Description
Approximately one-third of patients with epilepsy do not respond to typical first-line therapy with antiepileptic medications. Seizures that occur in these patients are referred to as refractory or drug-resistant. In patients with refractory epilepsy, combination antiepileptic therapy often results in increased risk of adverse events. Other nonpharmacologic treatment options are available, including surgical approaches, ketogenic diet, and responsive neurostimulation. One responsive neurostimulation device, the NeuroPace RNS System, has U.S. Food and Drug Administration (FDA) approval for the treatment of refractory focal (formerly partial) epilepsy.

Summary - Intro
Responsive neurostimulation for the treatment of epilepsy involves the use of 1 or more implantable electric leads that serve both a seizure detection and neurostimulation function. The device is programmed using a proprietary algorithm to recognize seizure patterns from electrocorticography output and to deliver electrical stimulation with the goal of terminating a seizure. The NeuroPace RNS System has U.S. FDA approval for the treatment of refractory focal (formerly partial) epilepsy.

For individuals who have refractory focal epilepsy who receive responsive neurostimulation, the evidence includes an industry-sponsored randomized controlled trial, which was used for FDA approval of the NeuroPace RNS System, as well as case series. Relevant outcomes are symptoms, morbid events, quality of life, and treatment-related mortality and morbidity. The randomized controlled trial was well-designed and well-conducted; it reported that responsive neurostimulation is associated with improvements in mean seizure frequency in patients with refractory focal epilepsy, with an absolute difference in change in seizure frequency of about 20% between groups; however, the percentage of treatment responders with at least a 50% reduction in seizures did not differ from sham control. Overall, the results suggested a modest reduction in seizure frequency in a subset of patients. The number of adverse events reported in the available studies is low, although the data on adverse events were limited because of small study samples. Generally, patients who are candidates for responsive neurostimulation are severely debilitated and have few other treatment options, so the benefits are likely high relative to the risks. In particular, patients who are not candidates for resective epilepsy surgery and have few treatment options may benefit from responsive neurostimulation. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information
Consensus input from clinical vetting recommended that responsive neurostimulation is medically necessary for a subgroup of patients with refractory focal epilepsy. Therefore, responsive neurostimulation may be considered medically necessary in patients with medication-refractory focal epilepsy who are not candidates for epilepsy surgery.

Background
Epilepsy Treatment
Medical Therapy for Seizures
Standard therapy for seizures, including focal seizures, includes treatment with one or more of various antiepileptic drugs, which include newer antiepileptic drugs, such as oxcarbazepine, lamotrigine, topiramate, gabapentin, pregabalin, levetiracetam, tiagabine, and zonisamide.¹ Currently, response to antiepileptic drugs is less than ideal: one systematic review comparing newer antiepileptic drugs for refractory focal epilepsy reported an overall average responder rate in treatment groups of 34.8%.¹ As a result, a substantial number of patients do not achieve good seizure control with medications alone.

Surgical Therapy for Seizures
When a discrete seizure focus can be identified, seizure control may be achieved through resection of the seizure focus (epilepsy surgery). For temporal lobe epilepsy, a randomized controlled trial has demonstrated that surgery for epilepsy was superior to prolonged medical therapy in reducing seizures associated with impaired awareness and in improving quality of life.² Surgery for refractory focal epilepsy (excluding simple focal seizures) is associated with 5-year freedom from seizure rates of 52%, with 28% of seizure-free individuals able to discontinue antiepileptic drugs.³ Selection of appropriate patients for epilepsy surgery is important, because those with nonlesional extratemporal lobe epilepsy have worse outcomes after surgery than those with nonlesional temporal lobe epilepsy.⁴ Some patients are not candidates for epilepsy surgery if the seizure focus is located in an eloquent area of the brain or other region that cannot be removed without risk of significant neurologic deficit.

Neurostimulation for Neurologic Disorders
Electrical stimulation at one of several locations in the brain has been used as therapy for epilepsy, either as an adjunct to or as an alternative to medical or surgical therapy. Vagus nerve stimulation has been widely used for refractory epilepsy, following U.S. Food and Drug Administration (FDA) approval of a vagus nerve stimulation device in 1997 and 2 randomized controlled trials evaluating vagus nerve stimulation in epilepsy.⁵ Although the mechanism of action for vagus nerve stimulation is not fully understood, vagus nerve stimulation is thought to reduce seizure activity through activation of vagal visceral afferents with diffuse central nervous system projections, leading to a widespread effect on neuronal excitability.

Stimulation of other locations in the neuroaxis has been studied for a variety of neurologic disorders. Electrical stimulation of deep brain nuclei (deep brain stimulation) involves the use of chronic, continuous stimulation of a target. It has been most widely used in the treatment of Parkinson disease and other movement disorders, and has been investigated for treating epilepsy. Deep brain stimulation of the anterior thalamic nuclei was studied in a randomized control trial, the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy trial, but deep brain stimulation is not currently approved by FDA for stimulation of the anterior thalamic nucleus.⁶ Stimulation of the cerebellar and hippocampal regions and the subthalamic, caudate, and centromedian nuclei have also been evaluated for the treatment of epilepsy.⁵

Responsive Neurostimulation for Epilepsy
Responsive neurostimulation shares some features with deep brain stimulation, but is differentiated by its use of direct cortical stimulation and by its use in both monitoring and stimulation. The responsive neurostimulation system provides stimulation in response to detection of specific epileptiform patterns, while deep brain stimulation provides continuous or intermittent stimulation at preprogrammed settings.

Development of the responsive neurostimulation system arose from observations related to the effects of cortical electrical stimulation for seizure localization. It has been observed that electrical cortical stimulation can terminate induced and spontaneous electrographic seizure activity in humans and animals.⁷ Patients with epilepsy may undergo implantation of subdural monitoring electrodes for the purposes of seizure localization, which at times have been used for neurostimulation to identify eloquent brain regions. Epileptiform discharges that occur during stimulation for localization can be stopped by a train of neighboring brief electrical stimulations.⁸

In tandem with the recognition that cortical stimulation can stop epileptiform discharges was development of fast pre-ictal seizure prediction algorithms. These algorithms interpret electrocorticographic data from detection leads situated over the cortex. The responsive neurostimulation process thus includes electrocorticographic monitoring via cortical electrodes, analysis of data through a proprietary seizure detection algorithm, and delivery of electrical stimulation via both cortical and deep implanted electrodes in an attempt to halt a detected epileptiform discharge.

One device, the NeuroPace RNS^® System, is currently approved by FDA and is commercially available.

Responsive Neurostimulation for Seizure Monitoring
Although the intent of the electrocorticography component of the responsive neurostimulation system is to provide input as a trigger for neurostimulation, it also provides continuous seizure mapping data (chronic unlimited cortical electrocorticography) that may be used by practitioners to evaluate patients’ seizures. In particular, the seizure mapping data have been used for surgical planning of patients who do not experience adequate seizure reduction with responsive neurostimulation placement. Several studies have described the use of responsive neurostimulation in evaluating seizure foci for epilepsy surgery⁹ or for identifying whether seizure foci are unilateral.^10,11

This review does not further address use of responsive neurostimulation exclusively for seizure monitoring.

Regulatory Status 
In November 2013, the NeuroPace RNS^® System (NeuroPace) was approved by FDA through the premarket approval process for the following indication:¹⁵

“The RNS^® System is an adjunctive therapy in reducing the frequency of seizures in individuals 18 years of age or older with partial onset seizures who have undergone diagnostic testing that localized no more than 2 epileptogenic foci, are 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^® System has demonstrated safety and effectiveness in patients who average 3 or more disabling seizures per month over the three most recent months (with no month with fewer than two seizures), and has not been evaluated in patients with less frequent seizures.”

FDA product code: PFN.

Related Policies
70120 Vagus Nerve Stimulation
70163 Deep Brain Stimulation

Policy 
Responsive neurostimulation may be considered MEDICALLY NECESSARY for patients with focal epilepsy who meet ALL of the following criteria:

• Are 18 years or older.
• Have a diagnosis of focal seizures with 1 or 2 well-localized seizure foci identified.
• Have an average of 3 or more disabling seizures (e.g., motor focal seizures, complex focal seizures, or secondary generalized seizures) per month over the prior 3 months.
• Are refractory to medical therapy (have failed ≥2 appropriate antiepileptic medications at therapeutic doses).
• Are not candidates for focal resective epilepsy surgery (e.g., have an epileptic focus near the eloquent cerebral cortex; have bilateral temporal epilepsy).
• Do not have contraindications for responsive neurostimulation device placement (see Policy Guidelines section).

Responsive neurostimulation is considered investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for all other indications.

Policy Guidelines 
Contraindications for responsive neurostimulation device placement include 3 or more specific seizure foci, presence of primary generalized epilepsy, or presence of a rapidly progressive neurologic disorder. 

Coding
Please see the Codes table for details.

Benefit Application 
BlueCard/National Account Issues 
State or federal mandates (e.g., Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Rationale  
This evidence review was created in November 2014 with searches of the PubMed database. The most recent literature update was performed through March 8, 2021.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function, including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. Randomized controlled trials are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Focal seizures (previously referred to as partial seizures) arise from a discrete area of the brain and can cause a range of symptoms, depending on the seizure type and the brain area involved.

Note that the term focal seizure in older literature may be referred to as “partial seizure.” The International League Against Epilepsy (2017) outlined updated terminology for seizure and epilepsy subtypes, dividing them into 3 groups: focal onset, generalized onset, and unknown onset.¹³ Focal-onset seizures are subdivided based on the associated level of consciousness, and subsequently into whether they are motor or non-motor-onset.

The International League Against Epilepsy defines drug-resistant epilepsy as epilepsy that has failed to achieve sustained freedom from seizures after adequate trials of 2 tolerated, appropriate, and used antiepileptic drugs (either alone or in combination).¹⁴ Epilepsy is drug-resistant in approximately 25% of newly diagnosed patients, and focal onset seizures have been found to be a risk factor.¹⁵

Clinical Context and Therapy Purpose
The purpose of responsive neurostimulation in individuals with refractory focal epilepsy is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does responsive neurostimulation therapy improve the net health outcome in patients with refractory focal epilepsy?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is individuals with refractory focal epilepsy. Focal seizures (previously referred to as partial seizures) arise from a discrete area of the brain and can cause a range of symptoms, depending on the seizure type and the brain area involved. Focal seizures are further grouped into simple focal seizures, which may be associated with motor, sensory, or autonomic symptoms, or complex focal seizures, in which consciousness is affected. Complex focal seizures may be associated with abnormal movements (automatisms). In some cases, focal seizures may result in secondary generalization, in which widespread brain electrical activity occurs after the onset of a focal seizure, thereby resulting in a generalized seizure.

Interventions
The therapy being considered is responsive neurostimulation.

One device, the NeuroPace RNS System is currently approved by the U.S. Food and Drug Administration (FDA) and is commercially available. The system consists of an implantable neurostimulator, a cortical strip lead, implantable components and accessories, a tablet and telemetry wand, a patient data management system, a remote monitor for use by the patient to upload data to the data management system, and a magnet for patients to withhold therapy or to activate electrocorticograhic storage. The responsive neurostimulation stimulator and implant monitor the brain’s electrical activity and deliver electrical stimulation when warranted. Before device implantation, the patient undergoes seizure localization, which includes inpatient video-electroencephalographic monitoring and magnetic resonance imaging for detection of epileptogenic lesions. Additional testing may include electroencephalography with intracranial electrodes, intraoperative or extraoperative stimulation with subdural electrodes, additional imaging studies, and/or neuropsychological testing, and intracarotid amytal testing (also referred to as Wada testing). The selection and location of the leads are based on the location of seizure foci. Cortical strip leads are recommended for seizure foci on the cortical surface, while the depth leads are recommended for seizure foci beneath the cortical surface. The implantable neurostimulator and cortical and/or depth leads are implanted intracranially. The neurostimulator is initially programmed in the operating room to detect electrocorticographic activity. Responsive therapy is initially set up using standard parameters from the electrodes from which electrical activity is detected. Over time, the responsive stimulation settings are adjusted on the basis of electrocorticography data, which are collected by the patient through interrogation of the device with the telemetry wand and transmitted to the data management system.¹⁶

Comparators
Because responsive neurostimulation is considered for patients refractory to other treatments, the appropriate comparison group could consist of other treatments for focal epilepsy considered to be efficacious, including medical therapy, surgical management, other types of implanted stimulators (e.g., vagus nerve stimulation), or a combination. In patients with treatment-refractory epilepsy, the disease is expected to have a natural history involving persistent seizures. Therefore, studies that compare seizure rates and seizure-free status pre- and post-responsive neurostimulation treatment may also provide evidence about the efficacy of the responsive neurostimulation device.

Outcomes
The general outcomes of interest are symptoms, morbid events, quality of life, and treatment-related mortality and morbidity.

Based on available literature, a minimum follow-up of 1 to 2 years is recommended, although 1 study followed patients for 7 years.

Study Selection Criteria
Methodologically credible studies were selected using the following principles: 

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs.

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence
The body of evidence addressing whether responsive neurostimulation is associated with improved health outcomes for patients with focal epilepsy includes an industry-sponsored RCT, which was used for the device’s FDA approval, as well as multiple case series and case reports.

RNS System Pivotal Study
Morrell et al. (2011) reported on the RNS System Pivotal Study, a multicenter, double-blinded, sham-controlled trial that served as the basis of the FDA’s approval of the device.¹⁷ This RCT included 191 patients with medically intractable focal epilepsy who were implanted with the responsive neurostimulation device and randomized to treatment or sham control after a 1-month postimplant period during which time no subjects had the device activated. Eligible patients were adults with focal seizures whose epilepsy had not been controlled with at least 2 trials of antiepileptic drugs, who had at least 3 disabling seizures (motor focal seizures, complex focal seizures, or secondary generalized seizures) per month on average, and who had standard diagnostic testing that localized 1 or 2 epileptogenic foci. Thirty-two percent of those implanted had prior epilepsy surgery, and 34% had a prior vagal nerve stimulator.

Patients were randomized to active stimulation (n = 97) or sham stimulation (n = 94). After the 4-week postoperative period, patients received either sham or active stimulation according to group assignment. There was a 4-week stimulation optimization period, followed by a 3-month blinded evaluation period. In the evaluation period, all outcome data were gathered by a physician blinded to group assignment, and the neurostimulator was managed by a nonblinded physician. One patient in each group did not complete the stimulus optimization period (1 due to subject preference in the active stimulation group; 1 due to death in the sham stimulation group). An additional patient in each group did not complete the blinded evaluation phase due to emergent explant of the device. After the 3-month blinded evaluation period, all patients received active stimulation during an open-label follow-up period. At the time of the Morrell publication, 98 subjects had completed the open-label period and 78 had not. Eleven patients did not complete the open-label follow-up period (5 due to death, 2 to emergent explant, 4 to study withdrawal).

The trial’s primary effectiveness objective was to demonstrate a significantly greater reduction in the frequency of total disabling seizures in the treatment group compared with the sham group during the blinded evaluation period relative to baseline (preimplant). The mean preimplant seizure frequency per month in the treatment group was 33.5 (range, 3 – 295) and 34.9 (range, 3 – 338) in the sham group.¹² Mean seizure frequency modeled using generalized estimating equations was significantly reduced in the treatment group compared with the sham group (p = 0.012). During the blinded evaluation period, the mean seizure frequency in the treatment group was 22.4 (range, 0.0 – 226.8) compared with 29.8 (range, 0.3 – 44.46) in the sham group. The treatment group experienced a -37.9% change in seizure frequency (95% confidence interval [CI], -46.7% to -27.7%), while the sham group experienced a -17.3% change in seizure frequency (95% CI, -29.9% to -2.3%).

By the third month of the blinded evaluation period, the treatment group had 27% fewer days with seizures while the sham group experienced 16% fewer days (p = 0.048). There were no significant differences between groups over the blinded evaluation period for secondary end points of responder rate (proportion of subjects who experienced a ≥ 50% reduction in mean disabling seizure frequency vs. the preimplant period), change in average frequency of disabling seizures, or change in seizure severity.

During the open-label period, subjects in the sham group demonstrated significant improvements in mean seizure frequency compared with the preimplant period (p = 0.04). For all subjects (treatment and sham control), the responder rate at 1 year postimplant was 43%. Overall quality of life scores improved for both groups compared with baseline at 1 year (p = 0.001) and 2 years postimplant (p = 0.016).

For the study’s primary safety endpoint, the significant adverse event rate over the first 28 days postimplant was 12%, which did not differ significantly from the prespecified literature-derived comparator of 15% for implantation of intracranial electrodes for seizure localization and epilepsy surgery. During the implant period and the blinded evaluation period, the significant adverse event rate was 18.3%, which did not differ significantly from the prespecified literature-derived comparator of 36% for implantation and treatment with deep brain stimulation for Parkinson disease. The treatment and sham groups did not differ significantly in terms of mild or serious adverse events during the blinded evaluation period. Intracranial hemorrhage occurred in 9 (4.7%) of 191 subjects; implant or incision site infection occurred in 10 (5.2%) of 191 subjects, and the devices were explanted from 4 of these subjects.

Follow-Up Analyses to the RNS System Pivotal Study Subjects
Heck et al. (2014) followed up on the RNS System Pivotal Study, comparing outcomes at 1 and 2 years post-implant with baseline for patients in both groups (sham and control) who had the responsive neurostimulation stimulation device implanted during the RNS System Pivotal Study.¹⁸ Of the 191 subjects implanted, 182 subjects completed follow-up to 1 year postimplant and 175 subjects completed follow-up to 2 years postimplant. Six patients withdrew from the trial, 4 underwent device explantation due to infection, and 5 died, with 1 due to sudden unexplained death in epilepsy. During the open-label period, at 2 years of follow-up, median percent reduction in seizures was 53% compared with the preimplant baseline (p < 0.001), and the responder rate was 55%.

Loring et al. (2015) analyzed one of the trial’s prespecified safety endpoints (neuropsychologic function) during the trial’s open-label period.¹⁹ Neuropsychological testing focused on language and verbal memory, measured by the Boston Naming Test and the Rey Auditory Verbal Learning Test. One hundred seventy-five subjects had cognitive assessment scores at baseline and at 1 or 2 years or both and were included in this analysis. The authors used reliable change indices to identify patients with changes in test scores beyond that attributed to practice effects or measurement error in the test-retest setting, with 90% reliable change indices used for classification. Overall, no significant group-level declines in any neuropsychological outcomes were detected. On the Boston Naming Test, 23.5% of subjects demonstrated reliable change index improvements while 6.7% had declines; on the Rey Auditory Verbal Learning Test, 6.9% of subjects demonstrated reliable change index improvements and 1.4% demonstrated declines.

Meador et al. (2015) reported on quality of life and mood outcomes for individuals in the RNS System Pivotal Study.²⁰ At the end of the blinded study period, both groups reported improvements in Quality of Life in Epilepsy Inventory-89 scores, with no statistically significant differences between groups. In analysis of those with follow-up to 2 years postenrollment, implanted patients had statistically significant improvements in Quality of Life in Epilepsy Inventory-89 scores from enrollment to 1- and 2-year follow-up. Mood, as assessed by the Beck Depression Inventory and the Profile of Mood States, did not worsen over time.

Systematic Reviews
Cox et al. (2014) reported on a systematic review of implantable neurostimulation devices, including responsive neurostimulation, along with vagus nerve stimulation and deep brain stimulation for refractory epilepsy.²¹ The evidence on responsive neurostimulation in this review was primarily from the RNS System Pivotal Study¹⁷ described previously. Reviewers concluded that responsive neurostimulation is “promising,” but that improvements in the accuracy of the seizure prediction method and standardization of electrical stimulation parameters were needed.

Gooneratne et al. (2016) performed a systematic review comparing neurostimulation technologies in refractory focal epilepsy.²² They performed a literature search for studies with long-term efficacy data (≥ 5 years) and at least 30 patients evaluating vagus nerve stimulation, cortical responsive stimulation, or deep brain stimulation in refractory focal or focal epilepsy through November 2015. No direct comparisons of the technologies were found. The previously described RNS System Pivotal Study was the only responsive neurostimulation study included. Indirect comparisons of the technologies were limited by differences in RCT inclusion criteria, definitions of response, and methods of data collection between studies. Reviewers concluded that all 3 neurostimulation technologies showed long-term efficacy, with progressively better seizure control over time.

Noncomparative Studies
Before and during conduct of the RNS System Pivotal Study to evaluate the responsive neurostimulation system, short- and long-term outcomes following the use of the device have been described in case series.

Bercu et al. (2020) reported on a case series of 6 pediatric patients with drug-resistant focal epilepsy not amenable to other therapies (e.g., resection or ablation) who were implanted with the RNS System.²³ The patients were aged 8 to 17 years at the time of implantation, and had epilepsy of durations between 2 and 12 years. Follow-up occurred for periods ranging from 5 to 39 months. All patients experienced a decrease in total number of daily clinical seizures, with a median seizure reduction reported by parents between 50% and 75%. One patient underwent removal of the RNS System at approximately 5 months due to increased seizure frequency and wound dehiscence and infection.

Nair et al. (2020) conducted a long-term prospective open-label study that included patients who participated in the 2-year feasibility or pivotal studies of the RNS System between 2004 and 2018. Patients were followed up for an additional 7 years.²⁴ Overall, 230 patients enrolled in the study, and 162 completed all 9 years of follow-up, providing a total of 1,895 patient-implantation years. Among 68 patients who discontinued the study, 4 experienced emergent explant, 5 were lost to follow up, 9 were deceased, and 50 withdrew (5 transferred care to a nonstudy center, 7 were noncompliant, 8 experienced insufficient efficacy, 10 pursued other treatments, and 20 chose not to replace neurostimulator). The mean follow-up period was 7.5 years. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001), 73% of patients were considered responders, and 35% had a ≥ 90% reduction in seizure frequency. Overall, 18.4% of patients experienced ≥ 1 year free of seizures. Overall scores for quality of life and epilepsy-targeted and cognitive domains of the Quality of Life in Epilepsy-89 inventory remained significantly improved at year 9 (p < 0.05). The only device-related serious adverse events that were reported in ≥ 5% of patients were implantation site infection and elective explantation of the neurostimulator, leads, or both. Overall, serious device-related implantation site infection occurred in 12.1% of patients. No serious adverse events occurred related to stimulation.

Lee et al. (2015) reported on outcomes after responsive neurostimulation implantation (40 surgeries in 10 patients) in their single-center study. ²⁵ In this series, 1 patient had an implant site infection requiring device explantation and another had multiple lead breakages.

Child et al. (2014) described cases in which chronic (i.e., not responsive to detected seizure activity) focal cortical stimulation was used to treat medically refractory epilepsy.²⁶ In these cases, cortical electrodes were placed during planned neurosurgical intervention for seizure mapping and were connected to a pulse generator.

Section Summary: Responsive Neurostimulation for Treatment of Refractory Focal Epilepsy
The most direct and rigorous evidence related to the effectiveness of responsive neurostimulation in the treatment of refractory focal seizures is from the RNS System Pivotal Study, in which patients who had focal epilepsy refractory to at least 2 medications and received responsive neurostimulation treatment demonstrated a significantly greater reduction in their rates of seizures compared with sham-control patients. Although this single RCT was relatively small (97 patients in the treatment group), it was adequately powered for its primary outcome, and all patients were treated with the device during the open-label period (97 in the original treatment group, 94 in the original sham group) and demonstrated a significant improvement in seizure rates compared with baseline. However, there were no differences in the percentage of patients who responded to responsive neurostimulation, and no difference on most of the other secondary outcomes. Follow-up has been reported to 5 years postimplantation, without major increases in rates of adverse events.

Adverse Events With the Responsive Neurostimulation System
As a surgical procedure, implantation of the responsive neurostimulation system is associated with the risks that should be balanced against the risks of alternative treatments, including antiepileptic drugs and other invasive treatments (vagal nerve stimulator and epilepsy surgery), and the risks of uncontrolled epilepsy. During the RNS System Pivotal Study, rates of serious adverse events were relatively low: 3.7% of patients had implant site infections, 6% had lead revisions or damage, and 2.1% percent had intracranial hemorrhages during initial implantation.¹⁸

The FDA’s summary of safety and effectiveness data for the responsive neurostimulation system summarized deaths and adverse events. As reported in the safety and effectiveness data, as of Oct. 24, 2012, there were 11 deaths in the responsive neurostimulation System trials, including the RNS System Pivotal Study and the ongoing long-term treatment study. Two of the deaths were suicides (1 each in the pivotal and long-term treatment studies), 1 due to lymphoma, 1due to complications of status epilepticus, and 7 were attributed to possible, probable, or definite sudden unexplained death in epilepsy. With 1,195 patient implant years, the estimated sudden unexplained death in epilepsy rate is 5.9 per 1,000 implant years, which is comparable with the expected rate for patients with refractory epilepsy.¹²

Additional safety outcomes have been reported to 5 years postimplantation through the device’s long-term treatment study (see above).

As of March 9, 2021 , there were 318 reports in the FDA Manufacturer and User Facility Device Experience database for product code PFN. Thirty-two were labeled as event type “Malfunction,” 1 was extended hospitalization due to aphasia, and all remaining reports were labeled as “Injury.” Among the “Injury” event narratives, 21 mentioned hemorrhages, 3 stroke, 6 fluid leakage, 132 infection, 15 swelling or edema, and 9 wound dehiscence.

Summary of Evidence
For individuals who have refractory focal epilepsy who receive responsive neurostimulation, the evidence includes an industry-sponsored randomized controlled trial, which was used for FDA approval of the NeuroPace RNS System, as well as case series. Relevant outcomes are symptoms, morbid events, quality of life, and treatment-related mortality and morbidity. The RCT was well-designed and well-conducted; it reported that responsive neurostimulation is associated with improvements in mean seizure frequency in patients with refractory focal epilepsy, with an absolute difference in change in seizure frequency of about 20% between groups; however, the percentage of treatment responders with at least a 50% reduction in seizures did not differ from sham control. Overall, the results suggested a modest reduction in seizure frequency in a subset of patients. The number of adverse events reported in the available studies is low, although the data on adverse events were limited because of small study samples. Generally, patients who are candidates for responsive neurostimulation are severely debilitated and have few other treatment options, so the benefits are likely high relative to the risks. In particular, patients who are not candidates for resective epilepsy surgery and have few treatment options may benefit from responsive neurostimulation. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

In response to requests, input was received from 2 specialty medical societies (3 responses) and 5 academic medical centers (4 responses) when this policy was under development in 2014. There was consensus among reviewers that responsive neurostimulation is medically necessary for patients with focal epilepsy with 1 to 2 foci who are not candidates for resective epilepsy surgery.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American Academy of Neurology
In 2013, guidelines on vagus nerve stimulation for the treatment of epilepsy were issued by the American Academy of Neurology, which were reaffirmed in 2019.²⁷ The guidelines made the following recommendations: “vagus nerve stimulation may be considered for seizures in children, for Lennox-Gastaut syndrome associated seizures, and for improving mood in adults with epilepsy (Level C). Vagus nerve stimulation may be considered to have improved efficacy over time (Level C). Children should be carefully monitored for site infection after vagus nerve stimulation implantation.” The Academy indicated that more information would be needed on the treatment of primary generalized epilepsy in adults (only 1 class II article addressed this population). The responsive neurostimulation system was not mentioned in these guidelines.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are shown in Table 1. 

Table 1. Summary of Key Trials  

NCT: national clinical trial.
^aDenotes industry-sponsored or cosponsored trial.   

References 

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Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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