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Rationale Psychogenic Nonepileptic Seizures (PNES) are seizure-like episodes without EEG abnormality, and are of psychological origin. Cognitive Behavioral Therapy (CBT), a type of psychological counseling, is known to be the best intervention to treat PNES and the underlying psychiatric symptoms. Yet, many remain untreated because of limited access to specialized counseling programs. In this study, first we intended to see if the positive outcomes of the CBTip can be replicated in our patient population using within-group comparison. We also aimed to examine the outcomes of patients who received a variable dose of treatment than the established treatment protocol. Method We obtained retrospective patient reported outcomes (PRO) data from patients treated with Cognitive Behavioral Therapy-informed psychotherapy (CBT-ip) from January 2015 to January 2020 in an outpatient tertiary care epilepsy center. The CBTip program is a 12-session intervention delivered weekly by a seizure counselor. Although the program comprises 12 sessions of treatment, we included patients who attended at least 7 sessions consistent with previous research that used a similar cutoff. We had a total of 160 patient PROs included in the analysis. Outcome variables including seizure frequency, depression, anxiety, and quality of life were examined using self-report outcome scores. Demographic and other clinical and psychosocial confounding variables were controlled. Results In the first analysis in which we compared pre-treatment scores with 3-month posttreatment scores, there was no significant change in seizure frequency, depression, anxiety, and quality-of-life outcomes. In the second analysis when we compared pre- and posttreatment scores in patients who completed the treatment in longer than 3-month time, there were significant improvement in primary and secondary outcomes. For seizure frequency, 10 patients had data for “seizures per day in the last 6 months” and 5 participants (50%) improved by 50% or more in the number of seizures per day. There were also significant reductions in depression and anxiety scores but not in quality of life. Implication and conclusions Our analysis showed that patients treated with CBTip with a minimum of 7 sessions in 3 months did not have significant improvement. However, attending at least 7 sessions of CBTip in longer than 3 months was effective for seizure control, depression, and anxiety. The observational and exploratory nature of our study, however, limits the generalizability of our findings outside of the single tertiary clinical care setting.

Hemispherectomy in Adults and Adolescents: Seizure and Functional Outcomes in 47 Patients McGovern RA, NV Moosa A, Jehi L, Busch R, Ferguson L, Gupta A, et al. Epilepsia. 2019;60(12):2416-2427. http://doi.org/10.1111/epi.16378.Objective:To examine longitudinal seizure and functional outcomes after hemispherectomy in adults and adolescents.Methods:We reviewed 47 consecutive patients older than 16 years who underwent hemispherectomy between 1996 and 2016 at our center. Clinical, electroencephalographic (EEG), imaging, neuropsychological, surgical, and functional status data were analyzed.Results:Thirty-six patients were 18 years or older at surgery; 11 were aged between 16 and 18 years. Brain injury leading to hemispheric epilepsy occurred before 10 years of age in 41 (87%) patients. At a mean follow-up of 5.3 postoperative years (median = 2.9 years), 36 (77%) had Engel class I outcome. Longitudinal outcome analysis showed 84% seizure freedom (Engel IA) at 6 months, 76% at 2 years, and 76% at 5 years and beyond, with stable longitudinal outcomes up to 12 years from surgery. Multivariate analysis demonstrated that acute postoperative seizures and contralateral interictal spikes at 6-month follow-up EEG were associated with seizure recurrence. Patients who could walk unaided preoperatively and had no cerebral peduncle atrophy on brain magnetic resonance imaging were more likely to experience worsening of motor function postoperatively. Otherwise, postoperative ambulatory status and hand function were unchanged. Of the 19 patients who completed neuropsychological testing, 17 demonstrated stable or improved postoperative outcomes.Significance:Hemispherectomy in adults is a safe and effective procedure, with seizure freedom rates and functional outcome similar to those observed in children.

BACKGROUND Previous reports have suggested an increasing rate of utilization of spinal fusions, but contemporary data have not been analyzed, and there has been little investigation of putative drivers of increased utilization. OBJECTIVE To investigate whether there is an ongoing trend of increased utilization of spinal fusions in recent data, and if there may be associations with an increasing proportion of elderly in the population, changing patterns of payer-types, and changing reimbursement rates. METHODS We analyze 7.1 million cases from the National Inpatient Sample between 1998 and 2014. We measure annual utilization per 100 000 persons and conduct trend analyses with subgroup analysis of the senior (65 + ) population. Spine surgery utilization is compared with nonspine surgical procedures (coronary artery bypass grafting, hernia repair, hip, and knee replacement). We assess trends in charges, payer type, Medicare reimbursement rates, and hospital type. RESULTS There was an 88% increase in the utilization rate of spinal fusion procedures from 1998 to 2014 (from 74 to 139 cases per 100 000 persons) with a significant upward trend (P

Objective The objective of this study was to compare the accuracy of clinical judgment in predicting seizure outcome after resective epilepsy surgery relative to two recently published statistical tools [the Epilepsy Surgery Nomogram (ESN) and the modified Seizure-Freedom score (m-SFS)]. Methods Details of presurgical evaluations of 20 patients who underwent epilepsy surgery were presented to 20 epilepsy experts. The final surgical treatment was also disclosed. The clinicians were asked to predict the likelihood of a good outcome (Engel 1) at 2 and 5 years in each case. The ESN and the m-SFS predictions were calculated with the data provided to the clinicians. The discriminative ability of clinical judgment, ESN, and m-SFS was assessed by calculating a concordance index (C-index). Expert opinion, the m-SFS and the ESN performances were compared using a Receiver Operating Characteristic (ROC) curve analysis. Results The mean age at surgery was 29 years (standard deviation [SD] = 14); 40% were male; 70% were right-handed, and thirteen (65%) had an Engel outcome 1 at 2 and 5 years. The mean C-index for the mean physician's prediction was 0.478 with a variance of 0.012. The ESN had an area under the curve (AUC) of 0.528 and 0.533 for the 2-year and 5-year predictions in comparison with the clinicians' predictions that was 0.476, and 0.466, respectively. For the m-SFS, the AUC at 2 years and 5 years was 0.539 and 0.539, respectively. No statistical difference was noted between the ESN and the clinicians or between m-SFS and the ESN, but there is a moderate statistical difference favoring the m-SFS to the clinicians (p 0.0960 and 0.0514, for 2 and 5 years). Significance Clinical judgment was not superior to the ESN nor to the m-SFS. Together with the interphysician's prediction variability, our findings reinforce the need for better tools to predict postoperative outcomes.

The American Epilepsy Society Meeting in New Orleans attracted more than 5900 attendees. There was a lively exchange of new science, innovation, education, clinical practice, and many other items related to epilepsy. Educational symposia were a major part of the meeting and explored varying topics of interest for all types of epilepsy professionals. This article reviews highlights of the meeting presented in major symposia. Topics ranged from how to treat varying aspects of epilepsy as a consultant in the hospital to finding the scientific underpinning of the interaction between sleep and epilepsy. Pros and cons of novel antiseizure medications, dietary, and stimulation treatments were discussed. Epilepsy may impair memory and we need to learn what is the pathophysiologic relationship. Febrile status epilepticus may have severe consequences for a later life with seizures. Epilepsy professionals should be very well aware of the ethical implications of devasting seizures and their associated disability. These are just a few select topics of the many that we need to study further to archive the final goal to improve the lives of patients with epilepsy.

OBJECTIVE: We aimed to determine the rates and predictors of resection and seizure freedom after bilateral stereo-electroencephalography (SEEG) implantation. METHODS: We reviewed 184 patients who underwent bilateral SEEG implantation (2009-2015). Noninvasive and invasive evaluation findings were collected. Outcomes of interest included subsequent resection and seizure freedom. Statistical analyses employed multivariable logistic regression and proportional hazard modeling. Preoperative and postoperative seizure frequency, severity, and quality of life scales were also compared. RESULTS: Following bilateral SEEG implantation, 106 of 184 patients (58%) underwent resection. Single seizure type (P = 0.007), a family history of epilepsy (P = 0.003), 10 or more seizures per month (P = 0.004), lower number of electrodes (P = 0.02), or sentinel electrode placement (P = 0.04) was predictive of undergoing a resection, as were lack of nonlocalized (P < 0.0001) or bilateral (P < 0.0001) ictal-onset zones on SEEG. Twenty-six of 81 patients (32% with follow-up greater than 1 year) remained seizure-free. Predictors of seizure freedom were single seizure type (P = 0.01), short epilepsy duration (P = 0.008), use of 2 or fewer antiepileptic drugs (AEDs) at the time of surgery (P = 0.0006), primary localization hypothesis involving the frontal lobe (P = 0.002), sentinel electrode placement only (P = 0.02), and lack of overlap between ictal-onset zone and eloquent cortex (P = 0.04), along with epilepsy substrate histopathology (P = 0.007). Complete resection of a suspected focal cortical dysplasia showed a trend to increased likelihood of seizure freedom (P = 0.09). The 44 of 55 patients (80%) who underwent resection and experienced seizure recurrence had >50% seizure reduction, as opposed to 26 of 45 patients (58%) who continued medical therapy alone (P = 0.003). Seventy-two percent of patients had a clinically meaningful quality of life improvement (>10% decrease in the Quality of Life in Epilepsy [QOLIE-10] score) at 1 year. SIGNIFICANCE: A strong preimplantation hypothesis of a suspected unifocal epilepsy increases the odds of resection and seizure freedom. We discuss a tailored approach, taking into account localization hypothesis and suspected epilepsy etiology in guiding implantation and subsequent surgical strategy.

Objective: To develop predictive models for in-hospital mortality and length of stay (LOS) for COVID-19 positive patients. Patients and Methods: We performed a multicenter retrospective cohort study of hospitalized COVID-19 positive patients. A total of 764 patients admitted to 14 different hospitals within the Cleveland Clinic from 03/09/2020 to 05/20/2020 who had reverse transcriptase-polymerase chain reaction proven coronavirus infection were included. We used LightGBM, a machine learning algorithm, to predict in-hospital mortality at different time points (after 7 days, 14 days, and 30 days of hospitalization) and in-hospital LOS. Results: Among 764 patients, 116 (15%) either died (n = 87) or were transitioned to hospice care (n = 29) during their hospitalization. The median LOS was 5 days (range 1 - 44 days) for patients admitted to the regular nursing floor and 10 days (range 1-38 days) for patients admitted to the intensive care unit (ICU). Patients who died during hospitalization were older, initially admitted to the ICU, more likely to be white and to have worse organ dysfunction compared to patients who survived their hospitalization. Using the 10 most important variables only, the final model's area under the Receiver Operating Characteristics curve was 0.86 for 7-day, 0.88 for 14-day, and 0.85 for 30-day mortality in the validation cohort. Conclusions: We developed a decision tool that can provide explainable and patient-specific prediction of in-hospital mortality and LOS for COVID-19 positive patients. The model can aid healthcare systems in bed allocation and distribution of vital resources.

Summary Background T cells control viral infection, promote vaccine durability, and in coronavirus disease 2019 (COVID-19) associate with mild disease. We investigated whether prior measles-mumps-rubella (MMR) or tetanus-diphtheria-pertussis (Tdap) vaccination elicits cross-reactive T cells that mitigate COVID-19. Methods Antigen-presenting cells (APC) loaded ex vivo with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), MMR, or Tdap antigens and autologous T cells from COVID-19-convalescent participants, uninfected individuals, and COVID-19 mRNA-vaccinated donors were co-cultured. T cell activation and phenotype were detected by interferon-γ (IFN-γ) enzyme-linked immunospot (ELISpot) assays and flow cytometry. ELISAs (enzyme-linked immunosorbant assays) and validation studies identified the APC-derived cytokine(s) driving T cell activation. TCR clonotyping and single-cell RNA sequencing (scRNA-seq) identified cross-reactive T cells and their transcriptional profile. A propensity-weighted analysis of COVID-19 patients estimated the effects of MMR and Tdap vaccination on COVID-19 outcomes. Findings High correlation was observed between T cell responses to SARS-CoV-2 (spike-S1 and nucleocapsid) and MMR and Tdap proteins in COVID-19-convalescent and -vaccinated individuals. The overlapping T cell population contained an effector memory T cell subset (effector memory re-expressing CD45RA on T cells [TEMRA]) implicated in protective, anti-viral immunity, and their detection required APC-derived IL-15, known to sensitize T cells to activation. Cross-reactive TCR repertoires detected in antigen-experienced T cells recognizing SARS-CoV-2, MMR, and Tdap epitopes had TEMRA features. Indices of disease severity were reduced in MMR- or Tdap-vaccinated individuals by 32%–38% and 20%–23%, respectively, among COVID-19 patients. Conclusions Tdap and MMR memory T cells reactivated by SARS-CoV-2 may provide protection against severe COVID-19. Funding This study was supported by a National Institutes of Health (R01HL065095, R01AI152522, R01NS097719) donation from Barbara and Amos Hostetter and the Chleck Foundation.

This cohort study examines health care utilization patterns for patients with COVID-19 who were enrolled vs not enrolled in a home monitoring program.

Background Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions. Methods In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer’s disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. Results We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals. Conclusion Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.

Multiple factors influence the outcomes of epilepsy surgery. Prognostic indicators varying from clinical characteristics, imaging findings, ictal, and interictal electrophysiological activity have been linked to surgical outcomes. In this review, we focus on the relatively under‐studied role of the underlying epilepsy histopathology in driving post‐surgical outcomes, specifically focusing on the broad categories of seizure outcomes and cognitive outcomes. For each of these two outcomes of interest, we answer two questions: 1)‐ does etiology matter? and 2)‐ how could it matter? The goal is to review the existing literature on the relationship between etiology and surgical outcomes to provide the best possible judgment as to whether a causal relationship exists between histopathology and the ultimate surgical outcome as an initial step. Then, we delve into the possible mechanisms via which such relationships can be explained. We conclude with a call to action to the epilepsy surgery and histopathology research community to push the mechanistic understanding of the pathology‐outcome interaction and identify actionable knowledge and biomarkers that could inform patient care in a timely fashion., In this review, we focus on the relatively under‐studied role of the underlying epilepsy histopathology in driving post‐surgical outcomes, specifically focusing on the broad categories of seizure outcomes and cognitive outcomes. For each of these two outcomes of interest, we answer two questions: (1) does etiology matter? and (2) how could it matter? We then delve into the mechanisms of these answers.

Background There is concern that the Patient Health Questionnaire-9 (PHQ-9) depression scale may be impacted by the presence of somatic symptoms (differential item functioning (DIF)) in patients with neurological conditions. We evaluated the PHQ-9 for the presence and impact of DIF in large clinical samples of neurological patients. Methods We conducted a cross-sectional study of patients seen at the Cleveland Clinic Cerebrovascular, Headache, Movement Disorder, and Neuromuscular clinics who completed the PHQ-9 and patient-reported disease severity measures as part of standard care between 7/29/2008-2/21/2013. We evaluated PHQ-9 items for DIF with respect to disease-specific severity for each condition. Salient DIF impact was characterized as a difference between DIF-adjusted and unadjusted PHQ-9 scores. Results Included in the study were 2,112 patients with stroke, 8,221 with migraine, 440 with amyotrophic lateral sclerosis (ALS), and 5,022 with Parkinson's disease (PD). Several PHQ-9 items demonstrated DIF with respect to disease-specific severity, although salient DIF was present in very few patients (stroke (n=0); migraine (n=1); ALS (n=13); PD (n=1)). Conclusions PHQ-9 items function consistently across disease severity, with salient levels of DIF impact found only for a very small proportion of people. These results suggest that the PHQ-9 provides a consistent measure of depression severity among people with neurological conditions associated with somatic symptoms that overlap with depression.

Multiple factors affect how health care stakeholders measure success, but at a minimum, clinicians must become more accountable for patient outcomes. While challenges in development and utilization...

BACKGROUND T cells control viral infection and promote vaccine durability and in COVID-19 associate with mild disease. We investigated whether prior Measles-Mumps-Rubella (MMR) or Tetanus-Diptheria-Pertussis (Tdap) vaccination elicit cross-reactive T cells that mitigate COVID-19. METHODS Antigen presenting cells (APC) loaded ex vivo with SARS-CoV-2, MMR or Tdap antigens and autologous T cells from COVID-19 convalescent and uninfected individuals, and COVID-19 mRNA vaccinated donors were co-cultured and T cell activation and phenotype were detected by IFN-γ ELISpot assays and flow cytometry. ELISA assays and validation studies identified the APC-derived cytokine(s) driving T cell activation. TCR clonotyping and scRNA-seq identified cross-reactive T cells and their transcriptional profile. A propensity-weighted analysis of COVID-19 patients estimated the effects of MMR and Tdap vaccination on COVID-19 outcomes. FINDINGS High correlation was observed between T cell responses to SARS-CoV-2 (Spike-S1 and Nucleocapsid) and MMR and Tdap proteins in COVID-19 convalescent and vaccinated individuals. The overlapping T cell population contained an effector memory T cell subset (TEMRA) implicated in protective, anti-viral immunity and their detection required APC-derived IL-15, known to sensitize T cells to activation. Cross-reactive TCR repertoires detected in antigen-experienced T cells recognizing SARS-CoV-2, MMR and Tdap epitopes had TEMRA features. Indices of disease severity were reduced in MMR or Tdap vaccinated individuals by 32-38% and 20-23% respectively, among COVID-19 patients. CONCLUSIONS Tdap and MMR memory T cells reactivated by SARS-CoV-2 may provide protection against severe COVID-19 disease. FUNDING National Institutes of Health (R01HL065095, R01AI152522, R01NS097719), donation from Barbara and Amos Hostetter and the Chleck Foundation., Graphical Abstract, T cells critically control infection and effective vaccination. In COVID-19 convalescent or COVID-19 vaccinated individuals, memory T cells previously generated by MMR or Tdap vaccines are reactivated by SARS-CoV-2 antigens and have features of TEMRA, implicated in anti-viral immunity. Prior MMR or Tdap vaccination may protect against severe COVID-19 disease.

Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.

Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial, and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied. Here we inspected sex differences in SARS-CoV-2 infection, hospitalization, admission to the intensive care unit (ICU), sera inflammatory biomarker profiling, and single-cell RNA-sequencing (scRNA-seq) profiles across nasal, bronchoalveolar lavage fluid (BALF), and peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with varying degrees of disease severities. Our propensity score-matching observations revealed that male individuals have a 29% elevated likelihood of SARS-CoV-2 positivity, with a hazard ratio (HR) 1.32 (95% confidence interval [CI] 1.18–1.48) for hospitalization and HR 1.51 (95% CI 1.24–1.84) for admission to ICU. Sera from male patients at hospital admission had elevated neutrophil–lymphocyte ratio and elevated expression of inflammatory markers (C-reactive protein and procalcitonin). We found that SARS-CoV-2 entry factors, including ACE2, TMPRSS2, FURIN, and NRP1, have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19. We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples, which offers potential molecular mechanism for sex-biased susceptibility to viral infection. Cell–cell interaction network analysis reveals potential epithelium–immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19. Mechanistically, monocyte-elevated expression of Toll-like receptor 7 (TLR7) and Bruton tyrosine kinase (BTK) is associated with severe outcomes in males with COVID-19. In summary, these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.

Sex differences in the risk of SARS-CoV-2 infection have been controversial and the underlying mechanisms of COVID-19 sexual dimorphism remain understudied. Here we inspected sex differences in SARS-CoV-2 positivity, hospitalization, admission to the intensive care unit (ICU), sera immune profiling, and two single-cell RNA-sequencing (snRNA-seq) profiles from nasal tissues and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients with varying degrees of disease severity. Our propensity score-matching observations revealed that male individuals have a 29% increased likelihood of SARS-CoV-2 positivity, with a hazard ration (HR) 1.32 (95% confidence interval [CI] 1.18-1.48) for hospitalization and HR 1.51 (95% CI 1.24-1.84) for admission to ICU. Sera from male patients at hospital admission had decreased lymphocyte count and elevated inflammatory markers (C-reactive protein, procalcitonin, and neutrophils). We found that SARS-CoV-2 entry factors, including ACE2, TMPRSS2, FURIN and NRP1, have elevated expression in nasal squamous cells from males with moderate and severe COVID-19. Cell-cell network proximity analysis suggests possible epithelium-immune cell interactions and immune vulnerability underlying a higher mortality in males with COVID-19. Monocyte-elevated expression of Toll like receptor 7 (TLR7) and Bruton tyrosine kinase (BTK) is associated with severe outcomes in males with COVID-19. These findings provide basis for understanding immune responses underlying sex differences, and designing sex-specific targeted treatments and patient care for COVID-19.

Introduction Central to the pathophysiology of SARS-CoV-2 is immune dysregulation and systemic inflammation, however, it is yet unknown whether sleep-related hypoxemia--which we have recently noted to be associated with worse COVID-19 clinical outcomes--is mediated by these biomarkers and pathways. Methods Data from patients who tested positive for SARS-CoV-2 and part of the integrated Cleveland Clinic COVID-19 and sleep laboratory registries from March-November 2020 were included. To assess the mediation effect of biomarkers, the relationship between sleep-related hypoxia measures (% sleep time Results The analytic sample included 446 patients hospitalized due to COVID-19: age:63.3.±13.8 years,51.3% female,39% African American with body mass index(BMI)=36.1±9.3kg/m2. Thirty-six percent used supplemental oxygen, 4% used high-flow or non-invasive ventilation,5% required ECMO or mechanical ventilation and 2% died. Hypoxic measures were associated with moderate/severe WHO-7 COVID-19 outcome: T90 median (>1.8%vs.≤1.8%) (OR=2.04, 95%CI:1.28-3.23,p=0.003), 5% increases in both mean SaO2 (OR=0.43, 95%CI: 0.26-0.70,p= Conclusion CRP appears to represent a relevant mediator of sleep-related hypoxia and WHO-7 clinical outcomes. Further investigation is needed to elucidate if treatment of sleep-related hypoxia downregulates biomarkers of systemic inflammation to modify disease course. Support (If Any)

Highlights • We present a report on continuous EEG (cEEG) findings in COVID-19 patients. • cEEG revealed findings consistent with encephalopathy independent of IV anesthetics. • Acute symptomatic seizures were noted in two patients., Objective As concerns regarding neurological manifestations in COVID-19 (coronavirus disease 2019) patients increase, limited data exists on continuous electroencephalography (cEEG) findings in these patients. We present a retrospective cohort study of cEEG monitoring in COVID-19 patients to better explore this knowledge gap. Methods Among 22 COVID-19 patients, 19 underwent cEEGs, and 3 underwent routine EEGs (

BACKGROUND Different states in the United States had different nonpharmaceutical public health interventions during the COVID-19 pandemic. The effects of those interventions on hospital use have not been systematically evaluated. The investigation could provide data-driven evidence to potentially improve the implementation of public health interventions in the future. OBJECTIVE We aim to study two representative areas in the United States and one area in China (New York State, Ohio State, and Hubei Province), and investigate the effects of their public health interventions by time periods according to key interventions. METHODS This observational study evaluated the numbers of infected, hospitalized, and death cases in New York and Ohio from March 16 through September 14, 2020, and Hubei from January 26 to March 31, 2020. We developed novel Bayesian generalized compartmental models. The clinical stages of COVID-19 were stratified in the models, and the effects of public health interventions were modeled through piecewise exponential functions. Time-dependent transmission rates and effective reproduction numbers were estimated. The associations of interventions and the numbers of required hospital and intensive care unit beds were studied. RESULTS The interventions of social distancing, home confinement, and wearing masks significantly decreased (in a Bayesian sense) the case incidence and reduced the demand for beds in all areas. Ohio’s transmission rates declined before the state’s “stay at home” order, which provided evidence that early intervention is important. Wearing masks was significantly associated with reducing the transmission rates after reopening, when comparing New York and Ohio. The centralized quarantine intervention in Hubei played a significant role in further preventing and controlling the disease in that area. The estimated rates that cured patients become susceptible in all areas were small ( CONCLUSIONS The series of public health interventions in three areas were temporally associated with the burden of COVID-19–attributed hospital use. Social distancing and the use of face masks should continue to prevent the next peak of the pandemic.

Focal epilepsy (FE) is clinically highly heterogeneous. It has been shown recently that not only rare but also a subset of common genetic variants confer risk for FE. The relatively modest power of genetic studies in FE suggests a high genetic heterogeneity of FE when grouped as one disorder. We hypothesize that the clinical heterogeneity of FE is correlated with genetic heterogeneity on a common risk variant level. To test the hypothesis, we used an FE polygenic risk score "FE-PRS" that combines small effect sizes of thousands of common variants from the largest FE-GWAS (genome-wide association study) into a single measure. We grouped 414 individuals with FE according to common clinical features into subgroups, either by one feature at a time or by all features combined in a cluster analysis. We examined their association with FE-PRS compared to 20 435 matched population controls and observed heterogeneous FE-PRS burden among the subgroups. The highest phenotypic variance explained by FE-PRS was identified in a cluster analysis-defined FE subgroup where all individuals had unknown etiologies and psychiatric comorbidities, and the majority had early onset seizures. Our results indicate that genetic factors associated with FE have differential burden among FE subtypes. Future studies using better-powered FE-PRS might have clinical utility.

Background Coronavirus disease 2019 (COVID-19) is sweeping the globe. Despite multiple case-series, actionable knowledge to tailor decision-making proactively is missing. Research Question Can a statistical model accurately predict infection with COVID-19? Study Design and Methods We developed a prospective registry of all patients tested for COVID-19 in Cleveland Clinic to create individualized risk prediction models. We focus here on the likelihood of a positive nasal or oropharyngeal COVID-19 test. A least absolute shrinkage and selection operator logistic regression algorithm was constructed that removed variables that were not contributing to the model’s cross-validated concordance index. After external validation in a temporally and geographically distinct cohort, the statistical prediction model was illustrated as a nomogram and deployed in an online risk calculator. Results In the development cohort, 11,672 patients fulfilled study criteria, including 818 patients (7.0%) who tested positive for COVID-19; in the validation cohort, 2295 patients fulfilled criteria, including 290 patients who tested positive for COVID-19. Male, African American, older patients, and those with known COVID-19 exposure were at higher risk of being positive for COVID-19. Risk was reduced in those who had pneumococcal polysaccharide or influenza vaccine or who were on melatonin, paroxetine, or carvedilol. Our model had favorable discrimination (c-statistic = 0.863 in the development cohort and 0.840 in the validation cohort) and calibration. We present sensitivity, specificity, negative predictive value, and positive predictive value at different prediction cutoff points. The calculator is freely available at https://riskcalc.org/COVID19 . Interpretation Prediction of a COVID-19 positive test is possible and could help direct health-care resources. We demonstrate relevance of age, race, sex, and socioeconomic characteristics in COVID-19 susceptibility and suggest a potential modifying role of certain common vaccinations and drugs that have been identified in drug-repurposing studies.

Background: Understanding the impact of the COVID-19 pandemic on healthcare workers (HCW) is crucial.Objective: Utilizing a health system COVID-19 research registry, we assessed HCW risk for COVID-19 infection, hospitalization and intensive care unit (ICU) admission.Design: Retrospective cohort study with overlap propensity score weighting.Participants: Individuals tested for SARS-CoV-2 infection in a large academic healthcare system (N=72,909) from March 8-June 9 2020 stratified by HCW and patient-facing status. Main Measures: SARS-CoV-2 test result, hospitalization, and ICU admission for COVID-19 infection. Key Results: Of 72,909 individuals tested, 9.0% (551) of 6,145 HCW tested positive for SARS-CoV-2 compared to 6.5% (4353) of 66,764 non-HCW. The HCW were younger than non-HCW (median age 39.7 vs. 57.5, pConclusions: In a large healthcare system, HCW had similar odds for testing SARS-CoV-2 positive, but lower odds of hospitalization compared to non-HCW. Patient-facing HCW had higher odds of a positive test. These results are key to understanding HCW risk mitigation during the COVID-19 pandemic.

Significant technological advances have improved our ability to localize epilepsy and investigate the electrophysiology in patients undergoing preparation for epilepsy surgery. Conversely, our process of decision-making and outcome prediction has remained essentially restricted to subjective clinical judgment. This may have hindered our ability to improve outcomes. In this review, we highlight the cognitive biases that interfere with medical decision-making and present data on the use of algorithms and statistical models in general health care, before pivoting to discuss applications in the context of epilepsy.

Background Stereoelectroencephalography (SEEG) is used to identify the epileptogenic zone (EZ) in patients with epilepsy for potential surgical intervention. Occasionally, the EZ is difficult to localize even after an SEEG implantation. Objective To demonstrate a safe technique for placing additional electrodes in ongoing SEEG evaluations. Describe efficacy, complications, and surgical outcomes. Methods An operative technique which involves maintaining previously placed electrodes and sterilely placing new electrodes was developed and implemented. All patients who underwent placement of additional SEEG electrodes during the same admission were retrospectively reviewed. Results A total of 14 patients met criteria and had undergone SEEG evaluation with 198 electrodes implanted. A total 93% of patients (13/14) had nonlesional epilepsy. After unsuccessful localization of the EZ after a mean of 9.6 d of monitoring, each patient underwent additional placement of electrodes (5.5 average electrodes per patient) to augment the original implantation. At no point did any patients develop new hemorrhage, infection, wound breakdown, or require any kind of additional antimicrobial treatment. A total 64% (9/14) of patients were able to undergo surgery aimed at removing the EZ guided by the additional SEEG electrodes. A total 44% (4/9) of surgical patients had Engel class I outcomes at an average follow-up time of 11 mo. Conclusion Placing additional SEEG electrodes, while maintaining the previously placed electrodes, appears to be safe, effective, and had no infectious complications. When confronted with difficult-to-localize epilepsy even after invasive monitoring, it appears to be safe and potentially clinically effective to place additional electrodes during the same admission.

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of coexisting medical conditions, while the underlying mechanisms remain unclear. Furthermore, there are no approved therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, disease manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus–host protein–protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measurement revealed underlying pathogenesis for broad COVID-19-associated disease manifestations. Analyses of single-cell RNA sequencing data show that co-expression of ACE2 and TMPRSS2 is elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn disease patients compared to uninflamed tissues, revealing shared pathobiology between COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicate that COVID-19 shares an intermediate inflammatory molecular profile with asthma (including IRAK3 and ADRB2). To prioritize potential treatments, we combined network-based prediction and a propensity score (PS) matching observational study of 26,779 individuals from a COVID-19 registry. We identified that melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56–0.91) is significantly associated with a 28% reduced likelihood of a positive laboratory test result for SARS-CoV-2 confirmed by reverse transcription–polymerase chain reaction assay. Using a PS matching user active comparator design, we determined that melatonin usage was associated with a reduced likelihood of SARS-CoV-2 positive test result compared to use of angiotensin II receptor blockers (OR = 0.70, 95% CI 0.54–0.92) or angiotensin-converting enzyme inhibitors (OR = 0.69, 95% CI 0.52–0.90). Importantly, melatonin usage (OR = 0.48, 95% CI 0.31–0.75) is associated with a 52% reduced likelihood of a positive laboratory test result for SARS-CoV-2 in African Americans after adjusting for age, sex, race, smoking history, and various disease comorbidities using PS matching. In summary, this study presents an integrative network medicine platform for predicting disease manifestations associated with COVID-19 and identifying melatonin for potential prevention and treatment of COVID-19., This study uses network medicine methodologies along with multiomic observations (including SARS-CoV-2 and human interactome, transcriptome, and proteome) to identify widespread disease manifestations and drug repurposing candidates (including melatonin) for COVID-19, validating these findings using a large-scale patient registry database.

BackgroundNeurological manifestations of COVID-19 have only recently been described, with a paucity of literature reporting the potential relationship between COVID-19 and acute symptomatic seizures. Two prior studies found no clinical or electrographic seizures in their cohorts of COVID-19 patients with altered mental status (AMS) and clinical seizure-like events (SLEs).MethodsIn this retrospective cohort study, 22 critically-ill COVID-19 patients above the age of 18 years who underwent EEG (electroencephalography) monitoring between April 20th, 2020 and May 20th, 2020 were studied. 19 patients underwent continuous EEG (cEEG) for at least 24 hours, and 3 patients underwent routine EEGs (Findings17 patients underwent EEG monitoring for unexplained altered mental status changes and 5 patients underwent monitoring for a seizure-like event. 5 patients had epileptiform abnormalities on EEG (4 patients on cEEG, 1 on routine EEG); and only 2 of 5 epileptic EEG patients had a prior history of epilepsy. 2 patients in our cohort had electrographic seizures in the absence of prior epilepsy history. No patients with epileptiform abnormalities or electrographic seizures had acutely abnormal neuroimaging on CT or MRI.InterpretationEncephalopathic COVID-19 positive patients had a range of EEG abnormalities, and a higher proportion of patients in this series had electrographic seizures than previous literature suggests. This may be influenced by the duration of monitoring with cEEG and the use of a 21 channel electrode system. cEEG findings may help to guide antiseizure medical therapy, as well as the workup of altered mental status in the setting of unremarkable neuroimaging.FundingNo funding was used for this study.

Psychogenic nonepileptic seizures (PNES) are diagnosed in approximately 30% of patients referred to tertiary care epilepsy centers. Little is known about the molecular pathology of PNES, much less about possible underlying genetic factors. We generated whole-exome sequencing and whole-genome genotyping data to identify rare, pathogenic (P) or likely pathogenic (LP) variants in 102 individuals with PNES and 448 individuals with focal (FE) or generalized (GE) epilepsy. Variants were classified for all individuals based on the ACMG-AMP 2015 guidelines. For research purposes only, we considered genes associated with neurological or psychiatric disorders as candidate genes for PNES. We observe in this first genetic investigation of PNES that six (5.88%) individuals with PNES without coexistent epilepsy carry P/LP variants (deletions at 10q11.22-q11.23, 10q23.1-q23.2, distal 16p11.2, and 17p13.3, and nonsynonymous variants in NSD1 and GABRA5). Notably, the burden of P/LP variants among the individuals with PNES was similar and not significantly different to the burden observed in the individuals with FE (3.05%) or GE (1.82%) (PNES vs. FE vs. GE (3 × 2 χ2), P = 0.30; PNES vs. epilepsy (2 × 2 χ2), P = 0.14). The presence of variants in genes associated with monogenic forms of neurological and psychiatric disorders in individuals with PNES shows that genetic factors are likely to play a role in PNES or its comorbidities in a subset of individuals. Future large-scale genetic research studies are needed to further corroborate these interesting findings in PNES.

BackgroundCoronavirus Disease 2019 is a pandemic that is straining healthcare resources, mainly hospital beds. Multiple risk factors of disease progression requiring hospitalization have been identified, but medical decision-making remains complex.ObjectiveTo characterize a large cohort of patients hospitalized with COVID-19, their outcomes, develop and validate a statistical model that allows individualized prediction of future hospitalization risk for a patient newly diagnosed with COVID-19.DesignRetrospective cohort study of patients with COVID-19 applying a least absolute shrinkage and selection operator (LASSO) logistic regression algorithm to retain the most predictive features for hospitalization risk, followed by validation in a temporally distinct patient cohort. The final model was displayed as a nomogram and programmed into an online risk calculator.SettingOne healthcare system in Ohio and Florida.ParticipantsAll patients infected with SARS-CoV-2 between March 8, 2020 and June 5, 2020. Those tested before May 1 were included in the development cohort, while those tested May 1 and later comprised the validation cohort.MeasurementsDemographic, clinical, social influencers of health, exposure risk, medical co-morbidities, vaccination history, presenting symptoms, medications, and laboratory values were collected on all patients, and considered in our model development.Results4,536 patients tested positive for SARS-CoV-2 during the study period. Of those, 958 (21.1%) required hospitalization. By day 3 of hospitalization, 24% of patients were transferred to the intensive care unit, and around half of the remaining patients were discharged home. Ten patients died. Hospitalization risk was increased with older age, black race, male sex, former smoking history, diabetes, hypertension, chronic lung disease, poor socioeconomic status, shortness of breath, diarrhea, and certain medications (NSAIDs, immunosuppressive treatment). Hospitalization risk was reduced with prior flu vaccination. Model discrimination was excellent with an area under the curve of 0.900 (95% confidence interval of 0.886-0.914) in the development cohort, and 0.813 (0.786, 0.839) in the validation cohort. The scaled Brier score was 42.6% (95% CI 37.8%, 47.4%) in the development cohort and 25.6% (19.9%, 31.3%) in the validation cohort. Calibration was very good. The online risk calculator is freely available and found at https://riskcalc.org/COVID19Hospitalization/.LimitationRetrospective cohort design.ConclusionOur study crystallizes published risk factors of COVID-19 progression, but also provides new data on the role of social influencers of health, race, and influenza vaccination. In a context of a pandemic and limited healthcare resources, individualized outcome prediction through this nomogram or online risk calculator can facilitate complex medical decision-making.

Objective Compared to other seizure types, generalized tonic-clonic (GTC) seizures may be disproportionately related to increased morbidity, and reducing seizure frequency could translate into improvements across measures of morbidity in medically treated patients with drug-resistant epilepsy (DRE). The primary objective of this analysis was to quantify the burden of patients with DRE who experience GTC seizures (GTC+) compared to patients with DRE who do not experience GTC seizures (GTC-). Methods Adult patients from the Cleveland Clinic Epilepsy Center-Neurological Institute from 2012-2016 with DRE with epilepsy for at least 1 year were eligible for inclusion and were divided into GTC ± groups based on whether the patient had experienced a GTC seizure in the year preceding the first visit. Epilepsy duration, comorbidities, antiepileptic drug use, patient-reported outcomes (PROs) and seizure type, frequency, and etiology were captured. Generalized linear models, negative binomial regression, logistic regression, and linear regression were used as appropriate for multivariate analyses. Results A total of 379 patients met inclusion criteria and had data at 1-year follow-up after their baseline visit (192 GTC+ and 187 GTC-). Although DRE patients experiencing GTC seizures had fewer seizures per day over the preceding 6 months than those not experiencing GTC seizures, seizure severity and levels of depression and anxiety were greater. GTC+ patients who reported five or more seizures in the preceding 4 weeks had 82% lower odds (1-0.18 = 0.82) of working than patients with no seizures. Significance Patients with DRE experience a significant burden and decreased quality of life. Multivariate analysis is necessary to understand the complex relationship between seizure type, frequency, and impact on health-related quality of life (HRQoL) and changes over time. Effective treatments to reduce the burden for DRE patients who experience GTC seizures continue to be needed.

Background and Purpose: The clinical characteristics and biological effects on the nervous system of infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain poorly understood. The aim of this study is to advance epidemiological and mechanistic understanding of the neurological manifestations of coronavirus disease 2019 (COVID-19) using stroke as a case study. Methods: We performed a meta-analysis of clinical studies reporting stroke history, intensive inflammatory response and procoagulant state (C-reactive protein (CRP), Procalcitonin (PCT) and coagulation indicator (D-dimer)) in patients with COVID-19. Via network-based analysis of SARS-CoV-2 host genes and stroke-associated genes in the human protein-protein interactome, we inspected the underlying inflammatory endophenotypes between COVID-19 and stroke. Finally, we further verified the network medicine-based findings using large-scale single-cell RNA-sequencing data generated from the lymphocytic choriomeningitis virus (LCMV) infected mouse model. Results: The overall pooled prevalence of stroke history was 2.98% (95% CI, 1.89 - 4.68; I2=69.2%) in the COVID-19 population. Notably, the severe group had a higher prevalence of stroke (6.06%; 95% CI 3.80 - 9.52; I2 = 42.6%) compare to the non-severe group (1.1%, 95% CI 0.72 - 1.71; I2 = 0.0%). In addition, there were increased CRP, PCT and D-dimer in severe illness, and the pooled mean difference was 40.7mg/L (95% CI, 24.3 - 57.1), 0.07mg/L (95% CI, 0.04 - 0.10) and 0.63mg/L (95% CI, 0.28 - 0.97) respectively. Vascular cell adhesion molecule 1 (VCAM-1), dimethylarginine dimethylaminohydrolase-1 (DDAH-1), CD59 and NOTCH-3 were selected from the results of the protein-protein interactome (PPI) network analysis. Among them, VCAM-1, one of the leukocyte adhesion molecules, is suspected to play a vital role in a holistic perspective. Even though the verification using LCMV data revealed no significant change could be observed in part of virus-host genes and stroke-associated genes, suggesting the relative importance of inflammatory responses in SARS-CoV-2 infection-associated neurological manifestations. Conclusion: In this study, we identified increased vulnerability of those with a history of stroke to severe COVID-19, suggesting monotonic relationships, thus implicating causality. Some candidates underlying inflammatory responses (i.e., VCAM-1) and procoagulant pathways were preliminarily identified for neurologists in caring COVID-19 patients with cerebrovascular disease, which requires future clinical and functional validation studies. Funding Statement: This work was supported by the National Heart, Lung, and Blood Institute (R00HL138272) and the National Institute of Aging (R01AG066707). Declaration of Interests: The authors declare that they have no conflict of interest.

ObjectiveTo develop and externally validate models to predict the probability of postoperative naming decline in adults following temporal lobe epilepsy surgery using easily accessible preoperative clinical predictors.MethodsIn this retrospective, prediction model development study, multivariable models were developed in a cohort of 719 patients who underwent temporal lobe epilepsy surgery at Cleveland Clinic and externally validated in a cohort of 138 patients who underwent temporal lobe surgery at one of 3 epilepsy surgery centers in the United States (Columbia University Medical Center, Emory University School of Medicine, University of Washington School of Medicine).ResultsThe development cohort was 54% female with an average age at surgery of 36 years (SD 12). Twenty-six percent of this cohort experienced clinically relevant postoperative naming decline. The model included 5 variables: side of surgery, age at epilepsy onset, age at surgery, sex, and education. When applied to the external validation cohort, the model performed very well, with excellent calibration and a c statistic (reflecting discriminatory ability) of 0.81. A second model predicting moderate to severe postoperative naming decline included 3 variables: side of surgery, age at epilepsy onset, and preoperative naming score. This model generated a c statistic of 0.84 in the external validation cohort and showed good calibration.ConclusionExternally validated nomograms are provided in 2 easy-to-use formats (paper version and online calculator) clinicians can use to estimate the probability of naming decline in patients considering epilepsy surgery for treatment of pharmacoresistant temporal lobe epilepsy.

Background Neurological conditions carry a high risk of depression. Given this risk, the Neurological Institute (NI) at Cleveland Clinic has initiated systematic screening for depression using the 9-item Patient Health Questionnaire-9 (PHQ-9) embedded within its electronic medical record and its data capture system, the Knowledge Program (KP)1. Objective We sought to (1) estimate the prevalence of depression among patients with epilepsy, stroke, and multiple sclerosis (MS); (2) identify risk factors for depression within each disease; and (3) determine differential risks and predictors across neurological disorders. Methods The KP1 database provided information on approximately 23,000 visits involving 7946 outpatients with epilepsy, stroke, or MS seen in neurology specialty clinics. The primary outcome measure was depression as defined as a PHQ-9 ≥ 10. Results Overall, the point prevalence of depression was 29.0%. For stroke, epilepsy, and MS, prevalence of depression was 23% (95% CI: 21–25%), 33% (95% CI: 31–35%), and 29% (95% CI: 28–30%), respectively. For all 3 conditions, increasing disease severity and decreased health-related quality of life were independent predictors of depression. In multivariable models, there was a significant interaction between age and condition, and condition with disease severity. In stroke and MS, increasing age was associated with reduced odds for depression, whereas in epilepsy, increasing age was associated with an increased odds for depression. Conclusions Although depression is common among patients with neurological disorders, our data suggest that predictors of depression such as age and disease severity varied by condition, supporting important possible phenomenological and pathophysiological differences of depression across these neurological conditions.

Summary We recently proposed that the maturation of a new epileptic focus (epileptogenesis) may explain late seizure recurrences, starting months to years after resective epilepsy surgery. We explore here the hypothesis that inherent transcriptomic changes may distinguish such “late relapsers.” An in‐depth clinical review of 2 patients with recurrent seizures starting years after surgery is contrasted to 4 controls who remained seizure‐free postoperatively. This clinical analysis is combined with RNA sequencing from the resected brain tissue, followed by unsupervised hierarchical clustering, independent pathway analysis, and multidimensional scaling analysis. Late‐recurrence patients clustered apart from seizure‐free patients, with late recurrence patients clustering together in the central space, whereas the seizure‐free patients clustered together in the periphery. We utilized RNA‐seq to identify differentially expressed genes between late‐recurrence and seizure‐free samples. We found 29 annotated genes with statistically significant differential expression (q < 0.05). The top canonical pathways identified as distinctly separating the late‐recurrence patients from the seizure‐free patients included the intrinsic prothrombin activation pathway (p = 1.55E‐06), the complement system (p = 4.57E‐05), and the atherosclerosis signaling pathway (p = 4.57E‐05). Our observations suggest that late recurrences after epilepsy surgery may be influenced partly by differences in gene expression in neuroinflammatory and brain healing/remodeling pathways. Such a hypothesis needs to be validated in the future.

Introduction There is lack of clarity of sleep disordered breathing (SDB)--including the role of nocturnal hypoxia and confounding influence of obesity--on the clinical course of human coronavirus disease 2019 (COVID-19). We postulate that SDB portends increased risk of adverse COVID-19 clinical outcomes even after accounting for confounding factors. Methods A retrospective cohort analysis of COVID-19 and sleep laboratory observational registries March-November 2020 within the Cleveland Clinic health system was performed. Ordinal logistic regression assessed the association of SDB indices and World Health Organization (WHO)-7 COVID-19 clinical outcome (hospitalization, use of supplemental oxygen, non-invasive ventilation, mechanical ventilation/ECMO and death) in an unadjusted model and adjusted for age, sex, race, body mass index(BMI,kg/m2),diabetes mellitus, hypertension, coronary artery disease, heart failure, asthma, chronic obstructive pulmonary disease (COPD), cancer and smoking using SAS software. Results Of 19,449 (32%) patients positive for SARS-CoV-2,2,290 (6%) had an available sleep study. The analytic sample included 1788 of which 1,484(64%) had an apnea hypopnea index (AHI, 3–4% hypopnea oxygen desaturation)≥5. The median duration from sleep study to COVID test was 5.8 years (IQR:3.3–9.0). Age was 56.5±14.4 years,50.4% female,28% African American with BMI=35.9±8.9kg/m2. Nine percent of patients were hospitalized,10% with supplemental oxygen,6% used non-invasive ventilation,2% required ECMO or mechanical ventilation and 2% died. For every AHI increase of 5, the odds of a higher WHO-7 level increased 2% (OR=1.02,95%CI1.01-1.04,p=0.005),but the association was mitigated in the adjusted model (OR=1.00,95%CI:0.98,1.02,p=0.80). Per 5% increase in time spent with SaO2 Conclusion Even after adjustment for obesity, underlying cardiopulmonary disease and smoking, sleep-related hypoxemia was a potential key pathophysiologic mechanism associated with increased morbidity and mortality in COVID-19. Elucidation of sleep-related hypoxemia as a risk stratification measure, particularly given the silent hypoxia inherent to early COVID-19, is critical for future investigation, as is the role of sleep-related hypoxia reversal as a target to improve COVID-19 outcomes. Support (if any) Cleveland Clinic Neurologic Institute Resource Development Award

Key Points Question Are sleep-disordered breathing and sleep-related hypoxia associated with SARS-CoV-2 infection and COVID-19 outcomes? Findings In this case-control study of 5402 patients in a large integrated health system, sleep-disordered breathing and sleep-related hypoxia were not associated with an increased likelihood of contracting SARS-CoV-2. After accounting for confounding factors including cardiopulmonary disease, cancer, and smoking exposure, sleep-related hypoxia indices were associated with more severe COVID-19 clinical outcomes, including hospitalization and mortality, in time-to-event analyses. Meaning These results suggest that baseline sleep-related hypoxia may portend worse clinical prognosis in COVID-19., This case-control study investigates the association of sleep-disordered breathing and sleep-related hypoxia with SARS-CoV-2 infection and COVID-19 outcomes., 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

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.

The authors report a case of 18-year-old woman with partial complex seizures compatible with temporal epilepsy by semiology. Due to medical refractoriness, she was referred to pre-surgical evaluation. Initially, MRI showed no significant structural abnormality and superficial scalp EEG demonstrated epileptiform activity in the frontotemporal areas. Due to the lack of clear MRI abnormalities and the potential involvement of dominant mesial temporal structures by seizure semiology and non-invasive data, extra-operative invasive evaluation using stereo-electroencephalography (SEEG) methodology was indicated. Invasive monitoring demonstrated seizure onset in the left temporal pole with early spread to ipsilateral amygdala. Surgical treatment resulted in resection of the temporal pole and amygdala, with preservation of the remaining mesial temporal lobe structures. Intraoperatively, it was observed that multiple dural defects in the anterior middle temporal fossa with invagination of adjacent temporal pole parenchyma are compatible with temporal encephalocele. Patient remains seizure-free since surgery (12 months follow-up period) with preservation of neuropsychological functions. Although temporal pole resection plus amygdalohippocampectomy has been described as an adequate surgical approach in temporal encephalocele cases, we demonstrated the usefulness of the SEEG methodology in minimizing the volume of temporal lobe resection without compromising seizure and neuropsychological outcomes. The optimal results in this case and the review of the literature may suggest that in medically refractory epilepsies caused by temporal pole encephaloceles, preservation of the temporal lobe mesial structures should be attempted.

This retrospective study examined the potential role of side and site of surgery in psychological symptom change after epilepsy surgery and determined the base rate of psychological change at the individual level. Two-hundred twenty-eight adults completed the Personality Assessment Inventory (PAI) before and after temporal (TLR; n=190) or frontal lobe resection (FLR; n=38). Repeated measures ANOVAs with bootstrapping examined differences in psychological outcome as a function of surgical site separately in patients who underwent left- versus right-sided resections. Individual's PAI score changes were then used to determine the prevalence of clinically meaningful postoperative symptom change. Following left-sided resections, there were significant group-by-time interactions on Somatic Complaints, Anxiety, and Anxiety Related Disorders. There was also a trend in this direction on the Depression scale. TLR patients endorsed greater preoperative symptoms than FLR patients on all of these scales, except the Somatic Complaints scale. After surgery, TLR patients reported symptom improvement on all four scales, while scores of FLR patients remained relatively stable over time. Endorsement of Mania-related symptoms increased in both TLR and FLR groups from pre-to post-surgical testing. Following right-sided resections, both groups endorsed symptom improvements on Somatic Complaints, Anxiety, and Depression scales following surgery. In addition, the TLR group endorsed more Mania-related symptoms than the FLR group regardless of time. Patterns of meaningful change in individual patients were generally consistent with group findings, with the most frequent improvements observed following TLR. However, there were a small subset of patients who reported symptom exacerbation after surgery. Our results suggest that surgical lateralization and localization are important factors in postoperative psychological outcome and highlight the importance of considering psychological change at the individual patient level. Further research is needed to identify potential risk factors for symptom exacerbation to aid in preoperative counseling and identify those patients most in need of postoperative psychological surveillance.

OBJECTIVE To analyze longitudinal seizure outcomes following epilepsy surgery, including reoperations, in patients with intractable focal epilepsy. METHODS Clinicoradiological characteristics of patients who underwent epilepsy surgery from 1995 to 2016 with follow-up of ≥1 year were reviewed. In patients undergoing reoperations, the latest resection was considered the index surgery. The primary outcome was complete seizure freedom (Engel I) at last follow-up. Potentially significant outcome variables were first identified using univariate analyses and then fit in multivariate Cox proportional hazards models. RESULTS Of 898 patients fulfilling study criteria, 110 had reoperations; 92 had one resection prior to the index surgery and 18 patients had two or more prior resective surgeries. Two years after the index surgery, 69% of patients with no prior surgeries had an Engel score of I, as opposed to only 42% of those with one prior surgery, and 33% of those with two or more prior resections (P

ObjectiveSurgery is an effective but costly treatment for many patients with drug-resistant temporal lobe epilepsy (DR-TLE). We aim to evaluate whether, in the United States, surgery is cost-effective compared to medical management for patients deemed surgical candidates and whether surgical evaluation is cost-effective for patients with DR-TLE in general.MethodsWe use a semi-Markov model to assess the cost-effectiveness of surgery and surgical evaluation over a lifetime horizon. We use second-order Monte Carlo simulations to conduct probabilistic sensitivity analyses to estimate variation in model output. We adopt both health care and societal perspectives, including direct health care costs (e.g., surgery, antiepileptic drugs) and indirect costs (e.g., lost earnings by patients and care providers.) We compare the incremental cost-effectiveness ratio to societal willingness to pay (∼$100,000 per quality-adjusted life-year [QALY]) to determine whether surgery is cost-effective.ResultsEpilepsy surgery is cost-effective compared to medical management in surgically eligible patients by virtue of being cost-saving ($328,000 vs $423,000) and more effective (16.6 vs 13.6 QALY) than medical management in the long run. Surgical evaluation is cost-effective in patients with DR-TLE even if the probability of being deemed a surgical candidate is only 5%. From a societal perspective, surgery becomes cost-effective within 3 years, and 89% of simulations favor surgery over the lifetime horizon.ConclusionFor surgically eligible patients with DR-TLE, surgery is cost-effective. For patients with DR-TLE in general, referral for surgical evaluation (and possible subsequent surgery) is cost-effective. Patients with DR-TLE should be referred for surgical evaluation without hesitation on cost-effectiveness grounds.