Levetiracetam Reduces Seizures After Brain Tumor Surgery

Caroline Helwick

October 17, 2013

NEW ORLEANS — A retrospective chart review of patients at high risk for seizures after brain tumor surgery shows that levetiracetam prevented postoperative seizures in 93% in the 7 days after the surgery.

"The incidence of seizures in patients treated with levetiracetam was definitely less than we would expect without AED [antiepileptic drug] prophylaxis, and we included a high-risk population, as compared to previous studies with heterogeneous populations," said Sankalp Gokhale, MD, from Duke University in Durham, North Carolina.

The risk for immediate postoperative seizures in supratentorial brain tumor surgery without prophylaxis with an AED is 15% to 20%, according to Dr. Gokhale, vs approximately 7% seen in this study. Factors responsible for this are intraoperative irritation of cortical tissue, tissue hypoxia or acidosis, and shifts in intracranial pressure and position.

Although the results look good, Dr. Gokhale acknowledged that this was a retrospective chart analysis lacking a control group (ie, another AED or no AED use). "We feel a prospective randomized controlled trial may be warranted in this population," Dr. Gokhale said.

The study was presented here at the American Neurological Association (ANA) 2013 Annual Meeting.

Study Design

"Immediate postoperative seizures increase mortality and morbidity," Dr. Gokhale said. "The risk depends on tumor pathology, location, and the surgical approach and is higher in patients with meningiomas or low-grade gliomas and in patients who have had prior preoperative seizures."

The role of prophylactic AEDs in general — their efficacy and side effects — is not clear, and "there is little data regarding the efficacy of levetiracetam in these patient populations," he said.

Levetiracetam is a second-generation AED increasingly being used in patients with brain tumor. Previous studies have shown the drug to be an effective agent with acceptable side effects. Compared with phenytoin, levetiracetam was more effective and better tolerated, he said, but the available studies have included a heterogeneous craniotomy patient population, he said.

Dr. Gokhale and his colleagues conducted a retrospective study of 165 patients undergoing craniotomy for brain tumor resection at Duke University Medical Center in 2010 and 2011. Patients were included if they had had seizures before surgery, irrespective of histology of the tumor or grade of glioma, or if they were undergoing a resection for supratentorial meningioma or supratentorial low-grade gliomas, irrespective of whether they had had a seizure preoperatively.

All patients received levetiracetam, 1000 to 3000 mg/day, in the immediate postoperative period. The primary outcome was incidence of postoperative seizures within 7 days of surgery. Secondary outcome measures were adverse effects associated with levetiracetam.

Of 165 patients, 12 (7.3%) developed clinical postoperative seizures. All patients had undergone total resection. Seizures were generalized in 83% and partial in 17%. The tumor histology was meningioma in 17%, glioma in 75%, and metastatic lesions in 8%.

Seven patients (4.2%) were noted to have somnolence attributed to the drug, and no patient developed psychosis, skin rash, or gastrointestinal disturbance.

"Other than somnolence in 7 patients, no major side effects were noted," Dr. Gokhale said.

Questions Raised

In discussion that followed the presentation, session moderator Alejandro Rabinstein, MD, from the Mayo Clinic, Rochester, Minnesota, questioned whether the historical seizure rate of 15% to 20% in the absence of AED prophylactic was accurate. "Was this with modern surgical techniques? How solid is that number?" he asked.

Dr. Gokhale said the estimate dates back to publications from the 1990s, and therefore the actual rate could be lower. "The neurosurgical techniques and steroid treatment were not on par with what we do today," he said, "so it's likely less now, but it's hard to say."

Co-moderator of the neurocritical care session, Thomas Bleck, MD, from Rush University, Chicago, Illinois, cautioned that when efficacy from clinical trials is assumed, it should be noted that "a number of patients are people who are likely to have seizures whether or not they have surgery, such as patients with meningiomas or oligodendrogliomas."

He told Medscape Medical News that a randomized controlled trial of levetiracetam compared with placebo or perhaps another AED is still needed.

"We are unlikely to see another trial comparing the drug to phenytoin, since levetiracetam is so much better tolerated than phenytoin. The obvious candidate I think is lacosamide. Both are intravenously available and work by slightly different mechanisms. It might make sense to compare one to the other," he said.

He further noted that the AAN guidelines say that anticonvulsants should not be used at all in patients with brain tumor, "although this was issued before levetiracetam and other new drugs were released."

The study was not supported by industry. Dr. Gokhale and Dr. Bleck have disclosed no relevant financial relationships.

American Neurological Association (ANA) 2013 Annual Meeting. Abstract #T1804.Presented October 15, 2013.

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