Drug Deposited Directly Into the Brain Effective in Severe Epilepsy

Pauline Anderson

December 12, 2017

WASHINGTON, DC — A microinfusion device that continuously delivers valproate directly to the brain is safe and effective in patients with refractory focal epilepsy, early research shows.

Delivery of valproate through the intracerebroventricular device avoids the sometimes significant side effects associated with the oral version of the drug. The study was small — only five patients so far — but researchers are excited about the potential of the investigational therapy.

"Anticonvulsant drugs have never before been delivered in this way for the treatment of chronic epilepsy, so this is really unique," lead author Mark J. Cook, MD, professor of neurology and director, Graeme Clark Institute, University of Melbourne, Australia, told Medscape Medical News.

The findings were presented here at the American Epilepsy Society (AES) 71st Annual Meeting 2017.

More than one third of patients with epilepsy continue to have seizures despite taking oral antiepileptic drugs (AEDs). In addition, many experience significant drug-related side effects.

Delivering epilepsy drugs directly to the seizure focus in the brain allows for higher, potentially more effective doses without these side effects.

Four of the five patients in the study are women, ranging in age from 25 to 38 years. All experienced at least 10 complex partial seizures per month that extensive imaging confirmed started in the mesial temporal structures. None of the patients was suitable for resection surgery and none responded to AEDs, including valproate.

"That was one of the exciting things about this study — we learned that a drug that hadn't been effective orally could be effective if given in this way," said Dr Cook.

Surgeons implanted a pump into the abdomen with a catheter running under the skin up through the chest and neck, and then through the skull to the brain. 

"It's exactly like a catheter that's used to shunt fluid out of the brain," said Dr Cook.

The mesial temporal structures are near the ventricles of the brain. "We put the catheter in those ventricles so that the hippocampus on the inner surface of the temporal lobe gets well covered by the drug," he added.

The pump continuously delivers a programmed amount of valproate. Patients in the trial are getting 60 to 100 mg a day.

The investigators opted to first test this approach using valproate because it is "well understood and known to be effective," said Dr Cook. "We thought we should probably start with something for which we had a reasonable expectation of efficacy."

In all patients, seizure frequency and severity decreased markedly, by 50% to 90%.

But statistics don't tell the whole story. For some patients, "it's been spectacularly successful," and in others, "while the seizures haven't been completely abolished, they're mild and don't interfere with the patient's life," said Dr Cook.

One woman had to be hospitalized for 2 months before undergoing the procedure because she frequently fell during seizures.

"Now, she's living independently and looking for a job. We can say pretty confidently that the people who have seizures that start in the mesial temporal region, so around the hippocampus, seem to get very good results," said Dr Cook.

He estimated that at least 30% of patients with focal epilepsy have seizures starting in this region.

In all study patients, the procedure and implantation were well tolerated.  Side effects included a feeling of being cold, nausea, and appetite loss, and some patients felt "a little hung over" when the drug dose was increased, said Dr Cook.

"There have been no serious central nervous system toxicities, and patients don't seem to be experiencing the side effects we expect from valproate, like tremor."

About 5% to 10% of the drug gets into the bloodstream. "That's a very low level," said Dr Cook, adding that the amounts used are very small compared to what's generally administered in oral form.

The lifespan of the pump is 5 to 8 years. During the study, one pump had to be replaced after 5 months because of a mechanical issue.

"This wasn't the purpose for which the pump was originally designed, and so there have been some minor problems," said Dr Cook. He added that these issues are being "ironed out."

The pump system (Prometra II Programmable Pump, Flowonix Medical) is approved by the US Food and Drugs Administration for infusion of drugs into the spinal cord for relief of pain or spasticity.

In study patients, the pump is refilled every 4 weeks. However, with more concentrated preparations, Dr Cook said he expects that frequency to be extended to every 2 to 3 months, depending on the dose.

The aim is to enroll up to about 20 patients in the study and then initiate an international multicenter trial.

The pump system could possibly delivery other epilepsy drugs, or drug combinations, said Dr Cook. "Maybe there are anticonvulsants that don't have oral formulations that are not ever used in the clinic that could now be administered by this technique."

The drug delivery system might also be used to treat other types of epilepsy and other neurologic conditions, such as Parkinson's disease and Alzheimer's disease.

"Very Cool"

Commenting on the study for Medscape Medical News, Jacqueline French, MD, professor, NYU Comprehensive Epilepsy Center in New York City, described the drug delivery system as "very cool."

"So far, results are very promising." There are numerous reasons why such a pump is superior to oral delivery, said Dr French.

Valproate is "a body poison," she said. "It makes you fat; it gives you all kinds of hormonal changes. It causes liver failure, and on top of that, it's teratogenic, so women who want to have children can't take it."

By delivering the drug directly to the brain, only a very small percentage of it gets into the bloodstream and these side effects are avoided, said Dr French.

This new approach could be a boon to patients with epilepsy who have tried and not responded to traditional administration of AEDs, she said.

The study was funded by Cerebral Therapeutics. Dr Cook and Dr French have disclosed no relevant financial relationships.

American Epilepsy Society (AES) 71st Annual Meeting 2017. Abstract 2.051. Presented December 3, 2017.

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