Neurostimulation Shows Sustained Seizure Reductions in Drug-Resistant Focal Epilepsy

Long-term real-world data from a large, open-label, postapproval study of the responsive neurostimulation (RNS) System (NeuroPace) suggest that brain-responsive neurostimulation may provide durable seizure control in adults with drug-resistant focal epilepsy, with safety outcomes that were generally consistent with earlier pivotal trials and other intracranial neuromodulation approaches.¹

The postapproval study enrolled 343 participants across 32 US epilepsy centers, with 324 patients ultimately implanted with the RNS device. Eligible patients met the FDA-approved indication for use, including medically refractory focal-onset seizures arising from 1 or 2 epileptogenic foci. The cohort had a mean age of 37 years and a mean epilepsy duration of nearly 18 years, reflecting a highly treatment-resistant population. Many participants had previously undergone intracranial monitoring, epilepsy surgery, or vagus nerve stimulation (VNS).¹

The study was conducted as a prospective, FDA-mandated postapproval study designed to evaluate whether outcomes in routine clinical practice differed from those observed in premarket randomized controlled trials. Published in Neurology, investigators reported that patients treated with the NeuroPace RNS System experienced a median 82% reduction in seizure frequency at 3 years, with more than 40% achieving at least a 90% reduction in seizures and approximately one-fifth experiencing seizure freedom for at least 12 months during follow-up.¹

The RNS System, initially approved by the FDA in 2013, delivers closed-loop electrical stimulation directly to seizure onset regions after detecting abnormal electrocorticographic activity.² Unlike scheduled stimulation systems, the device continuously records intracranial EEG activity and delivers responsive stimulation when predefined epileptiform patterns are detected.

Led by Dawn Eliashiv, professor of neurology and co-director of the UCLA Seizure Disorders Center, the study reported statistically significant seizure reductions beginning within the first 6 months after implantation. Median seizure frequency reduction was 62.5% at 6 months and progressively improved over time to 82% at the 30- to 36-month interval (P < .0001). A responder rate—defined as at least a 50% seizure reduction—was observed in 66% of patients at the most recent follow-up window. Additionally, 42.5% of participants experienced at least 1 seizure-free period lasting 6 months or longer, while 22% achieved seizure freedom for at least 12 months.¹

Importantly, seizure reduction appeared broadly consistent across seizure-onset subtypes, including mesial temporal, neocortical, and combined onset patterns. Outcomes also did not substantially differ based on prior epilepsy surgery, VNS exposure, intracranial monitoring history, or whether patients had 1 versus 2 seizure foci.¹

The observed efficacy exceeded outcomes reported in earlier pivotal and long-term treatment studies of the RNS platform.² In the original pivotal trial, seizure reduction reached approximately 53% at 2 years and 58% during longer-term follow-up.³ The authors suggested that evolving programming strategies, including gradual charge density escalation and greater use of 200-Hz stimulation protocols, may partly explain improved outcomes in contemporary practice.¹

The results add to a growing body of evidence supporting neuromodulation strategies for patients with focal epilepsy who are not candidates for curative resection or ablation. Approximately 30% of patients with epilepsy remain drug resistant despite antiseizure medication (ASM) therapy, and treatment options for multifocal or eloquent cortex-associated epilepsies remain limited.³

Although the study was not randomized and therefore subject to potential placebo effects and selection bias, the magnitude and durability of seizure reduction align with other recent real-world analyses of responsive neurostimulation. Investigators also noted that clinical responses to neuromodulation therapies often improve over time, raising questions about possible neuroplastic mechanisms associated with chronic stimulation.¹

Safety findings were generally consistent with prior intracranial neuromodulation studies. No serious adverse events (SAEs) related to chronic stimulation were reported.¹ Procedure-related SAEs occurred in 22 patients and included implant-site infections (2.2%), intracranial hemorrhage (1.8%), CSF leakage, and wound complications.¹ Most events resolved without long-term sequelae, although 1 participant had persistent mild expressive aphasia following hemorrhage.

Psychiatric SAEs were infrequent and not considered device related. Suicidal ideation and postictal psychosis were among the most commonly reported psychiatric events, largely occurring in patients with preexisting psychiatric histories.¹

Investigators also reported a combined sudden unexplained death in epilepsy (SUDEP) rate of 2.3 per 1000 patient-years across all prospective RNS studies, lower than historical placebo-arm rates reported in ASM trials.¹ However, they noted that interpretation of SUDEP comparisons remains challenging because of differences in patient populations and study methodologies.

The study carried several limitations inherent to open-label real-world research. Baseline seizure frequencies were retrospectively collected, and the absence of a control arm limits causal interpretation. Investigators also acknowledged that the COVID-19 pandemic disrupted some follow-up visits and contributed to missing data. Additionally, the study provides Class IV evidence under American Academy of Neurology criteria.¹

Still, the findings may influence how clinicians position responsive neurostimulation within the treatment algorithm for refractory focal epilepsy. The authors noted that fewer patients in the postapproval cohort had previously undergone resective surgery or VNS compared with earlier RNS trials, potentially suggesting earlier adoption of neuromodulation in clinical practice.¹

Further follow-up from the ongoing 5-year safety analysis is expected, alongside future efforts to refine stimulation paradigms using intracranial EEG data and machine learning approaches.

REFERENCES
1. Eliashiv D, Rao VR, Jobst BC, et al. Postapproval study for brain-responsive neurostimulation for drug-resistant focal epilepsy: three-year efficacy and interim safety results. Neurology. 2026;106(9):e214875. doi:10.1212/WNL.0000000000214875.
2. Bergey GK, Morrell MJ, Mizrahi EM, et al. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology. 2015;84(8):810-817. doi:10.1212/WNL.0000000000001280.
3. Löscher W, Potschka H, Sisodiya SM, Vezzani A. Drug resistance in epilepsy: clinical impact, potential mechanisms, and new innovative treatment options. Pharmacol Rev. 2020;72(3):606-638. doi:10.1124/pr.120.019539.