Closed-Loop Responsive Stimulation for Epilepsy

The Burden of Epilepsy

Epilepsy affects approximately 1% of the world’s population, with between 30% and 40% of these patients suffering from drug-resistant disease. Epilepsy surgery historically has been one of the best options for such refractory disease, and on average results in 62% of all patients becoming seizure free ( ). Resective surgery is not without risks, however, and is sometimes impossible due to a seizure focus inhabiting the eloquent cortex. The management of patients with drug-resistant epilepsy who are not candidates for resective surgery remains challenging, and a large proportion of these patients continue to have a diminished quality of life.

A History of Stimulation

In 1954 Penfield and Jasper were the first to report the effects of electrical stimulation on electrocorticogram (ECoG) activity. Over the following decades numerous descriptions of electrical brain stimulation for seizures were reported, targeting different anatomic regions and using various modes of scheduled stimulation.

Uncontrolled open-loop stimulation studies have shown varying control of drug-resistant seizures with stimulation of the cerebellar cortex, dentate nucleus ( ), anterior thalamic nucleus ( ), centromedian thalamic nucleus ( ), caudate head, hippocampus ( ), and subthalamic nucleus ( ). Vagal nerve stimulation, which is a cyclical type of open-loop stimulation, has been shown to reduce seizures with statistical significance ( ). Each of these modalities is similar, in that they passively transmit without any feedback-based modulation of stimulation.

In 1999 Lesser et al. conducted a study of brief stimulation of induced after-discharges (ADs). The study was performed by stimulating the cerebral cortex during intraoperative ECoG to the point of inducing an AD that was then suppressed by brief bursts of pulse stimulation ( ). The authors postulated that an implanted closed-loop device could both detect and abort epileptiform activity.

In 2001 an external closed-loop system was reported to deliver therapeutic stimulation dependent on seizure detection ( ). Further research in 2002 demonstrated that there may be optimal parameters for the electrical stimulation of induced afterdischarges ( ). External responsive neurostimulation (eRNS) system studies have shown that closed-loop stimulation can significantly affect duration of spontaneously occurring electrographic seizure activity ( ). A multicenter prospective clinical study of eRNS confirmed these initial promising pilot studies ( ).

The Pivotal Trial

In the United States the only currently approved device for direct electrical brain stimulation for epilepsy is the responsive neurostimulator system (RNS) (NeuroPace Inc., Mountain View, CA, USA) ( ).

In 2011 the Pivotal Trial established the safety and efficacy of the NeuroPace device. In 191 adults with refractory partial-onset seizures, either subdural or depth electrodes were implanted at one or two prespecified seizure foci. The patients were randomized 1 month later into either treatment or sham-stimulation groups. There was a 1-month patient-blinded postimplantation stimulation optimization period during which the treatment group, but not the sham group, had their stimulators turned on and optimized. Both groups then entered a 3-month blinded evaluation period in which the treatment group underwent stimulation. Patients in the sham group had their stimulators turned on after the 3-month blinded evaluation, and all participants entered an open-label period over 84 weeks ( ).

All patients had an initial reduction in seizure frequency right after implantation (which is common after implantation of any device and now called the “implantation effect”). Those in the treatment arm (n = 97) demonstrated a 37.9% decrease in self-reported seizures, while those in the nontreatment arm (n = 94) showed a 17.3% decrease over 12 weeks ( P < .01). During the subsequent open-label period, when all subjects received responsive stimulation, the improvement in the treatment group continued and the sham group exhibited a decrease in seizure frequency similar to that in the treatment group ( ).