LAS VEGAS—The therapeutic armamentarium for epilepsy, which includes an array of pharmacologic and surgical approaches as well as an open-loop neurostimulator, now includes an FDA-approved closed-loop stimulator. At the 17th Annual Meeting of the North American Neuromodulation Society, Karl A. Sillay, MD, discussed closed-loop stimulation as a treatment modality for epilepsy. Dr. Sillay is an Assistant Professor in the Department of Neurological Surgery at the University of Wisconsin Hospitals and Clinics in Madison.
Neuromodulation for Epilepsy
Many targets have been proposed and investigated in trials, Dr. Sillay said, noting that the trials have typically involved an open-loop stimulation modality. An open-loop stimulator provides a certain programmable frequency with a regular, periodic impulse. A device that could detect and have a countermeasure would be preferable, according to Dr. Sillay. “That’s where we’d like to be.”
Two neurostimulators are FDA-approved for epilepsy. The first is a vagal nerve stimulator, which is an open-loop modality. The second, which was granted FDA clearance more recently, is a closed-loop stimulator. “This is the first closed-loop stimulation device for neuromodulation and certainly for epilepsy,” said Dr. Sillay, “and it has been shown to help patients.”
Regarding open-loop stimulation, “the vagus nerve stimulator is attractive,” Dr. Sillay said, “because you’re really stimulating a peripheral nerve. You don’t have to open the brain, you’re not subjecting someone to intracranial hemorrhage or the risk of meningitis, and it is modulatable.” The drawback with vagus nerve stimulators, Dr. Sillay noted, is that fewer than 3% of patients with epilepsy become seizure-free.
Unlike an open-loop system, a closed-loop system can listen and deliver a stimulus. “Imagine you were able to not only listen to and stimulate one area, but perhaps even two,” Dr. Sillay said. A closed-loop stimulator, he explained, “has a switching system that allows the same electrode to listen to an electrographic focus and then deliver a stimulus. Telemetry is also possible.”
The Evolution and Mechanics of Closed-Loop Stimulation
Some of this work originated with intracranial stimulation at the time of epilepsy surgery to try to localize speech, language, and motor areas. During stimulation, investigators created an after-discharge and monitored it with recording electrodes. The investigators then asked whether the stimulation induced after discharge could be aborted. “That was the origination of this technology,” Dr. Sillay said. “We now have an implantable epilepsy monitoring unit (EMU), a device that can provide real-time telemetry of EEG signals in a potentially moving or ambulating patient, and place that in an area to deliver a countermeasure to abort the seizures.”
After having preoperatively localized the area with extracranial scalp electrodes or invasive monitoring and having placed depth or surface electrodes, investigators monitor EEG signals, Dr. Sillay explained. A seizure is then recorded. Various algorithms take into account amplifier saturation, line lengthening, and frequency for identifying clinical seizures.
“Many patients could benefit if you could determine when their seizure was happening,” Dr. Sillay said. Real-time telemetry allows EEGs to be recorded and examined to look for correlation. A web-based modality is available to the practitioner, as well as to the patient, potentially for uploading the data associated with programming, daily activities, and seizures. A physician can then look at recorded events and see how many times a suspected seizure was detected. If this task is done in the setting of an EMU, where video EEG could be obtained, then it could be determined in a particular patient whether electrographic seizure activity later becomes a clinical seizure.
At the time of detection, a snippet of EEG is recorded, as well as the countermeasure. “There are multiple different strategies, up to five that can occur, you can suggest stimulating through the anterior contact at a low frequency, and then at a higher frequency, moving to contact two, through a series of different stimulation parameters,” Dr. Sillay explained. “It can also then be determined whether after stimulation was provided the seizure actually halted or whether the seizure is progressing. If [it is] progressing, one can look at adding another stimulation modality.”
Clinical Trial Evidence
Closed-loop stimulation for epilepsy was approved based on the results of a prospective, randomized, double-blind, sham-stimulation-controlled investigation that included 191 patients implanted with NeuroPace’s RNS system. All subjects were required to be 18 to 70 and have partial-onset epilepsy that had not been effectively treated with two or more antiepileptic drugs. About half of the cases used depth electrodes, and half used surface electrodes. Many of the mesial electrodes were in the hippocampus and often bilateral. Trial data showed that in both the sham group and the stimulation group, seizures initially decreased, but by the end of blinded sham or stimulation period, a statistically significant improvement had occurred in the stimulation group versus the sham group. The sham stimulation group also received benefit after entering an open-label phase. Side effects included infection, intracranial hemorrhage, hydrocephalus, and the need to progress to resective surgery. These outcomes are “nothing out of the ordinary for neuromodulation,” Dr. Sillay said.