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Investigators reported that two different techniques to modify seizures were effective in clinical trials.
DR. ROBERT FISHER: “We all wish that it was even more effective and that we could predict the best responders in advance. Mostly, it is something different to try when nothing else is working.”
In two separate trials, deep brain stimulation of the anterior nucleus of the thalamus (by Medtronic) and responsive stimulation (by Neuropace) were found safe and effective for reducing the frequency of seizures in intractable epilepsy.
The two techniques are quite different in the way that they modify seizure activity. Anterior thalamic stimulation employs programmed chronic stimulation to reduce seizure frequency, while responsive stimulation is a novel closed-loop system that responds to early seizure activity and provides stimulation near the site of the seizure focus. Both treatments involve placement of electrodes in brain structures, but once implanted, the patient is not aware of the stimulation.
The data for both studies were presented in December at the American Epilepsy Society's annual meeting in San Antonio, TX.
In the SANTE (Stimulation of Anterior Nucleus of the Thalamus for Epilepsy) trial, electrodes were implanted and connected to a small battery tucked beneath the clavicle. Once the electrical parameters were set, a continuous high frequency pulse was delivered to the electrodes to help modulate the network and reduce symptoms.
The trial included 110 epilepsy patients from centers across the country who were refractory to medical or surgical interventions. In a blinded protocol, the participants were randomized to have the device activated or turned off. At the end of three months, the investigators analyzed the results, finding a significant reduction in seizure frequency in those who had the stimulator device activated. In that group, there was a 40.4 percent decline in seizure frequency compared to 14 percent in healthy controls (p<0.038).
The patients in the US study have continued using the deep brain stimulators as part of long-term follow-up. Vicenta Salanova, MD, professor of neurology and director of the Comprehensive Epilepsy Program at Indiana University, presented data from patients three years later. She noted that during this window of analysis, patients had other changes in their antiepileptic medications that could have affected the long-term data.
The patients are continuing to improve, Dr. Salanova said. At the end of three years, there was a 67 percent reduction in seizure frequency over baseline (p<0.002). In the first year, 43 percent of the patients showed a greater than 50 percent reduction in seizure frequency; at two years, the responder rate was 54 percent. Over the entire study period, 13 percent of subjects were seizure-free for at least six months, and four subjects were seizure-free for over two years. She said that there were no unanticipated adverse device effects and no symptomatic intracranial hemorrhages. Quality of Life measures also showed statistically significant improvement over baseline by one year, which continued to be significant at two and three years (p<0.001). Neuropsychological profiles remained stable.
Robert Fisher, MD, professor of neurology at Stanford University and the principal investigator of the SANTE trial, noted that these patients had had an average of 19.5 seizures per month at baseline. “We all wish that it was even more effective and that we could predict the best responders in advance,” he said. “Mostly, it is something different to try when nothing else is working.”
Last Spring, an FDA advisory panel voted seven to five in favor of recommending approval of the Medtronic device for intractable epilepsy, but the FDA is still reviewing the data for possible approval. In September, European drug regulators accepted the study results as proof that the device was safe and effective. The first European epilepsy patient had the Medtronic device implanted in November.
Commenting on the study, Orrin Devinsky, MD, professor of neurology and director of the Comprehensive Epilepsy Center at New York University Langone Medical Center, said: “Neuromodulation will ultimately provide a valuable modality for medically intractable epilepsy.”
“It offers a different way to change neural excitability, a fundamental problem in epilepsy,” said Dr. Devinsky, who was not involved with the study. It is also a targeted therapy — unlike medications that expose the entire body and all brain cells to the toxic effects of the agent, neural stimulation focuses the electrical stimulation on a very small region of the brain.
“These regions are either areas that modulate electrical excitability of the cortex (such as the anterior thalamic nucleus in the SANTE trial) or the site of origin of the seizures (the cortical epilepsy focus in the Neuropace trial).”
“We are at a very early stage in learning to employ this therapy,” Dr. Devinsky added. “We need to better define target zones and stimulation paradigms to achieve better results. We have patients suffering terribly from their refractory epilepsy. The benefits outweigh the risks for many of my patients.”
DR. VICENTA SALANOVA said that over the entire study period [for the SANTE trial], 13 percent of subjects were seizure-free for at least six months, and four subjects were seizure-free for over two years.
DR. GREGORY BERGEY said the investigators of the Neuropace devise were disappointed that they didn't have a more robust response in the trial, but, he noted, it could be a matter of not knowing the ideal parameters for stimulation. It is not known whether there may also be subgroups of patients who respond better than others, he added.
In the Neuropace trial, the company worked with investigators at 31 medical centers, who enrolled 191 patients. Patients accepted into the study had to have partial onset epilepsy, with seizures that start from one or two areas of the brain that had not been effectively treated with two or more antiepileptic medications alone or in combination.
The blinded evaluation period of the trial began eight weeks after the system was implanted and lasted an additional 12 weeks. Half the participants were randomly assigned to have responsive stimulation activated and half had it remain inactive. The primary endpoint was to demonstrate a significantly greater reduction in seizure frequency in the treatment group (responsive stimulation on) compared to the sham stimulation group (responsive stimulation off) during the three month blinded evaluation period.
Lawrence Hirsch, MD, professor of clinical neurology at Columbia University Medical Center, where he was the lead investigator of the trial site, reported that 29 percent of the patients in the active treatment group had their seizures reduced by 50 percent and there was a 38 percent reduction in seizure frequency compared to a 17.3 percent reduction in the sham stimulation group (p=0.012).
Gregory Bergey, MD, professor of neurology and director of Johns Hopkins Epilepsy Center at Johns Hopkins School of Medicine, where he was principal investigator of the trial site, said: “We are a little disappointed that we didn't have a more robust response.” But, he added, that it could be a matter of not knowing the ideal parameters for stimulation. It is not known whether there may also be subgroups of patients who respond better than others, he said.
The data have been submitted to the FDA for review.
DR. ORRIN DEVINSKY: “Neuromodulation will ultimately provide a valuable modality for medically intractable epilepsy.”
Gregory Krauss, MD, a professor of neurology at Johns Hopkins University of Medicine, said that the initial concept of the responsive stimulation design was that stimulation at the onset of a seizure would acutely disrupt the seizure. “It turned out that patients with uncontrolled seizures often have hundreds of epileptiform bursts that are similar to full seizure onsets each day and so most patients receive hundreds of stimulations per day with only a small fraction being events that would have been seizures,” said Dr. Krauss, who was not involved with the studies.
“This repeated stimulation possibly has long-term modulatory effects that might decrease seizures rather than the expected acute interruption. This makes for some difficulties in interpreting the sham-controlled stimulation study data.”
“The mesial temporal stimulation patients had a much higher responder rate than extratemporal patients with responsive stimulation,” he noted.
DR. GREGORY KRAUSS: “This repeated stimulation possibly has long-term modulatory effects that might decrease seizures rather than the expected acute interruption. This makes for some difficulties in interpreting the sham-controlled stimulation study data.”