Responsive Neurostimulation for the Treatment of Epilepsy

Neurostimulation in epilepsy has witnessed a century-long evolution that has resulted in the use of neurostimulation to both modulate and suppress abnormal neuronal firing. The recent development of advanced responsive stimulation via a closed-loop device (the RNS System) has provided evidence that surgical epilepsy treatment continues to move toward the possibility of reducing or eliminating seizures in medically refractory patients.

Early neurostimulation in epilepsy

The application of electrical stimulation as a means of modifying seizure activity has persisted since the development of early experimental epilepsy models and intraoperative seizure focus identification in the late 1800s. The initial school of thought maintained that electrical stimulation served primarily to produce, rather than prevent, epileptiform activity. One of the earliest reports of direct cortical electrical stimulation came from Rushton Parker and Francis Gotch in 1893. To localize and resect a presumed motor cortex seizure focus responsible for refractory, debilitating complex partial seizures in a 9-year-old boy, characterized by hand and arm “fits,” the authors performed intraoperative stimulation of the motor cortex via a single burrhole. As reported by Parker in the British Medical Journal , “Stimulation of the cortex at one point evoked movements of the thumb, and at an adjacent point movements of the wrist. The areas thus stimulated were scooped out with a sharp spoon…”

For the better part of the early 20th century, electrical stimulation was used for seizure induction in animal models of epilepsy. In 1957, Chapman and colleagues reported results of human electrical stimulation via depth electrodes placed in the amygdala of six patients with presumed temporal lobe epilepsy. Patients were stimulated 4 to 6 days after implantation, with 10, 20, or 60 pulses per second, 1-ms pulse duration, at 6 to 20 V. The authors made two useful observations: (1) depth electrode spikes were not always accompanied by scalp electroencephalogram (EEG) spikes, and (2) certain levels of stimulation seemed to induce auras similar to those experienced before seizures but not actual seizures. The first observation set the stage for understanding both the limitations of scalp EEG and the potential held by implanted depth electrodes in gathering a unique set of localized electrographic data. The second observation suggested electrical stimulation is capable of modifying endogenous activity.

Animal studies in the 1960s provided further evidence that brief pulses of direct cortical stimulation were capable of modulating underlying neuronal activity, without causing an epileptiform response. The hypothesis that low-level stimulation could actually modulate abnormal neuronal activity was tested in small case series of deep brain stimulation (DBS) in patients with refractory epilepsy. Few studies were published in the early 1980s showing a modest effect on seizure reduction with DBS of the cerebellum and anterior thalamus. For the next 20 years, data for DBS in various, mostly limbic anatomic locations thought responsible for epilepsy continued to come in the form of small case series, until the SANTE trial (Stimulation of the Anterior Nucleus of Thalamus for Epilepsy) was initiated in 2005. The SANTE trial was the first large-scale, randomized, controlled trial for DBS of the anterior thalamus in patients with medically refractory partial epilepsy. Recently published results showed a mean seizure frequency percent reduction of 40.4% in the stimulated group versus 14.5% in the control group (compared with a preimplant baseline) at the end of the 3-month blinded phase. Long-term follow-up, including all stimulated patients beyond the blinded phase, showed a mean seizure frequency reduction of 41% at 13 months and 56% at 25 months. This particular type of DBS for seizure reduction is considered a form of open loop stimulation, wherein electrical current is applied independent of endogenous electrical activity. The physicians set the stimulation parameters via an external programmer. When turned on, the electrical current continues at defined settings irrespective of any clinical or electrographic seizure activity.

Responsive Neurostimulation

With the advent of computing technology, the idea emerged that exogenous electrical stimulation could be programmed to occur in response to endogenous electrographic events, termed closed loop stimulation . In 1991, Nakagawa and Durand described one of the earliest models of experimental responsive neurostimulation in a model of spontaneous epileptiform activity from rat hippocampi bathed in high concentrations of potassium. The authors designed a two-step algorithm that detected the onset of epileptiform activity from the hippocampus through defining a voltage derivative threshold, and immediately delivered a programmable current via stimulation electrodes. The authors were able to suppress 100% of interictal bursts in 90% of hippocampal slices. Intracellular recordings suggested that the mechanism of suppression was through hyperpolarization of the somatic membrane via the applied current, resulting in suppression of neuronal firing. Several years later, Lesser and colleagues provided evidence suggesting that pulsed stimulation in humans could significantly decrease afterdischarges. The authors reported that patients receiving cortical stimulation using subdural electrodes for pre-resection evaluations often developed afterdischarges, and that brief bursts of pulse stimulation could abort and significantly decrease the duration of these discharges. These data were the first to support the hypothesis that electrical stimulation could be used to abort seizures in humans.

The first completely implantable closed-loop device developed for investigational use in humans is called the RNS System (NeuroPace, Inc, Mountain View, California). The device was designed to record electrocorticographic (ECoG) activity and use seizure-detection algorithms to deliver responsive stimulation via implanted electrodes. The device consists of a combination of one or two subdural and/or depth electrodes surgically implanted at the epileptogenic zones, connected to the neurostimulator. The neurostimulator is a programmable, battery-powered microprocessor that is placed in a full-thickness craniectomy. Physicians are able to set detection and stimulation parameters using a programmer with a telemetry interface. The programmer also allows physicians to retrieve ECoG data from the device, a remote monitor allows the patient to retrieve data from the device, and a computerized patient data management system stores retrieved data. Because the implanted neurostimulator has a limited capacity to store data, the computerized management system allows physicians to download and save long-term data.

The RNS System, like other surgical epilepsy interventions, was intended for use in patients with medically refractory epilepsy. Other surgical interventions predating responsive neurostimulation in development include anterior temporal lobectomy, selective focus resection, amygdalohippocampectomy, vagus nerve stimulation, and DBS. Compared with resective procedures, stimulation devices have the advantages of reversibility and modifiability, with the goal of causing no permanent injury to functional tissue. The RNS has an additional benefit over open-loop devices such as the vagus nerve stimulator and DBS, because it is capable of recording chronic ECoG data that may be useful for seizure focus localization, counts, and characterization. In particular, the RNS may be useful in patients with bitemporal epilepsy to determine laterality, and long-term ambulatory recordings with invasive electrodes have the potential to provide data that may be useful in resective planning. Furthermore, the device has the potential to provide patients with warning of an electrical seizure onset before the actual clinical onset occurs.

The RNS device has been under investigation since early results from patients enrolled in a phase I feasibility study were first reported at the 2004 American Epilepsy Society meeting. Vossler and colleagues reported their findings from four patients supporting the safety and potential efficacy of the device. Initial data regarding the device’s efficacy were later provided in an interim report of 24 patients. The investigators described a responder rate (>50% decrease in seizure frequency) of 43% for complex partial seizures and 35% for total disabling seizures.

The RNS pivotal trial was then initiated and subsequently presented at the 2009 American Epilepsy Society meeting. The trial was designed to be similar to other surgical epilepsy trials (in particular, the SANTE trial) as a randomized double-blind clinical trial, enrolling 191 patients with medically refractory epilepsy at 32 centers. Patients were randomized to stimulation or no stimulation for 12 weeks, beginning 8 weeks after device implantation. Of the 191 patients with medically refractory partial-onset epilepsy who underwent implantation, those in the treatment group (responsive stimulation active) experienced a mean reduction of 37.9% in their disabling seizures compared with 17.3% for those in the placebo stimulation group (responsive stimulation inactive) ( P <.012) during the blinded evaluation period.

At the 2010 American Epilepsy Society meeting the long-term follow-up results from the RNS feasibility study and the pivotal trial were presented. A total of 256 subjects were implanted, with a mean age of 34 years, mean number of antiepileptic drugs of 2.9, and a median seizure frequency of 10.1 seizures per 28 days. The median percent reduction in seizure frequency after 2 years postimplant was greater than 40% and the responder rate was greater than 45%. A responder rate of 53% was seen after 3 years, suggesting that the reduction in seizure frequency provided by the device has a sustained effect in this patient population. No difference was seen in adverse events between the treatment and sham groups, including an overall incidence of infection (2.6%) and extradural hematoma (1%). No changes in mood or neuropsychiatric testing occurred. Final results of the comprehensive RNS pivotal trial are accepted for publication and an application for FDA approval is being pursued.

Neurostimulation in epilepsy has witnessed a century-long evolution that began with cortical stimulation in an attempt to reproduce seizure activity, and progressed to the determination through experimental models that neurostimulation could be used to both modulate and suppress abnormal neuronal firing. The recent development of advanced responsive stimulation via a closed-loop device (the RNS System) has provided evidence that epilepsy treatment continues to move toward the possibility of reducing or eliminating seizures in medically refractory patients.

Dr Robert Goodman serves as a consultant for NeuroPace, Inc.

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