Nine-year prospective efficacy and safety of brain-responsive neurostimulation for focal epilepsy.

OBJECTIVE: To prospectively evaluate safety and efficacy of brain-responsive neurostimulation in adults with medically intractable focal onset seizures (FOS) over 9 years. METHODS: Adults 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. RESULTS: Of 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 χ2). CONCLUSIONS: Adjunctive 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. CLINICALTRIALSGOV IDENTIFIER: NCT00572195. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that brain-responsive neurostimulation significantly reduces focal seizures with acceptable safety over 9 years.

Sudden unexpected death in epilepsy in patients treated with brain-responsive neurostimulation.

OBJECTIVE: To study the incidence and clinical features of sudden unexpected death in epilepsy (SUDEP) in patients treated with direct brain-responsive stimulation with the RNS System. METHODS: All deaths in patients treated in clinical trials (N = 256) or following U.S. Food and Drug Administration (FDA) approval (N = 451) through May 5, 2016, were adjudicated for SUDEP. RESULTS: There were 14 deaths among 707 patients (2208 postimplantation years), including 2 possible, 1 probable, and 4 definite SUDEP events. The rate of probable or definite SUDEP was 2.0/1000 (95% confidence interval [CI] 0.7-5.2) over 2036 patient stimulation years and 2.3/1000 (95% CI 0.9-5.4) over 2208 patient implant years. Stored electrocorticograms around the time of death were available for 4 patients with probable/definite SUDEP and revealed the following: frequent epileptiform activity ending abruptly (n = 2), no epileptiform activity or seizures (n = 1), and an electrographic and witnessed seizure with cessation of postictal electrocorticography (ECoG) activity associated with apnea and pulselessness (n = 1). SIGNIFICANCE: The SUDEP rate of 2.0/1000 patient stimulation years among patients treated with the RNS System is favorable relative to treatment-resistant epilepsy patients randomized to the placebo arm of add-on drug studies or with seizures after resective surgery. Our findings support that treatments that reduce seizures reduce SUDEP risk and that not all SUDEPs follow seizures.

Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas.

OBJECTIVE: Evaluate the seizure-reduction response and safety of brain-responsive stimulation in adults with medically intractable partial-onset seizures of neocortical origin. METHODS: Patients with partial seizures of neocortical origin 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. Additional analyses considered safety and seizure reduction according to lobe and functional area (e.g., eloquent cortex) of seizure onset. RESULTS: There were 126 patients with seizures of neocortical onset. The average follow-up was 6.1 implant years. The median percent seizure reduction was 70% in patients with frontal and parietal seizure onsets, 58% in those with temporal neocortical onsets, and 51% in those with multilobar onsets (last observation carried forward [LOCF] analysis). Twenty-six percent of patients experienced at least one seizure-free period of 6 months or longer and 14% experienced at least one seizure-free period of 1 year or longer. Patients with lesions on magnetic resonance imaging (MRI; 77% reduction, LOCF) and those with normal MRI findings (45% reduction, LOCF) benefitted, although the treatment response was more robust in patients with an MRI lesion (p = 0.02, generalized estimating equation [GEE]). There were no differences in the seizure reduction in patients with and without prior epilepsy surgery or vagus nerve stimulation. Stimulation parameters used for treatment did not cause acute or chronic neurologic deficits, even in eloquent cortical areas. The rates of infection (0.017 per patient implant year) and perioperative hemorrhage (0.8%) were 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 adults with seizures of neocortical onset, and those with onsets from eloquent cortex.

Brain-responsive neurostimulation in patients with medically intractable mesial temporal lobe epilepsy.

OBJECTIVE: 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 ± (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.

Using a structured questionnaire improves seizure description by medical students.

OBJECTIVE: The purpose of this study was to evaluate a structured questionnaire for improving a medical students' ability to identify, describe and interpret a witnessed seizure. METHODS: Ninety two 3rd year medical students, blinded to seizure diagnosis, viewed videos of a primary generalized seizure and a complex partial seizure. Students next completed an unstructured questionnaire that asked the students to describe the seizure video recordings. The students then completed a structured questionnaire that asked the student to respond to 17 questions regarding specific features occurring during the seizures. We determined the number and types of correct responses for each questionnaire. RESULTS: Overall, the structured questionnaire was more effective in eliciting an average of 9.25 correct responses compared to the unstructured questionnaire eliciting an average of 5.30 correct responses (p < 0.001). Additionally, 10 of the 17 seizure features were identified more effectively with the structured questionnaire. Potentially confounding factors, prior knowledge of someone with epilepsy or a prior experience of viewing a seizure, did not predict the student's ability to correctly identify any of the 17 features. CONCLUSIONS: A structured questionnaire significantly improves a medical student's ability to provide an accurate clinical description of primary generalized and complex partial witnessed seizures. Our analysis identified the 10 specific features improved by using the structured questionnaire.

Long-term treatment with responsive brain stimulation in adults with refractory partial 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.

Posterior quadrant epilepsy surgery: predictors of outcome.

PURPOSE: To identify predictors of seizure recurrence following posterior quadrant epilepsy surgery. METHODS: Between 1983 and 2008, 43 medically refractory epilepsy patients underwent posterior quadrant epilepsy surgery. Epilepsy surgery involved the occipital lobe in all cases; some cases also included resection of the adjacent parietal or temporal cortex. Using a logistic regression model, we evaluated the relationship between outcome (Engel class I-IV) and 5 outcome predictors: absence of a visual aura, a temporal lobe type aura, versive head movement unaccompanied by a visual aura, non-focal interictal scalp EEG, and surgical pathology other than low grade tumor or cortical dysplasia. We also determined the relative risk for significant post-operative cognitive decline of Wechsler intelligence test score among those receiving complete lobectomies compared to those receiving partial lobectomies. RESULTS: Overall, outcome was favorable at 1 year following surgery: 22 (51.2%) patients Engel class I, 10 (24%) patients Engel class II, 5 (12%) patients Engel class III, and 6 (14%) patients Engel class IV. The 3 best univariate predictors of seizure recurrence were versive head movement unaccompanied by visual aura, non-focal interictal scalp EEG, and pathology other than low grade tumor or cortical dysplasia. A multivariate predictor combining temporal lobe type aura, versive head movement unaccompanied by visual aura, non-focal interictal scalp EEG, and pathology other than low grade tumor or cortical dysplasia was optimum. Complete lobectomy significantly increased the risk of post-operative decline of Wechsler intelligence score. CONCLUSIONS: These findings indicate that posterior quadrant epilepsy surgery may provide sustained seizure control. A multivariate model combining temporal lobe type aura, versive head movement unaccompanied by a visual aura, non-focal interictal scalp EEG, and pathology other than low grade tumor or cortical dysplasia may contribute to predicting seizure recurrence following posterior quadrant epilepsy surgery. The extent of cortical resection may predict significant cognitive decline in post-operative Wechsler intelligence score.

Abnormal interictal gamma activity may manifest a seizure onset zone in temporal lobe epilepsy.

Even though recent studies have suggested that seizures do not occur suddenly and that before a seizure there is a period with an increased probability of seizure occurrence, neurophysiological mechanisms of interictal and pre-seizure states are unknown. The ability of mathematical methods to provide much more sensitive tools for the detection of subtle changes in the electrical activity of the brain gives promise that electrophysiological markers of enhanced seizure susceptibility can be found even during interictal periods when EEG of epilepsy patients often looks 'normal'. Previously, we demonstrated in animals that hippocampal and neocortical gamma-band rhythms (30-100 Hz) intensify long before seizures caused by systemic infusion of kainic acid. Other studies in recent years have also drawn attention to the fast activity (>30 Hz) as a possible marker of epileptogenic tissue. The current study quantified gamma-band activity during interictal periods and seizures in intracranial EEG (iEEG) in 5 patients implanted with subdural grids/intracranial electrodes during their pre-surgical evaluation. In all our patients, we found distinctive (abnormal) bursts of gamma activity with a 3 to 100 fold increase in power at gamma frequencies with respect to selected by clinicians, quiescent, artifact-free, 7-20 min "normal" background (interictal) iEEG epochs 1 to 14 hours prior to seizures. Increases in gamma activity were largest in those channels which later displayed the most intensive electrographic seizure discharges. Moreover, location of gamma-band bursts correlated (with high specificity, 96.4% and sensitivity, 83.8%) with seizure onset zone (SOZ) determined by clinicians. Spatial localization of interictal gamma rhythms within SOZ suggests that the persistent presence of abnormally intensified gamma rhythms in the EEG may be an important tool for focus localization and possibly a determinant of epileptogenesis.

Closed-loop stimulation in the control of focal epilepsy of insular origin.

BACKGROUND: Previous studies have shown that closed-loop or responsive neurostimulation can abort induced or spontaneous epileptiform discharges. OBJECTIVE: To assess the effectiveness of a programmable cranially implanted closed-loop neurostimulation system in the control of seizures originating from an area relatively inaccessible by open craniotomy. METHOD: A patient with drug-resistant partial epilepsy had previously undergone open resection of the left frontal opercular cortex and the underlying insular area. Although subdural-depth electrode ictal recordings had been nonlocalizing, depth electrode insular stimulation had produced the patient's habitual aura. Postoperatively, there was a sustained 50% reduction in seizure frequency. The residual seizures were identical to the preoperative seizures. Repeat depth electrode monitoring revealed that the ictal focus was immediately posterior to the previously resected insular area. A closed-loop cranial internal pulse generator system including left anterior insular and posterior orbitofrontal depth electrodes was implanted. RESULT: There was an additional 60% reduction of seizures. CONCLUSION: Preliminary observation indicates that responsive neurostimulation may be an effective alternative to higher-risk resective epilepsy surgery.

Implantation of a closed-loop stimulation in the management of medically refractory focal epilepsy: a technical note.

Open-loop stimulation studies have shown varying control of seizures with stimulation of different anatomical targets. A recent multi-institutional clinical study utilizing an external closed-loop stimulation system had promising results. A novel implantable closed-loop Responsive Neurostimulation System (RNS) (Neuropace, Inc., Mountainview, Calif., USA) consisting of a cranially implanted pulse generator, one or two quadripolar subdural strip or depth leads and a programmer is under testing in a prospective clinical trial. The RNS pulse generator continuously analyzes the patient's electrocortigrams (ECoGs) and automatically triggers electrical stimulation when specific ECoG characteristics programmed by the clinician, as indicative of electrographic seizures or precursor of epileptiform activities, are detected. The pulse generator then stores diagnostic information detailing detections and stimulations, including multichannel stored ECoGs. The RNS programmer communicates transcutaneously with the implanted pulse generator when initiated by a clinician. The RNS programmer can download diagnostics and store ECoGs for review. The RNS programmer can then be used to program detection and stimulation parameters. In our current communication, we describe the selection criteria for implanting this system, the preparation of the surgical candidates as well as the surgical technique. We also present our preliminary results with 8 patients who had an RNS implanted. Seven patients (87.5%) had more than 45% decrease in their seizure frequency. The mean follow-up time in our series was 9.2 months. The implantation of a closed-loop stimulation system, in our experience, represents a safe and relatively simple surgical procedure. However, the efficacy of this new treatment modality remains to be determined in further multi-institutional, prospective clinical studies.

Spontaneous motor cortex encephalocele presenting with simple partial seizures and progressive hemiparesis. Case report and review of the literature.

Several cases of congenital or acquired temporal encephaloceles have been reported in the literature as the causative mechanism of simple and/or complex partial seizures. In this report the authors describe a rare case of spontaneous parietal encephalocele presenting with simple partial seizures and progressively increasing contralateral upper-extremity motor deficit. The unusual anatomical location of an encephalocele associated with seizures and the delayed seizure onset represent distinctive characteristics in this case. Preoperative imaging included surface electroencephalography, computerized tomography, and brain magnetic resonance imaging. Frameless neuronavigation and intraoperative cortical mapping were used to aid resection of the encephalocele, and the dural and bone defects were reconstructed. The surgical outcome in this case was excellent, and the patient has remained seizure free. The pertinent literature is reviewed in this report.

Effect of an external responsive neurostimulator on seizures and electrographic discharges during subdural electrode monitoring.

PURPOSE: Approved neural-stimulation therapies for epilepsy use prolonged intermittent stimulation paradigms with no ability to respond automatically to seizures. METHODS: A responsive neurostimulator that can automatically analyze electrocortical potentials, detect electrographic seizures, and rapidly deliver targeted electrical stimuli to suppress them was evaluated in an open multicenter trial in 50 patients, 40 of whom received responsive cortical stimulation via subdural electrodes implanted for epilepsy surgery evaluations. RESULTS: Four patients, ages 15 to 28 years, monitored at three institutions, with clinical and electrographic response to neurostimulation, are described. Electrographic seizures were altered and suppressed in these patients during trials of neurostimulation lasting < or =68 h, with no major side effects. In one patient, stimulation appeared also to improve the baseline EEG. CONCLUSIONS: Responsive cortical neurostimulation may be a safe and effective treatment for partial epilepsy. This information was derived from a small group of patients in an observation study. A double-blind, controlled Food and Drug Administration (FDA)-approved study of a permanently implanted responsive neurostimulation system to treat medically refractory partial seizures is under way.

A 10-year experience with magnetic source imaging in the guidance of epilepsy surgery.

Magnetic source imaging (MSI) of interictal epileptiform dipoles was studied in 100 epilepsy surgery candidates. Sixty underwent surgery. MSI epileptiform data were classified as focal, regional, multifocal, scattered or none. Resections of MSI epileptiform foci were classified as extensive (EXT) versus partial or none (P/N). MSI interictal epileptiform dipoles were found in 22 of 27 anterior temporal (ATL) cases, and in 31 of 33 extratemporal (XMT) cases. Of 10 EXT ATL cases, 5 (50%) were seizure free (SF). Of 12 P/N ATL cases, 7 (58%) were SF. Of 10 nonlesional EXT XMT resections, 8 (80%) were SF. Of 10 nonlesional P/N XMT resections, 1 (10%) was SF. Neither focality of MSI data or spatial agreement of electrographic and MSI data significantly affected outcomes.