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.

The ventral precuneal-posterior cingulate region as a site of epileptogenicity

The ventral precuneal and posterior cingulate area (VP-PC) represents a distinct but topographically variable mesial parietal site of epileptogenicity that may manifest as a common temporal lobe-mediated ictal expression. In a review of records of 62 presumptive epilepsy surgery cases, two cases of primary epileptogenicity expressed within the VP-PC were identified and are detailed to bring attention to this electroencephalographically-hidden area of ictal expression. Details of their investigation and surgical treatment illustrate distinctly different approaches addressing the problem and bringing about a seizure-free outcome.

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 corticothalamic stimulation in the pulvinar nucleus for the treatment of regional neocortical epilepsy: A case series.

Drug-resistant focal epilepsy with regional neocortical seizure onsets originating from the posterior quadrant can be particularly difficult to treat with resective surgery due to the overlap with eloquent cortex. Published reports indicate that corticothalamic treatment targeting the anterior or centromedian nucleus of the thalamus with direct brain-responsive stimulation may be an effective approach to treat regional neocortical epilepsy. The pulvinar has remained largely unstudied as a neurostimulation target to treat refractory epilepsy. Because the pulvinar has connections with the posterior quadrant, neurostimulation may be effective if applied to seizures originating in this area. We performed a retrospective chart review of patients with regional neocortical seizure onsets in the posterior quadrant treated with the RNS System. Demographics, epilepsy history, clinical seizure frequencies, and neuropsychological testing results were obtained from the chart. Electrocorticogram (ECoG) records stored by the RNS System were reviewed to evaluate electrographic seizure onset patterns. Our patients were followed for 10, 12.5, and 15 months. All patients were responders (≥50% seizure reduction), and two of the three patients experienced a ≥90% reduction in seizures at the last follow-up. Pre- and postsurgical neuropsychological evaluations were compared for two of the patients, and there was no evidence of cognitive decline found in either patient. Interestingly, mild cognitive improvements were reported. The third patient had only postimplant neuropsychological testing data available. Findings for this patient suggested executive dysfunction that was present prior to the RNS System which did not worsen with surgery. A visual inspection of ECoGs revealed near-simultaneous seizure onsets in neocortical and pulvinar leads in two patients. Seizure onsets in the third patient were more variable. This is the first published report of brain-responsive neurostimulation targeting the pulvinar to treat refractory regional onset epilepsy of posterior quadrant origin.

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.

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.

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.

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.