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NEWS FROM THE AAN ANNUAL MEETING: Simultaneous Polypharmacy Found More Effective Than Sequential Therapy for Status Epilepticus

Collins, Thomas R.

doi: 10.1097/
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In an animal model, investigators found that administering three drugs at once to inhibit status epilepticus was more effective than giving them sequentially with time delays between each drug.

PHILADELPHIA—Rats given a simultaneous, three-drug treatment during status epilepticus (SE) had better outcomes — with shorter seizure periods and brain activity that was more controlled — than those treated with the same drugs sequentially with waiting periods in between, researchers said here at the AAN Annual Meeting.

The results might be reason to evaluate this simultaneous therapy approach more thoroughly and include polytherapy arms in clinical trials, they said.

Research has shown that there is pharmacoresistance during seizures and that this resistance to therapy grows with the elapsed time of the seizures.

Claude Wasterlain, MD — a professor of neurology at the Brain Research Institute at the University of California, Los Angeles, who presented the study — and his lab previously found that the pharmacoresistance to benzodiazepines is likely related to the decrease in availability of functional gamma-aminobutyric acid(A), or GABA(A) post-synaptic receptors, which are key players in synaptic inhibition. Benzodiazepines enhance the effect of GABA, so if fewer GABA receptors are available, their effect will be diminished, prior research has found.

Standard therapy for SE is a benzodiazepine followed later by a second drug and then a third drug or general anesthesia.

Previous studies have found that the success rate of each subsequent drug is lower than the previous one. The Veterans Affairs Status Epilepticus Cooperative Study in 1998 found a 55.5 percent success rate for the first, 7.3 percent for the second, and 2 percent for the third.

In a 2012 New England Journal of Medicine study comparing intramuscular and intravenous pre-hospital therapy for SE, researchers found that a four-minute difference in the time of delivery resulted in significantly better outcomes, Dr. Wasterlain said. “So why wait for a drug to fail before starting the next drug?” he asked.

In the study reported at the AAN meeting, researchers set out to answer whether the increased pharmacoresistance during SE is correlated with time or with the number and severity of seizures, and whether drugs should be given simultaneously rather than one after the other to save time and prevent pharmacoresistance.

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The investigators induced SE in the rats with lithium-pilocarpine. In the sequential group, rats were given midazolam, a benzodiazepine, 40 minutes after seizure inducement. Thirty minutes later, they were given valproate, meant to further enhance inhibition. Thirty minutes after that, they were given ketamine, to reduce excitation in the glutamate receptors that mediate excitatory neurotransmission.

In the simultaneous group, all of those drugs were given at the same time.

Among their findings, SE lasted about five minutes in the group that received all three drugs simultaneously, compared with about 55 minutes in the sequential treatment group (p<.01). And EEG activity was greatly reduced in the simultaneous group compared to the sequential group, both one-hour and four-hours after treatment.



Researchers also found that the SE time and EEG activity was greatly reduced in the rats that received all three therapies simultaneously, compared with groups given monotherapy of each drug at triple the dose given in the simultaneous group — showing that even at much higher dosing, monotherapy yielded worse results than polytherapy.

“The timing of treatment for status epilepticus is a major determinant of outcome,” Dr. Wasterlain said. “That does not mean we should automatically start with three drugs with every patient we see. But at least we should consider the simultaneous polytherapy in our therapeutic trials. And if we ever have another controlled trial of status again, it should include a polytherapy arm.”

An audience member cautioned that the standard treatment for SE is lorazepam, followed by phenytoin, then phenobarbital or anesthesia, and wondered about the “generalizability of the data” since different drugs were used in these studies.

Dr. Wasterlain said that, in animal models, researchers have the freedom to try drastically different regimens, and that the intent was to show “a synergistic effect,” which they did.

“Nothing in what we have done in animal models detracts from using a benzodiazepine as the first line,” he said. “I think that's good and unquestioned. The question is whether we should add something to the benzodiazepine as first line,” after weighing the risks and benefits.

Another questioner wondered whether there is any sense of how long SE could go on before triple therapy becomes ineffective, noting that doctors often do not know precisely when SE began.

“It's on the list of things to do,” Dr. Wasterlain responded. “It's a good idea and we haven't done it yet.”

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Jacqueline A. French, MD, FAAN, a professor of neurology at the New York University Comprehensive Epilepsy Center, noted that the study addresses only induced SE; she questioned whether the findings would translate to cases where epilepsy is already established.

“In terms of treating status epilepticus, they could have a point if giving multiple therapies at once was safe,” said Dr. French, who serves on the editorial advisory board of Neurology Today. “We often do give benzodiazepine along with phenytoin or levetiracetam. But you can't ‘fire with both guns’ right from the start, because some people only need a single drug and status epilepticus will stop. Over- treating could lead to harmful consequences of its own, like an increased need for intubation due to respiratory depression. So it's a bit complicated in people.”

For more commentary on this paper, watch our Videos on Demand discussion with Neurology Editor-in-chief Robert A. Gross, MD, PhD, FAAN, and Neurology Today Editor-in-chief Steven P. Ringel, MD, FAAN, and Associate Editor Robert G. Holloway Jr., MD, FAAN:



VIDEOS ON DEMAND: Is polypharmacy more effective for stopping status epilepticus than sequential therapy? Watch the video here as Neurology Editor-in-chief Robert A. Gross, MD, PhD, FAAN, an epilepsy expert, discusses that question — and the limitations of the animal model and experiment — in a video with Neurology Today Editor-in-chief Steven P. Ringel, MD, FAAN, and Associate Editor Robert G. Holloway Jr., MD, FAAN: Read the original abstract from the meeting here:

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•. AAN Annual Meeting Abstract: Sequential versus simultaneous polytherapy in the treatment of status epilepticus:
    •. Naylor Liu Wasterlain. Trafficking of GABA(A) receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J Neurosci 2005;25(34): 7724–7733.
      •. Treiman Meyers Walton, et al. A comparison of four treatments for generalized convulsive status epilepticus. Veterans Affairs Status Epilepticus Cooperative Study Group. N Engl J Med 1998;17(12): 792–798.
        •. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012; 366(7): 591–600.
          © 2014 American Academy of Neurology