Discussion
cognitive impairment, epilepsy, seizure, seizures, memory complaints, temporal lobe epilepsy, depression, occipital lobe epilepsy
EPILEPSY, ADVERSE EVENTS, TEMPORAL LOBE EPILEPSY, OCCIPITAL LOBE EPILEPSY, COMPLICATIONS
The MORE multinational registry provides systematically collected real-world data about the safety and effectiveness of ANT DBS therapy in patients with DRE. Our results support the clinical efficacy and safety of ANT DBS therapy previously reported in the SANTE randomized controlled trial and single-center experiences. Key findings include a 33.1% median monthly SF reduction after 2 years of treatment; however, it was observed that seizure outcomes of the patients were affected by the treatment center experience. We did not identify new safety concerns regarding the surgical procedure– or treatment-related adverse events compared with the original SANTE trial.In the subgroup of patients reaching 5 years, the total SR was reported to be 55.1%. Results from this subgroup suggest that there was a continued decrease in SF beyond 2 years, which is consistent with SANTE resultsThe median monthly SF at 2 years of follow-up in MORE was 8.8 compared with 15.8 at baseline, representing a 33.1% median reduction across all seizure types. When categorizing the patients into 3 groups, 32% were responders, whereas 29% had no reduction in SF (no benefit). The remainder of patients had a decrease in SF (improvers) without reaching the response threshold of 50%. The SR of MORE at 2 years was not as high as the one in the open-label extension of SANTE, which showed a 56.0% median reduction in SF. In addition, 54% of patients had an SF reduction of at least 50%, whereas 10% had an increase in their seizure count.First, the presence or absence of cognitive impairment had some effect on seizure outcome in MORE without reaching statistical significance. Indeed, patients with cognitive impairment had a 26.0% median monthly SR by 2 years compared with 36.1% reduction in those without cognitive impairment. Conversely, SANTE excluded patients with an IQ of less than 70.Second, the region of the brain where the seizure most likely originates may be relevant for seizure outcomes. In the MORE registry, the responder group included numerically more patients with temporal lobe epilepsy compared with the no-benefit group. Only 39% of patients in MORE had temporal lobe epilepsy compared with 60% in SANTE, whereas the proportion of patients with frontal lobe, parietal lobe, or occipital lobe epilepsy was quite similar in both studies. Furthermore, in MORE, the patients with no benefit were more often found to have multifocal epilepsy than the responders, suggesting that those patients may be less likely to respond to ANT DBS therapy. Remarkably, only 9% of SANTE trial patients had diffuse or multifocal epilepsy compared with 24% of patients in MORE. In SANTE, by 2 years, patients with seizures of temporal origin achieved relatively greater benefit of stimulation compared with those with seizures originating from other lobes or multifocal in origin.Third, the distribution of seizure types and frequencies may have an effect on SR. The baseline median seizure frequencies were similar in MORE and SANTE, but in MORE, there was more variation in SF, which may have contributed to seizure outcomes in MORE. There was also more variation in MORE regarding seizure types, which may also reflect the inherent difficulty in seizure classification in real life.Fourth, in MORE, the median number of failed ASMs was 9, suggesting a very refractory group of patients with epilepsy. In SANTE, the number of failed ASMs had to be at least 3, but the total number of ASMs was not reported.Finally, in MORE, centers with over 10 implantations showed significantly better seizure outcomes compared with those with 10 or less implantations: 42.8% median monthly SR compared with 25.8%, respectively. Several factors may affect the greater outcome variability among the centers in MORE compared with that of SANTE. The surgical approach in MORE included both transventricular and extraventricular approaches, with 2 different lead models (3387 and 3389), whereas in SANTE, only the transventricular technique and lead model 3387 were used.Real-world epilepsy studies such as the MORE registry reliably provide safety-related information because the precision of tolerability reporting is more likely to be accurate than effectiveness-related data. This is of utmost importance because randomized and controlled studies have limitations regarding the inclusion of patients.In MORE, the rates of depression and memory complaints were in line with those reported in SANTE for the first 2 years of follow-up. In MORE, 13% of patients reported depression during the entire 2-year follow-up period compared with 15% of patients in the active group of SANTE during the 3-month double-blind period.Serious complications leading to discontinuation of the therapy were rare among patients in MORE confirming the safety data from SANTE. Indeed, none of the patients in the MORE registry discontinued the therapy during the first year after the implantation. Conversely, in SANTE, 5 patients discontinued the therapy during the initial 13-month open-label phase.The HRQOL measurements in MORE did not reach the minimally important clinical difference threshold in QOLIE-31. This finding was not unexpected because several studies suggest that the achievement of seizure freedom in patients with epilepsy, rather than any reduction in SF, significantly affects the HRQOL scales.The strengths of this study include a comprehensive and systematic data collection in a multinational multicenter setting enabling a practical and clinically relevant approach to explore patient characteristics, the surgical procedure, and both effectiveness and safety aspects. The MORE registry provides a real-world adjunct to the results of the SANTE randomized trial. Limitations include reduced reliability of the seizure diaries, nonprotocolized visit windows, and optional questionnaires (HRQOL and BDI performed only in a subset of patients), chosen to respect clinical practice. Finally, some patients were included in the MORE registry retrospectively rather than prospectively, a fact that may have resulted in selection bias.ANT DBS therapy is evolving as new versions of DBS devices are being developed. In the SANTE trial, the DBS model Kinetra (Medtronic) was used, whereas in the MORE registry, patients were implanted with the Activa PC. Recently, a new neurostimulator was introduced, which offers a recording of local field potentials. This may offer a possibility for better understanding the therapy and treatment optimization in patients with DRE.In conclusion, the large real-world MORE registry strengthens the evidence supporting the safety of ANT DBS therapy. We confirmed the effectiveness of the ANT DBS treatment and obtained important data suggesting cognitive impairment and region of the brain where the seizure most likely originates as possible features for optimal patient selection. In addition, ANT DBS should be considered in patients with DRE before increasing the ASM burden to avoid a negative effect in terms of side effects. The centers performing ANT DBS implantations should have a long-term comprehensive commitment to patient selection, implantation, and therapy optimization.