Patients with medically refractory epilepsy have historically had few effective treatment options. Electrical brain stimulation for seizures has been studied for decades and ongoing technological refinements have made possible the development of an implantable electrical brain stimulator. The NeuroPace responsive neurostimulator was recently approved by the FDA for clinical use and the initial reports are encouraging. This device continually monitors brain activity and delivers an electric stimulus when abnormal activity is detected.
Neuropace rns system fdating reports of efficacy suggest that the device is well tolerated and offers a reduction in seizure frequency by approximately half at 2 years.
Therefore, there has been a long-standing need for other treatment options for drug-resistant epilepsy. Penfield and Jasper were the first to report the effects of electrical stimulation on electrocorticogram ECoG activity. Early studies focused on stimulation of regions with widespread inhibitory output such as the cerebellum, 3 — 6 but the effects of stimulation of other regions including the hippocampus, 78 anterior thalamic nucleus, 9 and cortex 1011 have been reported.
Most of these studies included only small Neuropace rns system fdating without control groups. To date, there has been only one large randomized controlled study of scheduled deep brain stimulation performed in the US.
In the study period, patients had a This device is not approved in the US for epilepsy but is available in Europe. Vagus nerve stimulation VNS as a means of indirect brain stimulation has been used for seizure control, 13 — 15 and a recent Cochran Review summarizes that VNS is effective and well tolerated.
Currently, in the US, the only approved device for direct electrical brain stimulation Neuropace rns system fdating epilepsy is the responsive neurostimulator system RNS, NeuroPace, Inc. This device is approved for partial-onset, medically refractory epilepsy. In contrast to scheduled or continuous stimulation, the RNS delivers electrical stimulation in response to real-time ECoG activity.
The aim of this paper is to serve as an introduction to the principles of responsive brain stimulation and describe the indications, basis, safety, and efficacy of the currently available responsive neurostimulator RNS.
The anterior thalamic nucleus is an integral part of the limbic circuit and is therefore thought to influence seizure threshold. This mode of stimulation reduces seizure frequency with the stimulator on as compared with Neuropace rns system fdating. The RNS system is currently approved in the USA as an adjunctive therapy for medically resistant partial-onset seizures.
The RNS system consists of a stimulator, implanted leads, and a wireless programming wand with associated computer hardware and software. The stimulator is connected via thin flexible wires to electrodes that may be either implanted in deep structures such as the hippocampus or placed on the surface of brain Figure 1.
The target for stimulation is typically the seizure onset zone s.
The stimulation electrodes can be placed in "Neuropace rns system fdating" hemispheres as with bitemporal epilepsy or epilepsy with two seizure onset zones. Each electrode has four contacts that can be programmed as either anode or cathode; alternatively, the stimulator case can be programmed to serve as the cathode.
B Example of a bilateral hippocampal implantation. C Interrogation of the device with the wireless wand and the programmer. D ECoG and time-frequency analysis from the device with detection of an epileptic seizure and stimulation delivered vertical lines.
Example of a patient with both neocortical surface electrodes and hippocampal depth electrodes. The neurostimulator continuously monitors ECoG activity and uses several methods, or tools, to detect abnormal electrical activity. The area tool measures changes in overall EEG signal intensity, the line length tool monitors dynamic changes in electrical activity and frequency, and the half-wave tool is designed to detect spike discharged and activity within specific frequency bands.
The parameters of these tools can be Neuropace rns system fdating by the clinician to improve sensitivity and specificity of detection of abnormal ECoG activity in individual patients.
When any of the detection tools sense abnormal activity, a current-controlled, charge balanced biphasic electrical stimulation is delivered to the brain. The frequency of Neuropace rns system fdating can be adjusted from 1 Hz up to Hz, and currents ranging from 1 mA to 12 mA are available. Stimulation can be delivered between any two of the electrodes, or between any electrode and the neurostimulator case.
While detections and stimulations are frequent throughout the day, the total current density delivered remains low compared with deep brain stimulation. The initial report describing the safety and efficacy of the NeuroPace device in subjects was published in Patients with medically refractory partial-onset epilepsy were randomized to the stimulation or control group 2 months after implantation.
During a subsequent open-label period where 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 seen "Neuropace rns system fdating" the treatment group. Over a follow-up period of up to 7 years, closed-loop stimulation with the RNS does not appear to have a detrimental effect on mood.
Seven of Neuropace rns system fdating were attributed to SUDEP possible, probably, or definitetwo participants with a history of depression died by committing suicide, one participant with subtherapeutic antiepileptic drug levels died of status epilepticus, and one subject died from lymphoma. One of the earliest criticisms of the RNS studies was the reliance on self-reporting of seizures particularly given that the device is capable of recording eletrocorticography that could allow precise assessment of the number and nature of electrical abnormalities.
A complete record of this data over an extended duration is therefore not feasible, and self-reporting of seizures Neuropace rns system fdating the only viable method to track efficacy.
It was also noted that despite the potential for bias and error, self-reporting of seizure frequency is a commonly used method of data collection in epilepsy studies.
The mechanism mediating the effects of electrical brain stimulation on seizures is not clear, but there are probably multiple short and long-term effects. For comparison, four distinct effects on neural activity have been postulated to account for the effects of DBS on Parkinsonism: Some of the acute changes seen with electrical brain stimulation of epileptogenic regions appear to include disruption of synchronous activity and evolution into generalized seizures.
Thus, it appears that electrical stimulation has an acute, local inhibitory effect Figure 3. Stimulation is triggered by epileptiform activity in recorded channels A. The recording is turned off during stimulus. The average spectrogram B shows strongly reduced spectral power after stimulation.