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Return to Deep in the Brain, Doctors Tame Epilepsy Overview

More on Deep in the Brain, Doctors Tame Epilepsy

Deep in the Brain, Doctors Tame Epilepsy

Information from the SANTE Clinical Trial on Deep Brain Stimulation

New York (Aug 23, 2010)

illustration of a semi-transparent man with his brain shown

In epilepsy, uncontrolled electrical signals create a sort of electrical storm in the brain, which results in a seizure. Russian author Fyodor Dostoyevsky, himself an epileptic, describes the moments preceding his seizures as "of great calm, full of understanding." But these moments were simply "a premonition of that final second (never more than a second) with which the seizure itself began. That second was, of course, unbearable." While the frequency and severity of seizures varies from person to person, people with epilepsy can experience several disruptive seizures each day. Most people with epilepsy are helped by current anti-seizure medications or surgery to remove the brain tissue that is the source of the seizures. But about a quarter of patients do not respond to medications and are not eligible for surgery.

graphic of quote from article

A recently concluded study of deep brain stimulation (DBS), in which probes implanted bilaterally in the brain interfere with the errant electrical signals at work in epilepsy, showed that more than half of patients in the study – all of whom had not gotten relief from other treatments – experienced a reduction in the frequency of their seizures, and 13 percent were seizure-free for at least six months after implantation of the device. "The study showed significant improvements in seizure frequency in this very treatment-resistant population of patients, who were not responding very well to medical therapy," said Michael Kaplitt, a neurosurgeon at NewYork-Presbyterian/Weill Cornell Medical Center.

How DBS Works

Dr. Kaplitt and his colleagues, NewYork-Presbyterian/Weill Cornell neurologist Douglas Labar and Lawrence Hirsch, a neurologist at NewYork-Presbyterian/Columbia University Medical Center, all participated in the study, called SANTE (Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy). The patients in the trial underwent surgical implantation of a small device, a battery-operated neurostimulator similar to a heart pacemaker, which has a history of use in Parkinson's disease. "We've been using this device for Parkinson's disease and tremors for almost 10 years, it was simply going into a different spot in the brain," Dr. Kaplitt said.

Michael G. Kaplitt, M.D., Ph.D.
Michael G. Kaplitt, M.D.,
Ph.D.

In patients with Parkinson's surgeons implant the probes exactly into the spot in the brain where electrical nerve signals generate the P.D. symptom, usually the subthalamic nucleus or globus pallidus. In the SANTE study the probes are implanted in the anterior nucleus of the thalamus. Signals travel back and forth along the fibers that radiate to and from the thalamus to other parts of the brain, including areas that can generate seizures, Dr. Labar said.

"Seizures are believed to become full-blown by spreading from the hyperactive part of the brain through this circuit to the rest of the brain," Dr. Kaplitt added. "Patients then develop a generalized seizure or a more complex seizure." In the SANTE trial researchers tested this idea: if little electrical pulses are continuously sent through the probes into the anterior nucleus, the spread of the irregular signals will be interrupted and seizures will be prevented from spreading to the rest of the brain. "The constant stimulation in that area basically creates electrical noise that prevents signals generated in the hyperactive area from spreading to the rest of the brain," Dr. Kaplitt said.

Douglas R. Labar, M.D., Ph.D.
Douglas R. Labar, M.D.,
Ph.D.

SANTE Trial Design

The SANTE trial was divided into two phases. During the first phase, a three-month double-blind phase, 157 patients were implanted with the device and randomized to either have the device turned on or off. At the end of three months, their seizure frequencies were analyzed; those in the treated group had improved by about 40 percent, while the control group had improved by around 20 percent. Dr. Kaplitt speculated that the mild improvement in the control group was due to the placebo effect or because the presence of the electrode alone changed the circuitry, even without the battery on. "But, clearly, there was an added benefit when batteries were turned on," he said. At the conclusion of the blinded phase the devices in patients in the control arm were turned on and they improved fairly quickly to the same level as the patients in the treatment arm.

graphic of quote from article

In the open-label follow-up phase everybody's device was turned on, and the results showed continuous improvement, Dr. Kaplitt said. "At one year the patients were improved, at two years they were even further improved. By the end of two years, about 60 percent of patients had more than a 50 percent improvement in their seizure frequency," he added.

Lawrence J. Hirsch, M.D.
Lawrence J. Hirsch, M.D.

It's important to note that the safety profile of DBS looked really good in the study, said Dr. Hirsch. There were two potential adverse effects, though, he said, that have to be watched closely: more reports of depressed mood in the patients who had the stimulation on and more reports of memory problems. "Most of those who reported depression had prior depression that was simply exacerbated. And when the memory of the patients who reported memory problems was tested, on objective testing they did not have problems. So we're going to have to watch those things fairly closely," he added.

Food and Drug Administration Approval

Drs. Labar and Kaplitt participated in a Food and Drug Administration (FDA) expert review panel, which reviewed the results of this pivotal trial. Members of the panel voted in favor of approving DBS for medication-resistant partial-onset seizures. If DBS is approved for epilepsy, it is likely to become available for routine use some time next year. "There are a lot of needy patients whose seizures are persisting despite trials of a lot of medications, and it will be helpful to be able to offer them something with even a modest benefit," Dr. Labar said. "For these patients any degree of benefit is better than the alternatives, which are no alternatives."

Dr. Douglas Labar discusses the surgical treatments available to patients with epilepsy.

Future Research in Epilepsy

Researchers will continue to study the use of DBS in epilepsy and focus on fine-tuning how best to use the device, said Dr. Hirsch. "There are many different ways to set the stimulator. You can stimulate at all different frequencies. In SANTE the device was set to cycle with 30 seconds on and 5 minutes off. So we can test all different settings, and we may find settings that are better, or we may figure out how to pick patients that are more likely to respond. We've already proven that it works to some degree, and there's still a lot of hope for further improvement."

Dr. Labar described another type of stimulator in clinical trials for epilepsy, a cortical stimulator. This device stimulates the part of the brain where the seizures are originating. "It sounds like it could be a better approach since you're right at the seizure source, but that introduces the possibility of error if you don't get it quite in the right spot. One approach is less specific and more all-encompassing, the other approach is more highly focused but more subject to error, if you hit the wrong site," he added.

Dr. Labar said some epilepsy researchers are working on responsive drug infusion pumps designed to sense the onset of a seizure and release medication to treat it. "The problem with those approaches, although they're very promising and interesting, is that you want the pump's computer to react when or before the seizure happens, but it's very hard to teach a computer to recognize the onset of a seizure."

Dr. Kaplitt and collaborators have also reported data showing improvement in epilepsy in a variety of animal models using a gene-therapy technique similar to that pioneered at NewYork-Presbyterian/Weill Cornell for Parkinson's disease. "We expect that this approach might reach human clinical trials within the next one to two years," Dr. Kaplitt said.

Contributing faculty for this article:

Lawrence J. Hirsch, M.D., is an Attending Neurologist at NewYork-Presbyterian/Columbia University Medical Center and a Clinical Professor of Neurology at Columbia University College of Physicians and Surgeons.

Michael G. Kaplitt, M.D., Ph.D., is the Director of Stereotactic and Functional Neurosurgery at NewYork-Presbyterian/Weill Cornell Medical Center and an Associate Professor of Neurological Surgery in Neurology and Otorhinolaryngology at Weill Cornell Medical College.

Douglas R. Labar, M.D., Ph.D., is the Director of the Division of Clinical Neurophysiology at NewYork-Presbyterian/Weill Cornell Medical Center and a Professor of Neurology and Neuroscience at Weill Cornell Medical College.

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