Two years after receiving a responsive neural stimulator implant, nearly half of study participants achieved a 50 percent or greater reduction in seizures.
RESULTS of a new trial of a deep brain stimulation system have experts asking: Will the FDA approve it?
Responsive cortical stimulation is an effective treatment for medically intractable partial epilepsy, according to a new multicenter double-blinded randomized controlled trial conducted by the RNS [Responsive Neurostimulator] System in Epilepsy Study Group. But is the degree of benefit sufficient?
When queried by Neurology Today, several epilepsy experts answered in the affirmative, adding that they hoped the device wins FDA approval; but at least one commentator offered a more nuanced response.
“The question cannot be answered with a simple yes or no,” Robert S. Fisher, MD, professor of neurology and director of the Comprehensive Epilepsy Center at Stanford University in California, wrote in an editorial that accompanied the paper's publication in the Sept. 6 online edition of Neurology.
“Any answer must take into account the severe refractory nature of the population being tested and the common previous failure of mz ultiple medications, vagus nerve stimulation, or epilepsy surgery. In this context, the degree and duration of improvement can be considered to have been beneficial for at least a substantial segment of the study population. Furthermore, brain stimulation is an adjustable and reversible therapy that can be discontinued for those not receiving benefit.”
The study — which was funded by NeuroPace, the manufacturer of the RNS System — involved 191 adults with medically intractable partial epilepsy who experienced an average of at least three seizures per month and whose partial-onset seizures had not been controlled with two or more trials of antiepileptic drugs.
Martha J. Morrell, MD, clinical professor of neurology at Stanford University and chief medical officer for NeuroPace, Inc., and colleagues reported that participants received a responsive neurostimulator — cranially implanted — connected to leads placed at one or two pre-determined seizure foci. Upon EEG detection of seizure onset, the device initiates rapid counter-stimulation. One month after implantation, study participants were randomized to receive either stimulation in response to detections, or no stimulation. After the 12-week initial blinded period, all subjects received responsive stimulation during a subsequent 84-week open label period.
During the blinded period, the researchers reported a small but significant reduction in seizures among the treatment group (-37.9 percent) vs. the sham group (-17.3 percent, p=0.012), with no difference noted in adverse events. The difference in seizure frequency between the two increased over time, reaching its peak toward the end of the blinded evaluation period.
In the open-label phase, the improvements continued. Two years post-implant, nearly half of the study participants achieved a 50 percent or greater reduction in seizures. “Given the long duration and severity of their epilepsy, and many treatment failures, this sustained seizure reduction with responsive stimulation is clinically meaningful,” the authors wrote. The reduction in seizures also translated into notable improvements in quality of life measures, such as social function, health concerns, and cognition.
“This is a fairly seminal, landmark study,” said Joseph I. Sirven, MD, professor and chair of the department of neurology at the Mayo Clinic in Scottsdale, AZ, who was not involved with the study. “These findings change the equation. As opposed to when vagus nerve stimulation came out in 1997, this is the third iteration of a novel stimulation technique applied to epilepsy, and the question isn't ‘Will this work?’ anymore. It's ‘Who will this work for?’”
Dr. Sirven noted that the study's findings are all the more impressive given the refractory nature of the patients involved. “These are among the most difficult patients, many of whom have failed not only drugs but surgeries,” he said. “Having any positive result at all in these patients is already saying something.”
DR. JOSEPH SIRVEN: “These findings change the equation. As opposed to when vagus nerve stimulation came out in 1997, this is the third iteration of a novel stimulation technique applied to epilepsy, and the question isn't ‘Will this work?’ anymore. It's ‘Who will this work for?’”
Unlike vagus nerve stimulation, which involves an implant directly under the skin and can be used with for many epilepsy patients, this technique carries greater risks, with its more invasive surgical component, and requires careful patient selection, Dr. Sirven noted. “You have to know the foci. You still have to undertake the approach that you would for surgery, and answer the question of location, in order to deliver the best therapy, which you don't need for some of the devices,” he said.
“This technique is designed for focal or bifocal epilepsy with partial-onset seizures, in regions where you can't resect safely because of proximity to critical areas of the brain,” said Gregory Krauss, MD, professor of neurology at Johns Hopkins School of Medicine in Baltimore, MD, who was not involved with the study. “Other types of stimulation, like thalamic stimulation and vagus nerve stimulation, may turn out to be good for multiple seizure types, particularly patients with symptomatic multifocal seizures. This treatment may help people with uncontrolled partial seizures.”
That group may be a relatively large one, said Thomas R. Henry, MD, professor of neurology and director of the University of Minnesota Comprehensive Epilepsy Center. “When you combine patients with seizures that arise in about equal numbers independently from each hemisphere, who are not amenable to resective surgery or who are still refractory after surgery — those groups may constitute up to 15-20 percent of all patients with epilepsy,” he noted. “That's quite a large group of people who are going forward year after year with inadequate seizure control.”
One element of the study that intrigued many was the ongoing improvement during the open-label phase. “The device is designed to counter-stimulate at the onset of seizures, but patients who have frequent seizures also often have hundreds of brief rhythmic discharges each day. These are similar to seizure onset patterns but don't evolve into clinical events,” said Dr. Krauss. “Consequently, many of the patients with the NeuroPace device had cortical stimulation triggered hundreds of times a day. This suggests that the device may help some patients not just by disrupting seizures at onset, but through a long-term modulatory effect on the cortex by repeatedly discharging into the seizure zones and altering their seizure networks.”
Dr. Sirven agreed. “Something about the long-term stimulation appears to be helpful against these seizures, something that may not be readily apparent in the window these trials are designed to address for regulatory approval.”
Will that be a problem for the FDA, which is now considering the RNS device for approval? “It was a problem for deep brain stimulation,” concedes Dr. Sirven. “I hope they see beyond it.”
Dr. Sirven noted that this device has a potential added advantage over DBS, although not its raison d'être: it captures ongoing EEG data that neurologists can review and study. “It's not being looked at as a diagnostic tool, but it's a profound source of information that other devices don't give you,” he said.
But the FDA has been rather conservative in their attitude toward devices for epilepsy, said Jerome “Pete” Engel Jr., MD, PhD, Jonathan Sinay Distinguished Professor of neurology, neurobiology, psychiatry and biobehavior and director of the Seizure Disorder Center at the David Geffen School of Medicine at UCLA. “Their rejection of deep brain stimulation, while it was approved in Europe, was disappointing. We badly need new approaches for refractory patients, and even if the improvements are not dramatic, if a treatment offers benefit to some patients, I think it ought to be pursued.”
DR. GREGORY KRAUSS: “For highly drug-resistant epilepsy with fairly disabling seizures, I believe it's reasonable to approve the device with some type of risk-mitigation strategy that involves collecting more information about optimal treatment candidates and stimulation strategies.”
Dr. Engel noted that with all of the stimulation approaches — vagal, trigeminal, deep brain, and now responsive cortical stimulation — the effect appears to increase the longer a patient continues with the stimulation. “The long-term data are fairly impressive, but it's not controlled in these studies. For instance, with their decision on the deep brain stimulation study, the FDA wouldn't consider the continued improvement during the open-label phase.”
DR. JEROME “PETE” ENGEL JR.: “We badly need new approaches for refractory patients, and even if the improvements are not dramatic, if a treatment offers benefit to some patients, I think it ought to be pursued.”
Dr. Krauss hopes that the FDA will consider approving the device on a contingent basis if need be. “For highly drug-resistant epilepsy with fairly disabling seizures, I believe it's reasonable to approve the device with some type of risk-mitigation strategy that involves collecting more information about optimal treatment candidates and stimulation strategies,” he said.
For the moment, though, all epilepsy specialists can do is wait. “We have more than 100 patients walking around with this implanted, some with a very nice benefit, and we're stuck awaiting word on its approval,” said Dr. Sirven. “The FDA has to do the analysis of the data and call for a small group meeting before the advisory panel considers it, and that hasn't been scheduled so far as I know — they'd have to have open comment first. So we're in a holding pattern.”
That's disappointing, he said, and not just from an immediate treatment perspective. “I hate using the war analogy, but you want to bomb your bad guys, and not just identify the city without knowing the exact house, or even the suburb. In addition to the clinical benefit, the interrogative nature of this device means it may be able to detect things we have not looked for before. If it helps to give us more precise information about seizure location, it could be transformative to the field for purposes it wasn't initially intended for.”
But the editorialist Dr. Fisher is both enthusiastic and cautious. “These early trials leave many questions unanswered. Why do some patients benefit or even become seizure-free with stimulation, while others show no effect? Identification of factors predicting good outcome prior to electrode implantation would be of great value.”
While there remain unanswered questions, Dr. Fisher wrote this form of direct brain stimulation “is no longer ‘a possible treatment for epilepsy,’ but now a treatment for epilepsy. Patients with medication-resistant partial and secondarily generalized seizures, families, and clinicians eagerly await the opportunity to utilize this new therapy.”
Fisher RS. Editorial: Direct brain stimulation is an effective therapy for epilepsy. 2011; E-pub 2011 Sept. 6