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Epilepsy care generates multiple sources of high-dimensional data, including clinical, imaging, electroencephalographic, genomic, and neuropsychological information, that are collected routinely to establish the diagnosis and guide management. Thanks to high-performance computing, sophisticated graphics processing units, and advanced analytics, we are now on the cusp of being able to use these data to significantly improve individualized care for people with epilepsy. Despite this, many clinicians, health care providers, and people with epilepsy are apprehensive about implementing Big Data and accompanying technologies such as artificial intelligence (AI). Practical, ethical, privacy, and climate issues represent real and enduring concerns that have yet to be completely resolved. Similarly, Big Data and AI-related biases have the potential to exacerbate local and global disparities. These are highly germane concerns to the field of epilepsy, given its high burden in developing nations and areas of socioeconomic deprivation. This educational paper from the International League Against Epilepsy's (ILAE) Big Data Commission aims to help clinicians caring for people with epilepsy become familiar with how Big Data is collected and processed, how they are applied to studies using AI, and outline the immense potential positive impact Big Data can have on diagnosis and management., (© 2024 The Author(s). Epileptic Disorders published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Brain resection is curative for a subset of patients with drug resistant epilepsy but up to half will fail to achieve sustained seizure freedom in the long term. There is a critical need for accurate prediction tools to identify patients likely to have recurrent postoperative seizures. Results from preclinical models and intracranial EEG in humans suggest that the window of time immediately before and after a seizure ("peri-ictal") represents a unique brain state with implications for clinical outcome prediction. Using a dataset of 294 patients who underwent temporal lobe resection for seizures, we show that machine learning classifiers can make accurate predictions of postoperative seizure outcome using 5 min of peri-ictal scalp EEG data that is part of universal presurgical evaluation (AUC 0.98, out-of-group testing accuracy > 90%). This is the first approach to seizure outcome prediction that employs a routine non-invasive preoperative study (scalp EEG) with accuracy range likely to translate into a clinical tool. Decision curve analysis (DCA) shows that compared to the prevalent clinical-variable based nomogram, use of the EEG-augmented approach could decrease the rate of unsuccessful brain resections by 20%., (© 2024. The Author(s).)

We lack knowledge about prognostic factors of resective epilepsy surgery (RES) in older adults (≥60 years), especially the role of comorbidities, which are a major consideration in managing the care of people with epilepsy (PWE). We analyzed a single-center cohort of 94 older adults (median age = 63.5 years, 52% females) who underwent RES between 2000 and 2021 with at least 6 months of postsurgical follow-up. Three fourths of the study cohort had lesional magnetic resonance imaging and underwent temporal lobectomy. Fifty-four (57%) PWE remained seizure-free during a median follow-up of 3.5 years. Cox proportional hazard multivariable analysis showed that aura (hazard ratio [HR] = .52, 95% confidence interval [CI] = .27-1.00), single ictal electroencephalographic pattern (HR = .33, 95% CI = .17-.660), and Elixhauser Comorbidity Index (HR = 1.05, 95% CI = 1.00-1.10) were independently associated with seizure recurrence at last follow-up. A sensitivity analysis using the Charlson Combined Score (HR = 1.38, 95% CI = 1.03-1.84, p = .027) confirmed the association of comorbidities with worse seizure outcome. Our findings provide a framework for a better informed discussion about RES prognosis in older adults. More extensive, multicenter cohort studies are needed to validate our findings and reduce hesitancy in pursuing RES in suitable older adults., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Purpose of Review: Multiple complex medical decisions are necessary in the course of a chronic disease like epilepsy. Predictive tools to assist physicians and patients in navigating this complexity have emerged as a necessity and are summarized in this review., Recent Findings: Nomograms and online risk calculators are user-friendly and offer individualized predictions for outcomes ranging from safety of antiseizure medication withdrawal (accuracy 65-73%) to seizure-freedom, naming, mood, and language outcomes of resective epilepsy surgery (accuracy 72-81%). Improving their predictive performance is limited by the nomograms' inability to ingest complex data inputs. Conversely, machine learning offers the potential of multimodal and expansive model inputs achieving human-expert level accuracy in automated scalp electroencephalogram (EEG) interpretation but lagging in predictive performance or requiring validation for other applications., Summary: Good to excellent predictive models are now available to guide medical and surgical epilepsy decision-making with nomograms offering individualized predictions and user-friendly tools, and machine learning approaches offering the potential of improved performance. Future research is necessary to bridge the two approaches for optimal translation to clinical care., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

We highlight an under-recognized epileptic pathology in a 56-year-old left-handed female with progressive right facial numbness and weekly focal seizures characterized by episodic aphasia. She was found to have a left frontoparietal intradiploic meningoencephalocele (IDME). Her only epilepsy risk factor was minor head trauma 10 years prior to presentation. She underwent craniotomy for encephalocele resection and mesh cranioplasty without residual neurological deficits and excellent seizure outcome: at 3-year follow-up, she was still seizure-free since surgery, except for an isolated breakthrough seizure at 7 postoperative months when she discontinued her preoperative regimen of Lacosamide monotherapy. Traumatic IDME is a rare condition and rarely presents with seizures. Symptoms may arise up to decades following minor head trauma and are progressive in nature. The likely definitive treatment is cranioplasty and dural repair with or without resecting the protruding parenchyma., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

We sought to perform a systematic review and individual participant data meta-analysis to identify predictors of treatment response following thalamic neuromodulation in pediatric patients with medically refractory epilepsy. Electronic databases (MEDLINE, Ovid, Embase, and Cochrane) were searched, with no language or data restriction, to identify studies reporting seizure outcomes in pediatric populations following deep brain stimulation (DBS) or responsive neurostimulation (RNS) implantation in thalamic nuclei. Studies featuring individual participant data of patients with primary or secondary generalized drug-resistant epilepsy were included. Response to therapy was defined as >50% reduction in seizure frequency from baseline. Of 417 citations, 21 articles reporting on 88 participants were eligible. Mean age at implantation was 13.07 ± 3.49 years. Fifty (57%) patients underwent DBS, and 38 (43%) RNS. Sixty (68%) patients were implanted in centromedian nucleus and 23 (26%) in anterior thalamic nucleus, and five (6%) had both targets implanted. Seventy-four (84%) patients were implanted bilaterally. The median time to last follow-up was 12 months (interquartile range = 6.75-26.25). Sixty-nine percent of patients achieved response to treatment. Age, target, modality, and laterality had no significant association with response in univariate logistic regression. Until thalamic neuromodulation gains widespread approval for use in pediatric patients, data on efficacy will continue to be limited to small retrospective cohorts and case series. The inherent bias of these studies can be overcome by using individual participant data. Thalamic neuromodulation appears to be a safe and effective treatment for epilepsy. Larger, prolonged prospective, multicenter studies are warranted to further evaluate the efficacy of DBS over RNS in this patient population where resection for curative intent is not a safe option., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: This study was undertaken to conduct external validation of previously published epilepsy surgery prediction tools using a large independent multicenter dataset and to assess whether these tools can stratify patients for being operated on and for becoming free of disabling seizures (International League Against Epilepsy stage 1 and 2)., Methods: We analyzed a dataset of 1562 patients, not used for tool development. We applied two scales: Epilepsy Surgery Grading Scale (ESGS) and Seizure Freedom Score (SFS); and two versions of Epilepsy Surgery Nomogram (ESN): the original version and the modified version, which included electroencephalographic data. For the ESNs, we used calibration curves and concordance indexes. We stratified the patients into three tiers for assessing the chances of attaining freedom from disabling seizures after surgery: high (ESGS = 1, SFS = 3-4, ESNs > 70%), moderate (ESGS = 2, SFS = 2, ESNs = 40%-70%), and low (ESGS = 2, SFS = 0-1, ESNs < 40%). We compared the three tiers as stratified by these tools, concerning the proportion of patients who were operated on, and for the proportion of patients who became free of disabling seizures., Results: The concordance indexes for the various versions of the nomograms were between .56 and .69. Both scales (ESGS, SFS) and nomograms accurately stratified the patients for becoming free of disabling seizures, with significant differences among the three tiers (p < .05). In addition, ESGS and the modified ESN accurately stratified the patients for having been offered surgery, with significant difference among the three tiers (p < .05)., Significance: ESGS and the modified ESN (at thresholds of 40% and 70%) stratify patients undergoing presurgical evaluation into three tiers, with high, moderate, and low chance for favorable outcome, with significant differences between the groups concerning having surgery and becoming free of disabling seizures. Stratifying patients for epilepsy surgery has the potential to help select the optimal candidates in underprivileged areas and better allocate resources in developed countries., (© 2023 International League Against Epilepsy.)

Objective: Access to epilepsy specialist care is not uniform in the USA, with prominent gaps in rural areas. Understanding the reasons for nonattendance at epilepsy appointments may help identify access hurdles faced by patients. This study was undertaken to better understand clinic absenteeism in epilepsy and how it may be influenced by telemedicine., Methods: In this retrospective study, social determinants of health were collected for all adult patients scheduled in epilepsy clinic, as either an in-person or telemedicine appointment, at University of Kentucky between July 2021 and December 2022. The primary outcome measure was attendance or absence at the appointment. Subgroup analyses were done to better understand the drivers of attendance at telemedicine visits and evaluate telemedicine utilization by underserved populations., Results: A total of 3025 patient encounters of in-person and telemedicine visits were included. The no-show rate was significantly higher for in-person visits (32%) compared with telemedicine visits (20%, p < .001). A nominal logistic regression model identified seven factors increasing risk of absenteeism, including in-person visits, prior missed appointments, longer lead times to appointment, Medicaid/Medicare as payors, no significant other, lower mean annual income, and minority race. For each $10 000 increase in mean annual income, the odds of missing the appointment decreased by 8% (odds ratio = .92, 95% confidence interval = .89-.96, p < .001). Forty-one percent of underserved population opted for telemedicine visits, and they had a lower no-show rate (22%) as compared with in-person visits (33%, p < .001). Predictors of no-shows to televisits (1382) included Medicare/Medicaid coverage (as opposed to private insurance), no significant others, and a history of missing appointments., Significance: Telemedicine is effective at improving attendance, overcoming socioeconomic hurdles, and widening access to epilepsy care, particularly among underserved populations. Access to telecare depends on insurance coverage and emphasizes the need to include telemedicine in insurance plans to ensure uniform access to high-quality epilepsy care, irrespective of socioeconomic status., (© 2023 International League Against Epilepsy.)

Approximately 50% of individuals who undergo resective epilepsy surgery experience seizure recurrence. The heterogenous post-operative outcomes are not fully explained by clinical, imaging and electrophysiological variables. We hypothesized that molecular features may be useful in understanding surgical response, and that individuals with epilepsy can be classified into molecular subtypes that are associated with seizure freedom or recurrence after surgical resection. Pre-operative blood samples, brain tissue and post-operative seizure outcomes were collected from a cohort of 40 individuals with temporal lobe epilepsy, 23 of whom experienced post-operative seizure recurrence. Messenger RNA and microRNA extracted from the blood and tissue samples were sequenced. The messenger RNA and microRNA expression levels from the blood and brain were each subjected to a novel clustering approach combined with multiple logistic regression to separate individuals into genetic clusters that identify novel subtypes associated with post-operative seizure outcomes. We then compared the microRNAs and messenger RNAs from patient blood and brain tissue that were significantly associated with each subtype to identify signatures that are similarly over- or under-represented for an outcome and more likely to represent endophenotypes with common molecular aetiology. These target microRNAs and messenger RNAs were further characterized by pathway analysis to assess their functional role in epilepsy. Using blood-derived microRNA and messenger RNA expression levels, we identified two subtypes of epilepsy that were significantly associated with seizure recurrence (clusters A1 and B4) (adjusted P < 0.20). A total of 551 microRNAs and 2486 messenger RNAs were associated with clusters A1 and B4, respectively (adjusted P < 0.05). Clustering of brain-tissue messenger RNA expression levels revealed an additional subtype (C2) associated with seizure recurrence that had high overlap of dysregulated messenger RNA transcripts with cluster B4. Clusters A1, B4 and C2 also shared significant overlap of subjects, which altogether suggests a coordinated mechanism by which microRNA and messenger RNA transcripts may be related to seizure recurrence. Epileptic subtypes A1, B4 and C2 reveal both known and novel microRNA and messenger RNA targets in seizure recurrence. Furthermore, targets identified in A1 and B4 are quantifiable in pre-operative blood samples and could potentially serve as biomarkers for surgical resection outcomes., Competing Interests: D.M.R. holds an equity stake in Clarified Precision Medicine, LLC., and has received research support from Novo Nordisk and consulting honoraria from Interpares Biomedicine and Pharmazaam, LLC. C.E. is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: One consideration in pediatric stereoencephalography (SEEG) is decreased skull thicknesses compared with adults, which may limit traditional bolt-based anchoring of electrodes. The authors aimed to investigate the safety profile, complication rates, and technical adaptations of placing SEEG electrodes in pediatric patients., Methods: The authors retrospectively reviewed all patients aged 12 years or younger at the time of SEEG implantation at their institution. Postimplantation CT scans were used to measure skull thickness at the entry point of each SEEG lead. Postimplantation lead accuracy was also assessed., Results: Fifty-three patients were reviewed. The median skull thickness was 4.1 (interquartile range [IQR] 3.15-5.2) mm. There were 5 total complications: 1 retained bolt fragment, 3 asymptomatic subdural hematomas, and 1 asymptomatic intracranial hemorrhage. Median radial error from the lead target was 3.5 (IQR 2.24-5.25) mm. Linear regression analysis revealed that increasing skull thickness decreased the deviation from the intended target, implying an improved accuracy to target at thicker skull entry points; this trended towards improved accuracy, but did not achieve statistical significance (p = 0.54)., Conclusions: This study found a 1.9% hardware complication rate and a 9.4% asymptomatic hemorrhage rate. Suturing electrodes to the scalp may represent a reasonable option if there are concerns of young age or a thin skull. These data indicate that invasive SEEG evaluation is safe among patients 12 years old or younger.

Objective: The objective of this paper was to investigate the factors associated with successful epileptogenic zone (EZ) identification and postsurgical seizure freedom in pediatric patients with drug-resistant epilepsy who underwent first-time stereoelectroencephalography (SEEG)., Methods: The authors conducted a retrospective cohort study of all consecutive patients younger than 18 years of age at the time of recommendation for invasive evaluation with SEEG who were treated from July 2009 to June 2020. The authors excluded patients who had undergone failed prior resective epilepsy surgery or prior intracranial electrode evaluation for seizure localization. For their primary outcome, the authors evaluated the relationship between clinical and radiographic factors and successful identification of a putative EZ. For their secondary outcome, the authors investigated whether these factors had a significant relationship with seizure freedom (according to the Engel classification) at last follow-up., Results: The authors included 101 patients in this study. SEEG was safe, with no major morbidity or mortality experienced. The population was complex, with an MRI lesion present in less than 40% of patients and patients as young as 2.9 years included. A proposed EZ was identified in 88 (87%) patients. Patients with an older onset of epilepsy (OR 1.20/year, p = 0.04) or epilepsy etiology suspected to be due to a developmental lesion (OR 8.38, p = 0.02) were more likely to have proposed EZ identification. Patients with a preimplantation bilateral seizure-onset hypothesis (OR 0.29, p = 0.047) and those who underwent longer periods of monitoring (OR 0.86/day, p = 0.006) were somewhat less likely to have proposed EZ identification. The presence of an MRI lesion was a positive factor on secondary analyses (OR 4.18, p = 0.049; 1-tailed test). Fifty percent of patients who underwent surgical treatment with resection or laser ablation achieved Engel class I outcomes, in contrast to 0% of patients who underwent neuromodulation. Patients with a preimplantation hypothesis in the frontal/parietal lobes had increased odds of seizure freedom compared with patients with a hypothesis in other locations (OR 3.64, p = 0.01)., Conclusions: Pediatric SEEG is safe and often identifies a proposed resectable EZ. These results suggest that SEEG is effective in patients with frontal/parietal preimplantation hypothesis, with or without identified lesions on MRI.

Background and Objectives: Temporal lobe epilepsy (TLE) is the most common adult form of epilepsy and is associated with a high risk of cognitive deficits and depressed mood. However, little is known about the role of environmental factors on cognition and mood in TLE. This cross-sectional study examined the relationship between neighborhood deprivation and neuropsychological function in adults with TLE., Methods: Neuropsychological data were obtained from a clinical registry of patients with TLE and included measures of intelligence, attention, processing speed, language, executive function, visuospatial skills, verbal/visual memory, depression, and anxiety. Home addresses were used to calculate the Area Deprivation Index (ADI) for each individual, which were separated into quintiles (i.e., quintile 1 = least disadvantaged and quintile 5 = most disadvantaged). Kruskal-Wallis tests compared quintile groups on cognitive domain scores and mood and anxiety scores. Multivariable regression models, with and without ADI, were estimated for overall cognitive phenotype and for mood and anxiety scores., Results: A total of 800 patients (median age 38 years; 58% female) met all inclusion criteria. Effects of disadvantage (increasing ADI) were observed across nearly all measured cognitive domains and with significant increases in symptoms of depression and anxiety. Furthermore, patients in more disadvantaged ADI quintiles had increased odds of a worse cognitive phenotype ( p = 0.013). Patients who self-identified as members of minoritized groups were overrepresented in the most disadvantaged ADI quintiles and were 2.91 (95% CI 1.87-4.54) times more likely to be in a severe cognitive phenotype than non-Hispanic White individuals ( p < 0.001). However, accounting for ADI attenuated this relationship, suggesting neighborhood deprivation may account for some of the relationship between race/ethnicity and cognitive phenotype (ADI-adjusted proportional odds ratio 1.82, 95% CI 1.37-2.42)., Discussion: These findings highlight the importance of environmental factors and regional characteristics in neuropsychological studies of epilepsy. There are many potential mechanisms by which neighborhood disadvantage can adversely affect cognition (e.g., fewer educational opportunities, limited access to health care, food insecurity/poor nutrition, and greater medical comorbidities). Future research will seek to investigate these potential mechanisms and determine whether structural and functional alterations in the brain moderate the relationship between ADI and cognition., (© 2023 American Academy of Neurology.)

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7-11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9-2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8-0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9-1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63-0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64-0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants predominated in the United States since 2021. Understanding disease severity related to different SARS-CoV-2 variants remains limited., Method: Viral genome analysis was performed on SARS-CoV-2 clinical isolates circulating March 2021 through March 2022 in Cleveland, Ohio. Major variants were correlated with disease severity and patient outcomes., Results: In total 2779 patients identified with either Alpha (n 1153), Gamma (n 122), Delta (n 808), or Omicron variants (n 696) were selected for analysis. No difference in frequency of hospitalization, intensive care unit (ICU) admission, and death were found among Alpha, Gamma, and Delta variants. However, patients with Omicron infection were significantly less likely to be admitted to the hospital, require oxygen, or admission to the ICU (2 12.8, P .001; 2 21.6, P .002; 2 9.6, P .01, respectively). In patients whose vaccination status was known, a substantial number had breakthrough infections with Delta or Omicron variants (218/808 [26.9] and 513/696 [73.7], respectively). In breakthrough infections, hospitalization rate was similar regardless of variant by multivariate analysis. No difference in disease severity was identified between Omicron subvariants BA.1 and BA.2., Conclusions: Disease severity associated with Alpha, Gamma, and Delta variants is comparable while Omicron infections are significantly less severe. Breakthrough disease is significantly more common in patients with Omicron infection., (The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Brain surgery offers the best chance of seizure-freedom for patients with focal drug-resistant epilepsy, but only 50% achieve sustained seizure-freedom. With the explosion of data collected during routine presurgical evaluations and recent advances in computational science, we now have a tremendous potential to achieve precision epilepsy surgery: a data-driven tailoring of surgical planning. This review highlights the clinical need, the relevant computational science focusing on machine learning, and discusses some specific applications in epilepsy surgery., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Studying viral-host protein-protein interactions can facilitate the discovery of therapies for viral infection. We use high-throughput yeast two-hybrid experiments and mass spectrometry to generate a comprehensive SARS-CoV-2-human protein-protein interactome network consisting of 739 high-confidence binary and co-complex interactions, validating 218 known SARS-CoV-2 host factors and revealing 361 novel ones. Our results show the highest overlap of interaction partners between published datasets and of genes differentially expressed in samples from COVID-19 patients. We identify an interaction between the viral protein ORF3a and the human transcription factor ZNF579, illustrating a direct viral impact on host transcription. We perform network-based screens of >2,900 FDA-approved or investigational drugs and identify 23 with significant network proximity to SARS-CoV-2 host factors. One of these drugs, carvedilol, shows clinical benefits for COVID-19 patients in an electronic health records analysis and antiviral properties in a human lung cell line infected with SARS-CoV-2. Our study demonstrates the value of network systems biology to understand human-virus interactions and provides hits for further research on COVID-19 therapeutics., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objective: This study was undertaken to better understand the long-term palliative and disease-modifying effects of surgical resection beyond seizure freedom, including frequency reduction and both late recurrence and remission, in patients with drug-resistant epilepsy., Methods: This retrospective database-driven cohort study included all patients with >9 years of follow-up at a single high-volume epilepsy center. We included patients who underwent lobectomy, multilobar resection, or lesionectomies for drug-resistant epilepsy; we excluded patients who underwent hemispherectomies. Our main outcomes were (1) reduction in frequency of disabling seizures (at 6 months, each year up to 9 years postoperatively, and at last follow-up), (2) achievement of seizure remission (>6 months, >1 year, and longest duration), and (3) seizure freedom at last follow-up., Results: We included 251 patients; 234 (93.2%) achieved 6 months and 232 (92.4%) experienced 1 year of seizure freedom. Of these, the average period of seizure freedom was 10.3 years. A total of 182 (72.5%) patients were seizure-free at last follow-up (defined as >1 year without seizures), with a median 11.9 years since remission. For patients not completely seizure-free, the mean seizure frequency reduction at each time point was 76.2%, and ranged from 66.6% to 85.0%. Patients decreased their number of antiseizure medications on average by .58, and 53 (21.2%) patients were on no antiseizure medication at last follow-up. Nearly half (47.1%) of those seizure-free at last follow-up were not seizure-free immediately postoperatively., Significance: Patients who continue to have seizures after resection often have considerable reductions in seizure frequency, and many are able to achieve seizure freedom in a delayed manner., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Stereoelectroencephalography (SEEG) has gained popularity as an invasive monitoring modality for epileptogenic zone (EZ) localization. The need and indications for SEEG in patients with evident brain lesions or associated abnormalities on imaging is debated. We report our experience with SEEG as a presurgical evaluation tool for patients with lesional epilepsy., Methods: A retrospective cohort study was performed of 131 patients with lesional or magnetic resonance imaging abnormality-associated medically refractory focal epilepsy who underwent resections from 2010 to 2017. Seventy-one patients had SEEG followed by resection, and 60 had no invasive recordings. Volumetric analysis of resection cavities from 3T magnetic resonance imaging was performed., Results: Mean lesion and resection volumes for SEEG and non-SEEG were 16.2 (standard deviation [SD] = 29) versus 23.7 cm 3 (SD = 38.4) and 28.1 (SD = 23.2) versus 43.6 cm 3 (SD = 43.5), respectively (P = 0.009). Comparing patients with seizure recurrence and patients who remained seizure free, significantly associated variables with seizure recurrence included mean number of failed antiseizure medications (6.86 [SD = 0.32] vs. 5.75 [SD = 0.32]; P = 0.01) and in SEEG patients the mean number of electrodes implanted (8.1 [SD = 0.8] vs. 5.0 [SD = 0.8]; P = 0.005). After multivariate analysis, only failed numbers of medication remained significantly associated with seizure recurrence., Conclusions: Seizure outcomes did not correlate with final resection volume after SEEG evaluation. SEEG evaluation presurgically can be used to maintain the efficacy of resection and decrease the volume and subsequent risk of extensive tissue removal. We believe that this technology allows resective surgery to proceed in a subpopulation of patients with lesional epilepsy who may otherwise not have been considered surgical candidates., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Epilepsy surgery is the treatment of choice for patients with drug-resistant seizures. A timely evaluation for surgical candidacy can be life-saving for patients who are identified as appropriate surgical candidates, and may also enhance the care of nonsurgical candidates through improvement in diagnosis, optimization of therapy, and treatment of comorbidities. Yet, referral for surgical evaluations is often delayed while palliative options are pursued, with significant adverse consequences due to increased morbidity and mortality associated with intractable epilepsy. The Surgical Therapies Commission of the International League Against Epilepsy (ILAE) sought to address these clinical gaps and clarify when to initiate a surgical evaluation. We conducted a Delphi consensus process with 61 epileptologists, epilepsy neurosurgeons, neurologists, neuropsychiatrists, and neuropsychologists with a median of 22 years in practice, from 28 countries in all six ILAE world regions. After three rounds of Delphi surveys, evaluating 51 unique scenarios, we reached the following Expert Consensus Recommendations: (1) Referral for a surgical evaluation should be offered to every patient with drug-resistant epilepsy (up to 70 years of age), as soon as drug resistance is ascertained, regardless of epilepsy duration, sex, socioeconomic status, seizure type, epilepsy type (including epileptic encephalopathies), localization, and comorbidities (including severe psychiatric comorbidity like psychogenic nonepileptic seizures [PNES] or substance abuse) if patients are cooperative with management; (2) A surgical referral should be considered for older patients with drug-resistant epilepsy who have no surgical contraindication, and for patients (adults and children) who are seizure-free on 1-2 antiseizure medications (ASMs) but have a brain lesion in noneloquent cortex; and (3) referral for surgery should not be offered to patients with active substance abuse who are noncooperative with management. We present the Delphi consensus results leading up to these Expert Consensus Recommendations and discuss the data supporting our conclusions. High level evidence will be required to permit creation of clinical practice guidelines., (© 2022 International League Against Epilepsy.)

Objective: Seizure outcomes after brain surgery for drug-resistant epilepsy (DRE) are very heterogeneous and difficult to predict with models utilizing the current clinical, imaging, and electrophysiological variables. In this pilot study, we investigated whether genetic and molecular biomarkers (e.g., genomic, transcriptomic) can provide additional insight into differential response to surgery., Methods: Post-operative seizure-outcomes were collected at last follow-up (>6 months) for 201 adult patients with DRE who underwent surgery between 2004 and 2020. Resected tissue was sent for miRNA sequencing ( n = 132) and mRNA sequencing ( n = 135). Following the selection of 10 genes ( SCN1A, NBEA, PTEN, GABRA1, LGL1, DEPDC5, IL1A, ABCB1, C3, CALHM1 ), we investigated SNPs in those 10 genes from previously acquired exome sequencing data ( n = 106). Logistic regression was performed to test for associations between individual features (mRNAs, miRNAs, and SNPs) and post-operative seizure-outcome with an exploratory FDR P < 0.25 as the threshold for significance. Post-operative time-to-seizure analyses were performed for each SNP using a Cox proportional hazards model., Results: The majority of patients (83%) had temporal lobe epilepsy. Mean age at surgery was 38.3 years, and 56% were female. Three SNPs (rs10276036, rs11975994, rs1128503) in multi-drug resistance gene, ABCB1 , were associated with post-operative seizure outcomes. Patients with alternate alleles in ABCB1 were more likely to be seizure-free at last follow-up (52-56% reduction in seizure recurrence; FDR P = 0.24). All three SNPs were in linkage disequilibrium and highly correlated with each other. Median post-operative time-to-seizure was 63 months for patients with 2 alternate alleles, 24-33 months with 1 alternate allele, and 10-11 months with 0 alternate alleles. These SNPs improved outcome prediction beyond MRI and sex alone. No independent miRNAs or mRNAs were significantly associated with seizure-outcome ( P > 0.05). However, pathway analysis identified "cancer drug resistance by drug efflux" (mir-154 and mir-379) as enriched ( P = 0.02), supporting the role of drug response genes in post-operative seizure recurrence., Significance: ABCB1 may have a role in epileptogenesis and surgery outcomes independent of its drug efflux activity necessitating further investigation. SNPs in ABCB1 may serve as independent predictors of post-operative outcome., Competing Interests: Author DR has an equity stake in Clarified Precision Medicine, LLC. DR has received research support from Novo Nordisk, consulting honoraria from Interpares Biomedicine and Pharmazaam, LLC. Author CE is the Sondra J. and Stephen R. Hardis Endowed Chair of Cancer Genomic Medicine at the Cleveland Clinic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Louis, Busch, Lal, Hockings, Hogue, Morita-Sherman, Vegh, Najm, Ghosh, Bazeley, Eng, Jehi and Rotroff.)

Objective: The aim of this study was to conduct item reduction of the Memory Assessment Clinics Self-Rating Scale (MAC-S) to create a briefer measure that can be used to quickly evaluate subjective memory complaints in patients with epilepsy. Method: A total of 1333 adults with focal epilepsy completed the original 49-item MAC-S. The sample was randomly split into three subsamples, and a series of analyses (i.e. exploratory factor analysis, confirmatory factor analysis, and item response theory analyses) was conducted to identify an alternative factor structure, with a reduced number of items. A panel of 5 neuropsychologists independently reviewed the final model to assess appropriateness of each individual item as well as the factor loadings and overall factor structure. Final factor titles were subsequently decided as a group. Results: Five factors were identified: Attention, Working Memory, Retrieval, Semantic Memory, and Episodic Memory. The length of the MAC-S was reduced from 49 to 30 items, with items being removed because they failed to load onto any of the factors substantially, or because of poor item discrimination or threshold levels. Conclusions: The Memory Assessment Clinics Scale for Epilepsy (MAC-E), is an updated, brief measure of subjective memory functioning that can be used to efficiently assess relevant, every-day memory abilities in patients with epilepsy within both clinical and research settings.

Clinical practice guidelines (CPGs) are statements that provide evidence-based recommendations aimed at optimizing patient care. However, many other documents are often published as "guidelines" when they are not; these documents, although also important in clinical practice, are usually not systematically produced following rigorous processes linking the evidence to the recommendations. Specifically, the International League Against Epilepsy (ILAE) guideline development toolkit aims to ensure that high-quality CPGs are developed to fill knowledge gaps and optimize the management of epilepsy. In addition to adhering to key methodological processes, guideline developers need to consider that effective CPGs should lead to improvements in clinical processes of care and health care outcomes. This requires monitoring the effectiveness of epilepsy-related CPGs and interventions to remove the barriers to epilepsy CPG implementation. This article provides an overview of what distinguishes quality CPGs from other documents and discusses their benefits and limitations. We summarize the recently revised ILAE CPG development process and elaborate on the barriers and facilitators to guideline dissemination, implementation, and adaptation., (© 2022 International League Against Epilepsy.)

Objective: Anterior temporal lobectomy (ATL) is a widely performed and successful intervention for drug-resistant temporal lobe epilepsy (TLE). However, up to one third of patients experience seizure recurrence within 1 year after ATL. Despite the extensive literature on presurgical electroencephalography (EEG) and magnetic resonance imaging (MRI) abnormalities to prognosticate seizure freedom following ATL, the value of quantitative analysis of visually reviewed normal interictal EEG in such prognostication remains unclear. In this retrospective multicenter study, we investigate whether machine learning analysis of normal interictal scalp EEG studies can inform the prediction of postoperative seizure freedom outcomes in patients who have undergone ATL., Methods: We analyzed normal presurgical scalp EEG recordings from 41 Mayo Clinic (MC) and 23 Cleveland Clinic (CC) patients. We used an unbiased automated algorithm to extract eyes closed awake epochs from scalp EEG studies that were free of any epileptiform activity and then extracted spectral EEG features representing (a) spectral power and (b) interhemispheric spectral coherence in frequencies between 1 and 25 Hz across several brain regions. We analyzed the differences between the seizure-free and non-seizure-free patients and employed a Naïve Bayes classifier using multiple spectral features to predict surgery outcomes. We trained the classifier using a leave-one-patient-out cross-validation scheme within the MC data set and then tested using the out-of-sample CC data set. Finally, we compared the predictive performance of normal scalp EEG-derived features against MRI abnormalities., Results: We found that several spectral power and coherence features showed significant differences correlated with surgical outcomes and that they were most pronounced in the 10-25 Hz range. The Naïve Bayes classification based on those features predicted 1-year seizure freedom following ATL with area under the curve (AUC) values of 0.78 and 0.76 for the MC and CC data sets, respectively. Subsequent analyses revealed that (a) interhemispheric spectral coherence features in the 10-25 Hz range provided better predictability than other combinations and (b) normal scalp EEG-derived features provided superior and potentially distinct predictive value when compared with MRI abnormalities (>10% higher F1 score)., Significance: These results support that quantitative analysis of even a normal presurgical scalp EEG may help prognosticate seizure freedom following ATL in patients with drug-resistant TLE. Although the mechanism for this result is not known, the scalp EEG spectral and coherence properties predicting seizure freedom may represent activity arising from the neocortex or the networks responsible for temporal lobe seizure generation within vs outside the margins of an ATL., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: Rasmussen encephalitis (RE) is a rare inflammatory disease affecting one hemisphere, causing progressive neurological deficits and intractable seizures., Objective: To report long-term seizure outcomes, reoperations, and functional outcomes in patients with RE who underwent hemispherectomy at our institution., Methods: Retrospective review was performed for all patients with RE who had surgery between 1998 and 2020. We collected seizure history, postoperative outcomes, and functional data. Imaging was independently reviewed in a blinded fashion by 2 neurosurgeons and a neuroradiologist., Results: We analyzed 30 patients with RE who underwent 35 hemispherectomies (5 reoperations). Using Kaplan-Meier analysis, seizure-freedom rate was 81.5%, 63.6%, and 55.6% at 1, 5, and 10 years after surgery, respectively. Patients with shorter duration of hemiparesis preoperatively were less likely to be seizure-free at follow-up (P = .011) and more likely to undergo reoperation (P = .004). Shorter duration of epilepsy (P = .026) and preoperative bilateral MRI abnormalities (P = .011) were associated with increased risk of reoperation. Complete disconnection of diseased hemisphere on postoperative MRI after the first operation improved seizure-freedom (P = .021) and resulted in fewer reoperations (P = .034), and reoperation resulted in seizure freedom in every case., Conclusion: Obtaining complete disconnection is critical for favorable seizure outcomes from hemispherectomy, and neurosurgeons should have a low threshold to reoperate in patients with RE with recurrent seizures. Rapid progression of motor deficits and bilateral MRI abnormalities may indicate a subpopulation of patients with RE with increased risk of needing reoperation. Overall, we believe that hemispherectomy is a curative surgery for the majority of patients with RE, with excellent long-term seizure outcome., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Objective: The objectives of this study were to determine the relationship between the severity of pathology and seizure outcomes in patients who underwent hemispherectomy for Rasmussen encephalitis (RE) and to investigate which clinical factors correlated with severity of pathology., Methods: In this retrospective cohort study, we collected and reviewed pathology and clinical variables. We ascertained seizure outcomes using Engel's classification, and Pardo stages were used to grade pathology., Results: We included 29 unique patients who underwent 34 hemispherectomy procedures for analysis. There was no statistically significant correlation between Pardo stage and seizure outcome (P = 1). Increasing duration of epilepsy (β = 0.011, P = 0.02) and duration of hemiparesis (β = 0.024, P = 0.01) were significantly associated with a more severe Pardo stage. In contrast, the presence of epilepsia partialis continua had a negative relationship with Pardo stage (β = -0.49, P = 0.04). Twenty-six (89.75%) patients were Engel class I at the last follow-up, including all 5 patients who underwent redo hemispherectomy in our cohort., Conclusions: Consistent with the progressive nature of RE, more severe pathology was associated with a longer duration of epilepsy and longer duration of hemiparesis, while the presence of epilepsia partialis continua was associated with less severe pathology. Results from this series suggest the degree of cortical involvement with RE as assessed on surgical histopathology does not correlate with seizure outcome after hemispherectomy, which appears to be more dependent on surgical technique/complete disconnection., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: Summarize the current evidence on efficacy and tolerability of vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) through a systematic review and meta-analysis., Methods: We followed the Preferred Reporting Items of Systematic reviews and Meta-Analyses reporting standards and searched Ovid Medline, Ovid Embase, and the Cochrane Central Register of Controlled Trials. We included published randomized controlled trials (RCTs) and their corresponding open-label extension studies, as well as prospective case series, with ≥20 participants (excluding studies limited to children). Our primary outcome was the mean (or median, when unavailable) percentage decrease in frequency, as compared to baseline, of all epileptic seizures at last follow-up. Secondary outcomes included the proportion of treatment responders and proportion with seizure freedom., Results: We identified 30 eligible studies, six of which were RCTs. At long-term follow-up (mean 1.3 years), five observational studies for VNS reported a pooled mean percentage decrease in seizure frequency of 34.7% (95% confidence interval [CI]: -5.1, 74.5). In the open-label extension studies for RNS, the median seizure reduction was 53%, 66%, and 75% at 2, 5, and 9 years of follow-up, respectively. For DBS, the median reduction was 56%, 65%, and 75% at 2, 5, and 7 years, respectively. The proportion of individuals with seizure freedom at last follow-up increased significantly over time for DBS and RNS, whereas a positive trend was observed for VNS. Quality of life was improved in all modalities. The most common complications included hoarseness, and cough and throat pain for VNS and implant site pain, headache, and dysesthesia for DBS and RNS., Significance: Neurostimulation modalities are an effective treatment option for drug-resistant epilepsy, with improving outcomes over time and few major complications. Seizure-reduction rates among the three therapies were similar during the initial blinded phase. Recent long-term follow-up studies are encouraging for RNS and DBS but are lacking for VNS., (© 2022 International League Against Epilepsy.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection triggers cytokine-mediated inflammation, leading to a myriad of clinical presentations in COVID-19. The SARS-CoV-2 open reading frame 8 (ORF8) is a secreted and rapidly evolving glycoprotein. Patients infected with SARS-CoV-2 variants with ORF8 deleted are associated with mild disease outcomes, but the molecular mechanism behind this is unknown. Here, we report that SARS-CoV-2 ORF8 is a viral cytokine that is similar to but distinct from interleukin 17A (IL-17A) as it induces stronger and broader human IL-17 receptor (hIL-17R) signaling than IL-17A. ORF8 primarily targeted blood monocytes and induced the heterodimerization of hIL-17RA and hIL-17RC, triggering a robust inflammatory response. Transcriptome analysis revealed that besides its activation of the hIL-17R pathway, ORF8 upregulated gene expression for fibrosis signaling and coagulation dysregulation. A naturally occurring ORF8 L84S variant that was highly associated with mild COVID-19 showed reduced hIL-17RA binding and attenuated inflammatory responses. This study reveals how SARS-CoV-2 ORF8 by a viral mimicry of the IL-17 cytokine contributes to COVID-19 severe inflammation. IMPORTANCE Patients infected with SARS-CoV-2 variants lacking open reading frame 8 (ORF8) have been associated with milder infection and disease outcome, but the molecular mechanism behind how this viral accessory protein mediates disease pathogenesis is not yet known. In our study, we revealed that secreted ORF8 protein mimics host IL-17 to activate IL-17 receptors A and C (IL-17RA/C) and induces a significantly stronger inflammatory response than host IL-17A, providing molecular insights into the role of ORF8 in COVID-19 pathogenesis and serving as a potential therapeutic target.

Epilepsy surgery is an effective treatment option for drug-resistant focal epilepsy patients with associated structural brain lesions. However, little epidemiological data are available regarding the number of patients with these lesions. We reviewed data regarding (1) the prevalence and incidence of epilepsy; (2) the proportion of epilepsy patients with focal epilepsy, drug-resistant epilepsy, and drug-resistant focal epilepsies; and (3) the number of epilepsy presurgical evaluations and surgical resections. We also assessed the relative proportion of brain lesions using post-surgical histopathological findings from 541 surgical patients from the Cleveland Clinic and 9,523 patients from a European multi-center cohort. Data were combined to generate surgical candidate incidence and prevalence estimates and the first lesion-specific estimates for hippocampal sclerosis (HS), low-grade epilepsy-associated brain tumors (LEAT), malformations of cortical development (MCD), glial scars, vascular malformations, and encephalitis. The most frequently diagnosed brain lesions were HS (incidence = 2.32 ± 0.26 in 100,000, prevalence = 19.40 ± 2.16 in 100,000) for adults and MCD (incidence = 1.15 ± 0.34 in 100,000, prevalence = 6.52 ± 1.89 in 100,000) for children. Our estimates can guide patient advocacy groups, clinicians, researchers, policymakers in education, development of health care strategy, resource allocation, and reimbursement schedules., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Coronavirus disease 2019 (COVID-19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID-19 incidence and severity as a function of age. Our analysis leveraged age-specific COVID-19 mortality and laboratory testing from a large COVID-19 registry, along with epidemiological data of ~3.4 million individuals, large-scale deep immune cell profiling data, and single-cell RNA-sequencing data from aged COVID-19 patients across diverse populations. We found that decreased lymphocyte count and elevated inflammatory markers (C-reactive protein, D-dimer, and neutrophil-lymphocyte ratio) are significantly associated with age-specific COVID-19 severities. We identified the reduced abundance of naïve CD8 T cells with decreased expression of antiviral defense genes (i.e., IFITM3 and TRIM22) in aged severe COVID-19 patients. Older individuals with severe COVID-19 displayed type I and II interferon deficiencies, which is correlated with SARS-CoV-2 viral load. Elevated expression of SARS-CoV-2 entry factors and reduced expression of antiviral defense genes (LY6E and IFNAR1) in the secretory cells are associated with critical COVID-19 in aged individuals. Mechanistically, we identified strong TGF-beta-mediated immune-epithelial cell interactions (i.e., secretory-non-resident macrophages) in aged individuals with critical COVID-19. Taken together, our findings point to immuno-inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID-19 patients., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Purpose: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a disproportionately severe effect on men, suggesting that the androgen pathway plays a role in the disease. Studies on the effect of castration and androgen receptor blockade have been mixed, while 5α-reductase inhibitor (5ARI) use in men with COVID-19 (2019 novel coronavirus) have shown potential benefits. We assessed the association of 5ARI use on risk of community acquired SARS-CoV-2 infection., Materials and Methods: A total of 60,474 males in a prospective registry of people tested for SARS-CoV-2 between March 8, 2020 and February 15, 2021 were included. Using a matched cohort design, men using 5ARIs were matched 1:1 to non5ARI users. Independent analysis using unconditional multivariable logistic regression on the entire unmatched data set was completed for validation. Primary outcome measures were the association of 5ARI use on rates of SARS-Cov-2 positivity and disease severity., Results: Of the men 1,079 (1.8%) reported 5ARI use and 55,100 were available for matching. The final matched cohorts included 944 men each. Mean duration of use was 60.4 months (IQR 17-84 months). Absolute risk for infection was significantly lower in 5ARI users compared to nonusers, 42.3% (399/944) vs 47.2% (446/944), respectively (absolute risk reduction [ARR] 4.9%, OR 0.81, 95% CI 0.67-0.97, p=0.026). Unconditional multivariable logistic regression analysis of the entire study cohort of 55,100 men confirmed the protective association of 5ARI use (ARR 5.3%, OR=0.877, 95% CI 0.774-0.995, p=0.042). Use of 5ARIs was not associated with disease severity., Conclusions: Use of 5ARIs in men without prostate cancer was associated with a reduction in community acquired SARS-CoV-2 infection.

Background: Prior studies in the field of epilepsy surgical disparities have examined barriers in undergoing epilepsy surgical resections in disadvantaged populations involving trust in health providers, education level, social support, and fear of treatment. Few studies have analyzed the geographical locations of specialized epilepsy centers and their role in nationwide epilepsy surgical access and disparities., Objective: To better visualize the locations of epilepsy level IV centers in the United States with respect to epilepsy prevalence and socioeconomic disadvantage., Methods: We created heat maps of the United States to visualize geographical locations of level IV epilepsy centers with respect to the 2015 state-wide epilepsy prevalence and 2017 county-wide Area Deprivation Index (ADI) scores, a composite measure of socioeconomic disadvantage. Univariate logistic regression was used to test for associations between the presence or absence of epilepsy centers and socioeconomic disadvantage., Results: We found eight states within the United States without any level IV epilepsy centers. In states with level IV centers, centers were clustered in populated and metropolitan regions. Disadvantaged counties (with increased ADI scores) were less likely to have level IV centers compared to counties that were less disadvantaged (lower ADI scores) (p < 0.00001)., Conclusion: Further work is required to remedy the decreased access to specialized epilepsy care due to geographical disparities, and to better understand its contribution to overall disparities affecting epilepsy surgery referrals., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The aim was to compare the outcomes of subdural electrode (SDE) implantations versus stereotactic electroencephalography (SEEG), the 2 predominant methods of intracranial electroencephalography (iEEG) performed in difficult-to-localize drug-resistant focal epilepsy., Methods: The Surgical Therapies Commission of the International League Against Epilepsy created an international registry of iEEG patients implanted between 2005 and 2019 with ≥1 year of follow-up. We used propensity score matching to control exposure selection bias and generate comparable cohorts. Study endpoints were: (1) likelihood of resection after iEEG; (2) seizure freedom at last follow-up; and (3) complications (composite of postoperative infection, symptomatic intracranial hemorrhage, or permanent neurological deficit)., Results: Ten study sites from 7 countries and 3 continents contributed 2,012 patients, including 1,468 (73%) eligible for analysis (526 SDE and 942 SEEG), of whom 988 (67%) underwent subsequent resection. Propensity score matching improved covariate balance between exposure groups for all analyses. Propensity-matched patients who underwent SDE had higher odds of subsequent resective surgery (odds ratio [OR] = 1.4, 95% confidence interval [CI] 1.05, 1.84) and higher odds of complications (OR = 2.24, 95% CI 1.34, 3.74; unadjusted: 9.6% after SDE vs 3.3% after SEEG). Odds of seizure freedom in propensity-matched resected patients were 1.66 times higher (95% CI 1.21, 2.26) for SEEG compared with SDE (unadjusted: 55% seizure free after SEEG-guided resections vs 41% after SDE)., Interpretation: In comparison to SEEG, SDE evaluations are more likely to lead to brain surgery in patients with drug-resistant epilepsy but have more surgical complications and lower probability of seizure freedom. This comparative-effectiveness study provides the highest feasible evidence level to guide decisions on iEEG. ANN NEUROL 2021;90:927-939., (© 2021 American Neurological Association.)

Objective: To assess and validate the performance of a new tool developed for segmenting and characterizing lacunas in postoperative MR images of epilepsy patients., Methods: A MATLAB-based pipeline was implemented using SPM12 to produce the 3D mask of the surgical lacuna and estimate its volume. To validate its performance, we compared the manual and automatic lacuna segmentations obtained from 51 MRI scans of epilepsy patients who underwent temporal lobe resections., Results: The code is consolidated as a tool named ResectVol, which can be run via a graphical user interface or command line. The automatic and manual segmentation comparison resulted in a median Dice similarity coefficient of 0.77 (interquartile range: 0.71-0.81)., Significance: Epilepsy surgery is the treatment of choice for pharmacoresistant focal epilepsies, and despite the extensive literature on the subject, we still cannot predict surgical outcomes accurately. As the volume and location of the resected tissue are fundamentally relevant to this prediction, researchers commonly perform a manual segmentation of the lacuna, which presents human bias and does not provide detailed information about the structures removed. In this study, we introduce ResectVol, a user-friendly, fully automatic tool to accomplish these tasks. This capability enables more advanced analytical techniques applied to surgical outcomes prediction, such as machine-learning algorithms, by facilitating coregistration of the resected area and preoperative findings with other imaging modalities such as PET, SPECT, and functional MRI ResectVol is freely available at https://www.lniunicamp.com/resectvol., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Three neuromodulation therapies have been appropriately tested and approved in refractory focal epilepsies: vagus nerve stimulation (VNS), deep brain stimulation of the anterior nucleus of the thalamus (ANT-DBS), and closed-loop responsive neurostimulation of the epileptogenic zone or zones. These therapies are primarily palliative. Only a few individuals have achieved complete freedom from seizures for more than 12 months with these therapies, whereas more than half have benefited from long-term reduction in seizure frequency of more than 50%. Implantation-related adverse events primarily include infection and pain at the implant site. Intracranial haemorrhage is a frequent adverse event for ANT-DBS and responsive neurostimulation. Other stimulation-specific side-effects are observed with VNS and ANT-DBS. Biomarkers to predict response to neuromodulation therapies are not available, and high-level evidence to aid decision making about when and for whom these therapies should be preferred over other antiepileptic treatments is scant. Future studies are thus needed to address these shortfalls in knowledge, approve other forms of neuromodulation, and develop personalised closed-loop therapies with embedded machine learning. Until then, neuromodulation could be considered for individuals with intractable seizures, ideally after the possibility of curative surgical treatment has been carefully assessed and ruled out or judged less appropriate., Competing Interests: Declaration of interests PR has received speaker fees from Livanova, UCB Pharma, EISAI, and GW Pharma. SR has received speaker, consulting fees, or both, from UCB Pharma, EISAI, GW Pharma, Idiorsia, Livanova, and Arvelle Therapeutics. LJH has received consultation fees for advising from Accure, Aquestive, Ceribell, Marinus, Medtronic, Neuropace, and UCB, honoraria for speaking from Neuropace and Natus, and royalties from Wolters-Kluwer for authoring chapters for UpToDate-Neurology, and from Wiley for coauthoring the book Atlas of EEG in Critical Care, by Hirsch and Brenner. AS and LJ declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: The influence of sleep-disordered breathing (SDB) and sleep-related hypoxemia in SARS-CoV-2 viral infection and COVID-19 outcomes remains unknown. Controversy exists regarding whether to continue treatment for SDB with positive airway pressure given concern for aerosolization with limited data to inform professional society recommendations., Objective: To investigate the association of SDB (identified via polysomnogram) and sleep-related hypoxia with (1) SARS-CoV-2 positivity and (2) World Health Organization (WHO)-designated COVID-19 clinical outcomes while accounting for confounding including obesity, underlying cardiopulmonary disease, cancer, and smoking history., Design, Setting, and Participants: This case-control study was conducted within the Cleveland Clinic Health System (Ohio and Florida) and included all patients who were tested for COVID-19 between March 8 and November 30, 2020, and who had an available sleep study record. Sleep indices and SARS-CoV-2 positivity were assessed with overlap propensity score weighting, and COVID-19 clinical outcomes were assessed using the institutional registry., Exposures: Sleep study-identified SDB (defined by frequency of apneas and hypopneas using the Apnea-Hypopnea Index [AHI]) and sleep-related hypoxemia (percentage of total sleep time at <90% oxygen saturation [TST <90])., Main Outcomes and Measures: Outcomes were SARS-CoV-2 infection and WHO-designated COVID-19 clinical outcomes (hospitalization, use of supplemental oxygen, noninvasive ventilation, mechanical ventilation or extracorporeal membrane oxygenation, and death)., Results: Of 350 710 individuals tested for SARS-CoV-2, 5402 (mean [SD] age, 56.4 [14.5] years; 3005 women [55.6%]) had a prior sleep study, of whom 1935 (35.8%) tested positive for SARS-CoV-2. Of the 5402 participants, 1696 were Black (31.4%), 3259 were White (60.3%), and 822 were of other race or ethnicity (15.2%). Patients who were positive vs negative for SARS-CoV-2 had a higher AHI score (median, 16.2 events/h [IQR, 6.1-39.5 events/h] vs 13.6 events/h [IQR, 5.5-33.6 events/h]; P < .001) and increased TST <90 (median, 1.8% sleep time [IQR, 0.10%-12.8% sleep time] vs 1.4% sleep time [IQR, 0.10%-10.8% sleep time]; P = .02). After overlap propensity score-weighted logistic regression, no SDB measures were associated with SARS-CoV-2 positivity. Median TST <90 was associated with the WHO-designated COVID-19 ordinal clinical outcome scale (adjusted odds ratio, 1.39; 95% CI, 1.10-1.74; P = .005). Time-to-event analyses showed sleep-related hypoxia associated with a 31% higher rate of hospitalization and mortality (adjusted hazard ratio, 1.31; 95% CI, 1.08-1.57; P = .005)., Conclusions and Relevance: In this case-control study, SDB and sleep-related hypoxia were not associated with increased SARS-CoV-2 positivity; however, once patients were infected with SARS-CoV-2, sleep-related hypoxia was an associated risk factor for detrimental COVID-19 outcomes.

Background: Sites of entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly expressed in nasal epithelial cells; however, little is known about the impact of intranasal corticosteroids (INCS) on coronavirus disease 2019 (COVID-19)-related outcomes., Objective: To determine the association between baseline INCS use and COVID-19-related outcomes., Methods: Using the Cleveland Clinic COVID-19 Research Registry, we performed a propensity score matching for treatment with INCS before SARS-CoV-2 infection (April 1, 2020, to March 31, 2021). Of the 82,096 individuals who tested positive, 72,147 met inclusion criteria. Our endpoints included the need for hospitalization, admission to the intensive care unit (ICU), or in-hospital mortality., Results: Of the 12,608 (17.5%) who were hospitalized, 2935 (4.1%) required ICU admission and 1880 (2.6%) died during hospitalization. A significant proportion (n = 10,187; 14.1%) were using INCS before SARS-CoV-2 infection. Compared with nonusers, INCS users demonstrated lower risk for hospitalization (adjusted odds ratio [OR] [95% confidence interval (CI)]: 0.78 [0.72; 0.85]), ICU admission (adjusted OR [95% CI]: 0.77 [0.65; 0.92]), and in-hospital mortality (adjusted OR [95% CI]: 0.76 [0.61; 0.94]). These findings were replicated in sensitivity analyses where patients on inhaled corticosteroids and those with allergic rhinitis were excluded. The beneficial effect of INCS was significant after adjustment for baseline blood eosinophil count (measured before SARS-CoV-2 testing) in a subset of 30,289 individuals., Conclusion: INCS therapy is associated with a lower risk for COVID-19-related hospitalization, ICU admission, or death. Future randomized control trials are needed to determine if INCS reduces the risk for severe outcomes related to COVID-19., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)