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Objective: Temporal lobe epilepsy affects nearly 50 million people worldwide and is a major burden to families and society. A significant portion of patients are living in developing countries with limited access to therapeutic resources. This highlights the urgent need to develop more readily available, noninvasive treatments for seizure control. This research explored the effectiveness of transcranial photobiomodulation (tPBM), a non-invasive method utilizing photon-tissue interactions, for preventing epileptogenesis and controlling seizures., Methods: In a kainic acid (KA)-induced rat model of epilepsy, two different wavelengths of tPBM, 808 nm and 940 nm, were applied separately in two groups of animals (KA+808 and KA+940). The ability of tPBM for seizure control was evaluated by comparing the occurrence rate of interictal epileptiform discharges (IED) and behavioral seizures among three groups: KA, KA+808, KA+940. Prevention of epileptogenesis was assessed by comparing the occurrence rate of high frequency oscillations (HFOs), especially fast ripple (FR) rate, among the three groups. Nissl staining and immunostaining for the apoptosis marker caspase-3 were used as indications of neuroprotection., Results: The KA+808 group and the KA+940 group showed significantly lower FR and IED rates compared to the KA group. Weekly FR rates started to drop during the first week of tPBM treatment. The KA+808 and KA+940 groups also displayed milder seizure behaviors and less neuronal loss in hippocampal areas compared to KA rats without tPBM treatment. Similarly, lower caspase-3 levels in the KA+808 and KA+940 compared with the KA group suggested effectiveness of tPBM in reducing cell death., Significance: tPBM of 808 nm/940 nm showed effectiveness in suppressing epileptogenesis and ictogenesis in the KA-induced rat epilepsy model. This effectiveness of tPBM can be linked to the neuroprotection benefits of photon-tissue interactions. Further studies are warranted to elucidate the fundamental mechanism of tPBM protection, determine optimal treatment parameters and validate its effectiveness in other epilepsy models., Competing Interests: Declaration of competing interest All authors claim that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: Distinction of metastatic breast carcinoma (BC) to the pancreas from primary pancreatic adenocarcinoma (PAC) is essential but challenging. Breast carcinoma shares similar morphology and exhibits an overlapping immunohistochemistry (IHC) profile with PAC. We investigated the utility of recently reported trichorhinophalangeal syndrome type 1 (TRPS1) IHC in differentiating metastatic BC from PAC in fine-needle aspiration (FNA) specimens., Methods: We assessed consecutive patients of PAC (n = 49). Due to limited cases of metastatic BC to the pancreas (n = 3), cases of metastatic BC (n = 23) in various locations, including lymph node, lung, bone, or soft tissue, were included. Immunohistochemistry for TRPS1 was performed by using the cell blocks obtained from FNA. A quantitative score for TRPS1 expression was calculated by multiplying the intensity and the percentage of positive cells. Immunoreactivity scores were assigned as negative, low positive, intermediate positive, or high positive., Results: In 49 PAC cases, 47 (95.9%) exhibited negative while 2 (4.1%) exhibited low positive TRPS1 expression. However, TRPS1 expression was high positive in 23 (88.0%) of 26 metastatic BC cases, including 10 (83.3%) of 12 triple-negative BC (TNBC) and 13 (92.9%) of 14 non-TNBC cases., Conclusions: Our results suggest that TRPS1 IHC represents a highly accurate and reliable method for differentiating metastatic BC from PAC., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: Interictal high-frequency oscillations (HFOs) are a promising neurophysiological biomarker of the epileptogenic zone (EZ). However, objective criteria for distinguishing pathological from physiological HFOs remain elusive, hindering clinical application. We investigated whether the distinct mechanisms underlying pathological and physiological HFOs are encapsulated in their signal morphology in intracranial EEG (iEEG) recordings and whether this mechanism-driven distinction could be simulated by a deep generative model., Methods: In a retrospective cohort of 185 epilepsy patients who underwent iEEG monitoring, we analyzed 686,410 HFOs across 18,265 brain contacts. To learn morphological characteristics, each event was transformed into a time-frequency plot and input into a variational autoencoder. We characterized latent space clusters containing morphologically defined putative pathological HFOs (mpHFOs) using interpretability analysis, including latent space disentanglement and time-domain perturbation., Results: mpHFOs showed strong associations with expert-defined spikes and were predominantly located within the seizure onset zone (SOZ). Discovered novel pathological features included high power in the gamma (30-80 Hz) and ripple (>80 Hz) bands centered on the event. These characteristics were consistent across multiple variables, including institution, electrode type, and patient demographics. Predicting 12-month postoperative seizure outcomes using the resection ratio of mpHFOs outperformed unclassified HFOs (F1=0.72 vs. 0.68) and matched current clinical standards using SOZ resection (F1=0.74). Combining mpHFO data with demographic and SOZ resection status further improved prediction accuracy (F1=0.83)., Interpretation: Our data-driven approach yielded a novel, explainable definition of pathological HFOs, which has the potential to further enhance the clinical use of HFOs for EZ delineation., Competing Interests: COMPETING INTERESTS The authors have no conflict of interest to disclose.

Context.—: Urothelial denudation seen in transurethral biopsy specimens may occasionally indicate the presence of discohesive high-grade urothelial carcinoma (HGUC)., Objective.—: To determine if denuded urothelial cells can be detected in the supernatants of formalin solution collected from the containers of transurethral biopsy/resection specimens after the entire tissue was submitted for histologic examination., Design.—: We assessed the formalin supernatants by processing for cell block (n = 43) or ThinPrep smear (n = 57)., Results.—: In the cell block cohort, only 2 of 43 cases (5%) (1 pTa HGUC, 1 pT1 HGUC) showed rare urothelial cells. By contrast, in the ThinPrep method, the smear was satisfactory for evaluation in 52 of 57 cases (91%). The cytologic diagnosis of HGUC was made in the smears from 7 of 12 (58%) pTa/pT1 cases and 6 of 9 (67%) pTis cases. Remarkably, HGUC cells were detected in 2 of 5 cases (40%) with histologic diagnosis of urothelial atypia suspicious for but not diagnostic of urothelial carcinoma in situ. Additionally, in 31 cases exhibiting urothelial denudation without definitive cancer on hematoxylin-eosin-stained slides, HGUC cells (2 of 31; 6%), atypical urothelial cells (5 of 31; 16%), or benign-appearing urothelial cells (20 of 31; 65%) were present, and only 4 of 31 (13%) were unsatisfactory., Conclusions.—: Cytologic examination of ThinPrep smears from the formalin supernatants even following submission of the entire transurethral biopsy/resection specimens for histologic examination is useful for assessing denuded urothelial cells. This technique can particularly be applied to nonneoplastic cases showing extensive urothelial denudation to detect possible malignant cells and/or indeterminate cases to assist to make a more definitive diagnosis., (© 2024 College of American Pathologists.)

Objective: To confirm and investigate why pathological high-frequency oscillations (pHFOs), including ripples (80-200 Hz) and fast ripples (200-600 Hz), are generated during the UP-DOWN transition of the slow wave and if information transmission mediated by ripple temporal coupling is disrupted in the seizure-onset zone (SOZ)., Methods: We isolated 217 total units from 175.95 intracranial electroencephalography (iEEG) contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the SOZ, HFOs and associated action potentials (APs) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross-correlograms., Results: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p < < .001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p < < .001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d = .11-.83) and fast ripples (d = .36-.90) at the UP-DOWN transition (p < .05 f.d.r. corrected), respectively. By comparison, also in the SOZ, 6.6% (d = .14-.30) and 8.5% (d = .33-.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows that ripple and fast ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by >50% in the SOZ compared to the non-SOZ (N = 3)., Significance: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. Ripple temporal correlations across brain regions may be important in memory consolidation and are disrupted in the SOZ, perhaps by pHFO generation., (© 2023 International League Against Epilepsy.)

Importance: Published data about the impact of poststroke seizures (PSSs) on the outcomes of patients with stroke are inconsistent and have not been systematically evaluated, to the authors' knowledge., Objective: To investigate outcomes in people with PSS compared with people without PSS., Data Sources: MEDLINE, Embase, PsycInfo, Cochrane, LILACS, LIPECS, and Web of Science, with years searched from 1951 to January 30, 2023., Study Selection: Observational studies that reported PSS outcomes., Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist was used for abstracting data, and the Joanna Briggs Institute tool was used for risk-of-bias assessment. Data were reported as odds ratio (OR) and standardized mean difference (SMD) with a 95% CI using a random-effects meta-analysis. Publication bias was assessed using funnel plots and the Egger test. Outlier and meta-regression analyses were performed to explore the source of heterogeneity. Data were analyzed from November 2022 to January 2023., Main Outcomes and Measures: Measured outcomes were mortality, poor functional outcome (modified Rankin scale [mRS] score 3-6), disability (mean mRS score), recurrent stroke, and dementia at patient follow-up., Results: The search yielded 71 eligible articles, including 20 110 patients with PSS and 1 166 085 patients without PSS. Of the participants with PSS, 1967 (9.8%) had early seizures, and 10 605 (52.7%) had late seizures. The risk of bias was high in 5 studies (7.0%), moderate in 35 (49.3%), and low in 31 (43.7%). PSSs were associated with mortality risk (OR, 2.1; 95% CI, 1.8-2.4), poor functional outcome (OR, 2.2; 95% CI, 1.8-2.8), greater disability (SMD, 0.6; 95% CI, 0.4-0.7), and increased dementia risk (OR, 3.1; 95% CI, 1.3-7.7) compared with patients without PSS. In subgroup analyses, early seizures but not late seizures were associated with mortality (OR, 2.4; 95% CI, 1.9-2.9 vs OR, 1.2; 95% CI, 0.8-2.0) and both ischemic and hemorrhagic stroke subtypes were associated with mortality (OR, 2.2; 95% CI, 1.8-2.7 vs OR, 1.4; 95% CI, 1.0-1.8). In addition, early and late seizures (OR, 2.4; 95% CI, 1.6-3.4 vs OR, 2.7; 95% CI, 1.8-4.1) and stroke subtypes were associated with poor outcomes (OR, 2.6; 95% CI, 1.9-3.7 vs OR, 1.9; 95% CI, 1.0-3.6)., Conclusions and Relevance: Results of this systematic review and meta-analysis suggest that PSSs were associated with significantly increased mortality and severe disability in patients with history of stroke. Unraveling these associations is a high clinical and research priority. Trials of interventions to prevent seizures may be warranted.

Inter-ictal spikes aid in the diagnosis of epilepsy and in planning surgery of medication-resistant epilepsy. However, the localizing information from spikes can be unreliable because spikes can propagate, and the burden of spikes, often assessed as a rate, does not always correlate with the seizure onset zone or seizure outcome. Recent work indicates identifying where spikes regularly emerge and spread could localize the seizure network. Thus, the current study sought to better understand where and how rates of single and coupled spikes, and especially brain regions with high-rate and leading spike of a propagating sequence, informs the extent of the seizure network. In 37 patients with medication-resistant temporal lobe seizures, who had surgery to treat their seizure disorder, an algorithm detected spikes in the pre-surgical depth inter-ictal EEG. A separate algorithm detected spike propagation sequences and identified the location of leading and downstream spikes in each sequence. We analysed the rate and power of single spikes on each electrode and coupled spikes between pairs of electrodes, and the proportion of sites with high-rate, leading spikes in relation to the seizure onset zone of patients seizure free ( n = 19) and those with continuing seizures ( n = 18). We found increased rates of single spikes in mesial temporal seizure onset zone (ANOVA, P < 0.001, η 2 = 0.138), and increased rates of coupled spikes within, but not between, mesial-, lateral- and extra-temporal seizure onset zone of patients with continuing seizures ( P < 0.001; η 2 = 0.195, 0.113 and 0.102, respectively). In these same patients, there was a higher proportion of brain regions with high-rate leaders, and each sequence contained a greater number of spikes that propagated with a higher efficiency over a longer distance outside the seizure onset zone than patients seizure free (Wilcoxon, P = 0.0172). The proportion of high-rate leaders in and outside the seizure onset zone could predict seizure outcome with area under curve = 0.699, but not rates of single or coupled spikes (0.514 and 0.566). Rates of coupled spikes to a greater extent than single spikes localize the seizure onset zone and provide evidence for inter-ictal functional segregation, which could be an adaptation to avert seizures. Spike rates, however, have little value in predicting seizure outcome. High-rate spike sites leading propagation could represent sources of spikes that are important components of an efficient seizure network beyond the clinical seizure onset zone, and like the seizure onset zone these, too, need to be removed, disconnected or stimulated to increase the likelihood for seizure control., Competing Interests: The authors report no competing interests., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)

The neuronal circuit disturbances that drive inter-ictal and ictal epileptiform discharges remain elusive. Using a combination of extra-operative macro-electrode and micro-electrode inter-ictal recordings in six pre-surgical patients during non-rapid eye movement sleep, we found that, exclusively in the seizure onset zone, fast ripples (200-600 Hz), but not ripples (80-200 Hz), frequently occur <300 ms before an inter-ictal intra-cranial EEG spike with a probability exceeding chance (bootstrapping, P < 1e-5). Such fast ripple events are associated with higher spectral power ( P < 1e-10) and correlated with more vigorous neuronal firing than solitary fast ripple (generalized linear mixed-effects model, P < 1e-9). During the intra-cranial EEG spike that follows a fast ripple, action potential firing is lower than during an intra-cranial EEG spike alone (generalized linear mixed-effects model, P < 0.05), reflecting an inhibitory restraint of intra-cranial EEG spike initiation. In contrast, ripples do not appear to prime epileptiform spikes. We next investigated the clinical significance of pre-spike fast ripple in a separate cohort of 23 patients implanted with stereo EEG electrodes, who underwent resections. In non-rapid eye movement sleep recordings, sites containing a high proportion of fast ripple preceding intra-cranial EEG spikes correlate with brain areas where seizures begin more than solitary fast ripple ( P < 1e-5). Despite this correlation, removal of these sites does not guarantee seizure freedom. These results are consistent with the hypothesis that fast ripple preceding EEG spikes reflect an increase in local excitability that primes EEG spike discharges preferentially in the seizure onset zone and that epileptogenic brain regions are necessary, but not sufficient, for initiating inter-ictal epileptiform discharges., Competing Interests: M.R.S. has received compensation for speaking at continuing medical education (CME) programmes from Medscape, Projects for Knowledge, International Medical Press and Eisai. He has consulted for Medtronic, Neurelis and Johnson & Johnson. He has received research support from Eisai, Medtronic, Neurelis, SK Life Science, Takeda, Xenon, Cerevel, UCB Pharma, Janssen and Engage Pharmaceuticals. He has received royalties from Oxford University Press and Cambridge University Press. The remainder of the authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To confirm and investigate why pathological HFOs (pHFOs), including Ripples [80-200 Hz] and fast ripples [200-600 Hz], are generated during the UP-DOWN transition of the slow wave and if pHFOs interfere with information transmission., Methods: We isolated 217 total units from 175.95 iEEG contact-hours of synchronized macro- and microelectrode recordings from 6 patients. Sleep slow oscillation (0.1-2 Hz) epochs were identified in the iEEG recording. iEEG HFOs that occurred superimposed on the slow wave were transformed to phasors and adjusted by the phase of maximum firing in nearby units (i.e., maximum UP). We tested whether, in the seizure onset zone (SOZ), HFOs and associated action potentials (AP) occur more often at the UP-DOWN transition. We also examined ripple temporal correlations using cross correlograms., Results: At the group level in the SOZ, HFO and HFO-associated AP probability was highest during the UP-DOWN transition of slow wave excitability (p<<0.001). In the non-SOZ, HFO and HFO-associated AP was highest during the DOWN-UP transition (p<<0.001). At the unit level in the SOZ, 15.6% and 20% of units exhibited more robust firing during ripples (Cohen's d=0.11-0.83) and fast ripples (d=0.36-0.90) at the UP-DOWN transition (p<0.05 f.d.r corrected), respectively. By comparison, also in the SOZ, 6.6% (d=0.14-0.30) and 8.5% (d=0.33-0.41) of units had significantly less firing during ripples and fast ripples at the UP-DOWN transition, respectively. Additional data shows ripple temporal correlations, involving global slow waves, between the hippocampus, entorhinal cortex, and parahippocampal gyrus were reduced by ~50-80% in the SOZ compared to the non-SOZ (N=3)., Significance: The UP-DOWN transition of slow wave excitability facilitates the activation of pathological neurons to generate pHFOs. The pathological neurons and pHFOs disrupt ripple temporal correlations across brain regions that transfer information and may be important in memory consolidation.

Background: Functional seizures (FS) are paroxysmal episodes, resembling epileptic seizures, but without underlying epileptic abnormality. The aetiology and neuroanatomic associations are incompletely understood. Recent brain imaging data indicate cerebral changes, however, without clarifying possible pathophysiology. In the present study, we specifically investigated the neuroanatomic changes in subregions of the amygdala and hippocampus in FS., Methods: T1 MRI scans of 37 female patients with FS and 37 age-matched female seizure naïve controls (SNC) were analyzed retrospectively in FreeSurfer version 7.1. Seizure naïve controls included patients with depression and anxiety disorders. The analysis included whole-brain cortical thickness, subcortical volumes, and subfields of the amygdala and hippocampus. Group comparisons were carried out using multivariable linear models., Results: The FS and SNC groups did not differ in the whole hippocampus and amygdala volumes. However, patients had a significant reduction of the right lateral amygdala volume (p = 0.00041), an increase of the right central amygdala, (p = 0.037), and thinning of the left superior frontal gyrus (p = 0.024). Additional findings in patients were increased volumes of the right medial amygdala (p = 0.031), left anterior amygdala (p = 0.017), and left dentate gyrus of the hippocampus (p = 0.035)., Conclusions: The observations from the amygdala and hippocampus segmentation affirm that there are neuroanatomic associations of FS. The pattern of these changes aligned with some of the cerebral changes described in chronic stress conditions and depression. The pattern of detected changes further study, and may, after validation, provide biomarkers for diagnosis and treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Drs. Kerr, Stern, and Salamon have clinical responsibilities that include the diagnosis and treatment of patients with functional seizures. Drs. Stern and Kerr have received speaking fees and honoraria for articles on this topic. Dr. Kerr has consulting agreements on unrelated topics with SK Lifesciences, Biohaven Pharmaceuticals, Radius Health, and Janssen. The remaining authors have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The neuronal circuit disturbances that drive interictal and ictal epileptiform discharges remains elusive. Using a combination of extraoperative macro- and micro-electrode interictal recordings in six presurgical patients during non-rapid eye movement (REM) sleep we found that, exclusively in the seizure onset zone, fast ripples (FR; 200-600Hz), but not ripples (80-200 Hz), frequently occur <300 msec before an interictal intracranial EEG (iEEG) spike with a probability exceeding chance (bootstrapping, p<1e-5). Such FR events are associated with higher spectral power (p<1e-10) and correlated with more vigorous neuronal firing than solitary FR (generalized linear mixed-effects model, GLMM, p<1e-3) irrespective of FR power. During the iEEG spike that follows a FR, action potential firing is lower than during a iEEG spike alone (GLMM, p<1e-10), reflecting an inhibitory restraint of iEEG spike initiation. In contrast, ripples do not appear to prime epileptiform spikes. We next investigated the clinical significance of pre-spike FR in a separate cohort of 23 patients implanted with stereo EEG electrodes who underwent resections. In non-REM sleep recordings, sites containing a high proportion of FR preceding iEEG spikes correlate with brain areas where seizures begin more than solitary FR (p<1e-5). Despite this correlation, removal of these sites does not guarantee seizure freedom. These results are consistent with the hypothesis that FR preceding EEG spikes reflect an increase in local excitability that primes EEG spike discharges preferentially in the seizure onset zone and that epileptogenic brain regions are necessary, but not sufficient, for initiating interictal epileptiform discharges., Competing Interests: M.R.S has received compensation for speaking at continuing medical education (CME) programs from Medscape, Projects for Knowledge, International Medical Press, and Eisai. He has consulted for Medtronic, Neurelis, and Johnson & Johnson. He has received research support from Eisai, Medtronic, Neurelis, SK Life Science, Takeda, Xenon, Cerevel, UCB Pharma, Janssen, and Engage Pharmaceuticals. He has received royalties from Oxford University Press and Cambridge University Press. The remainder of the authors declare no competing interests.

Vision loss in diabetic retinopathy features damage to the blood-retinal barrier and neovascularization, with hypertension and the renin-angiotensin system (RAS) having causal roles. We evaluated if finerenone, a non-steroidal mineralocorticoid receptor (MR) antagonist, reduced vascular pathology and inflammation in diabetic and neovascular retinopathy. Diabetic and hypertensive transgenic (mRen-2)27 rats overexpressing the RAS received the MR antagonist finerenone (10 mg/kg/day, oral gavage) or the angiotensin-converting enzyme inhibitor perindopril (10 mg/kg/day, drinking water) for 12 weeks. As retinal neovascularization does not develop in diabetic rodents, finerenone (5 mg/kg/day, i.p.) was evaluated in murine oxygen-induced retinopathy (OIR). Retinal vasculopathy was assessed by measuring gliosis, vascular leakage, neovascularization, and VEGF. Inflammation was investigated by quantitating retinal microglia/macrophages, pro-inflammatory mediators, and anti-inflammatory regulatory T-cells (Tregs). In diabetes, both treatments reduced systolic blood pressure, gliosis, vascular leakage, and microglial/macrophage density, but only finerenone lowered VEGF, ICAM-1, and IL-1ß. In OIR, finerenone reduced neovascularization, vascular leakage, and microglial density, and increased Tregs in the blood, spleen, and retina. Our findings, in the context of the FIDELIO-DKD and FIGARO-DKD trials reporting the benefits of finerenone on renal and cardiovascular outcomes in diabetic kidney disease, indicate the potential of finerenone as an effective oral treatment for diabetic retinopathy.

Fast ripples (FR) are a biomarker of epileptogenic brain, but when larger portions of FR generating regions are resected seizure freedom is not always achieved. To evaluate and improve the diagnostic accuracy of FR resection for predicting seizure freedom we compared the FR resection ratio (RR) with FR network graph theoretical measures. In 23 patients FR were semi-automatically detected and quantified in stereo EEG recordings during sleep. MRI normalization and co-registration localized contacts and relation to resection margins. The number of FR, and graph theoretical measures, which were spatial (i.e., FR rate-distance radius) or temporal correlational (i.e., FR mutual information), were compared with the resection margins and with seizure outcome We found that the FR RR did not correlate with seizure-outcome (p > 0.05). In contrast, the FR rate-distance radius resected difference and the FR MI mean characteristic path length RR did correlate with seizure-outcome (p < 0.05). Retesting of positive FR RR patients using either FR rate-distance radius resected difference or the FR MI mean characteristic path length RR reduced seizure-free misclassifications from 44 to 22% and 17%, respectively. These results indicate that graph theoretical measures of FR networks can improve the diagnostic accuracy of the resection of FR events for predicting seizure freedom., (© 2023. The Author(s).)

Objective: Aiming to improve the feasibility and reliability of using high-frequency oscillations (HFOs) for translational studies of epilepsy, we present a pipeline with features specifically designed to reject false positives for HFOs to improve the automatic HFO detector., Methods: We presented an integrated, multi-layered procedure capable of automatically rejecting HFOs from a variety of common false positives, such as motion, background signals, and sharp transients. This method utilizes a time-frequency contour approach that embeds three different layers including peak constraints, power thresholds, and morphological identification to discard false positives. Four experts were involved in rating detected HFO events that were randomly selected from different posttraumatic epilepsy (PTE) animals for a comprehensive evaluation., Results: The algorithm was run on 768-h recordings of intracranial electrodes in 48 PTE animals. A total of 453 917 HFOs were identified by initial HFO detection, of which 450 917 were implemented for HFO refinement and 203 531 events were retained. Random sampling was used to evaluate the performance of the detector. The HFO detection yielded an overall accuracy of 0.95 ± 0.03 , with precision, recall, and F1 scores of 0.92 ± 0.05 , 0.99 ± 0.01 , and 0.94 ± 0.03 , respectively. For the HFO classification, our algorithm obtained an accuracy of 0.97 ± 0.02 . For the inter-rater reliability of algorithm evaluation, the agreement among four experts was 0.94 ± 0.03 for HFO detection and 0.85 ± 0.04 for HFO classification., Significance: Our approach shows that a segregated pipeline design with a focus on false-positive rejection can improve the detection efficiency and provide reliable results. This pipeline does not require customization and uses fixed parameters, making it highly feasible and translatable for basic and clinical applications of epilepsy., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Epileptiform spikes are used to localize epileptogenic brain tissue. The mechanisms that spontaneously trigger epileptiform discharges are not yet elucidated. Pathological fast ripple (FR, 200-600 Hz) are biomarkers of epileptogenic brain, and we postulated that FR network interactions are involved in generating epileptiform spikes. Using macroelectrode stereo intracranial EEG (iEEG) recordings from a cohort of 46 patients we found that, in the seizure onset zone (SOZ), propagating FR were more often followed by an epileptiform spike, as compared with non-propagating FR (p < 0.05). Propagating FR had a distinct frequency and larger power (p < 1e-10) and were more strongly phase coupled to the peak of iEEG delta oscillation, which likely correspond with the DOWN states during non-REM sleep (p < 1e-8), than non-propagating FR. While FR propagation was rare, all FR occurred with the highest probability within +/- 400 msec of epileptiform spikes with superimposed high-frequency oscillations (p < 0.05). Thus, a sub-population of epileptiform spikes in the SOZ, are preceded by propagating FR that are coordinated by the DOWN state during non-REM sleep., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Although moderate and severe traumatic brain injury (TBI) can cause posttraumatic epilepsy (PTE), many patients with functional seizures (FS) also report a history of mild TBI. To determine whether features of TBI history differ between patients with epileptic seizures (ES) and FS, we compared patient reports of TBI severity, symptoms, and causes of injury., Methods: We recruited patients undergoing video-EEG evaluation for the diagnosis of ES, FS, mixed ES and FS, or physiologic seizure-like events at an academic, tertiary referral center. Patients and their caregivers were interviewed before final video-EEG diagnosis regarding their TBI histories, including concussive symptoms and causes of injury., Results: Of 506 patients, a greater percentage of patients with FS reported a history of TBI than patients with ES (70% vs 59%, aOR = 1.75 [95% CI: 1.00-3.05], p = 0.047). TBI with loss of consciousness (LOC) lasting less than 30 minutes was more frequently reported among patients with FS than with ES (27% vs 13%, aOR = 2.38 [1.26-4.47], p < 0.01). The proportion of patients reporting other neurologic symptoms immediately after TBI was not significantly different between FS and ES (40% vs 29%, p = 0.08). Causes of TBI were found to differ, with TBIs caused by falls from a height (17% vs 10%, aOR = 2.24 [1.06-4.70], p = 0.03) or motor vehicle collisions (27% vs 11%, aOR = 2.96 [1.54-5.67], p < 0.01) reported more frequently in FS than ES., Discussion: Our findings further the association of mild TBI with FS and prompt reconsideration of typical assumptions regarding the significance of a reported TBI history in patients with previously undifferentiated seizures. Although common in both groups, TBI with LOC less than 30 minutes and causes of injury that are commonly believed to be more severe were reported more frequently in FS than ES. This suggests that a patient or caregiver reporting of these features does not imply that PTE is a more probable diagnosis than FS. Although a history of TBI with LOC and presumed high-risk causes of injury intuitively raises suspicion for PTE, clinicians should be cautioned that these historical factors also were a frequent finding in patients with FS., (© 2022 American Academy of Neurology.)

Purpose: Functional seizures (FS), also known as psychogenic nonepileptic seizures (PNES), are physical manifestations of acute or chronic psychological distress. Functional and structural neuroimaging have identified objective signs of this disorder. We evaluated whether magnetic resonance imaging (MRI) morphometry differed between patients with FS and clinically relevant comparison populations., Methods: Quality-screened clinical-grade MRIs were acquired from 666 patients from 2006 to 2020. Morphometric features were quantified with FreeSurfer v6. Mixed-effects linear regression compared the volume, thickness, and surface area within 201 regions-of-interest for 90 patients with FS, compared to seizure-naïve patients with depression (n = 243), anxiety (n = 68), and obsessive-compulsive disorder (OCD, n = 41), respectively, and to other seizure-naïve controls with similar quality MRIs, accounting for the influence of multiple confounds including depression and anxiety based on chart review. These comparison populations were obtained through review of clinical records plus research studies obtained on similar scanners., Results: After Bonferroni-Holm correction, patients with FS compared with seizure-naïve controls exhibited thinner bilateral superior temporal cortex (left 0.053 mm, p = 0.014; right 0.071 mm, p = 0.00006), thicker left lateral occipital cortex (0.052 mm, p = 0.0035), and greater left cerebellar white-matter volume (1085 mm 3 , p = 0.0065). These findings were not accounted for by lower MRI quality in patients with FS., Conclusions: These results reinforce prior indications of structural neuroimaging correlates of FS and, in particular, distinguish brain morphology in FS from that in depression, anxiety, and OCD. Future work may entail comparisons with other psychiatric disorders including bipolar and schizophrenia, as well as exploration of brain structural heterogeneity within FS., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Approximately half of the life-limiting events, such as cardiopulmonary arrests or cardiac arrhythmias occurring in hospitals, are considered preventable. These critical events are usually preceded by clinical deterioration. Rapid response teams (RRTs) were introduced to intervene early in the course of clinical deterioration and possibly prevent progression to an event. An RRT was introduced at the Cleveland Clinic in 2009 and transitioned to an anesthesiologist-led system in 2012. We evaluated the association between in-hospital mortality and: (1) the introduction of the RRT in 2009 (primary analysis), and (2) introduction of the anesthesiologist-led system in 2012 and other policy changes in 2014 (secondary analyses)., Methods: We conducted a single-center, retrospective analysis using the medical records of overnight hospitalizations from March 1, 2005, to December 31, 2018, at the Cleveland Clinic. We assessed the association between the introduction of the RRT in 2009 and in-hospital mortality using segmented regression in a generalized estimating equation model to account for within-subject correlation across repeated visits. Baseline potential confounders (demographic factors and surgery type) were controlled for using inverse probability of treatment weighting on the propensity score. We assessed whether in-hospital mortality changed at the start of the intervention and whether the temporal trend (slope) differed from before to after initiation. Analogous models were used for the secondary outcomes., Results: Of 628,533 hospitalizations in our data set, 177,755 occurred before and 450,778 after introduction of our RRT program. Introduction of the RRT was associated with a slight initial increase in in-hospital mortality (odds ratio [95% confidence interval {CI}], 1.17 [1.09-1.25]; P < .001). However, while the pre-RRT slope in in-hospital mortality over time was flat (odds ratio [95% CI] per year, 1.01 [0.98-1.04]; P = .60), the post-RRT slope decreased over time, with an odds ratio per additional year of 0.961 (0.955-0.968). This represented a significant improvement (P < .001) from the pre-RRT slope., Conclusions: We found a gradual decrease in mortality over a 9-year period after introduction of an RRT program. Although mechanisms underlying this decrease are unclear, possibilities include optimization of RRT implementation, anesthesiology department leadership of the RRT program, and overall improvements in health care delivery over the study period. Our findings suggest that improvements in outcome after RRT introduction may take years to manifest. Further work is needed to better understand the effects of RRT implementation on in-hospital mortality., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 International Anesthesia Research Society.)

Drug-resistant epilepsy (DRE) affects approximately one-third of the patients with epilepsy. Based on experimental findings from animal models and brain tissue from patients with DRE, different hypotheses have been proposed to explain the cause(s) of drug resistance. One is the intrinsic severity hypothesis that posits that drug resistance is an inherent property of epilepsy related to disease severity. Seizure frequency is one measure of epilepsy severity, but frequency alone is an incomplete measure of severity and does not fully explain basic research and clinical studies on drug resistance; thus, other measures of epilepsy severity are needed. One such measure could be pathological high-frequency oscillations (HFOs), which are believed to reflect the neuronal disturbances responsible for the development of epilepsy and the generation of spontaneous seizures. In this manuscript, we will briefly review the intrinsic severity hypothesis, describe basic and clinical research on HFOs in the epileptic brain, and based on this evidence discuss whether HFOs could be a clinical measure of epilepsy severity. Understanding the mechanisms of DRE is critical for producing breakthroughs in the development and testing of novel strategies for treatment., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Nodding syndrome (NS) is a poorly understood form of childhood-onset epilepsy that is characterized by the pathognomonic ictal phenomenon of repetitive vertical head drops. To evaluate the underlying ictal neurophysiology, ictal EEG features were evaluated in nine participants with confirmed NS from South Sudan, Tanzania, and Uganda and ictal presence of high frequency gamma oscillations on scalp EEG were assessed. Ictal EEG during the head nodding episode predominantly showed generalized slow waves or sharp-and-slow wave complexes followed by electrodecrement. Augmentation of gamma activity (30-70 Hz) was seen during the head nodding episode in all the participants. We confirm that head nodding episodes in persons with NS from the three geographically distinct regions in sub-Saharan Africa share the common features of slow waves with electrodecrement and superimposed gamma activity. ANN NEUROL 2022;92:75-80., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: To explore decision-making from patients' perceptions of risks and benefits of epilepsy surgery for refractory focal seizures., Methods: Using constructivist grounded theory, in-person interviews were conducted with 35 adults with refractory focal epilepsy who were undergoing a pre-surgical evaluation or who had consented for surgery., Results: For this sample of participants decision-making about surgery was complex, centering on the meaning of illness for the self and the impact of epilepsy and its treatment for significant others. Two interrelated categories crystalized from our data: the unique context of brain surgery and how the decisional counterweights of risks and benefits were considered., Discussion: Exploring components of decision-making from the patients' perspective afforded an opportunity to describe thought processes intrinsic to how people with drug-resistant epilepsy weighed their treatment options. Tensions were evident in how decisions were made. We use the analogy of an imaginary tightrope-walker to create a visual image of what patients face as they consider the illness experience (past and present), their hopes for the future, and the simultaneous uncertainty centered around balancing the counterweights of treatment risks and benefits.

The epileptic network hypothesis and epileptogenic zone hypothesis are two theories of ictogenesis. The network hypothesis posits that coordinated activity among interconnected nodes produces seizures. The epileptogenic zone hypothesis posits that distinct regions are necessary and sufficient for seizure generation. High-frequency oscillations, and particularly fast ripples, are thought to be biomarkers of the epileptogenic zone. We sought to test these theories by comparing high-frequency oscillation rates and networks in surgical responders and non-responders, with no appreciable change in seizure frequency or severity, within a retrospective cohort of 48 patients implanted with stereo-EEG electrodes. We recorded inter-ictal activity during non-rapid eye movement sleep and semi-automatically detected and quantified high-frequency oscillations. Each electrode contact was localized in normalized coordinates. We found that the accuracy of seizure onset zone electrode contact classification using high-frequency oscillation rates was not significantly different in surgical responders and non-responders, suggesting that in non-responders the epileptogenic zone partially encompassed the seizure onset zone(s) ( P  > 0.05). We also found that in the responders, fast ripple on oscillations exhibited a higher spectral content in the seizure onset zone compared with the non-seizure onset zone ( P  < 1 × 10 -5 ). By contrast, in the non-responders, fast ripple had a lower spectral content in the seizure onset zone ( P  < 1 × 10 -5 ). We constructed two different networks of fast ripple with a spectral content >350 Hz. The first was a rate-distance network that multiplied the Euclidian distance between fast ripple-generating contacts by the average rate of fast ripple in the two contacts. The radius of the rate-distance network, which excluded seizure onset zone nodes, discriminated non-responders, including patients not offered resection or responsive neurostimulation due to diffuse multifocal onsets, with an accuracy of 0.77 [95% confidence interval (CI) 0.56-0.98]. The second fast ripple network was constructed using the mutual information between the timing of the events to measure functional connectivity. For most non-responders, this network had a longer characteristic path length, lower mean local efficiency in the non-seizure onset zone, and a higher nodal strength among non-seizure onset zone nodes relative to seizure onset zone nodes. The graphical theoretical measures from the rate-distance and mutual information networks of 22 non- responsive neurostimulation treated patients was used to train a support vector machine, which when tested on 13 distinct patients classified non-responders with an accuracy of 0.92 (95% CI 0.75-1). These results indicate patients who do not respond to surgery or those not selected for resection or responsive neurostimulation can be explained by the epileptic network hypothesis that is a decentralized network consisting of widely distributed, hyperexcitable fast ripple-generating nodes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Biodegradable nanocomposite scaffolds have been used for bone regeneration by serving as provisional template with optimal mechanical and biological properties analogous to native extracellular matrix (ECM). Their unique biomimicking structures aid in cell adhesion, differentiation, and proliferation with similar characteristics of the cells' ECM. Researchers are currently faced with a roadblock on ways to develop emerging process techniques to make biodegradable nanocomposite scaffolds and imitate these in exact synthetic ECM environments. This chapter particularly focuses on the technique of electrospinning for fabricating synthetic bone substitute materials for promoting bone repair and regeneration., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Intracranially recorded interictal high-frequency oscillations have been proposed as a promising spatial biomarker of the epileptogenic zone. However, its visual verification is time-consuming and exhibits poor inter-rater reliability. Furthermore, no method is currently available to distinguish high-frequency oscillations generated from the epileptogenic zone (epileptogenic high-frequency oscillations) from those generated from other areas (non-epileptogenic high-frequency oscillations). To address these issues, we constructed a deep learning-based algorithm using chronic intracranial EEG data via subdural grids from 19 children with medication-resistant neocortical epilepsy to: (i) replicate human expert annotation of artefacts and high-frequency oscillations with or without spikes, and (ii) discover epileptogenic high-frequency oscillations by designing a novel weakly supervised model. The 'purification power' of deep learning is then used to automatically relabel the high-frequency oscillations to distill epileptogenic high-frequency oscillations. Using 12 958 annotated high-frequency oscillation events from 19 patients, the model achieved 96.3% accuracy on artefact detection (F1 score = 96.8%) and 86.5% accuracy on classifying high-frequency oscillations with or without spikes (F1 score = 80.8%) using patient-wise cross-validation. Based on the algorithm trained from 84 602 high-frequency oscillation events from nine patients who achieved seizure-freedom after resection, the majority of such discovered epileptogenic high-frequency oscillations were found to be ones with spikes (78.6%, P  < 0.001). While the resection ratio of detected high-frequency oscillations (number of resected events/number of detected events) did not correlate significantly with post-operative seizure freedom (the area under the curve = 0.76, P  = 0.06), the resection ratio of epileptogenic high-frequency oscillations positively correlated with post-operative seizure freedom (the area under the curve = 0.87, P  = 0.01). We discovered that epileptogenic high-frequency oscillations had a higher signal intensity associated with ripple (80-250 Hz) and fast ripple (250-500 Hz) bands at the high-frequency oscillation onset and with a lower frequency band throughout the event time window (the inverted T-shaped), compared to non-epileptogenic high-frequency oscillations. We then designed perturbations on the input of the trained model for non-epileptogenic high-frequency oscillations to determine the model's decision-making logic. The model confidence significantly increased towards epileptogenic high-frequency oscillations by the artificial introduction of the inverted T-shaped signal template (mean probability increase: 0.285, P  < 0.001), and by the artificial insertion of spike-like signals into the time domain (mean probability increase: 0.452, P  < 0.001). With this deep learning-based framework, we reliably replicated high-frequency oscillation classification tasks by human experts. Using a reverse engineering technique, we distinguished epileptogenic high-frequency oscillations from others and identified its salient features that aligned with current knowledge., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

To see whether acute intraoperative recordings using stereo EEG (SEEG) electrodes can replace prolonged interictal intracranial EEG (iEEG) recording, making the process more efficient and safer, 10 min of iEEG were recorded following electrode implantation in 16 anesthetized patients, and 1-2 days later during non-rapid eye movement (REM) sleep. Ripples on oscillations (RonO, 80-250 Hz), ripples on spikes (RonS), sharp-spikes, fast RonO (fRonO, 250-600 Hz), and fast RonS (fRonS) were semi-automatically detected. HFO power and frequency were compared between the conditions using a generalized linear mixed-effects model. HFO rates were compared using a two-way repeated measures ANOVA with anesthesia type and SOZ as factors. A receiver-operating characteristic (ROC) curve analysis quantified seizure onset zone (SOZ) classification accuracy, and the scalar product was used to assess spatial reliability. Resection of contacts with the highest rate of events was compared with outcome. During sleep, all HFOs, except fRonO, were larger in amplitude compared to intraoperatively (p < 0.01). HFO frequency was also affected (p < 0.01). Anesthesia selection affected HFO and sharp-spike rates. In both conditions combined, sharp-spikes and all HFO subtypes were increased in the SOZ (p < 0.01). However, the increases were larger during the sleep recordings (p < 0.05). The area under the ROC curves for SOZ classification were significantly smaller for intraoperative sharp-spikes, fRonO, and fRonS rates (p < 0.05). HFOs and spikes were only significantly spatially reliable for a subset of the patients (p < 0.05). A failure to resect fRonO areas in the sleep recordings trended the most sensitive and accurate for predicting failure. In summary, HFO morphology is altered by anesthesia. Intraoperative SEEG recordings exhibit increased rates of HFOs in the SOZ, but their spatial distribution can differ from sleep recordings. Recording these biomarkers during non-REM sleep offers a more accurate delineation of the SOZ and possibly the epileptogenic zone., (© 2021. The Author(s).)

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.)

This is a summary report of clinical and regulatory issues discussed at the 2018 NINDS workshop, entitled "Accelerating Therapies for Antiepileptogenesis and Disease Modification." The intent of the workshop was to optimize and accelerate development of therapies for antiepileptogenesis (AEG) and disease modification in the epilepsies. The working group discussed nomenclature for antiepileptogenic therapies, subdividing them into "antiepileptogenic therapies" and "disease modifying therapies," both of which are urgently needed. We use the example of traumatic brain injury to explain issues and complexities in designing a trial for disease-preventing antiepileptogenic therapies, including identifying timing of intervention, selecting the appropriate dose, and the need for biomarkers. We discuss the recent trials of vigabatrin to prevent onset and modify epilepsy outcome in children with tuberous sclerosis (Epistop and PreVeNT). We describe a potential approach to a disease modification trial in adults, using patients with temporal lobe epilepsy. Finally, we discuss regulatory hurdles for antiepileptogenesis and disease-modifying trials., (© 2021 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

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: The goal of the present study was to determine whether spike and wave discharges (SWDs) and SWDs with superimposed fast ripples (SWDFRs) could be biomarkers of posttraumatic epileptogenesis., Methods: Fluid percussion injury was conducted on 13-14-week old male Sprague Dawley rats. Immediately after traumatic brain injury (TBI), they were implanted with microelectrodes in the neocortex, hippocampus, and striatum bilaterally. Age-matched sham rats with the same electrode implantation montage acted as controls. Wideband brain electrical activity was recorded intermittently from Day 1 of TBI, and continued from 2 to 21 weeks after TBI. SWD and SWDFR analysis was performed during the first 2 weeks to investigate whether the occurrence of this pattern predicted development of epilepsy. The remaining 3-21 weeks were used for identifying which rats became epileptic (E+ group) and which did not (E- group)., Results: The E+ group (n = 9) showed a significant increase in SWD rate in prefrontal cortex during Weeks 1 and 2 after TBI. The E- group showed a significant increase in SWD rate only in the second week. One hundred percent of rats in the E+ group displayed SWDFRs beginning from the first week after TBI. The SWDFR pattern was observed in all recorded brain areas: prefrontal and perilesional cortices, hippocampus, and striatum. None of rats in the E- group showed coexistence of fast ripples with SWDs., Significance: Occurrence of SWDFRs after TBI, but not an increase in the rate of SWDs, could be a noninvasive electroencephalographic biomarker of posttraumatic epileptogenesis., (© 2021 International League Against Epilepsy.)

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.)

Objective: The current study aims to investigate functional brain network representations during the early period of epileptogenesis., Methods: Eighteen rats with the intrahippocampal kainate model of mesial temporal lobe epilepsy were used for this experiment. Functional magnetic resonance imaging (fMRI) measurements were made 1 week after status epilepticus, followed by 2-4-month electrophysiological and video monitoring. Animals were identified as having (1) developed epilepsy (E+, n = 9) or (2) not developed epilepsy (E-, n = 6). Nine additional animals served as controls. Graph theory analysis was performed on the fMRI data to quantify the functional brain networks in all animals prior to the development of epilepsy. Spectrum clustering with the network features was performed to estimate their predictability in epileptogenesis., Results: Our data indicated that E+ animals showed an overall increase in functional connectivity strength compared to E- and control animals. Global network features and small-worldness of E- rats were similar to controls, whereas E+ rats demonstrated increased small-worldness, including increased reorganization degree, clustering coefficient, and global efficiency, with reduced shortest pathlength. A notable classification of the combined brain network parameters was found in E+ and E- animals. For the local network parameters, the E- rats showed increased hubs in sensorimotor cortex, and decreased hubness in hippocampus. The E+ rats showed a complete loss of hippocampal hubs, and the appearance of new hubs in the prefrontal cortex. We also observed that lesion severity was not related to epileptogenesis., Significance: Our data provide a view of the reorganization of topographical functional brain networks in the early period of epileptogenesis and how it can significantly predict the development of epilepsy. The differences from E- animals offer a potential means for applying noninvasive neuroimaging tools for the early prediction of epilepsy., (© 2021 International League Against Epilepsy.)

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: Descriptions of seizure manifestations (SM), or semiology, can help localize the symptomatogenic zone and subsequently included brain regions involved in epileptic seizures, as well as identify patients with dissociative seizures (DS). Patients and witnesses are not trained observers, so these descriptions may vary from expert review of seizure video recordings of seizures. To better understand how reported factors can help identify patients with DS or epileptic seizures (ES), we evaluated the associations between more than 30 SMs and diagnosis using standardized interviews., Methods: Based on patient- and observer-reported data from 490 patients with diagnoses documented by video-electoencephalography, we compared the rate of each SM in five mutually exclusive groups: epileptic seizures (ES), DS, physiologic seizure-like events (PSLE), mixed DS and ES, and inconclusive testing., Results: In addition to SMs that we described in a prior manuscript, the following were associated with DS: light triggers, emotional stress trigger, pre-ictal and post-ictal headache, post-ictal muscle soreness, and ictal sensory symptoms. The following were associated with ES: triggered by missing medication, aura of déjà vu, and leftward eye deviation. There were numerous manifestations separately associated with mixed ES and DS., Conclusions: Reported SM can help identify patients with DS, but no manifestation is pathognomonic for either ES or DS. Patients with mixed ES and DS reported factors divergent from both ES-alone and DS-alone., Competing Interests: Declaration of Competing Interest Drs. Engel, Stern, Kerr and Al Banna have clinical practices that include the diagnosis and treatment of patients with epilepsy and non-epileptic seizures. The remaining authors have no declared conflicts of interest. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To develop a Dissociative Seizures Likelihood Score (DSLS), which is a comprehensive, evidence-based tool using information available during the first outpatient visit to identify patients with "probable" dissociative seizures (DS) to allow early triage to more extensive diagnostic assessment., Methods: Based on data from 1616 patients with video-electroencephalography (vEEG) confirmed diagnoses, we compared the clinical history from a single neurology interview of patients in five mutually exclusive groups: epileptic seizures (ES), DS, physiologic nonepileptic seizure-like events (PSLE), mixed DS plus ES, and inconclusive monitoring. We used data-driven methods to determine the diagnostic utility of 76 features from retrospective chart review and applied this model to prospective interviews., Results: The DSLS using recursive feature elimination (RFE) correctly identified 77% (95% confidence interval (CI), 74-80%) of prospective patients with either ES or DS, with a sensitivity of 74% and specificity of 84%. This accuracy was not significantly inferior than neurologists' impression (84%, 95% CI: 80-88%) and the kappa between neurologists' and the DSLS was 21% (95% CI: 1-41%). Only 3% of patients with DS were missed by both the fellows and our score (95% CI 0-11%)., Significance: The evidence-based DSLS establishes one method to reliably identify some patients with probable DS using clinical history. The DSLS supports and does not replace clinical decision making. While not all patients with DS can be identified by clinical history alone, these methods combined with clinical judgement could be used to identify patients who warrant further diagnostic assessment at a comprehensive epilepsy center., (Copyright © 2020 Elsevier Inc. All rights reserved.)

There are no pharmacological interventions to prevent the development of epilepsy, although many promising compounds have been identified in the animal laboratory. Clinical trials to validate their effectiveness, however, would currently be prohibitively expensive due to the large subject population and duration of follow-up necessary. There is, therefore, the need to identify biomarkers of epileptogenesis that could identify patients at high risk for epilepsy following a potential epileptogenic insult to enrich the subject population, as well as biomarkers that could determine the effectiveness of therapeutic intervention without the need to wait for seizures to occur. Putative biomarkers under investigation for epileptogenesis and its treatment include genetic, molecular, cellular, imaging, and electrophysiological measures that might reliably predict the development or progression of an epileptic condition, the effects of antiepileptogenic treatment, or cure after surgery. To be clinically useful for most purposes, ideal biomarkers should be noninvasive, and it is anticipated that a profile of multiple biomarkers will likely be required. Ongoing animal research involves a number of experimental models of epileptogenesis, with traumatic brain injury, offering the best potential for translational clinical investigations. Collaborative and multicenter research efforts by multidisciplinary teams of basic and clinical neuroscientists with access to robust, well-defined animal models, extensive patient populations, standardized protocols, and cutting-edge analytical methodologies are likely to be most successful. Such biomarker research should also provide insights into fundamental neuronal mechanisms of epileptogenesis suggesting novel targets for antiepileptogenic treatments. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Ripple oscillations (80-200 Hz) in the normal hippocampus are involved in memory consolidation during rest and sleep. In the epileptic brain, increased ripple and fast ripple (200-600 Hz) rates serve as a biomarker of epileptogenic brain. We report that both ripples and fast ripples exhibit a preferred phase angle of coupling with the trough-peak (or On-Off) state transition of the sleep slow wave in the hippocampal seizure onset zone (SOZ). Ripples on slow waves in the hippocampal SOZ also had a lower power, greater spectral frequency, and shorter duration than those in the non-SOZ. Slow waves in the mesial temporal lobe modulated the baseline firing rate of excitatory neurons, but did not significantly influence the increased firing rate associated with ripples. In summary, pathological ripples and fast ripples occur preferentially during the On-Off state transition of the slow wave in the epileptogenic hippocampus, and ripples do not require the increased recruitment of excitatory neurons., (Copyright © 2020 Weiss, Song, Leng, Pastore, Slezak, Waldman, Orosz, Gorniak, Donmez, Sharan, Wu, Fried, Sperling, Bragin, Engel, Nir and Staba.)

Microglial cells are important contributors to the neuroinflammation and blood vessel damage that occurs in ischemic retinopathies. We hypothesized that key effectors of the renin-angiotensin aldosterone system, angiotensin II (Ang II) and aldosterone, increase the density of microglia in the retina and stimulate their production of reactive oxygen species (ROS) as well as pro-angiogenic and pro-inflammatory factors. Two animal models were studied that featured up-regulation of Ang II or aldosterone and included transgenic Ren-2 rats which overexpress renin and Ang II in tissues including the retina, and Sprague Dawley rats with ischemic retinopathy and infused with aldosterone. Complementary studies were performed in primary cultures of retinal microglia from neonatal Sprague Dawley rats exposed to hypoxia (0.5% O 2 ) and inhibitors of the angiotensin type 1 receptor (valsartan), the mineralocorticoid receptor (spironolactone) or aldosterone synthase (FAD286). In both in vivo models, the density of ionized calcium-binding adaptor protein-1 labelled microglia/macrophages was increased in retina compared to genetic or vehicle controls. In primary cultures of retinal microglia, hypoxia increased ROS (superoxide) levels as well as the expression of the NADPH oxidase (NOX) isoforms, NOX1, NOX2 and NOX4. The elevated levels of ROS as well as NOX2 and NOX4 were reduced by all of the treatments, and valsartan and FAD286 also reduced NOX1 mRNA levels. A protein cytokine array of retinal microglia revealed that valsartan, spironolactone and FAD286 reduced the hypoxia-induced increase in the potent pro-angiogenic and pro-inflammatory agent, vascular endothelial growth factor as well as the inflammatory factors, CCL5 and interferon γ. Valsartan also reduced the hypoxia-induced increase in IL-6 and TIMP-1 as well as the chemoattractants, CXCL2, CXCL3, CXCL5 and CXCL10. Spironolactone and FAD286 reduced the levels of CXCL2 and CXCL10, respectively. In conclusion, our findings that both Ang II and aldosterone influence the activation of retinal microglia implicates the renin-angiotensin aldosterone system in the pathogenesis of ischemic retinopathies., (Copyright © 2019 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.)

Objective: The aim of this study was to identify specific ictal hand postures (HPs) as localizing signs of the epileptogenic zone (EZ) in patients with frontal or temporal lobe epilepsy., Methods: In this study, we retrospectively analyzed ictal semiology of 489 temporal lobe or frontal lobe seizures recorded over a 6-year period at the Seizure Disorder Center at University of California, Los Angeles in the USA (45 patients) or at the C. Munari Epilepsy Surgery Center at Niguarda Hospital in Milan, Italy (34 patients). Our criterion for EZ localization was at least 2 years of seizure freedom after surgery. We analyzed presence and latency of ictal HP. We then examined whether specific initial HPs are predictive for EZ localization., Results: We found that ictal HPs were present in 72.5% of patients with frontal and 54.5% of patients with temporal lobe seizures. We divided HPs into 6 classes depending on the reciprocal position of the fingers ("fist," "cup," "politician's fist," "pincer," "extended hand," "pointing"). We found a striking correlation between EZ localization and ictal HP. In particular, fist and pointing HPs are strongly predictive of frontal lobe EZ; cup, politician's fist, and pincer are strongly predictive of temporal lobe EZ., Interpretation: Our study offers simple ictal signs that appear to clarify differential diagnosis of temporal versus frontal lobe EZ localization. These results are meant to be used as a novel complementary tool during presurgical evaluation for epilepsy. At the same time, they give us important insight into the neurophysiology of hand movements. ANN NEUROL 2019;86:793-800., (© 2019 American Neurological Association.)

At the time of the first meeting of the International League Against Epilepsy (ILAE) in 1909, surgical treatment for epilepsy had been accepted as an alternative therapy for over two decades, but was rarely practiced, considered a last resort for carefully selected patients. Localization was based on ictal semiology and identification of a structural lesion. Very few papers on epilepsy surgery were presented at ILAE meetings or published in Epilepsia during the first half of the 20 th century. A modest explosion in interest in epilepsy surgery at mid-century resulted from recognition that "invisible" epileptogenic lesions could be identified by EEG, especially for temporal lobe epilepsy. Epilepsy surgery received a second boost in popularity toward the end of the 20 th century with the advent of structural and functional neuroimaging, and the number of epilepsy centers worldwide doubled between the first Palm Desert conference in 1986 and the second Palm Desert conference in 1992. Neuroimaging also helped to increase application of surgical treatment to infants and young children with severe epilepsies. Epilepsy surgery was accepted as standard of care for drug-resistant focal epilepsy and was well-represented at international ILAE congresses and in Epilepsia. Advances continue into the 21 st century with the introduction of laser ablation, and palliative neuromodulation approaches, which have greatly increased the population of patients who can benefit from surgery. Modern presurgical evaluation techniques have also made surgical treatment possible in many countries with limited resources. Three randomized control trials now have definitively proved the safety and efficacy of epilepsy surgery, however, this alternative therapy remains under-utilized even in the industrialized world, where less than 1% of potential candidates are being referred to epilepsy centers. Furthermore, those who are referred receive surgery an average of 20 years after onset of epilepsy, often too late to avoid irreversible disability. The major challenges in realizing the full potential of epilepsy surgery, therefore, are not as much in the continued improvement of the treatment itself, as they are in addressing the treatment gap that is preventing appropriate patients from being referred to full-service epilepsy centers.

Angiotensin II and aldosterone are the main effectors of the renin-angiotensin aldosterone system (RAAS) and have a central role in hypertension as well as cardiovascular and renal disease. The localization of RAAS components within the retina has led to studies investigating the roles of angiotensin II, aldosterone and the counter regulatory arm of the pathway in vision-threatening retinopathies. This review will provide a brief overview of RAAS components as well as the vascular pathology that develops in the retinal diseases, retinopathy of prematurity, diabetic retinopathy and neovascular age-related macular degeneration. The review will discuss pre-clinical and clinical evidence that modulation of the RAAS alters the development of vasculopathy and inflammation in the aforementioned retinopathies, as well as the emerging role of aldosterone and the mineralocorticoid receptor in central serous chorioretinopathy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)