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Long-Term Evaluation of Anterior Thalamic Deep Brain Stimulation for Epilepsy
abstract
This abstract is available on the publisher's site.
Access this abstract nowOBJECTIVE
Short-term outcomes of deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS) were reported for people with drug-resistant focal epilepsy (PwE). Because long-term data are still scarce, the Medtronic Registry for Epilepsy (MORE) evaluated clinical routine application of ANT-DBS.
METHODS
In this multicenter registry, PwE with ANT-DBS were followed up for safety, efficacy, and battery longevity. Follow-up ended after 5 years or upon study closure. Clinical characteristics and stimulation settings were compared between PwE with no benefit, improvers, and responders, that is, PwE with average monthly seizure frequency reduction rates of ≥50%.
RESULTS
Of 170 eligible PwE, 104, 62, and 49 completed the 3-, 4-, and 5-year follow-up, respectively. Most discontinuations (68%) were due to planned study closure as follow-up beyond 2 years was optional. The 5-year follow-up cohort had a median seizure frequency reduction from 16 per month at baseline to 7.9 per month at 5-year follow-up (p < .001), with most-pronounced effects on focal-to-bilateral tonic-clonic seizures (n = 15, 77% reduction, p = .008). At last follow-up (median 3.5 years), 41% (69/170) of PwE were responders. Unifocal epilepsy (p = .035) and a negative history of epilepsy surgery (p = .002) were associated with larger average monthly seizure frequency reductions. Stimulation settings did not differ between response groups. In 179 implanted PwE, DBS-related adverse events (AEs, n = 225) and serious AEs (n = 75) included deterioration in epilepsy or seizure frequency/severity/type (33; 14 serious), memory/cognitive impairment (29; 3 serious), and depression (13; 4 serious). Five deaths occurred (none were ANT-DBS related). Most AEs (76.3%) manifested within the first 2 years after implantation. Activa PC depletion (n = 37) occurred on average after 45 months.
SIGNIFICANCE
MORE provides further evidence for the long-term application of ANT-DBS in clinical routine practice. Although clinical benefits increased over time, side effects occurred mainly during the first 2 years. Identified outcome modifiers can help inform PwE selection and management.
Additional Info
Long-term evaluation of anterior thalamic deep brain stimulation for epilepsy in the European MORE registry
Epilepsia 2024 Jun 05;[EPub Ahead of Print], E Kaufmann, J Peltola, AJ Colon, K Lehtimäki, M Majtanik, JK Mai, B Bóné, C Bentes, V Coenen, A Gil-Nagel, AJ Goncalves-Ferreira, P Ryvlin, R Taylor, TC Brionne, F Gielen, S Song, P BoonFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is a rapidly growing treatment option for refractory seizures, and its history and outcomes have been extensively reviewed since the pivotal SANTE trial.1-5 Kaufmann and colleagues have now published the results of a European Medtronic Registry for Epilepsy (MORE) registry–based study examining the long-term outcomes of a real-world cohort of patients undergoing ANT-DBS. The investigators are to be congratulated for organizing and completing this multicenter real-world study, which was not an easy task.
The results were fairly similar to those of the SANTE trial, which is encouraging.4,5 At 5 years, the rate of focal aware seizures (FAS), focal impaired-awareness seizures, and focal-to-bilateral tonic–clonic seizures were reduced by 55%, 48%, and 77%, respectively. The latter two reductions were statistically significant; but, as with the SANTE trial, FAS rate reductions only showed a trend. This may be because ANT-DBS blocks propagation but not initiation of seizures or because it transforms focal impaired-awareness seizures to FAS. Reductions of at least 50% occurred in 41% of the patients (“responders”) at a median duration of 3.5 years; only 4% became seizure-free. Overall, the results were slightly worse than those of the SANTE trial, possibly because: 1) the MORE registry comprised more extratemporal and multifocal epilepsies; 2) only 75% of the patients had a contact in the ANT; and 3) patients from inexperienced centers fared worse.
About one-third in the MORE registry had DBS-related side effects, most commonly memory or cognitive issues. Depression occurred in 6% of the patients but improved from baseline to 4 years. The sudden unexpected death in epilepsy rate was 1.62 per 1000 person-years, which is lower than that expected for a surgical population.6 Sleep disturbances did not appear in their table of side effects, although sleep effects can emerge owing to ANT stimulation, because the thalamus is a key component of sleep mechanisms.6
Registries have inherent limitations. Enrollment of diverse individuals can make variability high, subgroups small, and interpretations difficult. Real-world trials cannot account for other factors, such as medication changes. Seizure diaries are an Achilles heel of trials.7 The MORE registry’s “constant cohort” with adequate diaries only comprised 27% of the cohort. Perhaps the study’s largest flaw was that only 29% of the initial 170 enrollees continued to 5 years, primarily because the study was originally planned for only 2 years. The SANTE trial partially compensated for drop-out bias with a “last observation carried forward” method, keeping participants in the analysis with their seizure frequency set at the time of discontinuation; no such correction was implemented in the MORE registry.
We still need better preoperative predictors of good responders. Epilepsy is a network disorder, and, over time, neuromodulation influences networks. Only recently have we come to recognize that the ANT is not always a major way-station for seizures involving the temporal lobe and probably not the optimal neuromodulation target for some temporal seizures.8,9 In experimental models, tailoring the stimulation frequency makes a big difference.10 Should we be using individual seizure characteristics to set stimulation parameters?
Despite the limitations of “real-world” registries, it is encouraging to observe efficacy close to that noted in the pivotal trial, improvement over time, and no major emergent unexpected side effects. As more (no pun intended) data accrue, patient outcomes should only improve.
References