breakthrough seizures raises the question of whether everyone benefits from the addition of medication, said Dr. Jehi. “Every patient who has been seizure free deserves a chance to know whether they need to continue taking medications,” she said.
The investigators looked at the frequency of seizures during the first and second year post-surgery and found that those who remained on medicines for another year did not have any more protection than those whose medications were reduced or stopped a year after surgery. They reviewed data at four, six, and ten years. [See “Longitudinal Data on Seizures Post-Surgery.”] After a decade, approximately 50 percent of the patients in both groups were seizure free.
“I don't think we can assure patients taking two or three medicines that this practice will protect them from seizures,” Dr. Jehi added. “These medicines have side effects. Many physicians are afraid to wean their post-surgical patients off medicines, but maybe medication withdrawal is not as scary as we have assumed.”
The ultimate goal, the Cleveland Clinic neurologists said, is to identify biomarkers to identify those patients who can successfully stop or reduce their medications after surgery. And then they want to figure out the best time to do so.
They are also hoping that results from a prospective study can lead to guidelines that the field can follow. “The problem right now is that everyone has an opinion and no one has facts on which to base their opinion.”
That the medications were shown to work in these previously treatment refractory patients also suggest that the surgery may have made their brains pharmacologically more responsive to medicines.
EXPERTS WEIGH IN
“I always tell my patients considering surgery that they may have to continue taking their medicines,” said Jacqueline French, MD, professor of neurology at the New York University Comprehensive Epilepsy Center and president of the American Epilepsy Society. “This study tells us that people who discontinue their medications after surgery have a 50 percent risk of having another seizure. Many patients are not comfortable taking that risk.” Breakthrough seizures can also occur in patients who are on their pre-surgical baseline dose, said Dr. French, who also serves on the editorial advisory board of Neurology Today.
She said that about ten percent of those who go off their medications will no longer be responsive to them should they have to resume them following a seizure.
“As physicians get older and have more experience taking care of treatment refractory patients who undergo surgery, we get a lot more circumspect about withdrawing medications. We don't see surgery as a cure but an intervention that helps patients be more sensitive to antiepileptic medicines,” said Dr. French. “There is a large cohort of people who you can't tell whether they will go on to have seizures or not. It is like Russian roulette.” She agrees with the Cleveland neurologists that patients should be given the information on what is known and they “deserve to have a choice about what they want to do.”
Part of the problem, Dr. French said, is that breakthrough seizures in adults can have consequences. “If they are driving when a seizure occurs they could lose their license. If they are a lawyer or a teacher having seizures can put their jobs in jeopardy. This decision will have different value for different people,” she said.
She agrees that a prospective trial should be done to resolve some of these issues.
Gregory D. Cascino, MD, the Whitney MacMillan, Jr. professor of neuroscience at the Mayo Clinic College of Medicine and chair of the Division of Epilepsy at Mayo Clinic, said that there is “controversy over the discontinuance of AED therapy following successful epilepsy surgery because of a lack of appropriate pivotal studies.” His group published an observational study in Neurology in 2000 examining seizure recurrence in 210 patients undergoing epilepsy surgery. The seizure recurrence rate after complete AED withdrawal was 14 percent and 36 percent, respectively, at two and five years. In contrast, only 3 percent and 7 percent of the 30 patients who did not alter AED treatment after surgery had recurrent seizures in the same time intervals.
Based on those findings, Dr. Cascino said that he takes a conservative approach and continues AED medication for at least two years postoperatively. AED therapy may be reduced if patients are experiencing dose-related adverse effects or are receiving polytherapy prior to that time after surgery. Discontinuance of AED medication is usually not considered unless there is a compelling reason such as concerns regarding pregnancy, AED side effects, or drug interactions.
“The most important factor after surgery is for the patient to be seizure free because of the putative beneficial effects of surgery that allow driving, working, and living independently,” Dr. Cascino said. “It would be lovely to reduce medications but quality of life is very important to our patients. They work and drive and go to school. They want to minimize the risk of seizures.” By two years, he tries to reduce the dose of AED therapy and get patients down to one medicine.
He agrees that a multicenter prospective study would be useful to identify biomarkers that may predict favorable candidates for discontinuance of AED therapy and provide appropriate practice guidelines.
LONGITUDINAL DATA ON SEIZURES POST-SURGERY
* By four years, 89 percent of the study patients whose medicines were continued remained seizure free. By comparison, 72 percent of those whose medications were stopped or reduced were seizure free.
* At the six-year post-surgical mark, around 60 percent of those whose medicines were withdrawn or reduced were seizure free versus 70 percent of those whose medicines had stayed the same.
* At 10 years, 50 percent of patients were seizure free, whether or not they continued to take antiepileptic drugs post surgery.
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