Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy

Abstract

Objective: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.

Methods: Adults treated with brain-responsive neurostimulation in 2-year feasibility or randomized controlled trials were enrolled in a long-term prospective open label trial (LTT) to assess safety, efficacy, and quality of life (QOL) over an additional 7 years. Safety was assessed as adverse events (AEs), efficacy as median percent change in seizure frequency and responder rate, and QOL with the Quality of Life in Epilepsy (QOLIE-89) inventory.

Results: Of 256 patients treated in the initial trials, 230 participated in the LTT. At 9 years, the median percent reduction in seizure frequency was 75% (p < 0.0001, Wilcoxon signed rank), responder rate was 73%, and 35% had a ≥90% reduction in seizure frequency. We found that 18.4% (47 of 256) experienced ≥1 year of seizure freedom, with 62% (29 of 47) seizure-free at the last follow-up and an average seizure-free period of 3.2 years (range 1.04-9.6 years). Overall QOL and epilepsy-targeted and cognitive domains of QOLIE-89 remained significantly improved (p < 0.05). There were no serious AEs related to stimulation, and the sudden unexplained death in epilepsy (SUDEP) rate was significantly lower than predefined comparators (p < 0.05, 1-tailed χ²).

Conclusions: Adjunctive brain-responsive neurostimulation provides significant and sustained reductions in the frequency of FOS with improved QOL. Stimulation was well tolerated; implantation-related AEs were typical of other neurostimulation devices; and SUDEP rates were low.

Clinicaltrialsgov identifier: NCT00572195.

Classification of evidence: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Figure 1. RNS System

Left, RNS neurostimulator and NeuroPace cortical strip and depth leads. Top right, record of the number of electrographic events detected by the neurostimulator over time for an individual patient. Bottom right, snapshots of electrographic activity recorded by the RNS System for an individual patient. Copyright © 2020 NeuroPace, Inc.

Figure 2. RNS System studies, participant accountability

^aFeasibility study: 6 participants discontinued before completing the study; 2 participants completed the study but elected not to enroll in the long-term treatment (LTT) study. Thus, 57 participants in the feasibility study enrolled in the LTT study. ^bPivotal study: 16 participants discontinued before completing the study; 4 participants completed the study but elected not to enroll in the LTT study. Two participants who discontinued early were granted waivers and were allowed to enroll, resulting in 173 pivotal participants enrolling into LTT. A total of 230 participants chose to enroll in the LTT study, and 162 participants completed the study. ^cReasons for early withdrawal from the LTT study included the following: chose not to replace neurostimulator (n = 20); to pursue other treatment options (n = 10); insufficient efficacy (n = 8); study noncompliance (n = 7); and to receive medical care at a nonstudy center (n = 5).

Figure 3. RNS System long term clinical response

Plot showing the median percent reduction ± IQR in seizure frequency for the last 6 months of each year in the long-term treatment study (years 3 through 9 of treatment) compared to baseline for the 91-day minimum diary requirement population, the constant cohort population, and the last observation carried forward (LOCF) population. (A) Median percent reduction ± interquartile range (IQR) over time. (B) Individual changes in clinical seizure frequency. Changes in clinical seizure frequency during the last 6 months of follow-up before the year 9 visit for each participant who had at least 91 days of seizure diary data. Negative values indicate a seizure frequency reduction compared with baseline. (C) Bar graph showing the percent of all participants (All) and participants with onsets in the mesial temporal lobe (MTL) or neocortex (Neo) with at least 1 period of seizure freedom lasting at least 3, 6, and 12 months.