Gavvala, Jay R.

Abstract Objective Interictal epileptiform spikes (IESs) are widely used biomarkers of epileptogenic tissue in presurgical epilepsy evaluation. However, their reliability for seizure onset zone (SOZ) localization in high‐density intracranial electroencephalography (iEEG) remains inconsistent. It is underexplored whether this variability reflects methodological differences across detection algorithms or a limitation of IESs as a biomarker. This study evaluates whether IES detection alone provides sufficient spatial specificity for accurate SOZ localization in iEEG. Methods We systematically benchmarked eight established IES detection algorithms using iEEG recordings from 35 patients with drug‐resistant focal epilepsy. To provide a clinically meaningful reference, algorithm performance was evaluated against the clinically defined SOZ. To refine detection outputs and move beyond only IES detection, we applied masking strategies to isolate informative IES subsets based on rate, amplitude, frequency, and co‐occurrence with high‐frequency oscillations (HFOs). Conceptually, masking acts as a spatial refinement strategy that progressively restricts diffuse IES activity to more focal, pathologically relevant event populations. Results Despite substantial variability in detection characteristics, SOZ localization performance (ratio of events originating from SOZ divided by total number of events) converged within a narrow range (.23–.51), suggesting that IESs exhibit an intrinsic ceiling in SOZ localization performance when used alone. Amplitude‐based masking yielded modest improvements, whereas frequency‐based masking reduced performance. In contrast, IES‐HFO co‐occurrence markedly improved localization, particularly when combined with rate‐based masking, achieving a median SOZ localization ratio of .89, exceeding IESs (.37) and HFOs (.63) evaluated independently. Significance These findings demonstrate that IES‐based SOZ localization may require moving beyond detection‐only approaches. The integration of informed, biomarker‐driven masking strategies provides a more robust framework for identifying the activity most relevant to the epileptogenic network and paves the way for future incorporation into the clinical decision‐making pipeline.

Abstract Objective This study was undertaken to evaluate the safety and effectiveness of responsive thalamic stimulation as adjunctive therapy for drug‐resistant idiopathic generalized epilepsy (IGE) with generalized tonic–clonic seizures (GTCSs). Methods NAUTILUS is a prospective, multicenter, single‐blind, randomized sham‐controlled pivotal trial. Patients were ≥12 years of age with drug‐resistant IGE and ≥2 GTCSs over a 3‐month baseline. Bilateral depth leads were targeted to the centromedian thalamus. One month later, patients were randomized to Active (responsive stimulation, n = 44) or Sham (no stimulation, n = 43). The effectiveness evaluation period (EEP) began 3 months postimplant through 1 year. After a second GTCS in the EEP, patients transitioned to open‐label active stimulation. The primary safety endpoint was the serious adverse device‐related event (SADE) rate at 84 days postimplant. The primary effectiveness endpoint was time‐to‐second‐GTCS during the EEP. Additional endpoints included median percent change in days with any generalized seizure, GTCS frequency, and responder rate (RR). Results Eighty‐seven patients were implanted across 23 US centers. The SADE rate was significantly below the performance goal (6.9%, p < .0001), with no adverse effects on cognition, mood, or sleep. The prespecified primary effectiveness endpoint was not significant. However, a post hoc mixed‐effects model considering all EEP days demonstrated greater GTCS reduction in the originally randomized Active group (61%) compared to patients originally randomized to Sham (49%, p = .030). Eighteen‐month outcomes included 76.8% median GTCS reduction, 62.5% RR, 40% GTCS‐free at that timepoint, and 77.8% median reduction in days with any generalized seizure. More than 90% of patients and 86% of physicians reported improvement on Global Impression of Change scales. Significance NAUTILUS is the first randomized controlled neuromodulation trial in IGE. Responsive thalamic stimulation provided a clinically meaningful and durable reduction in seizures with an acceptable safety profile, offering a much‐needed option for drug‐resistant IGE.

Abstract Objective To measure the relative levels of signal and noise in expert diagnosis of epilepsy. Methods Twenty multinational epileptologists independently reviewed 50 vignettes of adult and pediatric patients presenting with suspected seizure(s) on two separate occasions with a ≥30‐day washout period. Experts provided a diagnosis of epilepsy or non‐epilepsy based on clinical information and, if requested, routine EEG and neuroimaging data. Cases had an established clinical diagnosis of epilepsy or non‐epilepsy based on capture of habitual paroxysmal events on video‐EEG or long‐term clinical follow‐up. Experts' judgments were analyzed to decompose variability into different sources: signal (objective differences between cases), level noise (experts' bias toward over/under‐diagnosis), pattern noise (experts' idiosyncratic reactions to specific case features), and occasion noise (inconsistency across occasions). Results The probability of an expert making a different diagnosis for a given case on two different occasions was 16%. The probability of two different experts making a different diagnosis for the same case was 26%. Signal (case “difficulty”) accounted for 66–69% of total variation, with 31–34% attributable to noise. Level noise was the largest contributor in the absence of EEG/neuroimaging results (23%), while pattern noise dominated when test results were available (24%). Occasion noise contributed relatively little (1%) but was still sufficient to cause diagnostic reversals in 16–22% between occasions. Significance The degree of noise in expert diagnosis of epilepsy is substantial, stemming primarily from physicians' idiosyncratic interpretations of case features and variable dispositions toward over‐ or under‐diagnosis. Strategies to improve reliability are needed, including standardized data collection protocols and structured decision algorithms. For “difficult cases,” where expert reliability and accuracy are lowest, our findings support current clinical practice which favors early referral for video‐EEG monitoring over reliance on diagnostic anchoring. This diagnostic pathway may become more accessible with advances in EEG technology (e.g., wearable devices) and artificial intelligence.

Purpose: These consensus guidelines by the American Clinical Neurophysiology Society (ACNS) describe best practices for performing intraoperative Electrocorticography (ioECoG) using subdural or depth electrodes for adult and pediatric population. Methods: A group of ACNS members was convened to develop technical standards for performing ioECoG. PubMed searches were performed to identify pertinent peer-reviewed literature. Sections were assigned to individual authors based on expertise. Consensus was achieved during subsequent group discussions to develop evidence-based recommendations to the extent possible. Recommendations: Communication between the neurosurgical and the neurophysiology teams is essential in verifying and documenting the location of the contacts. Most authors recommend ioECoG recordings of at least 5 and up to 30 minutes in duration to allow for sufficient observation of interictal activity. The anesthesia should be adjusted to allow continuous EEG activity and to minimize the effect on the ioECoG recording during general anesthesia or awake surgery. The surgical procedure and technical report should separate ioECoG recordings to define the irritative zone from ioECoG findings during functional mapping. The neurophysiology physician’s physical presence in the operating room is required in the definition of the services. Conclusion: These consensus guidelines by the ACNS describe best practices for performing intraoperative ECoG based on published literature and expert consensus.

Purpose: To understand the current state of epilepsy surgery education delivered to epilepsy fellows in the United States. Methods: An online survey focused on characteristics of epilepsy surgery education was distributed to all 93 epilepsy fellowship program directors listed on the ACGME website (accessed in May 2022). Programs were stratified per the number of fellows currently enrolled: 0 to 3 (group A) and ≥4 (group B). Results: Forty-one of 93 (44%) epilepsy fellowship programs were included in the study. The average number of resective surgeries, ablations, or corpus callosotomies per year was mostly 0 to 30 (54%) in group A and mostly >30 (80%) in group B ( P = 0.05). The average number of intracranial implantations per year was mostly 0 to 20 (58%) in group A and mostly >20 (80%) in group B ( P < 0.05). The average number of neurostimulation implantations per year was 15 (range 0–90; vagal nerve stimulation), 7 (range 0–25; responsive neurostimulation), and 4 (range 0–10; deep brain stimulation). In 78% of programs, fellows are not required to present a minimum number of epilepsy surgery cases in multidisciplinary conference before graduation. Roughly half of programs (51%) reported not using objective measures to assess fellow competency in epilepsy surgery. Conclusions: Our results suggest significant variability in epilepsy surgery volume and, consequently, fellow exposure to surgical cases and lack of standardized, objective measures in fellow teaching and assessment in the field of epilepsy surgery across programs in the United States. We advocate development of a core epilepsy surgery curriculum including minimum standards at the national level.

Objective Epilepsy surgery is vital in managing of children with drug-resistant epilepsy. Noninvasive and invasive testing modalities allow for evaluation and treatment of children with drug-resistant epilepsy. Evidence-based algorithms for this process do not exist. This study examines expert response to a vignette of pediatric nonlesional epilepsy to assess associations in evaluation and treatment choices. Methods We analyzed annual report data and an epilepsy practice survey reported in 2020 from 135 pediatric epilepsy center directors in the United States. Characteristics of centers along with noninvasive and invasive testing and surgical treatment strategies were collected. Multivariable logistic regression modeling was performed. Results The response rate was 100% with 135 responses included in the analyses. Most used noninvasive testing modalities included Neuropsychology evaluation (90%), interictal brain fluorodeoxyglucose-positron emission tomography (85%), and functional magnetic resonance imaging (MRI) (72%) with nearly half obtaining genetic testing. Choosing functional MRI was associated with stereo electroencephalography (EEG) ( P = .025) and selecting Wada with subdural grid/strips ( P = .038). Directors from pediatric-only centers were more likely to choose stereo EEG as opposed to combined centers ( P = .042). Laser interstitial thermal therapy was almost 7 times as likely to be chosen as a treatment modality compared with open resection in dedicated pediatric centers (OR 6.96, P = .002). Significance In a vignette of nonlesional childhood drug-resistant epilepsy, epilepsy center directors’ patterns of noninvasive testing, invasive testing, and treatment were examined. Management choices were associated with pediatric versus combined pediatric/adult center characteristics. Expert opinions demonstrated equipoise in evaluation and management of children with drug-resistant epilepsy and the need for evidence-based management strategies.

Abstract Objective The evaluation to determine candidacy and treatment for epilepsy surgery in persons with drug‐resistant epilepsy (DRE) is not uniform. Many non‐invasive and invasive tests are available to ascertain an appropriate treatment strategy. This study examines expert response to clinical vignettes of magnetic resonance imaging (MRI)–positive lesional focal cortical dysplasia in both temporal and extratemporal epilepsy to identify associations in evaluations and treatment choice. Methods We analyzed annual report data and a supplemental epilepsy practice survey reported in 2020 from 206 adult and 136 pediatric epilepsy center directors in the United States. Non‐invasive and invasive testing and surgical treatment strategies were compiled for the two scenarios. We used chi‐square tests to compare testing utilization between the two scenarios. Multivariable logistic regression modeling was performed to assess associations between variables. Results The supplemental survey response rate was 100% with 342 responses included in the analyses. Differing testing and treatment approaches were noted between the temporal and extratemporal scenarios such as chronic invasive monitoring selected in 60% of the temporal scenario versus 93% of the extratemporal scenario. Open resection was the most common treatment choice; however, overall treatment choices varied significantly ( p < .001). Associations between non‐invasive testing, invasive testing, and treatment choices were present in both scenarios. For example, in the temporal scenario stereo‐electroencephalography (SEEG) was more commonly associated with fluorodeoxyglucose–positron emission tomography (FDG‐PET) (odds ratio [OR] 1.85; 95% confidence interval [CI] 1.06–3.29; p = .033), magnetoencephalography (MEG) (OR 2.90; 95% CI 1.60–5.28; p = <.001), high density (HD) EEG (OR 2.80; 95% CI 1.27–6.24; p = .011), functional MRI (fMRI) (OR 2.17; 95% CI 1.19–4.10; p = .014), and Wada (OR 2.16; 95% CI 1.28–3.66; p = .004). In the extratemporal scenario, choosing SEEG was associated with increased odds of neuromodulation over open resection (OR 3.13; 95% CI 1.24–7.89; p = .016). Significance In clinical vignettes of temporal and extratemporal lesional DRE, epilepsy center directors displayed varying patterns of non‐invasive testing, invasive testing, and treatment choices. Differences in practice underscore the need for comparative trials for the surgical management of DRE.

Abstract Objective Persons with drug‐resistant epilepsy may benefit from epilepsy surgery and should undergo presurgical testing to determine potential candidacy and appropriate intervention. Institutional expertise can influence use and availability of evaluations and epilepsy surgery candidacy. This census survey study aims to examine the influence of geographic region and other center characteristics on presurgical testing for medically intractable epilepsy. Methods We analyzed annual report and supplemental survey data reported in 2020 from 206 adult epilepsy center directors and 136 pediatric epilepsy center directors in the United States. Test utilization data were compiled with annual center volumes, available resources, and US Census regional data. We used Wilcoxon rank‐sum, Kruskal–Wallis, and chi‐squared tests for univariate analysis of procedure utilization. Multivariable modeling was also performed to assign odds ratios (ORs) of significant variables. Results The response rate was 100% with individual element missingness < 11% across 342 observations undergoing univariate analysis. A total of 278 complete observations were included in the multivariable models, and significant regional differences were present. For instance, compared to centers in the South, those in the Midwest used neuropsychological testing (OR = 2.87, 95% confidence interval [CI] = 1.2–6.86; p = .018) and fluorodeoxyglucose–positron emission tomography (OR = 2.74, 95% CI = = 1.14–6.61; p = .025) more commonly. For centers in the Northeast (OR = .46, 95% CI = .23–.93; p = .031) and West (OR = .41, 95% CI = .19–.87; p = .022), odds of performing single‐photon emission computerized tomography were lower by nearly 50% compared to those in the South. Center accreditation level, demographics, volume, and resources were also associated with varying individual testing rates. Significance Presurgical testing for drug‐resistant epilepsy is influenced by US geographic region and other center characteristics. These findings have potential implications for comparing outcomes between US epilepsy centers and may inject disparities in access to surgical treatment.