Abstract
The first edition of Neuromodulation was published in 2009, 4 years prior to the approval of the responsive neurostimulation system (RNS) by the United States Food and Drug Administration. Since that time much has been revealed about the effects of closed-loop neurostimulation. The results of the Pivotal Trial (2011) demonstrated the benefits of the RNS in the treatment of intractable epilepsy, and long-term follow-up has confirmed the continued benefit. In this chapter we describe the history of responsive neurostimulation, the RNS components, features, surgical implantation, current usage, and proposed mechanism of action, and future directions.
Keywords
Closed loop, Epilepsy, NeuroPace, Responsive neurostimulation, RNS, Seizures
Introduction
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 ( ).
Closed Loop Neurostimulation
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 ( ).
Long-Term Results
Long-term open-label results found that self-reported seizures were reduced by 44% at 1 year and 53% at 2 years after implantation. Further seizure reduction ranging between 48% and 66% was observed over years 3 through 6. Adverse events during the first year included implant site pain (15.7%), headache (10.5%), and dysesthesias (6.3%). The most common long-term complications reported with the NeuroPace device were implant site infection (9.0%) and stimulator explantation (4.7%) ( ). Impedance variation over time was retrospectively reviewed, and found to be present but clinically insignificant ( ).
Over a follow-up period of up to 7 years the RNS does not appear to have a negative effect on mood ( ). Quality of life is another important metric used to characterize the effects of epilepsy treatment; using the QOLIE-89 assessment ( ), participants demonstrated an increase in scores at 5 years ( ).
Mechanisms of Action
The mechanisms mediating the effects of electrical brain stimulation on seizures are not entirely clear, but there are likely multiple short- and long-term effects ( ). Four distinct effects on neural activity have been postulated to account for the effects of deep brain stimulation (DBS) on Parkinsonism: depolarization blockade of voltage-gated ion channels leading to local inhibition, direct synaptic inhibition of the distal axon by electrical stimulation, synaptic depression occurring through depletion of neurotransmitters at the axon terminal ( ), and electrical stimulation in any of these prior ways modulating the activity of pathologic networks ( ).
Some of the acute changes seen with electrical brain stimulation of epileptogenic regions include the disruption of synchronous activity and evolution into seizures ( Fig. 84.1 ) ( ). Electrical stimulation also appears to influence short-term activity distant to the site of stimulation, modulating function at the network level ( ). There is some evidence that these acute effects of cortical stimulation might be related to changes in gamma-aminobutyric acid (GABA)-mediated hyperpolarization. High-frequency stimulation at >100 Hz appears to up-regulate glutamic acid decarboxylase while down-regulating calmodulin-dependent protein kinase II, and thereby leads to local inhibition ( ). Repetitive electrical stimulation of CA3 mossy fibers leads to increased intracellular chloride ( ), also consistent with a GABA-mediated mechanism ( ).
The progressive reduction in seizure frequency over time ( ) suggests that electrical stimulation might have effects beyond those on ion channels. Drawing again from the field of DBS for movement disorders, rat studies suggest that part of the beneficial effects of DBS for Parkinsonism might be related to modulation of neurotrophic factors at the site of stimulation ( ). Modulation of gene expression might not be spatially limited to the area of stimulation. Rats undergoing stimulation of the mediodorsal thalamic nucleus exhibited increased expression of neurotrophic factors in the orbitofrontal and premotor cortex, regions known to receive input from the mediodorsal thalamus ( ). It would seem that some of the long-term effects of brain stimulation might be related to modulation of genetic expression, both locally and in regions receiving projections from the area of stimulation. Based on these observations and reports of continual improvement in seizure frequency over months of stimulation, it seems that modulation of gene expression might underlie some to the effects of brain stimulation for epilepsy ( ).
The Responsive Neurostimulator System
Responsive Neurostimulator System Candidates
Candidates for RNS implantations should be 18 years of age or older with a history of partial-onset seizures, have undergone diagnostic testing that localizes to no more than two epileptogenic foci, be refractory to two or more antiepileptic medications, and currently have frequent and disabling seizures (motor partial seizures, complex partial seizures, and/or secondarily generalized seizures) ( ). The RNS has demonstrated safety and effectiveness in patients who average three or more disabling seizures per month over the three most recent months (with no month with fewer than two seizures) ( ).
In our institution, localization of epileptogenic foci is achieved through a multitude of techniques: ictal and interictal surface electroencephalogram (EEG), video EEG monitoring, magnetoencephalography, brain magnetic resonance imaging (MRI), subtraction ictal SPECT coregistered to MRI (SISCOM), positron emission tomography, and detailed neuropsychological evaluation, including functional MRI and invasive EEG via depth stereoencephalography and/or subdural electrodes. Prospective patients for RNS implantation will either not be candidates for resective surgery due to the eloquent nature of the involved cortex, the presence of bilateral epileptogenic foci, prior history of resective surgery for seizure control, or unilateral memory from the involved hippocampus, or not wishing to undergo resective surgery but willing to undergo surgical implantation of an RNS due to the reversible character of the stimulator implantation ( ).
The RNS is contraindicated for patients at high risk for surgical complications and those with medical devices implanted that deliver electrical energy directly to the brain. In addition, some medical procedures are contraindicated for patients implanted with the RNS: MRI, diathermy procedures, electroconvulsive therapy, and transcranial magnetic stimulation. The safety and efficacy of the RNS have not been studied in pregnant women, but pregnancy is not a contraindication.
Device Description
The implanted closed-loop RNS consists of the components listed below.
Neurostimulator . The neurostimulator is a hermetically sealed pulse generator containing the electronics, battery, telemetry coil, and connector hardware to accommodate one or two leads. Its dimensions are 41 mm wide, 60 mm long, and 7 mm thick. The neurostimulator is curved in shape to facilitate cranial implantation; it is positioned extradurally in a tailored cranial defect and held in place with a ferrule. The neurostimulator analyzes the patient’s ECoGs and triggers electrical stimulation when specific electrographic seizures or precursor epileptiform activities are detected. The neurostimulator then stores diagnostic information detailing detections and stimulations, including multichannel stored ECoGs (Fountas et al., 2005).
Depth Lead . The depth leads are quadripolar leads designed for stereotactic implantation. Depth leads are available with 3.5 and 10 mm interelectrode spacings, and in lengths of 30 and 44 cm. Electrodes are composed of 90% platinum and 10% iridium (Fountas et al., 2005).
Strip Lead. The strip leads are quadripolar leads with circular electrodes 4 mm in diameter and interelectrode spacings of 10 mm. Leads are available in 15 and 25 cm lengths. Electrodes are composed of 90% platinum and 10% iridium ( ).
Programmer. The programmer is a notebook computer with specialized software and a telemetry wand that communicates with the neurostimulator. The programmer can download diagnostic and ECoG data from the neurostimulator, analyze ECoGs, simulate detection setting performance, and program the neurostimulator. The programmer also has an electrophysiology study mode that allows real-time stimulation with simultaneous ECoG viewing to test stimulation paradigms ( ).
Remote Monitor . The remote monitor is a notebook computer similar to the programmer which is given to the patient. A USB-enabled telemetry wand connects to the remote monitor and communicates with the neurostimulator. The remote monitor downloads and stores diagnostic and ECoG data from the neurostimulator. Data stored on the remote monitor can then be transferred to the patient data management system (PDMS) via internet connection, where it is viewable by the epilepsy provider.
Magnet . This is a doughnut-shaped magnet given to the patient which stores ECoG data when swiped over the implanted neurostimulator. The purpose of the magnet is to time-stamp the ECoG recording and store the data at the time of a clinical seizure.
Surgical Technique
The surgery for device placement requires careful planning and consideration of desired lead placement, craniotomy for ferrule insertion, and the vascular supply to the scalp incision. Further complicating the matter is the frequent presence of prior incisions and craniotomies. Preoperative MRI of the brain for registration and planning should be utilized for frameless stereotactic placement of depth electrodes.
The patient is induced under general endotracheal anesthesia and placed in a Mayfield skull clamp. An incision should be planned to allow access to the desired electrode implant sites and placement of the neurostimulator ferule while respecting vascular supply to the skin flap. One incision is preferable, but often intracerebral electrodes are placed through remote burr holes requiring small separate incisions. At our institution intracerebral electrodes are precisely placed using the ROSA robotic surgical assistant (Medtech Surgical, Newark, NJ, USA) ( Fig. 84.2 ). Electrodes are carefully tunneled and placed around the neurostimulator while avoiding lying directly under the incision. A complete or partial-thickness craniotomy is outlined and performed to accommodate the neurostimulator ferrule, which is bolted to the skull with titanium microscrews ( Fig. 84.3 ). Planning of ferrule placement is important so that the generator sits flush with the outer table of the skull. The profile of the implant means that a thicker area of skull is ideal, such as the parietal and occipital region. Frontal placement is limited by cosmetic appearance, and squamous temporal bone is often too thin to allow the ferrule to sit flush with the outer table.
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