A multicenter retrospective study of patients treated in the thalamus with responsive neurostimulation.

Introduction: For drug resistant epilepsy patients who are either not candidates for resective surgery or have already failed resective surgery, neuromodulation is a promising option. Neuromodulatory approaches include responsive neurostimulation (RNS), deep brain stimulation (DBS), and vagal nerve stimulation (VNS). Thalamocortical circuits are involved in both generalized and focal onset seizures. This paper explores the use of RNS in the centromedian nucleus of the thalamus (CMN) and in the anterior thalamic nucleus (ANT) of patients with drug resistant epilepsy. Methods: This is a retrospective multicenter study from seven different epilepsy centers in the United States. Patients that had unilateral or bilateral thalamic RNS leads implanted in the CMN or ANT for at least 6 months were included. Primary objectives were to describe the implant location and determine changes in the frequency of disabling seizures at 6 months, 1 year, 2 years, and > 2 years. Secondary objectives included documenting seizure free periods, anti-seizure medication regimen changes, stimulation side effects, and serious adverse events. In addition, the global clinical impression scale was completed. Results: Twelve patients had at least one lead placed in the CMN, and 13 had at least one lead placed in the ANT. The median baseline seizure frequency was 15 per month. Overall, the median seizure reduction was 33% at 6 months, 55% at 1 year, 65% at 2 years, and 74% at >2 years. Seizure free intervals of at least 3 months occurred in nine patients. Most patients (60%, 15/25) did not have a change in anti-seizure medications post RNS placement. Two serious adverse events were recorded, one related to RNS implantation. Lastly, overall functioning seemed to improve with 88% showing improvement on the global clinical impression scale. Discussion: Meaningful seizure reduction was observed in patients who suffer from drug resistant epilepsy with unilateral or bilateral RNS in either the ANT or CMN of the thalamus. Most patients remained on their pre-operative anti-seizure medication regimen. The device was well tolerated with few side effects. There were rare serious adverse events. Most patients showed an improvement in global clinical impression scores.

Magnetoencephalography-identified preictal spiking correlates to preictal spiking on stereotactic EEG.

Magnetoencephalography (MEG) is a noninvasive diagnostic modality that directly measures neuronal signaling by recording the magnetic field created from dendritic, intracellular, electrical currents of the neuron at the surface of the head. In clinical practice, MEG is used in the epilepsy presurgical evaluation and most commonly is an "interictal" study that can provide source localization of spike-wave discharges. However, seizures may be recorded during MEG ("ictal MEG") and mapping of these discharges may provide more accurate localization of the seizure onset zone. In addition, spike-negative EEG with unique MEG spike-waves may be present in up to 1/3 of MEG studies and unique MEG seizures (EEG-negative seizures) have been reported. This case report describes a patient with unique MEG seizures that exhibited MEG pre-ictal spiking in a tight cluster consistent with the independent interictal epileptiform activity. Stereotactic EEG demonstrated pre-ictal spiking concordant with the MEG pre-ictal spiking.

Brain-Responsive Neurostimulation for the treatment of adults with epilepsy in tuberous sclerosis complex: A case series.

OBJECTIVE: Tuberous sclerosis complex (TSC) is a genetic disorder primarily characterized by the development of multisystem benign tumors. Epilepsy is the most common neurologic manifestation, affecting 80%-90% of TSC patients. The diffuse structural brain abnormalities and the multifocal nature of epilepsy in TSC pose diagnostic challenges when evaluating patients for epilepsy surgery. METHODS: We retrospectively reviewed the safety experience and efficacy outcomes of five adult TSC patients who were treated with direct brain-responsive neurostimulation (RNS System, NeuroPace, Inc). RESULTS: The average follow-up duration was 20 months. All five patients were responders (≥50% disabling seizure reduction) at last follow-up. The median reduction in disabling seizures was 58% at 1 year and 88% at last follow-up. Three of the five patients experienced some period of seizure freedom ranging from 3 months to over 1 year. SIGNIFICANCE: In this small case series, we report the first safety experience and efficacy outcomes in patients with TSC-associated drug-resistant focal epilepsy treated with direct brain-responsive neurostimulation.

Brain-responsive corticothalamic stimulation in the centromedian nucleus for the treatment of regional neocortical epilepsy.

OBJECTIVE: The aim of the study was to determine if corticothalamic responsive stimulation targeting the centromedian nucleus of the thalamus (CMT) is a potential treatment for neocortical epilepsies with regional onsets. METHODS: We assessed efficacy and safety of CMT and neocortical responsive stimulation, detection, and stimulation programming, methods for implantation, and location and patterns of electrographic seizure onset and spread in 7 patients with medically intractable focal seizures with a regional neocortical onset. RESULTS: The median follow-up duration was 17 months (average: 17 months, range: 8-28 months). The median % reduction in disabling seizures (excludes auras) in the 7 patients was 88% (mean: 80%, range: 55-100%). The median % reduction in all seizure types (disabling + auras) was 73% (mean: 67%, range: 15-94%). There were no adverse events related to implantation of the responsive neurostimulator and leads or related to the delivery of responsive stimulation. Stimulation-related contralateral paresthesias were addressed by adjusting stimulation parameters in the clinic during stimulation testing. Electrographic seizures were detected in the CMT and neocortex in all seven patients. Four patients had simultaneous or near simultaneous seizure onsets in the neocortex and CMT and three had onsets in the neocortex with spread to the CMT. CONCLUSION: In this small series of patients with medically intractable focal seizures and regional neocortical onset, responsive neurostimulation to the neocortex and CMT improved seizure control and was well tolerated. SIGNIFICANCE: Responsive corticothalamic neurostimulation of the CMT and neocortex is a potential treatment for patients with regional neocortical epilepsies.

Real-world experience with direct brain-responsive neurostimulation for focal onset seizures.

OBJECTIVE: The RNS System is a direct brain-responsive neurostimulation system that is US Food and Drug Administration-approved for adults with medically intractable focal onset seizures based on safety and effectiveness data from controlled clinical trials. The purpose of this study was to retrospectively evaluate the real-world safety and effectiveness of the RNS System. METHODS: Eight comprehensive epilepsy centers conducted a chart review of patients treated with the RNS System for at least 1 year, in accordance with the indication for use. Data included device-related serious adverse events and the median percent change in disabling seizure frequency from baseline at years 1, 2, and 3 of treatment and at the most recent follow-up. RESULTS: One hundred fifty patients met the criteria for analysis. The median reduction in seizures was 67% (interquartile range [IQR] = 33%-93%, n = 149) at 1 year, 75% (IQR = 50%-94%, n = 93) at 2 years, 82% (IQR = 50%-96%, n = 38) at ≥3 years, and 74% (IQR = 50%-96%, n = 150) at last follow-up (mean = 2.3 years). Thirty-five percent of patients had a ≥90% seizure frequency reduction, and 18% of patients reported being clinically seizure-free at last follow-up. Seizure frequency reductions were similar regardless of patient age, age at epilepsy onset, duration of epilepsy, seizure onset in mesial temporal or neocortical foci, magnetic resonance imaging findings, prior intracranial monitoring, prior epilepsy surgery, or prior vagus nerve stimulation treatment. The infection rate per procedure was 2.9% (6/150 patients); five of the six patients had an implant site infection, and one had osteomyelitis. Lead revisions were required in 2.7% (4/150), and 2.0% (3/150) of patients had a subdural hemorrhage, none of which had long-lasting neurological consequences. SIGNIFICANCE: In this real-world experience, safety was similar and clinical seizure outcomes exceeded those of the prospective clinical trials, corroborating effectiveness of this therapy and suggesting that clinical experience has informed more effective programming.

A Comparison of Vagal Nerve Stimulation and Responsive Neurostimulation for the Treatment of Medically Refractory Complex Partial Epilepsy.

BACKGROUND: Neuromodulatory applications such as vagus nerve stimulation (VNS) and responsive neurostimulation (RNS) are safe and effective strategies for medically intractable epilepsy secondary to complex partial seizures, but researchers have yet to compare their efficacies. OBJECTIVE: The goal of this study is to compare VNS and RNS efficacy at reducing seizure frequency and complication rates in subjects with medically intractable epilepsy secondary to complex partial seizures. METHODS: This is a retrospective chart review of 30 patients with medically intractable complex partial epilepsy, who underwent either VNS or RNS placement at a single institution between June 2012 and January 2016. There was a mean follow-up of 19 months. Seizure frequency reduction and complications were identified. RESULTS: The median seizure frequency reduction was similar for VNS (66%) and RNS (58%). There was no major morbidity or mortality, and the frequency of minor complications was similar between VNS (15%) and RNS (18%). CONCLUSION: We found that VNS and RNS reduced the median seizure frequency similarly with no difference in morbidity or mortality. Further prospective studies are warranted as VNS and RNS therapy improves over time.

Intracranial electrographic analysis of preictal spiking and ictal onset in uni- and bitemporal epilepsy.

AIM: Ictal onset patterns in bilateral mesial temporal lobe epilepsy have not been comprehensively studied. A retrospective review of intracranial electrographic data was undertaken to establish whether it is possible to distinguish between unilateral and bilateral mesial temporal lobe epilepsy based on ictal onset patterns, including periodic preictal spiking. METHODS: A total of 470 ictal onset patterns were analyzed by bitemporal extraoperative electrocorticography in 13 patients with medically intractable mesial temporal lobe epilepsy. Ictal onset patterns were categorized, by frequency, as type A (<12 Hz), type B (12-40 Hz) and type C (>40 Hz). Preictal rhythmic spiking, of at least five seconds duration, and time to contralateral propagation were also measured with each ictal event. We determined if the proportion of "ictal onset pattern frequencies" or "incidence of preictal spiking" differed between unilateral and bilateral mesial temporal lobe epilepsy. RESULTS: Seven patients with unilateral mesial temporal lobe epilepsy received surgery and achieved Engel class I outcomes, while the remaining six did not undergo resective surgery, due to the bilateral ictal onsets in extraoperative electrocorticography. The proportion of patients experiencing any preictal spikes was higher in unitemporal than in bitemporal cases (100% vs 50%;p=0.069). Ofthe470 ictal onset patterns analyzed (174 unitemporal and 296 bitemporal), a significant greater percentage of preictal spikes was found in unilateral cases (78% unitemporal vs 14% bitemporal; p=0.002). Low-frequency patterns were more evident in bitemporal cases (45%) than in unitemporal (10%), although the difference was not statistically significant (p=0.129). No differences were detected between the unitemporal and bitemporal groups regarding age at onset or at presentation. CONCLUSION: A greater proportion of pre ictal spiking, based on extraoperative electrocorticography, was present in unilateral, compared to bilateral, mesial temporal lobe epilepsy. Further studies are warranted to determine the causal significance of preictal spiking in mesial temporal lobe epilepsy.

Retigabine as adjunctive therapy in adults with partial-onset seizures: integrated analysis of three pivotal controlled trials.

We assessed the efficacy and tolerability of retigabine (RTG; international non-proprietary name)/ezogabine (EZG; US adopted name) as adjunctive therapy in adults with partial-onset seizures in an integrated analysis of three trials. Studies 205, 301 (NCT00232596), and 302 (NCT00235755) were randomized, double-blind, placebo-controlled studies in adults having ≥4 partial-onset seizures per 28 days and receiving 1-3 antiepileptic drugs with/without vagus nerve stimulator. Patients underwent titration to RTG/EZG 600, 900, or 1200 mg/day or to placebo followed by 8 or 12 weeks maintenance. For efficacy analyses, placebo was compared with RTG/EZG 600 and 900 mg/day in Studies 205 and 302, and RTG/EZG 1200 mg/day in Studies 205 and 301. Responder rates (≥50% reduction in baseline seizure frequency) were 35% and 45% for RTG/EZG 600 and 900 mg/day, respectively (placebo=21%; p<0.001), and 50% for RTG/EZG 1200 mg/day (placebo=24%, p<0.001). Reductions in 28-day total partial-seizure frequency (medians: placebo=14%; 600 mg/day=26%, p=0.003; 900 mg/day=37%, p<0.001; placebo=15%; 1200 mg/day=39%, p<0.001) were significantly greater with all RTG/EZG doses vs. placebo from baseline to the double-blind phase, and similarly during the maintenance phase. The most commonly reported (>10%) treatment-emergent adverse events were dizziness, somnolence, headache, and fatigue. RTG/EZG demonstrated efficacy and was generally tolerated as adjunctive therapy in adults with partial-onset seizures in this integrated analysis.

Learning clinical neurophysiology: gaming is better than lectures.

We sought to find evidence for generalizability of a game and team oriented educational intervention in clinical neurophysiology in a neurology residency program. A prospective educational intervention was studied in a single neurology residency program and compared with a historical control. Seventeen PGY 2-4 residents studied neurophysiology in 2004-2005. The historical control was 20 PGY 2-4 residents from 1998 to 2002. The neurophysiology educational intervention consisted of weekly presentations, followed by a game show-type oral quiz which was team-based and required all residents to participate. The control group attended faculty-prepared didactic lectures. Outcome measures were percent correct subset neurophysiology Residency Inservice Training Examination scores. United States Medical Licensing Examination step 1 scores were also compared between the groups. Data were analyzed with analysis of variance methods accounting for multiple measurements. The mean+/-standard error neurophysiology subset percent correct Residency Inservice Training Examination score was 63.6+/-4.12 for the intervention group and 49.4+/-2.35 for the control (P=0.002). There was no difference in United States Medical Licensing Examination step 1 scores between the two groups (P=0.11). We found evidence for generalizability of the effectiveness of a team-oriented educational intervention in clinical neurophysiology with gaming and oral quizzing in improving subset Residency Inservice Training Examination performance compared with faculty prepared didactics.

Two prospective educational interventions in a neurology residency: effect on RITE performance.

BACKGROUND: To evaluate the effect of 2 educational interventions on Residency In-service Training Examination (RITE) scores. Two prospective educational interventions were studied in 2 consecutive neurology resident cohorts from a single program and compared with a historical control. Fourteen PGY 2-4 residents studied neuropharmacology in 2002-2003. Fifteen PGY 2-4 residents studied neuroanatomy in 2003-2004. The historical control were 20 PGY 2-4 residents from 1998-2002. Neuropharmacology educational intervention: residents prepared weekly presentations with weekly written quizzes, with quiz results available to the individual resident and program director. Neuroanatomy educational intervention: resident prepared weekly presentations, but quizzes were team based and oral, requiring resident participation. CONTROL GROUP: attended faculty prepared didactic lectures. Outcome measures were percent correct and yearly change in subset RITE scores. Data was analyzed with analysis of variance methods accounting for multiple measurements. REVIEW SUMMARY: The mean +/- standard error neuropharmacology subset percent correct RITE score was 43.3 +/- 1.94 for the intervention group and 47.3 +/- 1.91 for the control (P = 0.96), while the mean yearly percent correct change was 4.8 +/- 2.43 for the intervention group and 3.5 +/- 1.67 for the control (P = 0.71). The mean neuroanatomy subset percent correct RITE score was 60.3 +/- 3.54 for the intervention group and 50.9 +/- 3.04 for the control (P = 0.02), with a mean yearly percent correct change of 22.4 +/- 5.77 for the intervention group and 9.4 +/- 1.52 for the control (P = 0.02). CONCLUSION: A team-oriented intervention with oral quizzing resulted in improved subset RITE performance.

Effects of kindling and irradiation on neuronal density in the rat dentate gyrus.

Low-dose radiosurgery is presently in use as a treatment modality for focal epilepsy, but the mechanisms underlying the associated changes in seizure expression are poorly understood. We investigated whether total and parvalbumin expressing (PV+) neuronal densities within the hippocampus and amygdala are affected by analogous focal irradiation in amygdala-kindled rats. Adult rats were kindled by electrical stimulation through 10 stage 5 seizures. The kindled amygdala was then focally irradiated at 18 or 25 Gy, and generalized seizure thresholds were subsequently monitored for approximately 6 months. Histological and immunohistochemical assays of total and PV+ neuronal densities were performed bilaterally throughout the hippocampus and within the basolateral amygdala. PV+ neuronal densities were unaffected by kindling or irradiation in these regions. Kindling selectively reduced neuronal densities in the dentate granule cell layer, and medial CA3 pyramidal cell layer. Irradiation at 25 Gy, but not at 18 Gy, prevented or reversed this kindling-associated reduction in density.

Initiation of an effective neurology resident ethics curriculum.

The authors' neurology residency program used a case-based curriculum developed by the American Academy of Neurology's Ethics, Law and Humanities Committee to provide a resident education course in ethics. A pretest and post-test were developed and administered. A survey was completed at the end of the course to evaluate resident satisfaction. Post-test scores improved an average of 19% and this increase was significant (p < 0.0004). Residents found the course useful for their education and the time commitment acceptable.