Epilepsy is defined by the seemingly random occurrence of spontaneous seizures. The ability to anticipate seizures would enable preventative treatment strategies. A central but unresolved question concerns the relationship of seizure timing to fluctuating rates of interictal epileptiform discharges (here termed interictal epileptiform activity, IEA), a marker of brain irritability observed between seizures by electroencephalography (EEG). Here, in 37 subjects with an implanted brain stimulation device that detects IEA and seizures over years, we find that IEA oscillates with circadian and subject-specific multidien (multi-day) periods. Multidien periodicities, most commonly 20–30 days in duration, are robust and relatively stable for up to 10 years in men and women. We show that seizures occur preferentially during the rising phase of multidien IEA rhythms. Combining phase information from circadian and multidien IEA rhythms provides a novel biomarker for determining relative seizure risk with a large effect size in most subjects.

ObjectiveTo demonstrate the safety and effectiveness of responsive stimulation at the seizure focus as an adjunctive therapy to reduce the frequency of seizures in adults with medically intractable partial onset seizures arising from one or two seizure foci.MethodsRandomized multicenter double-blinded controlled trial of responsive focal cortical stimulation (RNS System). Subjects with medically intractable partial onset seizures from one or two foci were implanted, and 1 month postimplant were randomized 1:1 to active or sham stimulation. After the fifth postimplant month, all subjects received responsive stimulation in an open label period (OLP) to complete 2 years of postimplant follow-up.ResultsAll 191 subjects were randomized. The percent change in seizures at the end of the blinded period was −37.9% in the active and −17.3% in the sham stimulation group (p = 0.012, Generalized Estimating Equations). The median percent reduction in seizures in the OLP was 44% at 1 year and 53% at 2 years, which represents a progressive and significant improvement with time (p < 0.0001). The serious adverse event rate was not different between subjects receiving active and sham stimulation. Adverse events were consistent with the known risks of an implanted medical device, seizures, and of other epilepsy treatments. There were no adverse effects on neuropsychological function or mood.SignificanceResponsive stimulation to the seizure focus reduced the frequency of partial-onset seizures acutely, showed improving seizure reduction over time, was well tolerated, and was acceptably safe. The RNS System provides an additional treatment option for patients with medically intractable partial-onset seizures.

Objective:The long-term efficacy and safety of responsive direct neurostimulation was assessed in adults with medically refractory partial onset seizures.Methods:All participants were treated with a cranially implanted responsive neurostimulator that delivers stimulation to 1 or 2 seizure foci via chronically implanted electrodes when specific electrocorticographic patterns are detected (RNS System). Participants had completed a 2-year primarily open-label safety study (n = 65) or a 2-year randomized blinded controlled safety and efficacy study (n = 191); 230 participants transitioned into an ongoing 7-year study to assess safety and efficacy.Results:The average participant was 34 (±11.4) years old with epilepsy for 19.6 (±11.4) years. The median preimplant frequency of disabling partial or generalized tonic-clonic seizures was 10.2 seizures a month. The median percent seizure reduction in the randomized blinded controlled trial was 44% at 1 year and 53% at 2 years (p < 0.0001, generalized estimating equation) and ranged from 48% to 66% over postimplant years 3 through 6 in the long-term study. Improvements in quality of life were maintained (p < 0.05). The most common serious device-related adverse events over the mean 5.4 years of follow-up were implant site infection (9.0%) involving soft tissue and neurostimulator explantation (4.7%).Conclusions:The RNS System is the first direct brain responsive neurostimulator. Acute and sustained efficacy and safety were demonstrated in adults with medically refractory partial onset seizures arising from 1 or 2 foci over a mean follow-up of 5.4 years. This experience supports the RNS System as a treatment option for refractory partial seizures.Classification of evidence:This study provides Class IV evidence that for adults with medically refractory partial onset seizures, responsive direct cortical stimulation reduces seizures and improves quality of life over a mean follow-up of 5.4 years.

SUMMARYObjective: Evaluate the seizure-reduction response and safety of mesial temporal lobe (MTL) brain-responsive stimulation in adults with medically intractable partial-onset seizures of mesial temporal lobe origin. Methods: Subjects with mesial temporal lobe epilepsy (MTLE) were identified from prospective clinical trials of a brain-responsive neurostimulator (RNS System, NeuroPace). The seizure reduction over years 2-6 postimplantation was calculated by assessing the seizure frequency compared to a preimplantation baseline. Safety was assessed based on reported adverse events. Results: There were 111 subjects with MTLE; 72% of subjects had bilateral MTL onsets and 28% had unilateral onsets. Subjects had one to four leads placed; only two leads could be connected to the device. Seventy-six subjects had depth leads only, 29 had both depth and strip leads, and 6 had only strip leads. The mean follow-up was 6.1 AE (standard deviation) 2.2 years. The median percent seizure reduction was 70% (last observation carried forward). Twenty-nine percent of subjects experienced at least one seizure-free period of 6 months or longer, and 15% experienced at least one seizure-free period of 1 year or longer. There was no difference in seizure reduction in subjects with and without mesial temporal sclerosis (MTS), bilateral MTL onsets, prior resection, prior intracranial monitoring, and prior vagus nerve stimulation. In addition, seizure reduction was not dependent on the location of depth leads relative to the hippocampus. The most frequent serious device-related adverse event was soft tissue implant-site infection (overall rate, including events categorized as device-related, uncertain, or not device-related: 0.03 per implant year, which is not greater than with other neurostimulation devices). Significance: Brain-responsive stimulation represents a safe and effective treatment option for patients with medically intractable epilepsy, including patients with unilateral or bilateral MTLE who are not candidates for temporal lobectomy or who have failed a prior MTL resection.

references) using comprehensive electronic search strategies combining terms "epilepsy", "seizures", "prediction", "forecasting", "cycles", "patterns", "circadian", and "multidien", with no language restrictions. Identified studies used different outcome measures, but most involved analyses of electroencephalography (EEG) to predict seizures minutes in advance, with variable success. A single prospective trial of an implanted device for chronic EEG demonstrated abovechance accuracy of warnings for imminent seizures in 9 out of 15 enrolled subjects. Two studies in independent cohorts of subjects chronically implanted with intracranial electrodes showed that rates of interictal epileptiform activity oscillate in circadian and multiday (multidien) cycles that help determine seizure likelihood. Circadian cycles and seizure diaries were used in three studies to forecast seizures over short horizons, but we found no results on forecasting seizures several days in advance. Added value of this study:In a large cohort of people with drug-resistant focal epilepsy who had chronic EEG recorded by an approved clinical device, we demonstrate that circadian and multidien cycles can be leveraged to forecast seizures up to three days in advance in some subjects and 24 hours in advance in the majority of subjects. These results highlight the feasibility of seizure forecasting over horizons longer than previously possible. Implications of all the available evidence: Seizures are not entirely random events. Using cyclical patterns of brain activity to forecast seizures hours to days in advance may enable novel seizure warning systems and prevention strategies. Convergence of findings from multiple independent datasets suggests the generalizability of this approach in people with epilepsy, though this will require direct testing in prospective clinical trials.