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Abstract The responsive neurostimulator (RNS ®, NeuroPace Inc.) has been available clinically since 2013 for the treatment of medically refractory partial epilepsy. Using intracranial electrodes and a cranially implanted device, RNS ® provides on-demand electrical cortical stimulation to reduce seizures. A randomized, multicenter, double-blind clinical trial demonstrated seizure reduction compared with sham stimulation. Seizure reduction was improved and sustained over years in a long-term treatment trial. The RNS ® provides chronic ambulatory electrographic monitoring over years giving unprecedented insight into epilepsy dynamics. Studies to date have looked at the length of time to detecting bilateral seizure onsets in mesial temporal lobe epilepsy (MTLE), demonstrated biorhythms in interictal epileptiform activity over varied time scales, and shown promise in early detection of benefits of adding a new antiepileptic drug. Questions remain as to the boundaries of patient selection and lead placement. "This article is part of the Supplement issue Neurostimulation for Epilepsy." Highlights • RNS ® is closed-loop stimulation in response to ECOG seizure detections. • Seizure reduction was significant and sustained up to 8 years. • Chronic ECOG provides unprecedented insights into focal epilepsy dynamics. • Neurostimulation may require different considerations than typical epilepsy surgery. [ABSTRACT FROM AUTHOR]

Abstract For drug-resistant epilepsy, nonpharmacologic treatments should be considered early rather than late. Of the nondrug treatments, only resective surgery can be curative. Neurostimulation is palliative, i.e., not expected to achieve a seizure-free outcome. While resective surgery is the goal, other options are necessary because the majority of patients with drug-resistant epilepsy are not surgical candidates, and others have seizures that fail to improve with surgery or have only partial improvement but not seizure freedom. Neurostimulation modalities include vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS), each with its own advantages, disadvantages, and side effects. In most scenarios, determined by noninvasive evaluation, especially EEG and MRI, several strategies are reasonable. For focal epilepsies, the choices are between resective surgery, with or without intracranial EEG, and all three modalities of neurostimulation. In situations where resective surgery is likely to result in seizure freedom, such as mesiotemporal lobe epilepsy or lesional focal epilepsy, resection (standard, laser, or radiofrequency) is preferred. For difficult cases like extratemporal nonlesional epilepsies, neurostimulation offers a less invasive option than resective surgery. For generalized and multifocal epilepsies, VNS is an option, RNS is not, and DBS has only limited evidence. "This article is part of the Supplement issue Neurostimulation for Epilepsy." Highlights • Non-drug treatments are generally not well known by the lay public, and there are misconceptions (about) among neurologists. • As a result, the delay for referrals to epilepsy centers remains very long. • There are options beyond medications. Some are more ambitious and more aggressive, some less ambitious and less aggressive. • In most scenarios, there are several reasonable options, which are not mutually exclusive. • Comprehensive epilepsy centers should be ... comprehensive and offer all available options beyond medications. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Patients with autism spectrum disorder and epilepsy manifest diverse focal and generalized seizures. • Interictal or ictal EEG recordings can be successfully done in many patients with autism. • EEG recordings were essential to diagnose generalized epilepsies and Lennox-Gastaut syndrome, allowing appropriate therapies. Autism spectrum disorder (ASD) is a neurodevelopmental disorder frequently associated with epilepsy and epilepsy is a leading cause of death in ASD patients. Despite growing interest in genetic, neurophysiological and clinical overlaps, data on ictal electroencephalographic (EEG) recordings in ASD are lacking since behavioral disorders often make it difficult to obtain EEG recordings. We examined ictal EEG features in a consecutive series of patients with ASD and epilepsy. We retrospectively identified 400 consecutive patients with ASD and epilepsy at our Level 4 Epilepsy center between 2015 and 2019; 45 had at least one EEG-recorded seizure captured. Demographics, age of nonfebrile seizure onset, age of ASD diagnosis, language, magnetic resonance imagining findings, genetic testing and EEG studies were reviewed. Seizures were classified by semiologic and electrographic features. Ictal findings were analyzed. A total of 497 seizures were captured in 45 patients: 20 patients with focal onset epilepsy had 126 seizures (median: 1, range: 1-30), 17 patients with generalized onset epilepsy had 88 seizures (median: 2, range: 1-15), 7 patients with Lennox-Gastaut syndrome had 270 seizures (median: 12, range: 1-74) and one patient had both right hemisphere focal and generalized onsets (12 focal, 1 generalized). Our study is the first to analyze a large set of ictal data in patients with autism spectrum disorder, a population traditionally difficult to obtain ictal recordings. Our results confirm the diverse spectrum of seizure types and provide clinical-EEG correlates of seizures in ASD patients. Both focal-onset and generalized-onset seizures were recorded, confirming that ASD patients have higher rates of both focal and generalized epilepsy syndromes. Among patients with focal epilepsy, temporal and frontal onsets were frequent, suggesting the possibility of epilepsy surgery or brain stimulation. EEG to classify seizures and epilepsies is critical to determine therapeutic options and effort should be made to obtain EEGs in this heterogenous population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data‐driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks. Methods: We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes. Results: A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types. Significance: Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective To 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. Methods Randomized 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. Results All 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. Significance Responsive 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. [ABSTRACT FROM AUTHOR]

Purpose Lennox- Gastaut syndrome ( LGS) is a devastating childhood-onset epilepsy syndrome. The cause is unknown in 25% of cases. Little has been described about the specific clinical or electroencephalography ( EEG) features of LGS of unknown or genetic cause ( LGSu). The Epilepsy Phenome/ Genome Project ( EPGP) aims to characterize LGSu by phenotypic analysis of patients with LGSu and their parents. Methods One hundred thirty-five patients with LGS with no known etiology and their parents were enrolled from 19 EPGP centers in the United States and Australia. Clinical data from medical records, standardized questionnaires, imaging, and EEG were collected with use of online informatics systems developed for EPGP. Key Findings LGSu in the EPGP cohort had a broad range of onset of epilepsy from 1 to 13 years, was male predominant (p < 0.0002), and was associated with normal development prior to seizure onset in 59.2% of patients. Despite the diagnosis, almost half of the adult patients with LGSu completed secondary school. Parents were cognitively normal. All subjects had EEG recordings with generalized epileptiform abnormalities with a spike wave frequency range of 1-5 Hz (median 2 Hz), whereas 8.1% of subjects had EEG studies with a normal posterior dominant rhythm. Almost 12% of patients evolved from West syndrome. Significance LGSu has distinctive characteristics including a broad age range of onset, male predominance, and often normal development prior to the onset of seizures. Cognitive achievements such as completion of secondary school were possible in half of adult patients. Our phenotypic description of LGSu coupled with future genetic studies will advance our understanding of this epilepsy syndrome. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Studies have reported improved seizure control with increased duration of vagus nerve stimulation (VNS) but are prone to methodological biases. We analyzed the efficacy of VNS over time in patients with treatment-resistant epilepsy (TRE) who underwent VNS therapy 10 or more years. Methods: We retrospectively reviewed 65 consecutive patients (29 females) who underwent VNS therapy ≥10years. The mean age at VNS insertion was 30.0years. Forty-four adults (≥18years; 67.7%) and 21 children (32.3%) were included. Seizure frequency and antiepileptic drug (AED) regimens were recorded prior to VNS and, following VNS insertion, at 6months, 1year, 2years, and every 2years thereafter. Results: The mean duration of VNS therapy for this group was 10.4years, and the mean decrease in seizure frequency at last follow-up was 76.3%. The mean reduction in seizures at 6months and years 1, 2, 4, 6, 8, and 10years was 35.7, 52.1, 58.3, 60.4, 65.7, 75.5, and 75.5%, respectively. Seizure frequency was significantly reduced from baseline at each of the recorded intervals (P <0.001). There was a trend toward increased AED burden in the latter years of the follow-up period. Conclusion: Following a “ramp-up” and accommodation period throughout the initial 24months after VNS implantation, seizure control improved slightly over the subsequent years of therapy and eventually stabilized. Variation in seizure frequency, however, was common, and frequent changes in AED regimens or stimulation parameters were likely an important and possibly synergistic component of seizure control. [Copyright &y& Elsevier]

Abstract: Objective: The goal of this study was to assess the efficacy and safety of vagus nerve stimulation in a consecutive series of adults and children with treatment-resistant epilepsy (TRE). Methods: In this retrospective review of a prospectively created database of 436 consecutive patients who underwent vagus nerve stimulator implantation for TRE between November 1997 and April 2008, there were 220 (50.5%) females and 216 (49.5%) males ranging in age from 1 to 76years at the time of implantation (mean: 29.0±16.5). Thirty-three patients (7.6%) in the primary implantation group had inadequate follow-up (<3months from implantation) and three patients had early device removal because of infection and were excluded from seizure control outcome analyses. Results: Duration of vagus nerve stimulation treatment varied from 10days to 11years (mean: 4.94years). Mean seizure frequency significantly improved following implantation (mean reduction: 55.8%, P <0.0001). Seizure control ≥90% was achieved in 90 patients (22.5%), ≥75% seizure control in 162 patients (40.5%), ≥50% improvement in 255 patients (63.75%), and <50% improvement in 145 patients (36.25%). Permanent injury to the vagus nerve occurred in 2.8% of patients. Conclusion: Vagus nerve stimulation is a safe and effective palliative treatment option for focal and generalized TRE in adults and children. When used in conjunction with a multidisciplinary and multimodality treatment regimen including aggressive antiepileptic drug regimens and epilepsy surgery when appropriate, more than 60% of patients with TRE experienced at least a 50% reduction in seizure burden. Good results were seen in patients with non-U.S. Food and Drug Administration-approved indications. Prospective, randomized trials are needed for patients with generalized epilepsies and for younger children to potentially expand the number of patients who may benefit from this palliative treatment. [ABSTRACT FROM AUTHOR]

Drug-resistant focal epilepsy (DRFE) in children can impair cognition and behavior, and lead to premature death. Increased pediatric epilepsy surgery numbers reflect the improvements in seizure control and long-term developmental outcomes. Yet, many children with DRFE are not candidates for surgical resection due to overlap of the seizure network with eloquent cortex or multiple seizure-onset zones, making surgery dangerous or ineffective. In adults, responsive neurostimulation (RNS System) therapy is safe and effective treatment for DRFE with one or two seizure foci, especially when the seizure focus is in eloquent cortex. We present six pediatric patients with DRFE who underwent RNS implantation. Our outcomes demonstrate safety, decreased clinical seizure frequency, as well as improved functional status and quality of life. Changes in the clinical seizure semiology and frequency occurred in conjunction with adjustments to the stimulation parameters, supporting the efficacy of responsive neuromodulation in children. [ABSTRACT FROM AUTHOR]