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Objective: The clinical characteristics of functional seizures may vary based on age-of-onset or age-of-presentation. Description of age-related differences has focused on three categories: pediatric, young-adult, and older-adult. We evaluated how factors continuously varied based on age-of-presentation across the adult lifespan., Methods: Based on cross-sectional data from 365 adult (18 to 88 years old) patients with documented diagnoses of functional seizures, we evaluated how the quantity and prevalence of specific ictal behaviors, historical factors, and comorbidities varied based on patient age-of-presentation using sequential weighted averages., Results: Four factors changed prominently with age-of-presentation: female predominance decreased at two inflection points - ages 35 and 62; the prevalence of work disability was higher until age-of-presentation 30 then plateaued at 80%; there was greater delay to diagnosis in older patients; and comorbidities was higher with age-of-presentation, starting from early adulthood. The proportion of patients who presented with functional seizures decreased after 50. Ictal behavior did not substantially vary with age-of-presentation., Conclusion: The time from onset to diagnosis increased with age-of-presentation, which may be related to increased comorbidities and the misconception that FS do not start in older age. The female predominance decreased nonlinearly with age. By age 30, most patients' seizures already had substantial association with unemployment. These findings emphasize that patients can develop functional seizures at any age. The rapid development of disability relatively early in life, which then stays at a high prevalence rate, demonstrates the need for prompt referral for definitive diagnosis and treatment., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Functional seizures often are managed incorrectly as a diagnosis of exclusion. However, a significant minority of patients with functional seizures may have abnormalities on neuroimaging that typically are associated with epilepsy, leading to diagnostic confusion. We evaluated the rate of epilepsy-associated findings on MRI, FDG-PET, and CT in patients with functional seizures., Methods: We studied radiologists' reports from neuroimages at our comprehensive epilepsy center from a consecutive series of patients diagnosed with functional seizures without comorbid epilepsy from 2006 to 2019. We summarized the MRI, FDG-PET, and CT results as follows: within normal limits, incidental findings, unrelated findings, non-specific abnormalities, post-operative study, epilepsy risk factors (ERF), borderline epilepsy-associated findings (EAF), and definitive EAF., Results: Of the 256 MRIs, 23% demonstrated ERF (5%), borderline EAF (8%), or definitive EAF (10%). The most common EAF was hippocampal sclerosis, with the majority of borderline EAF comprising hippocampal atrophy without T2 hyperintensity or vice versa. Of the 87 FDG-PETs, 26% demonstrated borderline EAF (17%) or definitive EAF (8%). Epilepsy-associated findings primarily included focal hypometabolism, especially of the temporal lobes, with borderline findings including subtle or questionable hypometabolism. Of the 51 CTs, only 2% had definitive EAF., Significance: This large case series provides further evidence that, while uncommon, EAF are seen in patients with functional seizures. A significant portion of these abnormal findings are borderline. The moderately high rate of these abnormalities may represent framing bias from the indication of the study being "seizures," the relative subtlety of EAF, or effects of antiseizure medications., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Transcranial Focused Ultrasound (tFUS) is a promising new potential neuromodulation tool. However, the safety of tFUS neuromodulation has not yet been assessed adequately. Patients with refractory temporal lobe epilepsy electing to undergo an anterior temporal lobe resection present a unique opportunity to evaluate the safety and efficacy of tFUS neuromodulation. Histological changes in tissue after tFUS can be examined after surgical resection, while further potential safety concerns can be assessed using neuropsychological testing., Methods: Neuropsychological functions were assessed in eight patients before and after focused ultrasound sonication of the temporal lobe at intensities up to 5760 mW/cm 2 . Using the BrainSonix Pulsar 1002, tFUS was delivered under MR guidance, using the Siemens Magnetom 3T Prisma scanner. Neuropsychological changes were assessed using various batteries. Histological changes were assessed using hematoxylin and eosin staining, among others., Results: With respect to safety, the histological analysis did not reveal any detectable damage to the tissue, except for one subject for whom the histology findings were inconclusive. In addition, neuropsychological testing did not show any statistically significant changes in any test, except for a slight decrease in performance on one of the tests after tFUS., Significance: This study supports the hypothesis that low-intensity Transcranial Focused Ultrasound (tFUS) used for neuromodulation of brain circuits at intensities up to 5760 mW/cm 2 may be safe for use in human research. However, due to methodological limitations in this study and inconclusive findings, more work is warranted to establish the safety. Future directions include greater number of sonications as well as longer exposure at higher intensity levels to further assess the safety of tFUS for modulation of neuronal circuits., Competing Interests: Declaration of competing interest Dr. Korb is a Vice-President of BrainSonix Inc. Dr. Schafer is the Chief Technology Officer of BrainSonix Inc. Dr. Bystritsky is the Founder and Chief Executive Officer of BrainSonix Inc. Drs. Korb, Schafer, Bystritsky also own shares in the company. Other authors report no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Electroencephalogram (EEG) recording is essential in the evaluation of complex movement and behaviors during sleep, but in particular for differentiating epileptic versus nonepileptic events. In general, epileptiform discharges occur with greater density in the first few nonerapid eye movement cycles, and approximately 12% to 20% of seizures occur exclusively at night. This review examines the epilepsy types and syndromes whose presentation is strongly influenced by the sleep state, with an appraisal about the role that sleep plays in facilitating seizures, while deleaneatign EEG findings and clinical manifestation. The review will summarize the typical semiology of sleep-related hypermotor seizures and contrasted with those occurring during none/rapid eye movement parasomnias and sleep-related movement disorders., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To assess the association between hypometabolic extension of 18 F-fluorodeoxyglucose positron emission tomography and diffusion tensor imaging indices, including mean diffusivity (MD) and fractional anisotropy (FA), in hippocampal sclerosis (HS)., Methods: Thirty-six unilateral HS were retrospectively selected and stratified into two groups: broad and localized hypometabolic groups (hypometabolism beyond [n = 26] and within the temporal lobe [n = 10]). Forty-one pairs of gray matter (GM) regions of interest (ROIs) were segmented using FreeSurfer software. The GM ROIs were applied to MD maps, and median MD values within each ROI were compared between hemispheres ipsilateral and contralateral to HS using a mixed effect model. Tract-Based Spatial Statistics (TBSS) was used to evaluate FA of white matter (WM) tracts between hemispheres ipsilateral and contralateral to HS. Disease laterality was controlled for., Results: The MD values in the thalamus, caudate, hippocampus, amygdala, superior frontal gyrus, middle and inferior temporal gyrus, temporal pole, and isthmus cingulate gyrus were significantly higher in the HS side than the contralateral side for the broad hypometabolic group. Those in the amygdala and superior temporal sulcus were significantly higher in the HS side than the contralateral side for the localized group. The TBSS analyses showed significantly decreased FA in the WM tracts of the temporal and frontal lobes for the broad hypometabolic group, while no tracts showed significant differences for the localized group., Conclusion: The hypometabolic extension for HS was associated with the abnormalities of MD and FA in GM and WM, respectively, with more widespread microstructural alterations for broad hypometabolic HS., (Copyright © 2021. Published by Elsevier Ltd.)

Introduction: We report the final results of the phase 3 IMpower132 study evaluating atezolizumab plus carboplatin or cisplatin plus pemetrexed (APP) in patients with nonsquamous NSCLC., Methods: Chemotherapy-naive patients with stage IV nonsquamous NSCLC without sensitizing EGFR or ALK genetic alterations were randomized in a one-to-one ratio to receive four or six cycles of carboplatin or cisplatin plus pemetrexed (PP) or APP every 3 weeks, followed by maintenance therapy with atezolizumab plus pemetrexed or pemetrexed alone. Co-primary end points were overall survival (OS) and investigator-assessed progression-free survival (PFS)., Results: The intention-to-treat population included 578 patients (APP, n = 292; PP, n = 286). At the primary PFS analysis (May 22, 2018; median follow-up, 14.8 mo), APP exhibited significant PFS improvement versus PP (median = 7.6 versus 5.2 mo, stratified hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.49-0.72, p < 0.0001). OS for the APP group was numerically better but not statistically significant at the interim (May 22, 2018; median = 18.1 versus 13.6 mo, stratified HR = 0.81, 95% CI: 0.64-1.03, p = 0.0797) and final analyses (July 18, 2019; median = 17.5 versus 13.6 mo; stratified HR = 0.86, 95% CI: 0.71-1.06, p = 0.1546). The OS and PFS results favored APP versus PP across subgroups. Grade 3 or 4 treatment-related adverse events occurred in 54.6% (APP) and 40.1% (PP) of patients; grade 5 treatment-related events occurred in 3.8% and 2.9%, respectively., Conclusions: IMpower132 met its co-primary PFS end point but not its co-primary OS end point, with numerical improvement for OS in the APP arm. APP had a manageable safety profile, with no new or unexpected safety signals identified., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: While certain clinical factors suggest a diagnosis of dissociative seizures (DS), otherwise known as functional or psychogenic nonepileptic seizures (PNES), ictal video-electroencephalography monitoring (VEM) is the gold standard for diagnosis. Diagnostic delays were associated with worse quality of life and more seizures, even after treatment. To understand why diagnoses were delayed, we evaluated which factors were associated with delay to VEM., Methods: Using data from 341 consecutive patients with VEM-documented dissociative seizures, we used multivariate log-normal regression with recursive feature elimination (RFE) and multiple imputation of some missing data to evaluate which of 76 clinical factors were associated with time from first dissociative seizure to VEM., Results: The mean delay to VEM was 8.4 years (median 3 years, IQR 1-10 years). In the RFE multivariate model, the factors associated with longer delay to VEM included more past antiseizure medications (0.19 log-years/medication, standard error (SE) 0.05), more medications for other medical conditions (0.06 log-years/medication, SE 0.03), history of physical abuse (0.75 log-years, SE 0.27), and more seizure types (0.36 log-years/type, SE 0.11). Factors associated with shorter delay included active employment or student status (-1.05 log-years, SE 0.21) and higher seizure frequency (0.14 log-years/log[seizure/month], SE 0.06)., Conclusions: Patients with greater medical and seizure complexity had longer delays. Delays in multiple domains of healthcare can be common for victims of physical abuse. Unemployed and non-student patients may have had more barriers to access VEM. These results support earlier referral of complex cases to a comprehensive epilepsy center., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Video-electroencephalographic monitoring (VEM) is a core component to the diagnosis and evaluation of epilepsy and dissociative seizures (DS)-also known as functional or psychogenic seizures-but VEM evaluation often occurs later than recommended. To understand why delays occur, we compared how patient-reported clinical factors were associated with time from first seizure to VEM (TVEM) in patients with epilepsy, DS or mixed., Methods: We acquired data from 1245 consecutive patients with epilepsy, VEM-documented DS or mixed epilepsy and DS. We used multivariate log-normal regression with recursive feature elimination (RFE) to evaluate which of 76 clinical factors interacting with patients' diagnoses were associated with TVEM., Results: The mean and median TVEM were 14.6 years and 10 years, respectively (IQR 3-23 years). In the multivariate RFE model, the factors associated with longer TVEM in all patients included unemployment and not student status, more antiseizure medications (current and past), concussion, and ictal behavior suggestive of temporal lobe epilepsy. Average TVEM was shorter for DS than epilepsy, particularly for patients with depression, anxiety, migraines, and eye closure. Average TVEM was longer specifically for patients with DS taking more medications, more seizure types, non-metastatic cancer, and with other psychiatric comorbidities., Conclusions: In all patients with seizures, trials of numerous antiseizure medications, unemployment and non-student status was associated with longer TVEM. These associations highlight a disconnect between International League Against Epilepsy practice parameters and observed referral patterns in epilepsy. In patients with dissociative seizures, some but not all factors classically associated with DS reduced TVEM., (Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: This study specifically investigated differences of amygdalar and hippocampal volumes between patients with dissociative seizures (DS), mesial temporal lobe sclerosis (MTS), and normal controls (NC)., Methods: Between 2003 and 2018, 127 patients diagnosed with DS and 278 with MTS were recruited. An additional 52 NC subjects were recruited between 2015 and 2018. We retrospectively selected 29 patients with DS (male:female, 6:23) with absence of structural confounding factors and obtained sex- and age-matched MTS and NC. We used Neuroreader to assess the volume of the amygdala and hippocampus as a percentage of total intracranial volume based on thin-slice (0.9-1.2 mm) T1-weighted images. Statistical analyses controlled for psychiatric comorbidity and logistic regression were used to evaluate efficacy of these values for individual-level diagnosis., Results: The left amygdala and right hippocampus were significantly smaller in DS compared to NC (both p = 0.04), which was not explained by differences in psychiatric comorbidity. When controlling for ipsilateral hippocampal or amygdala volume, which was seen equally in all groups (Spearman, p < 0.02), these differences were no longer significant (amygdala, p = 0.16, hippocampus, p = 0.18), suggesting that amygdalar and hippocampal atrophy may reflect network or regional changes rather than focal abnormalities. The three-way accuracy for differentiating DS, MTS, and NC using these data was 64 % (95 % confidence interval: 54-74 %)., Conclusion: Volumetric analysis demonstrates smaller left amygdalar and right hippocampal volumes in patients with DS compared to NC, which may mirror abnormalities in functional networks seen in conversion disorders and post-traumatic stress disorder., Competing Interests: Declarations of Competing Interest None., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: Differentiating psychogenic non-epileptic seizures (PNES) from epileptic seizures (ES) can be difficult, even when expert clinicians have video recordings of seizures. Moreover, witnesses who are not trained observers may provide descriptions that differ from the expert clinicians', which often raises concern about whether the patient has both ES and PNES. As such, quantitative, evidence-based tools to help differentiate ES from PNES based on patients' and witnesses' descriptions of seizures may assist in the early, accurate diagnosis of patients., Methods: Based on patient- and observer-reported data from 1372 patients with diagnoses documented by video-elect roencephalography (vEEG), we used logistic regression (LR) to compare specific peri-ictal behaviors and seizure triggers in five mutually exclusive groups: ES, PNES, physiologic non-epileptic seizure-like events, mixed PNES plus ES, and inconclusive monitoring. To differentiate PNES-only from ES-only, we retrospectively trained multivariate LR and a forest of decision trees (DF) to predict the documented diagnoses of 246 prospective patients., Results: The areas under the receiver operating characteristic curve (AUCs) of the DF and LR were 75% and 74%, respectively (empiric 95% CI of chance 37-62%). The overall accuracy was not significantly higher than the naïve assumption that all patients have ES (accuracy DF 71%, LR 70%, naïve 68%, p > 0.05)., Conclusions: Quantitative analysis of patient- and observer-reported peri-ictal behaviors objectively changed the likelihood that a patient's seizures were psychogenic, but these reports were not reliable enough to be diagnostic in isolation. Instead, our scores may identify patients with "probable" PNES that, in the right clinical context, may warrant further diagnostic assessment., (Copyright © 2019 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Previous studies showed more adverse events with coronary bioresorbable vascular scaffolds (BVS) than with metallic drug-eluting stents (DES), although in one randomised trial angina was reduced with BVS. However, these early studies were unmasked, lesions smaller than intended for the scaffold were frequently enrolled, implantation technique was suboptimal, and patients with myocardial infarction, in whom BVS might be well suited, were excluded., Methods: In the active-controlled, blinded, multicentre, randomised ABSORB IV trial, patients with stable coronary artery disease or acute coronary syndromes aged 18 years or older were recruited from 147 hospitals in five countries (the USA, Germany, Australia, Singapore, and Canada). Enrolled patients were randomly assigned (1:1) to receive polymeric everolimus-eluting BVS (Absorb; Abbott Vascular, Santa Clara, CA, USA) with optimised implantation technique or cobalt-chromium everolimus-eluting stents (EES; Xience; Abbott Vascular, Santa Clara, CA, USA). Randomisation was stratified by diabetic status, whether patients would have been eligible for enrolment in the previous ABSORB III trial, and site. Patients and clinical assessors were masked to randomisation. The primary endpoint was target lesion failure (cardiac death, target vessel myocardial infarction, or ischaemia-driven target lesion revascularisation) at 30 days, tested for non-inferiority with a 2·9% margin for the risk difference. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT02173379, and is closed to accrual., Findings: Between Aug 15, 2014, and March 31, 2017, we screened 18 722 patients for eligibility, 2604 of whom were enrolled. 1296 patients were assigned to BVS, and 1308 patients were assigned to EES. Follow-up data at 30 days and 1 year, respectively, were available for 1288 and 1254 patients with BVS and for 1303 and 1272 patients with EES. Biomarker-positive acute coronary syndromes were present in 622 (24%) of 2602 patients, and, by angiographic core laboratory analysis, 78 (3%) of 2893 of lesions were in very small vessels. Target lesion failure at 30 days occurred in 64 (5·0%) patients assigned to BVS and 48 (3·7%) patients assigned to EES (difference 1·3%, upper 97·5% confidence limit 2·89; one-sided p non-inferiority =0·0244). Target lesion failure at 1 year occurred in 98 (7·8%) patients assigned to BVS and 82 (6·4%) patients assigned to EES (difference 1·4%, upper 97·5% confidence limit 3·4; one-sided p non-inferiority =0·0006). Angina, adjudicated by a central events committee at 1 year, occurred in 270 (20·3%) patients assigned to BVS and 274 (20·5%) patients assigned to EES (difference -0·3%, 95% CI -3·4% to 2·9%; one-sided p non-inferiority =0·0008; two-sided p superiority =0·8603). Device thrombosis within 1 year occurred in nine (0·7%) patients assigned to BVS and four (0·3%) patients assigned to EES (p=0·1586)., Interpretation: Polymeric BVS implanted with optimised technique in an expanded patient population resulted in non-inferior 30-day and 1-year rates of target lesion failure and angina compared with metallic DES., Funding: Abbott Vascular., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To test the utility of a novel semi-automated method for detecting, validating, and quantifying high-frequency oscillations (HFOs): ripples (80-200 Hz) and fast ripples (200-600 Hz) in intra-operative electrocorticography (ECoG) recordings., Methods: Sixteen adult patients with temporal lobe epilepsy (TLE) had intra-operative ECoG recordings at the time of resection. The computer-annotated ECoG recordings were visually inspected and false positive detections were removed. We retrospectively determined the sensitivity, specificity, positive and negative predictive value (PPV/NPV) of HFO detections in unresected regions for determining post-operative seizure outcome., Results: Visual validation revealed that 2.81% of ripple and 43.68% of fast ripple detections were false positive. Inter-reader agreement for false positive fast ripple on spike classification was good (ICC = 0.713, 95% CI: 0.632-0.779). After removing false positive detections, the PPV of a single fast ripple on spike in an unresected electrode site for post-operative non-seizure free outcome was 85.7 [50-100%]. Including false positive detections reduced the PPV to 64.2 [57.8-69.83%]., Conclusions: Applying automated HFO methods to intraoperative electrocorticography recordings results in false positive fast ripple detections. True fast ripples on spikes are rare, but predict non-seizure free post-operative outcome if found in an unresected site., Significance: Semi-automated HFO detection methods are required to accurately identify fast ripple events in intra-operative ECoG recordings., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Generalized tonic-clonic seizures are accompanied by cardiovascular and respiratory sequelae that threaten survival. The frequency of these seizures is a major risk factor for sudden unexpected death in epilepsy (SUDEP), a leading cause of untimely death in epilepsy. The circumstances accompanying such fatal events suggest a cardiovascular or respiratory failure induced by unknown neural processes rather than an inherent cardiac or lung deficiency. Certain cortical regions, especially the insular, cingulate, and orbitofrontal cortices, are key structures that integrate sensory input and influence diencephalic and brainstem regions regulating blood pressure, cardiac rhythm, and respiration; output from those cortical regions compromised by epilepsy-associated injury may lead to cardiorespiratory dysregulation. The aim here was to assess changes in cortical integrity, reflected as cortical thickness, relative to healthy controls. Cortical alterations in areas that influence cardiorespiratory action could contribute to SUDEP mechanisms., Methods: High-resolution T1-weighted images were collected with a 3.0-Tesla MRI scanner from 53 patients with generalized tonic-clonic seizures (Mean age ± SD: 37.1 ± 12.6 years, 22 male) at Case Western Reserve University, University College London, and the University of California at Los Angeles. Control data included 530 healthy individuals (37.1 ± 12.6 years; 220 male) from UCLA and two open access databases (OASIS and IXI). Cortical thickness group differences were assessed at all non-cerebellar brain surface locations ( P  < 0.05 corrected)., Results: Increased cortical thickness appeared in post-central gyri, insula, and subgenual, anterior, posterior, and isthmus cingulate cortices. Post-central gyri increases were greater in females, while males showed more extensive cingulate increases. Frontal and temporal cortex, lateral orbitofrontal, frontal pole, and lateral parietal and occipital cortices showed thinning. The extents of thickness changes were sex- and hemisphere-dependent, with only males exhibiting right-sided and posterior cingulate thickening, while females showed only left lateral orbitofrontal thinning. Regional cortical thickness showed modest correlations with seizure frequency, but not epilepsy duration., Significance: Cortical thickening and thinning occur in patients with generalized tonic-clonic seizures, in cardiovascular and somatosensory areas, with extent of changes sex- and hemisphere-dependent. The data show injury in key autonomic and respiratory cortical areas, which may contribute to dysfunctional cardiorespiratory patterns during seizures, as well as to longer-term SUDEP risk.

Objective: To develop and validate a detector that identifies ripple (80-200 Hz) events in intracranial EEG (iEEG) recordings in a referential montage and utilizes independent component analysis (ICA) to eliminate or reduce high-frequency artifact contamination. Also, investigate the correspondence of detected ripples and the seizure onset zone (SOZ)., Methods: iEEG recordings from 16 patients were first band-pass filtered (80-600 Hz) and Infomax ICA was next applied to derive the first independent component (IC1). IC1 was subsequently pruned, and an artifact index was derived to reduce the identification of high-frequency events introduced by the reference electrode signal. A Hilbert detector identified ripple events in the processed iEEG recordings using amplitude and duration criteria. The identified ripple events were further classified and characterized as true or false ripple on spikes, or ripples on oscillations by utilizing a topographical analysis to their time-frequency plot, and confirmed by visual inspection., Results: The signal to noise ratio was improved by pruning IC1. The precision of the detector for ripple events was 91.27 ± 4.3%, and the sensitivity of the detector was 79.4 ± 3.0% (N = 16 patients, 5842 ripple events). The sensitivity and precision of the detector was equivalent in iEEG recordings obtained during sleep or intra-operatively. Across all the patients, true ripple on spike rates and also the rates of false ripple on spikes, that were generated due to filter ringing, classified the seizure onset zone (SOZ) with an area under the receiver operating curve (AUROC) of >76%. The magnitude and spectral content of true ripple on spikes generated in the SOZ was distinct as compared with the ripples generated in the NSOZ (p < .001)., Conclusions: Utilizing ICA to analyze iEEG recordings in referential montage provides many benefits to the study of high-frequency oscillations. The ripple rates and properties defined using this approach may accurately delineate the seizure onset zone., Significance: Strategies to improve the spatial resolution of intracranial EEG and reduce artifact can help improve the clinical utility of HFO biomarkers., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To develop a reliable software method using a topographic analysis of time-frequency plots to distinguish ripple (80-200 Hz) oscillations that are often associated with EEG sharp waves or spikes (RonS) from sinusoid-like waveforms that appear as ripples but correspond with digital filtering of sharp transients contained in the wide bandwidth EEG., Methods: A custom algorithm distinguished true from false ripples in one second intracranial EEG (iEEG) recordings using wavelet convolution, identifying contours of isopower, and categorizing these contours into sets of open or closed loop groups. The spectral and temporal features of candidate groups were used to classify the ripple, and determine its duration, frequency, and power. Verification of detector accuracy was performed on the basis of simulations, and visual inspection of the original and band-pass filtered signals., Results: The detector could distinguish simulated true from false ripple on spikes (RonS). Among 2934 visually verified trials of iEEG recordings and spectrograms exhibiting RonS the accuracy of the detector was 88.5% with a sensitivity of 81.8% and a specificity of 95.2%. The precision was 94.5% and the negative predictive value was 84.0% (N = 12). Among, 1,370 trials of iEEG recording exhibiting RonS that were reviewed blindly without spectrograms the accuracy of the detector was 68.0%, with kappa equal to 0.01 ± 0.03. The detector successfully distinguished ripple from high spectral frequency 'fast ripple' oscillations (200-600 Hz), and characterize ripple duration and spectral frequency and power. The detector was confounded by brief bursts of gamma (30-80 Hz) activity in 7.31 ± 6.09% of trials, and in 30.2 ± 14.4% of the true RonS detections ripple duration was underestimated., Conclusions: Characterizing the topographic features of a time-frequency plot generated by wavelet convolution is useful for distinguishing true oscillations from false oscillations generated by filter ringing., Significance: Categorizing ripple oscillations and characterizing their properties can improve the clinical utility of the biomarker., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objectives: Resective epilepsy surgery has been shown to have up to 70-80% success rates in patients with intractable seizure disorder. Around 20-30% of patients with Engel Classification III and IV will require reevaluation for further surgery. Common reasons for first surgery failures include incomplete resection of seizure focus, incorrect identification of seizure focus and recurrence of tumor., Patient and Methods: Clinical chart review of seventeen patients from a single adult comprehensive epilepsy program who underwent reoperation from 2007 to 2014 was performed. High resolution Brain MRI, FDG-PET, Neuropsychometric testing were completed in all cases in both the original surgery and the second procedure. Postoperative outcomes were confirmed by prospective telephone follow up and verified by review of the patient's electronic medical records. Outcomes were classified according to the modified Engel classification system: Engel classes I and II are considered good outcomes., Results: A total of seventeen patients (involving 10 females) were included in the study. The average age of patients at second surgery was 42 (range 23-64 years). Reasons for reoperation included: incomplete first resection (n=13) and recurrence of tumor (n=4). Median time between the first and second surgery was 60 months. After the second surgery, ten of the seventeen patients (58.8%) achieved seizure freedom (Engel Class I), in agreement with other published reports. Of the ten patients who were Engel Class I, seven required extension of the previous resection margins, while three had surgery for recurrence of previously partially resected tumor., Conclusions: We conclude that since the risk of complications from reoperation is low and the outcome, for some, is excellent, consideration of repeat surgery is justified., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: The average delay from first seizure to diagnosis of psychogenic non-epileptic seizures (PNES) is over 7 years. The reason for this delay is not well understood. We hypothesized that a perceived decrease in seizure frequency after starting an anti-seizure medication (ASM) may contribute to longer delays, but the frequency of such a response has not been well established., Methods: Time from onset to diagnosis, medication history and associated seizure frequency was acquired from the medical records of 297 consecutive patients with PNES diagnosed using video-electroencephalographic monitoring. Exponential regression was used to model the effect of medication trials and response on diagnostic delay., Results: Mean diagnostic delay was 8.4 years (min 1 day, max 52 years). The robust average diagnostic delay was 2.8 years (95% CI: 2.2-3.5 years) based on an exponential model as 10 to the mean of log10 delay. Each ASM trial increased the robust average delay exponentially by at least one third of a year (Wald t=3.6, p=0.004). Response to ASM trials did not significantly change diagnostic delay (Wald t=-0.9, p=0.38)., Conclusion: Although a response to ASMs was observed commonly in these patients with PNES, the presence of a response was not associated with longer time until definitive diagnosis. Instead, the number of ASMs tried was associated with a longer delay until diagnosis, suggesting that ASM trials were continued despite lack of response. These data support the guideline that patients with seizures should be referred to epilepsy care centers after failure of two medication trials., (Copyright © 2016 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: This study sought to predict postsurgical seizure freedom from pre-operative diagnostic test results and clinical information using a rapid automated approach, based on supervised learning methods in patients with drug-resistant focal seizures suspected to begin in temporal lobe., Method: We applied machine learning, specifically a combination of mutual information-based feature selection and supervised learning classifiers on multimodal data, to predict surgery outcome retrospectively in 20 presurgical patients (13 female; mean age±SD, in years 33±9.7 for females, and 35.3±9.4 for males) who were diagnosed with mesial temporal lobe epilepsy (MTLE) and subsequently underwent standard anteromesial temporal lobectomy. The main advantage of the present work over previous studies is the inclusion of the extent of ipsilateral neocortical gray matter atrophy and spatiotemporal properties of depth electrode-recorded seizures as training features for individual patient surgery planning., Results: A maximum relevance minimum redundancy (mRMR) feature selector identified the following features as the most informative predictors of postsurgical seizure freedom in this study's sample of patients: family history of epilepsy, ictal EEG onset pattern (positive correlation with seizure freedom), MRI-based gray matter thickness reduction in the hemisphere ipsilateral to seizure onset, proportion of seizures that first appeared in ipsilateral amygdala to total seizures, age, epilepsy duration, delay in the spread of ipsilateral ictal discharges from site of onset, gender, and number of electrode contacts at seizure onset (negative correlation with seizure freedom). Using these features in combination with a least square support vector machine (LS-SVM) classifier compared to other commonly used classifiers resulted in very high surgical outcome prediction accuracy (95%)., Conclusions: Supervised machine learning using multimodal compared to unimodal data accurately predicted postsurgical outcome in patients with atypical MTLE., (Published by Elsevier Ltd.)

The objective of this article is to review the dramatic changes that have occurred in the field of epilepsy surgery since the founding of Epilepsy Action in 1950. We have chosen to consider these advances from the biomedical perspective (the physician and basic scientist), and the behavioral perspective (the psychologist and the patient). Both these viewpoints are equally important in understanding the evolution of epilepsy surgery over the past 60 years, but may not always be well synchronized., (Copyright © 2010 British Epilepsy Association. All rights reserved.)

Operative treatment of epileptogenic cavernous malformations (CM) continues under debate. Most studies focus on surgery for supratentorial CM in general. For temporal lobe CM, surgical decision-making concerns in particular whether to perform lesionectomy alone or the additional excision of mesial temporal structures. The purpose of this case series was to evaluate operative strategies used to treat epileptogenic temporal CM and to report resultant postoperative seizure outcomes. Twelve consecutive cases of patients with medically intractable epilepsy who underwent operation for temporal CM between 1996 and 2006 were retrospectively reviewed. When the temporal CM directly invaded the hippocampus or amygdala, the affected structures were resected in addition to the lesion; when the CM was located in the superficial temporal cortex, and there was no radiographic evidence of hippocampal sclerosis, lesionectomy alone was done; with CM located between the superficial temporal cortex and the mesial temporal region, other factors were considered in decision-making, such as lesion proximity to the deep mesiotemporal structures and preoperative epilepsy duration. For six of the twelve patients, extended lesionectomy (EL) alone was done; for the other six, tailored anteromedial temporal resection with hippocampectomy and/or amygdalectomy was performed in addition to EL. Postoperatively, 11 patients - all with preoperative VEM demonstrating electroclinical seizure patterns concordant with lesion location - were seizure-free. We conclude that epileptogenic temporal CM are surgically remediable, when approached with the above operative strategies and presurgical VEM. On the basis of these postoperative seizure control results, we recommend consideration of concurrent resection of mesial temporal structures with EL for certain temporal CM., (Copyright 2009 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: We reviewed published data and our own data to determine a quantitative incidence of seizure in subjects with epilepsy undergoing single- and paired-pulse transcranial magnetic stimulation (spTMS and ppTMS) and to explore conditions that may increase this risk., Methods: A PubMed literature search was performed, and articles from this search were reviewed. Subjects from our institution also were included., Results: The crude risk of a TMS-associated seizure ranges from 0.0 to 2.8% for spTMS and 0.0-3.6% for ppTMS. Medically intractable epilepsy and lowering antiepileptic drugs were associated with increased incidence. There was significant center-to-center variability that could not be explained by differences in patient population or by differences in reported stimulation parameters. In all cases, seizures were similar to each subject's typical seizure and without long-term adverse outcome. In most cases, doubt was expressed in the original reports as to whether the seizures were induced by TMS or merely coincidental., Conclusions: The incidence of seizure in a subject with epilepsy during spTMS and ppTMS appears to be small and not associated with long-term adverse outcome. The incidence is higher under the specific conditions mentioned above., Significance: These findings may enable researchers to more accurately inform subjects of seizure risk during TMS.

Focal symptomatic epilepsy is the most common and most refractory form of human epilepsy and is an important subject of basic research. Although advanced diagnostic technologies and epilepsy surgery facilities are providing increasing opportunities to carry out investigations directly on patients with focal epilepsy, inherent limitations make research with animal models essential to elucidate basic mechanisms, improve diagnosis, and test potential therapies. Numerous animal models are available, but proper use requires that they be validated for specific investigative purposes and, preferably, studied along with patients, employing reiterative parellel experimental paradigms. Clinical research establishes the critical questions that cannot be completely answered with human investigation, while results of animal research carried out to resolve these questions must be reexamined clinically to confirm their relevance to the human condition. Better and cheaper animal models are necessary for optimum cost-effective parallel research activities, which includes not only models of specific types of acute epileptic seizures, and chronic epilepsy, but models of component parts of seizures and epilepsy that can be used as surrogate, or biological, markers of epileptogenesis and epileptogenicity. Appropriate use of markers such as FR could greatly reduce the expense, and time required, to produce the necessary research results.

Evidence is presented, in this volume, for and against the thesis that single, self-limited seizures can damage the brain. Consideration must be given to the fact that there are many different types of seizures, which undoubtedly induce a variety of postictal consequences. Whether any of these consequences constitute brain damage depends upon the definition of damage, which could range from enduring functional changes of single neurons or circuits, to actual cell death. Although many seizure-induced mechanisms have been postulated, or even demonstrated, that can give rise to persistent neuronal disturbances, including neuronal death, they are only of clinical concern if they result in interictal neurological or cognitive dysfunction, developmental delay, or progressive epileptogenesis that makes seizures worse. Although animal studies indicate it is very likely that some seizures, under some circumstances, do, in fact, damage the brain in a clinically meaningful manner, the principal contribution of this volume is to identify areas of future basic and clinical research designed to identify those seizures which present a risk of causing enduring neuronal disruption, the circumstances under which these changes are likely to occur, their nature and effects on behavior, and, ultimately, rational approaches to prevention.