Long-term Treatment With Responsive Brain Stimulation in Adults With Refractory Partial Seizures
Bergey GK, Morrell MJ, Mizrahi EM, et al
Neurology. 2015;84:810-817
Study Summary
The study goals were to examine the long-term efficacy and safety of the RNS® System (NeuroPace, Inc.; Mountain View, California), the first direct brain responsive neurostimulator, in adults with medically refractory partial-onset seizures. The RNS System consists of a cranially implanted responsive neurostimulator and electrodes delivering stimulation to one or two seizure foci in response to detection of specific electrocorticographic patterns.
Based on a multicenter, double-blinded, randomized, sham-stimulation controlled trial and an earlier feasibility study, the US Food and Drug Administration approved the RNS System for reducing seizure frequency in this patient population.
Sixty-five participants had completed a 2-year primarily open-label safety study, and 191 had taken part in a 2-year, randomized, blinded, controlled safety and efficacy study. To determine safety and efficacy, 230 of these participants transitioned into an ongoing 7-year study. The mean patient age was 34 ± 11.4 years; their mean duration of epilepsy was 19.6 ± 11.4 years; and the median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures per month.
In the randomized, blinded, controlled trial, the median percent seizure reduction was 44% at 1 year and 53% at 2 years (P < .0001). In the long-term study, the median percent seizure reduction over postimplant years 3 through 6 ranged from 48% to 66%, with sustained improvements in quality of life (P < .05).
During follow-up (mean duration, 5.4 years), soft tissue implant site infection and neurostimulator explantation were the most common serious device-related adverse events, occurring in 9.0% and 4.7% of patients, respectively. Rates of hemorrhage and infection were not higher than reported with implantation of intracranial electrodes to localize the seizure focus, with epilepsy surgery, or with deep brain stimulation devices for the treatment of movement disorders.
The number of seizure-related adverse events did not exceed those in randomized controlled drug trials for adjunctive treatment of partial-onset seizures. Mortality was similar to that in patients with medically intractable partial-onset seizures.
Viewpoint
In adults with medically refractory partial-onset seizures stemming from one or two foci, responsive direct cortical stimulation with the RNS System had short- and long-term efficacy and safety over a mean follow-up of 5.4 years. The presence of an acute as well as a delayed therapeutic effect of brain stimulation suggests multiple mechanisms of action. Acute effects may result from changes in cellular inhibition or excitation, changes in cerebral blood flow, or axonal and glial release of neurotransmitters. Chronic effects may result from changes in synaptic plasticity, neurogenesis, and/or cortical reorganization.
A limitation of this study is its open-label design. Nonetheless, this class IV evidence supports use of the RNS System as a treatment option for refractory partial seizures, particularly for those who are not good candidates for epilepsy surgery. To further improve clinical benefits and avoid stimulation-related adverse events, detection and stimulation parameters can be adjusted. Future research and clinical experience should help optimize patient selection as well as stimulation targets and parameters.
Abstract