NAUTILUS
(2026)Objective
To evaluate the safety and effectiveness of responsive thalamic (centromedian nucleus) stimulation as adjunctive therapy for drug-resistant idiopathic generalized epilepsy (IGE) with generalized tonic-clonic seizures (GTCSs).
Study Summary
• Prespecified primary effectiveness endpoint (time-to-second-GTCS during EEP) NOT significant: HR 0.895 (95% CI 0.53–1.50, p=.675)
• Post hoc mixed-effects model showed 61% GTCS reduction in Active vs 49% in Sham group (p=.030)
• At 18 months: 76.8% median GTCS reduction, 62.5% responder rate, 40% GTCS-free
• 77.8% median reduction in days with any generalized seizure
• >90% of patients and 80% of physicians reported improvement on Global Impression of Change scales (paper's abstract states 86%, but Main Results text reports 80%)
• No adverse effects on cognition, mood, or sleep
Intervention
Responsive neurostimulation (RNS System, NeuroPace) with bilateral depth leads targeted to the centromedian nucleus of the thalamus, delivering closed-loop electrical stimulation in response to detected abnormal iEEG patterns.
Inclusion Criteria
Age ≥12 years; confirmed IGE diagnosis by history and EEG; drug-resistant epilepsy (failure of ≥2 appropriate ASMs); GTCSs with or without absence or myoclonic seizures; ≥2 GTCSs during the 3-month baseline period.
Study Design
Arms: Active responsive thalamic stimulation (n=44) vs Sham/no stimulation (n=43)
Patients per Arm: Active n=44; Sham n=43 (87 implanted of 100 enrolled)
Outcome
• Prespecified primary effectiveness endpoint (time-to-second-GTCS) NOT met: HR 0.895 (95% CI 0.53–1.50, p=.675)
• Post hoc analysis: 61% GTCS reduction (Active) vs 49% (Sham), p=.030
• 18-month median GTCS reduction: 76.8%
• 18-month responder rate: 62.5%; 40% GTCS-free
• 77.8% median reduction in days with any generalized seizure
• One definite SUDEP event; no adverse effects on cognition, mood, or sleep
Bottom Line
Responsive thalamic (centromedian nucleus) stimulation with the RNS System missed its prespecified primary effectiveness endpoint (HR 0.895, 95% CI 0.53–1.50, p=.675) but demonstrated an acceptable safety profile (SADE 6.9%) and clinically meaningful, durable seizure reductions at 18 months (76.8% median GTCS reduction, 62.5% responder rate, 40% GTCS-free), offering a much-needed neuromodulation option for drug-resistant idiopathic generalized epilepsy.
Major Points
- First randomized controlled neuromodulation trial for drug-resistant IGE
- Primary safety endpoint met: SADE rate 6.9% at 84 days, well below 25% performance goal (p<.0001)
- Prespecified primary effectiveness endpoint (time-to-second-GTCS during EEP) NOT met: HR 0.895 (95% CI 0.53–1.50, p=.675); median time to second GTCS 76.0 days (Active) vs 67.0 days (Sham)
- Post hoc mixed-effects model with monthly seizure counts showed 61% GTCS reduction in Active vs 49% in Sham (p=.030)
- 18-month outcomes: 76.8% median GTCS reduction, 62.5% responder rate, 40% GTCS-free
- 77.8% median reduction in days with any generalized seizure
- >90% of patients and 80% of physicians reported improvement on Global Impression of Change scales (paper's abstract states 86% for physicians, but Main Results text reports 80% — internal inconsistency)
- No adverse effects on cognition, mood, or sleep
- One definite SUDEP event; combined RNS clinical trial dataset (N=693) showed SUDEP rate of 2.9/1000 patient-years, lower than expected rates in surgical candidates (9.3/1000) and ASM placebo arms (6.1/1000)
Study Design
- Study Type
- Prospective, multicenter, single-blind, randomized, sham-controlled pivotal trial
- Randomization
- Yes
- Blinding
- Single-blind (patients blinded to randomization assignment until final 24-month study visit); Sham patients underwent simulated stimulation programming to maintain blinding
- Sample Size
- 87
- Follow-up
- 18 months (with 24-month total study duration)
- Centers
- 23
- Countries
- United States
Primary Outcome
Definition: Time to second GTCS during the 9-month effectiveness evaluation period (EEP) — prespecified analysis (Cox proportional hazards stratified by baseline GTCS frequency and prior VNS); primary safety endpoint was rate of serious adverse device-related events (SADEs) at 84 days postimplant
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Sham group (n=43) | Active group (n=44) | 0.895 (Effectiveness HR: 0.53-1.50; Safety SADE: 2.9%-14.5%) | Effectiveness: p=.675 (NS); Safety: p<.0001 |
Limitations & Criticisms
- Prespecified primary effectiveness endpoint (time-to-second-GTCS) was not met; positive effectiveness conclusions rely on a post hoc mixed-effects model
- Single-blind design (patients blinded but not investigators)
- Sham patients transitioned to open-label active stimulation after a second GTCS, limiting long-term comparison between groups
- Single-country (US-only) trial with predominantly White (80.5%) and non-Hispanic (85.1%) population may limit generalizability
- Reliance on patient-reported electronic seizure diaries for outcome ascertainment
- Industry-sponsored trial (NeuroPace) with multiple authors affiliated with the sponsor
Citation
Uysal U, et al. Responsive stimulation of the thalamus for idiopathic generalized epilepsy: Results of the randomized controlled NAUTILUS trial through 18 months. Epilepsia. 2026;00:1-14. doi:10.1002/epi.70321