Abstract
Long-Term Efficacy and Safety of Thalamic Stimulation for Drug-Resistant Partial Epilepsy
Salanova V, Witt T, Worth R, Henry TR, Gross RE, Nazzaro JM, Labar D, Sperling MR, Sharan A, Sandok E, Handforth A, Stern JM, Chung S, Henderson JM, French J, Baltuch G, Rosenfeld WE, Garcia P, Barbaro NM, Fountain NB, Elias WJ, Goodman RR, Pollard JR, Tröster AI, Irwin CP, Lambrecht K, Graves N, Fisher R; SANTE Study Group. Neurology 2015;84:2017–1025.
OBJECTIVE: To report long-term efficacy and safety results of the SANTE trial investigating deep brain stimulation of the anterior nucleus of the thalamus (ANT) for treatment of localization-related epilepsy. METHODS: This long-term follow-up is a continuation of a previously reported trial of 5- vs 0-V ANT stimulation. Long-term follow-up began 13 months after device implantation with stimulation parameters adjusted at the investigators’ discretion. Seizure frequency was determined using daily seizure diaries. RESULTS: The median percent seizure reduction from baseline at 1 year was 41%, and 69% at 5 years. The responder rate (=50% reduction in seizure frequency) at 1 year was 43%, and 68% at 5 years. In the 5 years of follow-up, 16% of subjects were seizure-free for at least 6 months. There were no reported unanticipated adverse device effects or symptomatic intracranial hemorrhages. The Liverpool Seizure Severity Scale and 31-item Quality of Life in Epilepsy measure showed statistically significant improvement over baseline by 1 year and at 5 years p (< 0.001). CONCLUSION: Long-term follow-up of ANT deep brain stimulation showed sustained efficacy and safety in a treatment-resistant population. CLASSIFICATION OF EVIDENCE: This long-term follow-up provides Class IV evidence that for patients with drug-resistant partial epilepsy, anterior thalamic stimulation is associated with a 69% reduction in seizure frequency and a 34% serious device-related adverse event rate at 5 years.
Commentary
One-third of all patients with epilepsy are medically intractable and have increased risks of psychiatric and cognitive comorbidities as well as higher mortality rates. Despite the proliferation of newer generation antiseizure medications in the past two decades, approximately one-fifth of persons with generalized epilepsies and up to half of those with focal epilepsies continue to be pharmacoresistant (1). Epilepsy surgery can be very effective in some intractable subjects, but is heavily underutilized (2), and only half of patients evaluated for resective surgery are found to be good surgical candidates (3). Available treatments for intractable epilepsy include diet therapies and electric stimulation.
Interest in electrical stimulation for treatment of intractable epilepsy is not new, but controlled trials are rare. Stimulation has targeted the cerebellum, hippocampus, subthalamic nucleus, caudate nucleus, centromedian nucleus, seizure focus (4), white matter tracts (5), and anterior nucleus of the thalamus (ANT). The latter target has been studied in a large, blinded, randomized, controlled trial, the electrical Stimulation of the Anterior Nucleus of Thalamus for Epilepsy (SANTE) trial (6), which showed a significant reduction in mean seizure frequency in the stimulated group. A total of 110 patients with intractable focal seizures at 17 sites were enrolled and randomized to 5-V versus 0-V stimulation. During the 3-month blinded phase of the trial, the treatment group experienced 38% reduction of seizure frequency compared with 14.5% in the 0-V group. Subgroup analysis showed greater seizure reduction in those with temporal lobe epilepsy. ANT stimulation was generally safe, with unproven worsening of depression or memory, but no death. In the unblinded phase of the SANTE, the efficacy of ANT stimulation improved over time with 41% median seizure frequency reduction at 13 months and 56% at 2 years. The rates of those who achieved =50% reduction in seizure rates also continued to increase, reaching 43% at 13 months, 54% at 2 years, and 67% at 3 years (6).
Salanova et al. (7) recently published the results of a long-term follow-up of safety and efficacy of the SANTE trial beginning at 13 months after device implantation and continuing for 4 years. During the follow-up, antiseizure medication regimens and stimulation parameters were changed at the discretion of the treating investigators. The follow-up provided Class IV evidence that ANT stimulation was associated with a 69% reduction in seizures and a 34% serious device-related adverse event rate at 5 years. The rates of those who achieved =50% reduction in seizure rates were 43% at 1 year and 68% at 5 years. In addition, 16% of subjects with implants reported at least 6 months of seizure freedom, and six subjects experienced seizure freedom for more than 2 continuous years. The median reduction of seizure frequency by 5 years was 76% for those with temporal lobe epilepsy compared with 59% for those with frontal lobe epilepsy. The investigators also reported improvement of quality of life as assessed by the 31-item Quality of Life in Epilepsy measure and improvement in seizure severity as assessed by the Liverpool Seizure Severity Scale (p < 0.001). Neuropsychological testing revealed statistically significant improvements in attention, executive function, anxiety, depression, and cognition.
Serious adverse events occurred in 35.5% of subjects, including infection at the implant site in 10% and the lead not being within target in 8.2%. Depression was reported in 37.3% of subjects, of whom 66% had a history of depression. In addition, suicidal ideation was reported by 11.8% of the subjects, and one subject completed suicide. Memory impairment occurred in 27.3% and was not related to stimulation parameters or seizure frequency. Four cases of sudden unexplained death in epilepsy occurred in the course of the study.
Interestingly, during the five years of the study, 58% of the subjects added at least one antiseizure medication. In almost half of these subjects, the added medication was lacosamide, which was approved as an adjunctive treatment for focal epilepsy in the United States in 2008. However, no specific medication was associated with improvement, and seizure reduction was similar in subjects with added medications and those without added medications. Similarly, subjects with and without prior VNS both experienced 69% seizure reduction at 5 years. In addition, seizure improvement did not appear to be related to stimulation parameters.
The benefit achieved by ANT simulation is comparable with that reported in VNS studies (8) and the NeuroPace Responsive Neurostimulator (RNS). A recent long-term follow-up of patients treated with RNS found seizure reduction in 56% of 126 subjects and improvements in quality-of-life measures (9). Regardless of the mode of neuromodulation, whether stimulating a cranial nerve, the actual seizure focus in a closed-loop manner, or a thalamic nucleus in a scheduled manner, the benefits appear to be comparable in terms of improvement of seizure frequency and continue to improve over time, and a very small percentage of patients achieve seizure freedom. It is difficult to speculate on the mechanisms of continued improvement in the long term, but they may be related to induction of plastic changes in the seizure network that limit seizure origination or propagation. Of note, the reported benefits of ANT stimulation do not appear to be overestimated by dropout of subjects not benefiting from the device as the authors considered that factor in the analysis of this study. Finally, the fact that the authors found no stimulation parameter to be favorable may be related to the heterogeneity of focal epilepsy in terms of localization and pathophysiology. In the future, we may see more data from ANT stimulation that will help identify subsets of patients who will benefit the most from this modality.