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Medical Policy Responsive Neurostimulation for the Treatment of Refractory Focal Epilepsy Table of Contents • Policy: Commercial • Coding Information
• Information Pertaining to All Policies
• Policy: Medicare • Description
• References
• Authorization Information • Policy History

Policy Number: 716 BCBSA Reference Number: 7.01.143 (For Plan internal use only) NCD/LCD: NA

Related Policies
• Vagus Nerve Stimulation, #474 • Deep Brain Stimulation, #473 Policy Commercial Members: Managed Care (HMO and POS), PPO, and Indemnity
Medicare HMO BlueSM and Medicare PPO BlueSM Members

Responsive neurostimulation may be considered MEDICALLY NECESSARY for individuals with partial 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 (eg, motor focal, complex focal, or secondary generalized seizures) per month over the prior 3 months; • Are refractory to medical therapy (have failed 2 or more appropriate antiepileptic medications at therapeutic doses); • Are not candidates for focal resective epilepsy surgery (eg, have an epileptic focus near eloquent cerebral cortex; have bilateral temporal epilepsy); and
• Do not have contraindications* for RNS placement.

*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.

Responsive neurostimulation is considered INVESTIGATIONAL for all other indications.

Prior Authorization Information
Inpatient

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• For services described in this policy, precertification/preauthorization IS REQUIRED if the procedure is performed inpatient.
Outpatient • For services described in this policy, see below for situations where prior authorization might be required if the procedure is performed outpatient.

Outpatient Commercial Managed Care (HMO and POS) This procedure is performed in the inpatient setting. Commercial PPO and Indemnity This procedure is performed in the inpatient setting. Medicare HMO BlueSM This procedure is performed in the inpatient setting. Medicare PPO BlueSM This procedure is performed in the inpatient setting.

CPT Codes / HCPCS Codes / ICD Codes
Inclusion or exclusion of a code does not constitute or imply member coverage or provider reimbursement. Please refer to the member’s contract benefits in effect at the time of service to determine coverage or non-coverage as it applies to an individual member.

Providers should report all services using the most up-to-date industry-standard procedure, revenue, and diagnosis codes, including modifiers where applicable.

The following codes are included below for informational purposes only; this is not an all-inclusive list. CPT Codes CPT codes Code Description 61889 Skull-mounted cranial neurostimulator pulse generator or receiver insertion with direct or inductive coupling, and connection to depth or cortical electrode array(s) 61863 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (eg, thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array 61864 Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (eg, thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; each additional array (List separately in addition to primary procedure)

Description Epilepsy Treatment

Medical Therapy for Focal Seizures 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.

Standard therapy for seizures, including focal seizures, includes treatment with 1 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: 1 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 individuals 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

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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 individuals for epilepsy surgery is important, because those with non-lesional extratemporal lobe epilepsy have worse outcomes after surgery than those with non-lesional temporal lobe epilepsy. 4, Some individuals 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, Individuals 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 individuals' seizures. In particular, the seizure mapping data have been used for surgical planning of individuals who do not experience adequate seizure reduction with responsive neurostimulation placement. Several studies have

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described the use of responsive neurostimulation in evaluating seizure foci for epilepsy surgery 9, or for identifying whether seizure foci are unilateral. 10,11,

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

Summary Description Approximately one-third of individuals with epilepsy do not respond to typical first-line therapy with antiepileptic medications. Seizures that occur in these individuals are referred to as refractory or drug- resistant. In individuals 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 of Evidence 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 several published follow-up analyses. 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 individuals 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 individuals. 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, individuals 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, individuals 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.

Policy History Date Action 9/2025 Clarified coding information. 6/2025 Annual policy review. Policy updated with literature review through February 21, 2025; reference added. Policy statements unchanged. 3/2025 Clarified coding information. 2/2024 Clarified coding information. 6/2024 Annual policy review. Description, summary, and references updated. Policy statements unchanged. Clarified coding information and prior authorization table. 1/2024 Clarified coding information.
6/2023 Annual policy review. Minor editorial refinements to policy statements; intent unchanged. 6/2022 Annual policy review. Policy statements unchanged. 5/2021 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 6/2020 Annual policy review. Description, summary, and references updated. Policy statements unchanged.

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5/2019 Annual policy review. Description, summary, and references updated. Policy statements unchanged. 6/2018 Annual policy review. Policy clarified: partial epilepsy changed to focal epilepsy throughout text and title to be consistent with current terminology. Prior Authorization Information reformatted. 5/2017 Annual policy review. New references added. 5/2016 Annual policy review. New references added. 4/2015 New medical policy describing medically necessary and investigational indications.
Effective 4/1/2015. Information Pertaining to All Blue Cross Blue Shield Medical Policies Click on any of the following terms to access the relevant information: Medical Policy Terms of Use Managed Care Guidelines Indemnity/PPO Guidelines Clinical Exception Process Medical Technology Assessment Guidelines

References

1. Costa J, Fareleira F, Ascenção R, et al. Clinical comparability of the new antiepileptic drugs in refractory partial epilepsy: a systematic review and meta-analysis. Epilepsia. Jul 2011; 52(7): 1280-91. PMID 21729036
2. Wiebe S, Blume WT, Girvin JP, et al. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N Engl J Med. Aug 02 2001; 345(5): 311-8. PMID 11484687
3. de Tisi J, Bell GS, Peacock JL, et al. The long-term outcome of adult epilepsy surgery, patterns of seizure remission, and relapse: a cohort study. Lancet. Oct 15 2011; 378(9800): 1388-95. PMID 22000136
4. Noe K, Sulc V, Wong-Kisiel L, et al. Long-term outcomes after nonlesional extratemporal lobe epilepsy surgery. JAMA Neurol. Aug 2013; 70(8): 1003-8. PMID 23732844
5. Fridley J, Thomas JG, Navarro JC, et al. Brain stimulation for the treatment of epilepsy. Neurosurg Focus. Mar 2012; 32(3): E13. PMID 22380854
6. Fisher RS. Therapeutic devices for epilepsy. Ann Neurol. Feb 2012; 71(2): 157-68. PMID 22367987
7. Kossoff EH, Ritzl EK, Politsky JM, et al. Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring. Epilepsia. Dec 2004; 45(12): 1560-7. PMID 15571514
8. Anderson WS, Kossoff EH, Bergey GK, et al. Implantation of a responsive neurostimulator device in patients with refractory epilepsy. Neurosurg Focus. Sep 2008; 25(3): E12. PMID 18759613
9. DiLorenzo DJ, Mangubat EZ, Rossi MA, et al. Chronic unlimited recording electrocorticography-guided resective epilepsy surgery: technology-enabled enhanced fidelity in seizure focus localization with improved surgical efficacy. J Neurosurg. Jun 2014; 120(6): 1402-14. PMID 24655096
10. King-Stephens D, Mirro E, Weber PB, et al. Lateralization of mesial temporal lobe epilepsy with chronic ambulatory electrocorticography. Epilepsia. Jun 2015; 56(6): 959-67. PMID 25988840
11. Spencer D, Gwinn R, Salinsky M, et al. Laterality and temporal distribution of seizures in patients with bitemporal independent seizures during a trial of responsive neurostimulation. Epilepsy Res. Feb 2011; 93(2-3): 221-5. PMID 21256715
12. Food and Drug Administration. Summary of Safety and Effectiveness Data: RNS System 2013; https://www.accessdata.fda.gov/cdrh_docs/pdf10/P100026b.pdf. Accessed February 21, 2025.
13. Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia. Apr 2017; 58(4): 522-530. PMID 28276060
14. Kwan P, Arzimanoglou A, Berg AT, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia. Jun 2010; 51(6): 1069-77. PMID 19889013
15. Xue-Ping W, Hai-Jiao W, Li-Na Z, et al. Risk factors for drug-resistant epilepsy: A systematic review and meta-analysis. Medicine (Baltimore). Jul 2019; 98(30): e16402. PMID 31348240

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16. Neuropace, Inc. RNS(R) System Physician Manual for the RNS(R) Neurostimulator Model RNS-320. Revised November 2024. https://www.neuropace.com/wp-content/uploads/2021/02/neuropace-rns- system-manual-320.pdf. Accessed February 21, 2025.
17. Morrell MJ, King-Stephens D, Massey AD, et al. Responsive cortical stimulation for the treatment of medically intractable partial epilepsy. Neurology. Sep 27 2011; 77(13): 1295-304. PMID 21917777
18. Heck CN, King-Stephens D, Massey AD, et al. Two-year seizure reduction in adults with medically intractable partial onset epilepsy treated with responsive neurostimulation: final results of the RNS System Pivotal trial. Epilepsia. Mar 2014; 55(3): 432-41. PMID 24621228
19. Loring DW, Kapur R, Meador KJ, et al. Differential neuropsychological outcomes following targeted responsive neurostimulation for partial-onset epilepsy. Epilepsia. Nov 2015; 56(11): 1836-44. PMID 26385758
20. Meador KJ, Kapur R, Loring DW, et al. Quality of life and mood in patients with medically intractable epilepsy treated with targeted responsive neurostimulation. Epilepsy Behav. Apr 2015; 45: 242-7. PMID 25819949
21. Nair DR, Laxer KD, Weber PB, et al. Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy. Neurology. Sep 01 2020; 95(9): e1244-e1256. PMID 32690786
22. Skrehot HC, Englot DJ, Haneef Z. Neuro-stimulation in focal epilepsy: A systematic review and meta- analysis. Epilepsy Behav. May 2023; 142: 109182. PMID 36972642
23. Shi J, Lu D, Wei P, et al. Comparative Efficacy of Neuromodulatory Strategies for Drug-Resistant Epilepsy: A Systematic Review and Meta-Analysis. World Neurosurg. Oct 16 2024; 193: 373-396. PMID 39321920