Summary
Objective
We evaluated the efficacy and safety of deep brain anterior thalamus stimulation after 7 and 10 years, and report the incidence of sudden unexpected death in epilepsy (SUDEP) and ...overall mortality in adults in the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy (SANTÉ) study.
Methods
After the 3‐month blinded and 9‐month unblinded phases, subjects continued to be assessed during long‐term follow‐up (LTFU) and later a continued therapy access phase (CAP), to further characterize adverse events and the incidence of SUDEP. Stimulus parameter and medication changes were allowed.
Results
One hundred ten implanted subjects accumulated a total of 938 device‐years of experience (69 subjects during the LTFU phase and 61 subjects in the CAP phase). Prior to study closure, 57 active subjects continued therapy at 14 study centers, with follow‐up of at least 10 (maximum 14) years. At 7 years, median seizure frequency percent reduction from baseline was 75% (p < .001), with no outcome differences related to prior vagus nerve stimulation or resective surgery. The most severe seizure type, focal to bilateral tonic–clonic, was reduced by 71%. Adding new antiseizure medications did not impact the pattern of seizure reduction over time. There were no unanticipated serious adverse events in the study. The definite‐plus‐probable SUDEP rate, based on SANTÉ study experience (two deaths in 938 years) and previous pilot studies (0 deaths in 76 years), indicated a rate of 2.0 deaths for 1000 person‐years. Overall mortality was 6.9 deaths per 1000 person‐years.
Significance
The long‐term efficacy and safety profiles of the deep brain stimulation (DBS) system for epilepsy are favorable and demonstrate stable outcomes. Improvement in frequency of the most severe seizure type may reduce SUDEP risk. The SUDEP rate with DBS (2.0) is comparable to other neuromodulation treatments (i.e., vagus nerve stimulation, responsive neurostimulation) for drug‐resistant focal epilepsy.
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 investigatorsʼ 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.
The efficacy and safety of deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) for epilepsy (SANTE) trial was demonstrated by a randomized trial by Fisher et al. (2010). Based ...on this trial, the U.S. Food and Drug Administration recently granted approval for DBS therapy for epilepsy; the indication is as follows: “Bilateral stimulation of the anterior nucleus of the thalamus (ANT) for epilepsy is indicated as an adjunctive therapy for reducing the frequency of seizures in individuals 18 years of age or older diagnosed with epilepsy characterized by partial onset seizures with or without secondary generalization that are refractory to three or more antiepileptic medications”. This paper reviews the experimental data and the clinical experience using DBS for the treatment of epilepsy.
“This article is part of the Supplement issue Neurostimulation for Epilepsy.”
Objective
To describe the development of the Stereotactic Laser Ablation for Temporal Lobe Epilepsy study protocol in the context of current practice. An ideal treatment for drug‐resistant epilepsy ...remains an ongoing area of research. Although there are several options available, each has challenges that not only make deciding on the appropriate treatment not clear‐cut but also create difficulties in designing clinical studies to provide evidence in support of the treatment.
Methods
A prospective, single‐arm, multicenter study designed to evaluate safety and efficacy of the VisualaseTM MRI‐Guided Laser Ablation System for the treatment of temporal lobe epilepsy will include up to 150 patients with a primary efficacy endpoint of seizure freedom (defined as Engel Class I) for the first 12 months following the procedure and a primary safety endpoint of incidence of qualifying device‐, procedure‐, or anesthesia‐related adverse events through 12 months following the procedure.
Results
Primary endpoints will be assessed against historical values of safety and efficacy of anterior temporal lobectomy.
Significance
The scientific and payor communities typically demand randomized controlled trials (RCTs) as definitive evidence for safety and efficacy claims. However, in circumstances where the medical device has already been cleared by regulatory authorities and is readily available in the market, an RCT may not be feasible to execute. It is therefore crucial to gain acceptance by both the scientific community and regulators to design a study that will satisfy all concerned.
Sympathetic nerve activity is important to cardiac arrhythmogenesis.
The purpose of this study was to develop a method for simultaneous noninvasive recording of skin sympathetic nerve activity (SKNA) ...and electrocardiogram (ECG) using conventional ECG electrodes. This method (neuECG) can be used to adequately estimate sympathetic tone.
We recorded neuECG signals from the skin of 56 human subjects. The signals were low-pass filtered to show the ECG and high-pass filtered to show nerve activity. Protocol 1 included 12 healthy volunteers who underwent cold water pressor test and Valsalva maneuver. Protocol 2 included 19 inpatients with epilepsy but without known heart diseases monitored for 24 hours. Protocol 3 included 22 patients admitted with electrical storm and monitored for 39.0 ± 28.2 hours. Protocol 4 included 3 patients who underwent bilateral stellate ganglion blockade with lidocaine injection.
In patients without heart diseases, spontaneous nerve discharges were frequently observed at baseline and were associated with heart rate acceleration. SKNA recorded from chest leads (V
-V
) during cold water pressor test and Valsalva maneuver (protocol 1) was invariably higher than during baseline and recovery periods (P < .001). In protocol 2, the average SKNA correlated with heart rate acceleration (r = 0.73 ± 0.14, P < .05) and shortening of QT interval (P < .001). Among 146 spontaneous ventricular tachycardia episodes recorded in 9 patients of protocol 3, 106 episodes (73%) were preceded by SKNA within 30 seconds of onset. Protocol 4 showed that bilateral stellate ganglia blockade by lidocaine inhibited SKNA.
SKNA is detectable using conventional ECG electrodes in humans and may be useful in estimating sympathetic tone.
Objective
The safety, efficacy, and morbidity of radiosurgery (RS) must be established before it can be offered as an alternative to open surgery for unilateral mesial temporal lobe epilepsy. We ...report the 3‐year outcomes of a multicenter, prospective pilot study of RS.
Methods
RS was randomized to 20 or 24Gy targeting the amygdala, hippocampus, and parahippocampal gyrus. Seizure diaries evaluated the final seizure remission between months 24 and 36. Verbal memory was evaluated at baseline and 24m with the Wechsler Memory Scale–Revised (WMS‐R) and California Verbal Learning Test (CVLT). Patients were classified as having “significant improvement,” “no change,” and “significant impairment” based on relative change indices.
Results
Thirteen high‐dose and 17 low‐dose patients were treated. Both groups showed significant reductions in seizures by 1 year after treatment. At the 36‐month follow‐up evaluation, 67% of patients were free of seizures for the prior 12 months (high dose: 10/13, 76.9%; low dose: 10/17, 58.8%). Use of steroids, headaches, and visual field defects did not differ by dose or seizure remission. The prevalence of verbal memory impairment was 15% (4/26 patients); none declined on more than one measure. The prevalence of significant verbal memory improvements was 12% (3/26).
Interpretation
RS for unilateral mesial temporal lobe epilepsy offers seizure remission rates comparable with those reported previously for open surgery. There were no major safety concerns with high‐dose RS compared with low‐dose RS. Additional research is required to determine whether RS may be a treatment option for some patients with mesial temporal lobe epilepsy. Ann Neurol 2009
Patients with parietal lobe epilepsy (PLE) exhibit an electroclinical epilepsy syndrome that is rarely seen even at large epilepsy centers. Clinically, most patients with PLE exhibit a somatosensory ...aura that may include painful dysesthesias, though vertigo, aphasia, disturbances of one's body image also occur, when ictal propagation occurs from the parietal lobe to the supplementary motor area, hypermotor manifestations are noted. When temporolimbic propagation occurs, complex visual or auditory hallucinations and automatisms may appear. Scalp electroencephalogram (EEG) is often nonlocalizing. Ictal EEG is rarely localizing in PLE, and invasive EEG is often required for definitive localization and functional mapping. Recent advances in clinical neurophysiology during the evaluation of patients with refractory partial epilepsy include Ictal magnetic source imaging (MSI). Combined EEG and functional magnetic resonance imaging (EEG-fMRI) may be useful for patients with PLE to refine the localization in patients undergoing a presurgical evaluation. High-frequency oscillations (HFOs) are more concentrated inside the seizure onset zone (SOZ), indicating that they may be used as interictal scalp EEG biomarker for the SOZ. When medical therapy fails, resective epilepsy surgery can result in seizure freedom or significant reduction especially when a lesion is present.
Purpose: There are few studies of prolonged longitudinal follow‐up after temporal resections.
Methods: We analyzed 145 consecutive patients with temporal lobe epilepsy treated surgically. Patients ...had a comprehensive presurgical evaluation, including video‐EEG, psychometric testing, magnetic resonance imaging (MRI), single‐photon emission computed tomography (SPECT), intracarotid amobarbital procedure (IAP), and recently, volumetric head MRIs and F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) scans. Most had en bloc temporal resections, and a few had lesionectomies and resection of the epileptogenic zone. There was no surgical mortality. Longitudinal follow‐up data of the seizure outcome were analyzed by actuarial analysis. Patients were followed up at 6 weeks, 3 months, 6 months, and then on a yearly basis. The mean follow‐up was 5.6 years.
Results: Sixty‐six percent were seizure free at 1 year, 63% at 2 years, 60% at 5 years, and 55% at 10 years follow‐up. Moreover, 85%, became seizure free for ≤2 at the time of last follow‐up or had rare seizures. Patients who were seizure free for 1 and 2 years after surgery, had an 83% and 92% probability, respectively, of remaining seizure free at the time of last follow‐up. Ninety‐one percent of patients with small tumors and cavernous angiomas became seizure free compared with 69% of patients with hippocampal sclerosis.
Conclusions: Actuarial analysis showed that the long‐term surgical outcome of temporal lobe epilepsy remains favorable. Follow‐up at 1 and 2 years is highly predictive of the long‐term outcome. Patients with discrete lesions had the best outcome. Most of the patients with late recurrences had hippocampal sclerosis or temporal lobe gliosis. Some patients with postoperative seizures eventually became seizure free, reflecting the running‐down phenomenon.
Purpose: A prospective study to investigate health‐related quality of life (HRQOL) outcome in patients with temporal lobe epilepsy treated with anterior temporal lobectomy (ATL).
Methods: The ...majority of the patients with medically refractory focal epilepsy had Quality of Life in Epilepsy‐89 (QOLIE‐89) assessment at the time of prolonged video/EEG monitoring as part of their presurgical evaluation. Thirty‐seven patients who were not treated surgically constituted the control group, and 53 patients who underwent ATL made up the surgery group. Both control and surgery groups had HRQOL assessment repeated at ∼1‐ and 2‐year intervals. Repeated measures analysis of variance (ANOVA) was used to test for differences between the two groups.
Results: For the overall score and almost every scale, the surgery group had a higher baseline mean than the control group. Because of this baseline difference, change scores were used in further analysis. The overall score and 10 of 17 scales in QOLIE‐89 showed significant HRQOL improvement after ATL, and the improvement was significant relative to score changes of the nonsurgical comparison group. Scores improved in overall QOL, emotional well‐being, attention/concentration, language, social isolation, health perception, role limitations‐physical, work/drive/social, health discouragement, and seizure worry. For the first five scales, there was group‐time interaction; the improvement was significantly more on the 2‐year than on the 1‐year follow‐up. When the surgery patients were divided into four categories (class IA‐, completely seizure free; class IA+, seizure free with aura; class II, rare seizures; class III, worthwhile improvement in seizure control; and class IV, no improvement), the improved HRQOL in the surgery group was almost entirely contributed by the class IA‐ outcome patients who were totally seizure free. The class IA+ patients with continuing aurae and class II/III/IV patients had no significant improvement in their overall HRQOL scores at 1‐ or 2‐year follow‐up.
Conclusions: Overall score and 10 of the 17 scales of QOLIE‐89 significantly improved in patients with medically refractory temporal lobe epilepsy after ATL. For some scales, there was delay in the improvement to manifest. The HRQOL improvement was related to achieving an entirely seizure‐free status (i.e., no seizures or aurae postoperatively).
OBJECTIVETo prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years.
METHODSAdults 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.
RESULTSOf 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 χ).
CONCLUSIONSAdjunctive 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.
CLINICALTRIALS.GOV IDENTIFIERNCT00572195.
CLASSIFICATION OF EVIDENCEThis study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.
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