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Historians and sociologists have argued that the practices of confession played a major role in the transition to modern, introspective individuality. Until the 1970s, tough, the literature had dealt mostly with Protestantism and Protestant modes of confession, first and foremost the practice of writing spiritual diaries and then reading and rereading them. The article looks at Catholic confessional practices and how they, too, have shaped modern notion of subjecthood. Centering on Foucault’s contribution, the article argue that Catholic confession, just like its Protestant avatar, paved a route to modernity.

The appearance of language or behavioral regression in previously normal children is a devastating experience for both the family and the patients. In some cases, evaluation with prolonged sleep electroencephalograms ( EEGs ) reveals a dramatic activation of epileptiform activities. These may be continuous and diffusely appearing spike-wave discharges in slow-wave sleep, also known as 'electrical status epileptic us in sleep' (ESES), or they may be more focal but very frequent temporal, centrotemporal, or multifocal spikes. The typical syndromes are the encephalopathy associated with ESES or continuous spike waves during slow-wave sleep (CSWS) and Landau-Kleffner syndrome (LKS). A significant minority of children with pre-existing impairments in sociability, communication, and behavior, typical of autistic spectrum disorders, may manifest epileptiform abnormalities, which perhaps further exacerbate the language or neuropsychiatric dysfunction. Patients with autistic regression with epileptiform EEGs (AREE) may have clinical and electrographic similarities with CSWS or LKS children. In this review, we will summarize the existing knowledge about these syndromes and the existing therapeutic strategies. Awareness about these syndromes is of paramount importance in order to implement early detection and treatment, which may ameliorate the outcome.KEY WORDS. Autism, autistic regression, centrotemporal spikes, electrical status epilepticus in sleep, epilepsy, Landau-Kleffner syndrome, Rett syndrome. [ABSTRACT FROM AUTHOR]

Objective: To test whether anti-inflammatory and antioxidant drugs that inhibit the nuclear factor kappa light chain enhancer of activated B cells (NF-kB), celastrol and edaravone, suppress spasms and improve developmental outcomes in the multiple-hit rat model of refractory infantile spasms (IS) due to structural lesions., Methods: Postnatal day 3 (PN3) Sprague-Dawley rats were treated according to the multiple-hit IS model protocol. Using a randomized, blinded, vehicle-controlled, dose- and time-response study design, we tested the effects of single celastrol [1, 2, or 4 mg/kg intraperitoneally (i.p.), 10-14 rats/group] or edaravone (1, 10 or 30 mg/kg i.p., 14-17 rats/group) injections vs their vehicles on behavioral and electroclinical spasms and developmental milestones. Video-EEG monitoring was done on PN6-7 (n = 11-12 rats/group). Pulse celastrol treatment effects (PN4: 4 mg/kg, PN5-6: 2 mg/kg/day i.p.) were determined on spasms, developmental milestones and Barnes maze. Celastrol and edaravone pharmacokinetics in plasma and neocortex were assessed. Linear mixed model analysis of raw or normalized log-transformed spasm frequencies, considering repeated observations was used., Results: Single (2-4 mg/kg i.p) or pulse celastrol, but not edaravone, reduced behavioral and electroclinical spasms frequencies within 5hrs. Pulse celastrol did not affect spasm-freedom, survival, developmental milestones or Barnes maze performance. Celastrol had erratic i.p. absorption with maximum concentrations observed between 2-4 h, when effects on spasms were seen. Edaravone had low blood-to-brain permeability., Conclusions: Celastrol's efficacy on spasms is partially explained by its better brain penetration than edaravone's. NFkB inhibitors may be useful in treating drug-resistant IS but delivery methods with improved bioavailability and brain permeability are needed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: S.L.M. was associate editor of Neurobiology of Disease until December 2021. He is on the editorial board of Brain and Development, Pediatric Neurology, Annals of Neurology, MedLink, and Physiological Research. He has previously received compensation from Elsevier for his work as associate editor for Neurobiology of Disease and currently from MedLink for his work as associate editor, and royalties from two books he coedited. SLM holds a US patent for the multiple hit rat model (#7863499); no financial profits or conflicts have ensued as a resultof this patent. He has no conflicts of interest in regards to this study. A.S.G. was editor-in-chief of Epilepsia Open until August 2024 and is associate editor for Neurobiology of Disease and has received royalties from Elsevier and Wolters Kluwer for publications. She has no conflicts of interest in regards to this study. None of the other authors have competing interests to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This review systematically analyzes potential biomarker candidates for post-traumatic epilepsy (PTE) in humans who have experienced moderate to severe traumatic brain injury (TBI). Focusing on biomarkers across biofluid-based protein, genetic, neuroimaging, and neurophysiological categories, this review distinguishes between TBI patients who develop PTE and those who do not. The review adheres to established methodologies outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Data presentation follows the Meta-analyses of Observational Studies (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medline, Embase, and Web of Science were systematically searched and yielded 7538 records, of which 18 met inclusion criteria (moderate-severe TBI in humans, follow-up of at least 6 months, and no prior history of epilepsy). The review aggregates data from 15 cohort and 3 case-control studies (risk of bias was assessed using the Newcastle-Ottawa Scale). Statistically significant biomarkers were identified, with neurophysiological biomarkers showing the strongest effect size in a two-study meta-analysis. PTE, a severe long-term outcome of TBI affecting 2% to 53% of individuals with TBI, lacks validated biomarkers for forecasting development, crucial for designing preventive clinical trials. A multimodal approach, integrating biofluid-based protein, genetic, neuroimaging, and neurophysiological data, offers a promising strategy to enhance the predictability of PTE development and, potentially, its treatment. The study's protocol is registered in the International Prospective Register of Systematic Reviews PROSPERO (Registration ID: CRD42023470245)., (© 2024 International League Against Epilepsy.)

Early onset epilepsies occur in newborns and infants, and to date, genetic aberrations and variants have been identified in approximately one quarter of all patients. With technological sequencing advances and ongoing research, the genetic diagnostic yield for specific seizure disorders and epilepsies is expected to increase. Genetic variants associated with epilepsy include chromosomal abnormalities and rearrangements of various sizes as well as single gene variants. Among these variants, a distinction can be made between germline and somatic, with the latter being increasingly identified in epilepsies with focal cortical malformations in recent years. The identification of the underlying genetic mechanisms of epilepsy syndromes not only revolutionizes the diagnostic schemes but also leads to a better understanding of the diseases and their interrelationships, ultimately providing new opportunities for therapeutic targeting. At the XVI Workshop on Neurobiology of Epilepsy (WONOEP 2022, Talloires, France, July 2022), various etiologies, research models, and mechanisms of genetic early onset epilepsies were presented and discussed., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Epilepsy has a peak incidence during the neonatal to early childhood period. These early onset epilepsies may be severe conditions frequently associated with comorbidities such as developmental deficits and intellectual disability and, in a significant percentage of patients, may be medication-resistant. The use of adult rodent models in the exploration of mechanisms and treatments for early life epilepsies is challenging, as it ignores significant age-specific developmental differences. More recently, models developed in immature animals, such as rodent pups, or in three-dimensional organoids may more closely model aspects of the immature brain and could result in more translatable findings. Although models are not perfect, they may offer a more controlled screening platform in studies of mechanisms and treatments, which cannot be done in pediatric patient cohorts. On the other hand, more simplified models with higher throughput capacities are required to deal with the large number of epilepsy candidate genes and the need for new treatment options. Therefore, a combination of different modeling approaches will be beneficial in addressing the unmet needs of pediatric epilepsy patients. In this review, we summarize the discussions on this topic that occurred during the XVI Workshop on Neurobiology of Epilepsy, organized in 2022 by the Neurobiology Commission of the International League Against Epilepsy. We provide an overview of selected models of early onset epilepsies, discussing their advantages and disadvantages. Heterologous expression models provide initial functional insights, and zebrafish, rodent models, and brain organoids present increasingly complex platforms for modeling and validating epilepsy-related phenomena. Together, these models offer valuable insights into early onset epilepsies and accelerate hypothesis generation and therapy discovery., (© 2024 International League Against Epilepsy.)

Objective: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy., Methods: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes., Results: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities., Significance: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status., (© 2024 International League Against Epilepsy.)

Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies. The incidence of PTE after traumatic brain injury (TBI) depends on the severity of injury, approaching one in three in groups with the most severe injuries. The repeated seizures that characterize PTE impair neurological recovery and increase the risk of poor outcomes after TBI. Given this high risk of recurrent seizures and the relatively short latency period for their development after injury, PTE serves as a model disease to understand human epileptogenesis and trial novel anti-epileptogenic therapies. Epileptogenesis is the process whereby previously normal brain tissue becomes prone to recurrent abnormal electrical activity, ultimately resulting in seizures. In this Review, we describe the clinical course of PTE and highlight promising research into epileptogenesis and treatment using animal models of PTE. Clinical, imaging, EEG and fluid biomarkers are being developed to aid the identification of patients at high risk of PTE who might benefit from anti-epileptogenic therapies. Studies in preclinical models of PTE have identified tractable pathways and novel therapeutic strategies that can potentially prevent epilepsy, which remain to be validated in humans. In addition to improving outcomes after TBI, advances in PTE research are likely to provide therapeutic insights that are relevant to all epilepsies., (© 2024. Springer Nature Limited.)

Objective: Infantile epileptic spasms (IS) are epileptic seizures that are associated with increased risk for developmental impairments, adult epilepsies, and mortality. Here, we investigated coherence-based network dynamics in scalp EEG of infants with IS to identify frequency-dependent networks associated with spasms. We hypothesized that there is a network of increased fast ripple connectivity during the electrographic onset of clinical spasms, which is distinct from controls., Methods: We retrospectively analyzed peri-ictal and interictal EEG recordings of 14 IS patients. The data was compared with 9 age-matched controls. Wavelet phase coherence (WPC) was computed between 0.2 and 400 Hz. Frequency- and time-dependent brain networks were constructed using this coherence as the strength of connection between two EEG channels, based on graph theory principles. Connectivity was evaluated through global efficiency (GE) and channel-based closeness centrality (CC), over frequency and time., Results: GE in the fast ripple band (251-400 Hz) was significantly greater following the onset of spasms in all patients (P < 0.05). Fast ripple networks during the first 10s from spasm onset show enhanced anteroposterior gradient in connectivity (posterior > central > anterior, Kruskal-Wallis P < 0.001), with maximum CC over the centroparietal channels in 10/14 patients. Additionally, this anteroposterior gradient in CC connectivity is observed during spasms but not during the interictal awake or asleep states of infants with IS. In controls, anteroposterior gradient in fast ripple CC was noted during arousals and wakefulness but not during sleep. There was also a simultaneous decrease in GE in the 5-8 Hz range after the onset of spasms (P < 0.05), of unclear biological significance., Significance: We identified an anteroposterior gradient in the CC connectivity of fast ripple hubs during spasms. This anteroposterior gradient observed during spasms is similar to the anteroposterior gradient in the CC connectivity observed in wakefulness or arousals in controls, suggesting that this state change is related to arousal networks., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The National Childhood Vaccine Injury Act of 1986 created the National Vaccine Injury Compensation Program (VICP), a no-fault alternative to the traditional tort system. Since 1988, the total compensation paid exceeds $5 billion. Although epilepsy is one of the leading reasons for filing a claim, there has been no review of the process and validity of the legal outcomes given current medical information. The objectives were to review the evolution of the VICP program in regard to vaccine-related epilepsy and assess the rationale behind decisions made by the court., Methods: Publicly available cases involving epilepsy claims in the VICP were searched through Westlaw and the US Court of Federal Claims websites. All published reports were reviewed for petitioner's theories supporting vaccine-induced epilepsy, respondent's counterarguments, the final decision regarding compensation, and the rationale underlying these decisions. The primary goal was to determine which factors went into decisions regarding whether vaccines caused epilepsy., Results: Since the first epilepsy case in 1989, there have been many changes in the program, including the removal of residual seizure disorder as a vaccine-related injury, publication of the Althen prongs, release of the acellular form of pertussis, and recognition that in genetic conditions the underlying genetic abnormality rather than the immunization causes epilepsy. We identified 532 unique cases with epilepsy: 105 with infantile spasms and 427 with epilepsy without infantile spasms. The petitioners' experts often espoused outdated, erroneous causation theories that lacked an acceptable medical or scientific foundation and were frequently criticized by the court., Significance: Despite the lack of epidemiological or mechanistic evidence indicating that childhood vaccines covered by the VICP result in or aggravate epilepsy, these cases continue to be adjudicated. After 35 years of intense litigation, it is time to reconsider whether epilepsy should continue to be a compensable vaccine-induced injury., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Sodium selenate (SS) activates protein phosphatase 2 (PP2A) and reduces phosphorylated tau (pTAU) and late post-traumatic seizures after lateral fluid percussion injury (LFPI). In EpiBioS4Rx Project 2, a multi-center international study for post-traumatic targets, biomarkers, and treatments, we tested the target relevance and modification by SS of pTAU forms and PP2A and in the LFPI model, at two sites: Einstein and Melbourne. In Experiment 1, adult male rats were assigned to LFPI and sham (both sites) and naïve controls (Einstein). Motor function was monitored by neuroscores. Brains were studied with immunohistochemistry (IHC), Western blots (WBs), or PP2A activity assay, from 2 days to 8 weeks post-operatively. In Experiment 2, LFPI rats received SS for 7 days (SS0.33: 0.33 mg/kg/day; SS1: 1 mg/kg/day, subcutaneously) or vehicle (Veh) post-LFPI and pTAU, PR55 expression, or PP2A activity were studied at 2 days and 1 week (on treatment), or 2 weeks (1 week off treatment). Plasma selenium and SS levels were measured. In Experiment 1 IHC, LFPI rats had higher cortical pTAU-Ser 202 /Thr 205 -immunoreactivity (AT8-ir) and pTAU-Ser 199/202 -ir at 2 days, and pTAU-Thr 231 -ir (AT180-ir) at 2 days, 2 weeks, and 8 weeks, ipsilaterally to LFPI, than controls. LFPI-2d rats also had higher AT8/total-TAU5-ir in cortical extracts ipsilateral to the lesion (WB). PP2A (PR55-ir) showed time- and region-dependent changes in IHC, but not in WB. PP2A activity was lower in LFPI-1wk than in sham rats. In Experiment 2, SS did not affect neuroscores or cellular AT8-ir, AT180-ir, or PR55-ir in IHC. In WB, total cortical AT8/total-TAU-ir was lower in SS0.33 and SS1 LFPI rats than in Veh rats (2 days, 1 week); total cortical PR55-ir (WB) and PP2A activity were higher in SS1 than Veh rats (2 days). SS dose dependently increased plasma selenium and SS levels. Concordant across-sites data confirm time and pTAU form-specific cortical increases ipsilateral to LFPI. The discordant SS effects may either suggest SS-induced reduction in the numbers of cells with increased pTAU-ir, need for longer treatment, or the involvement of other mechanisms of action.

Despite progress in the development of anti-seizure medications (ASMs), one third of people with epilepsy have drug-resistant epilepsy (DRE). The working definition of DRE, proposed by the International League Against Epilepsy (ILAE) in 2010, helped identify individuals who might benefit from presurgical evaluation early on. As the incidence of DRE remains high, the TASK1 workgroup on DRE of the ILAE/American Epilepsy Society (AES) Joint Translational Task Force discussed the heterogeneity and complexity of its presentation and mechanisms, the confounders in drawing mechanistic insights when testing treatment responses, and barriers in modeling DRE across the lifespan and translating across species. We propose that it is necessary to revisit the current definition of DRE, in order to transform the preclinical and clinical research of mechanisms and biomarkers, to identify novel, effective, precise, pharmacologic treatments, allowing for earlier recognition of drug resistance and individualized therapies., (© 2023 International League Against Epilepsy.)

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Post-traumatic epilepsy (PTE) occurs in some patients after moderate/severe traumatic brain injury (TBI). Although there are no approved therapies to prevent epileptogenesis, levetiracetam (LEV) is commonly given for seizure prophylaxis due to its good safety profile. This led us to study LEV as part of the Epilepsy Bioinformatics Study for Antiepileptogenic Therapy (EpiBioS4Rx) Project. The objective of this work is to characterize the pharmacokinetics (PK) and brain uptake of LEV in naïve control rats and in the lateral fluid percussion injury (LFPI) rat model of TBI after either single intraperitoneal doses or a loading dose followed by a 7-day subcutaneous infusion. Sprague-Dawley rats were used as controls and for the LFPI model induced at the left parietal region using injury parameters optimized for moderate/severe TBI. Naïve and LFPI rats received either a bolus injection (intraperitoneal) or a bolus injection followed by subcutaneous infusion over 7 days. Blood and parietal cortical samples were collected at specified time points throughout the study. LEV concentrations in plasma and brain were measured using validated high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) methods. Noncompartmental analysis and a naive-pooled compartmental PK modeling approach were used. Brain-to-plasma ratios ranged from 0.54 to 1.4 to 1. LEV concentrations were well fit by one-compartment, first-order absorption PK models with a clearance of 112 ml/h per kg and volume of distribution of 293 ml/kg. The single-dose pharmacokinetic data were used to guide dose selection for the longer-term studies, and target drug exposures were confirmed. Obtaining LEV PK information early in the screening phase allowed us to guide optimal treatment protocols in EpiBioS4Rx. SIGNIFICANCE STATEMENT: The characterization of levetiracetam pharmacokinetics and brain uptake in an animal model of post-traumatic epilepsy is essential to identify target concentrations and guide optimal treatment for future studies., (Copyright © 2023 by The Author(s).)

Objective: We used the lateral fluid percussion injury (LFPI) model of moderate-to-severe traumatic brain injury (TBI) to identify early plasma biomarkers predicting injury, early post-traumatic seizures or neuromotor functional recovery (neuroscores), considering the effect of levetiracetam, which is commonly given after severe TBI., Methods: Adult male Sprague-Dawley rats underwent left parietal LFPI, received levetiracetam (200 mg/kg bolus, 200 mg/kg/day subcutaneously for 7 days [7d]) or vehicle post-LFPI, and were continuously video-EEG recorded (n = 14/group). Sham (craniotomy only, n = 6), and naïve controls (n = 10) were also used. Neuroscores and plasma collection were done at 2d or 7d post-LFPI or equivalent timepoints in sham/naïve. Plasma protein biomarker levels were determined by reverse phase protein microarray and classified according to injury severity (LFPI vs. sham/control), levetiracetam treatment, early seizures, and 2d-to-7d neuroscore recovery, using machine learning., Results: Low 2d plasma levels of Thr 231 -phosphorylated tau protein (pTAU-Thr 231 ) and S100B combined (ROC AUC = 0.7790) predicted prior craniotomy surgery (diagnostic biomarker). Levetiracetam-treated LFPI rats were differentiated from vehicle treated by the 2d-HMGB1, 2d-pTAU-Thr 231 , and 2d-UCHL1 plasma levels combined (ROC AUC = 0.9394) (pharmacodynamic biomarker). Levetiracetam prevented the seizure effects on two biomarkers that predicted early seizures only among vehicle-treated LFPI rats: pTAU-Thr 231 (ROC AUC = 1) and UCHL1 (ROC AUC = 0.8333) (prognostic biomarker of early seizures among vehicle-treated LFPI rats). Levetiracetam-resistant early seizures were predicted by high 2d-IFNγ plasma levels (ROC AUC = 0.8750) (response biomarker). 2d-to-7d neuroscore recovery was best predicted by higher 2d-S100B, lower 2d-HMGB1, and 2d-to-7d increase in HMGB1 or decrease in TNF (P < 0.05) (prognostic biomarkers)., Significance: Antiseizure medications and early seizures need to be considered in the interpretation of early post-traumatic biomarkers., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: The International League Against Epilepsy (ILAE) Neonatal Seizure Framework was tested by medical personnel., Methods: Attendees at the 2016 ILAE European Congress on Epileptology in Prague, the International Video-EEG Course in Pediatric Epilepsies in Madrid 2017, and a local meeting in Utrecht 2018, were introduced to the proposed ILAE neonatal classification system with teaching videos covering the seven types of clinical seizures in the proposed neonatal classification system. Five test digital video recordings of electroencephalography (EEG)-confirmed motor neonatal seizures were then shown and classified by the rater based on their knowledge of the proposed ILAE Neonatal Seizure Framework. A multi-rater Kappa statistic was used to assess the agreement between observers and the true diagnosis., Results: The responses of 194 raters were obtained. There was no single predominant classification system that was currently used by the raters. Using the ILAE framework, 78%-93% of raters correctly identified the clinical seizure type for each neonate; the overall inter-rater agreement (Kappa statistic) was 0.67. The clonic motor seizure type was most frequently accurately identified (93% of the time; κ = 0.870). EEG technicians correctly identified all presented motor seizure types more frequently than any other group (accuracy = 0.9)., Significance: The ILAE Neonatal Seizure Framework was judged by most raters to be better than other systems for the classification of clinical seizures. Among all seizure types presented, clonic seizures appeared to be the easiest to accurately identify. Average accuracy across the five seizure types was 84.5%. These data suggest that the ILAE neonatal seizure classification may be used by all healthcare professionals to correctly identify the predominant clinical seizure type., (© 2023 International League Against Epilepsy.)

Epilepsy syndromes have been recognized for >50 years, as distinct electroclinical phenotypes with therapeutic and prognostic implications. Nonetheless, no formally accepted International League Against Epilepsy (ILAE) classification of epilepsy syndromes has existed. The ILAE Task Force on Nosology and Definitions was established to reach consensus regarding which entities fulfilled criteria for an epilepsy syndrome and to provide definitions for each syndrome. We defined an epilepsy syndrome as "a characteristic cluster of clinical and electroencephalographic features, often supported by specific etiological findings (structural, genetic, metabolic, immune, and infectious)." The diagnosis of a syndrome in an individual with epilepsy frequently carries prognostic and treatment implications. Syndromes often have age-dependent presentations and a range of specific comorbidities. This paper describes the guiding principles and process for syndrome identification in both children and adults, and the template of clinical data included for each syndrome. We divided syndromes into typical age at onset, and further characterized them based on seizure and epilepsy types and association with developmental and/or epileptic encephalopathy or progressive neurological deterioration. Definitions for each specific syndrome are contained within the corresponding position papers., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and infant with seizure onset up to 2 years of age. The incidence of epilepsy is high in this age group and epilepsy is frequently associated with significant comorbidities and mortality. The licensing of syndrome specific antiseizure medications following randomized controlled trials and the development of precision, gene-related therapies are two of the drivers defining the electroclinical phenotypes of syndromes with onset in infancy. The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an individual both by syndrome and etiology. For each syndrome, we report epidemiology, clinical course, seizure types, electroencephalography (EEG), neuroimaging, genetics, and differential diagnosis. Syndromes are separated into self-limited syndromes, where there is likely to be spontaneous remission and developmental and epileptic encephalopathies, diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. The emerging class of etiology-specific epilepsy syndromes, where there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected individuals as well as consistent EEG, neuroimaging, and/or genetic correlates, is presented. The number of etiology-defined syndromes will continue to increase, and these newly described syndromes will in time be incorporated into this classification. The tables summarize mandatory features, cautionary alerts, and exclusionary features for the common syndromes. Guidance is given on the criteria for syndrome diagnosis in resource-limited regions where laboratory confirmation, including EEG, MRI, and genetic testing, might not be available., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The goal of this paper is to provide updated diagnostic criteria for the epilepsy syndromes that have a variable age of onset, based on expert consensus of the International League Against Epilepsy Nosology and Definitions Taskforce (2017-2021). We use language consistent with current accepted epilepsy and seizure classifications and incorporate knowledge from advances in genetics, electroencephalography, and imaging. Our aim in delineating the epilepsy syndromes that present at a variable age is to aid diagnosis and to guide investigations for etiology and treatments for these patients., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

In 2017, the International League Against Epilepsy (ILAE) Classification of Epilepsies described the "genetic generalized epilepsies" (GGEs), which contained the "idiopathic generalized epilepsies" (IGEs). The goal of this paper is to delineate the four syndromes comprising the IGEs, namely childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. We provide updated diagnostic criteria for these IGE syndromes determined by the expert consensus opinion of the ILAE's Task Force on Nosology and Definitions (2017-2021) and international external experts outside our Task Force. We incorporate current knowledge from recent advances in genetic, imaging, and electroencephalographic studies, together with current terminology and classification of seizures and epilepsies. Patients that do not fulfill criteria for one of these syndromes, but that have one, or a combination, of the following generalized seizure types: absence, myoclonic, tonic-clonic and myoclonic-tonic-clonic seizures, with 2.5-5.5 Hz generalized spike-wave should be classified as having GGE. Recognizing these four IGE syndromes as a special grouping among the GGEs is helpful, as they carry prognostic and therapeutic implications., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

The 2017 International League Against Epilepsy classification has defined a three-tier system with epilepsy syndrome identification at the third level. Although a syndrome cannot be determined in all children with epilepsy, identification of a specific syndrome provides guidance on management and prognosis. In this paper, we describe the childhood onset epilepsy syndromes, most of which have both mandatory seizure type(s) and interictal electroencephalographic (EEG) features. Based on the 2017 Classification of Seizures and Epilepsies, some syndrome names have been updated using terms directly describing the seizure semiology. Epilepsy syndromes beginning in childhood have been divided into three categories: (1) self-limited focal epilepsies, comprising four syndromes: self-limited epilepsy with centrotemporal spikes, self-limited epilepsy with autonomic seizures, childhood occipital visual epilepsy, and photosensitive occipital lobe epilepsy; (2) generalized epilepsies, comprising three syndromes: childhood absence epilepsy, epilepsy with myoclonic absence, and epilepsy with eyelid myoclonia; and (3) developmental and/or epileptic encephalopathies, comprising five syndromes: epilepsy with myoclonic-atonic seizures, Lennox-Gastaut syndrome, developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep, hemiconvulsion-hemiplegia-epilepsy syndrome, and febrile infection-related epilepsy syndrome. We define each, highlighting the mandatory seizure(s), EEG features, phenotypic variations, and findings from key investigations., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: This is a systematic review aimed at summarizing the evidence related to instruments that have been developed to measure stigma or attitudes toward epilepsy and on stigma-reducing interventions., Methods: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. A broad literature search (1985-2019) was performed in 13 databases. Articles were included if they described the development and testing of psychometric properties of an epilepsy-related stigma or attitude scale or stigma-reducing interventions. Two reviewers independently screened abstracts, reviewed full-text articles, and extracted data. Basic descriptive statistics are reported., Results: We identified 4234 abstracts, of which 893 were reviewed as full-text articles. Of these, 38 met inclusion criteria for an instrument development study and 30 as a stigma-reduction intervention study. Most instruments were initially developed using well-established methods and were tested in relatively large samples. Most intervention studies involved educational programs for adults with pre- and post-evaluations of attitudes toward people with epilepsy. Intervention studies often failed to use standardized instruments to quantify stigmatizing attitudes, were generally underpowered, and often found no evidence of benefit or the benefit was not sustained. Six intervention studies with stigma as the primary outcome had fewer design flaws and showed benefit. Very few or no instruments were validated for regional languages or culture, and there were very few interventions tested in some regions., Significance: Investigators in regions without instruments should consider translating and further developing existing instruments rather than initiating the development of new instruments. Very few stigma-reduction intervention studies for epilepsy have been conducted, study methodology in general was poor, and standardized instruments were rarely used to measure outcomes. To accelerate the development of effective epilepsy stigma-reduction interventions, a paradigm shift from disease-specific, siloed trials to collaborative, cross-disciplinary platforms based upon unified theories of stigma transcending individual conditions will be needed., (© 2022 International League Against Epilepsy.)

Objective: Infantile spasms may evolve into persistent epilepsies including Lennox-Gastaut syndrome. We compared adult epilepsy outcomes in models of infantile spasms due to structural etiology (multiple-hit model) or focal cortical inflammation and determined the anti-epileptogenic effects of pulse-rapamycin, previously shown to stop spasms in multiple-hit rats., Methods: Spasms were induced in 3-day-old male rats via right intracerebral doxorubicin/lipopolysaccharide (multiple-hit model) infusions. Controls and sham rats were used. Separate multiple-hit rats received pulse-rapamycin or vehicle intraperitoneally between postnatal days 4 and 6. In adult mice, video-EEG (electroencephalography) scoring for seizures and sleep and histology were done blinded to treatment., Results: Motor-type seizures developed in 66.7% of multiple-hit rats, usually from sleep, but were reduced in the pulse-rapamycin-treated group (20%, p = .043 vs multiple-hit) and rare in other groups (0-9.1%, p < .05 vs multiple-hit). Spike-and-wave bursts had a slower frequency in multiple-hit rats (5.4-5.8Hz) than in the other groups (7.6-8.3Hz) (p < .05); pulse rapamycin had no effect on the hourly spike-and-wave burst rates in adulthood. Rapamycin, however, reduced the time spent in slow-wave-sleep (17.2%), which was increased in multiple-hit rats (71.6%, p = .003). Sham rats spent more time in wakefulness (43.7%) compared to controls (30.6%, p = .043). Multiple-hit rats, with or without rapamycin treatment, had right more than left corticohippocampal, basal ganglia lesions. There was no macroscopic pathology in the other groups., Significance: Structural corticohippocampal/basal ganglia lesions increase the risk for post-infantile spasms epilepsy, Lennox-Gastaut syndrome features, and sleep dysregulation. Pulse rapamycin treatment for infantile spasms has anti-epileptogenic effects, despite the structural lesions, and decreases the time spent in slow wave sleep., (© 2021 International League Against Epilepsy.)

Objective: To determine whether there is a disparity in access to telemedical care that may be a function of socioeconomic status, language, or other demographic factors during the peak of the coronavirus disease 2019 (COVID-19) pandemic at a highly affected urban center (Montefiore Medical Center) in Bronx, NY., Methods: We retrospectively investigated potential patient characteristics that might be associated with an increased likelihood of receiving a telephone visit as opposed to a televideo visit for patients followed in the pediatric neurology, adult epilepsy, and general neurology practices at Montefiore Medical Center during the 30-day period starting April 2, 2020, at the peak of the COVID-19 pandemic in New York., Results: We found that patients who had telephone encounters, as opposed to televideo encounters, were overall older, less likely to have commercial insurance, and more likely to have Medicaid. Among pediatric patients, a preferred language other than English was also associated with a higher proportion of telephone encounters. New patients in both the adult and pediatric groups were more likely to have televideo visits., Conclusions: Our findings identify demographic factors, including age, insurance type, and language preference, which may play a role in access to televideo encounters among neurology patients in an urban center during the COVID-19 pandemic. We suggest several potential practice, institution, and community-based interventions, which might further expand access to televideo care for neurology patients., (© 2020 American Academy of Neurology.)

Seizures are the most common neurological emergency in the neonatal period and in contrast to those in infancy and childhood, are often provoked seizures with an acute cause and may be electrographic-only. Hence, neonatal seizures may not fit easily into classification schemes for seizures and epilepsies primarily developed for older children and adults. A Neonatal Seizures Task Force was established by the International League Against Epilepsy (ILAE) to develop a modification of the 2017 ILAE Classification of Seizures and Epilepsies, relevant to neonates. The neonatal classification framework emphasizes the role of electroencephalography (EEG) in the diagnosis of seizures in the neonate and includes a classification of seizure types relevant to this age group. The seizure type is determined by the predominant clinical feature. Many neonatal seizures are electrographic-only with no evident clinical features; therefore, these are included in the proposed classification. Clinical events without an EEG correlate are not included. Because seizures in the neonatal period have been shown to have a focal onset, a division into focal and generalized is unnecessary. Seizures can have a motor (automatisms, clonic, epileptic spasms, myoclonic, tonic), non-motor (autonomic, behavior arrest), or sequential presentation. The classification allows the user to choose the level of detail when classifying seizures in this age group., (© 2021 International League Against Epilepsy.)

Objective: Our epilepsy population recently experienced the acute effects of the COVID-19 pandemic in New York City. Herein, we aimed to determine patient-perceived seizure control during the surge, specific variables associated with worsened seizures, the prevalence of specific barriers to care, and patient-perceived efficacy of epilepsy care delivered via telephone and live video visits during the pandemic., Methods: We performed a cross-sectional questionnaire study of adult epilepsy patients who had a scheduled appointment at a single urban Comprehensive Epilepsy Center (Montefiore Medical Center) between March 1, 2020 and May 31, 2020 during the peak of the COVID-19 pandemic in the Bronx. Subjects able to answer the questionnaire themselves in English or Spanish were eligible to complete a one-time survey via telephone or secure online platform (REDCap)., Results: Of 1212 subjects screened, 675 were eligible, and 177 adequately completed the questionnaire. During the COVID-19 pandemic, 75.1% of patients reported no change in seizure control, whereas 17.5% reported that their seizure control had worsened, and 7.3% reported improvement. Subjects who reported worsened seizure control had more frequent seizures at baseline, were more likely to identify stress and headaches/migraines as their typical seizure precipitants, and were significantly more likely to report increased stress related to the pandemic. Subjects with confirmed or suspected COVID-19 did not report worsened seizure control. Nearly 17% of subjects reported poorer epilepsy care, and 9.6% had difficulty obtaining their antiseizure medications; these subjects were significantly more likely to report worse seizure control., Significance: Of the nearly 20% of subjects who reported worsened seizure control during the COVID-19 pandemic, stress and barriers to care appear to have posed the greatest challenge. This unprecedented pandemic exacerbated existing and created new barriers to epilepsy care, which must be addressed., (© 2020 International League Against Epilepsy.)

Competing Interests: We have no conflicts of interest to declare in regard to this response. AS Galanopoulou is co‐editor in Chief of Epilepsia Open and has received royalties for publications from Elsevier and Morgan & Claypool publishers. SR Haut serves on the editorial board of Epilepsy and Behavior. SL Moshé is serving as associate editor of Neurobiology of Disease and serves on the editorial board of Brain and Development, Pediatric Neurology, and Physiological Research. He receives from Elsevier an annual compensation for his work as associate editor in Neurobiology of Disease and royalties from two books he co‐edited. He has received consultant's fees from UCB and Pfizer. AB Boro is site PI for clinical trials sponsored by Biogen, SK Life Science, Neurelis, and UCB. He receives no salary support for other reimbursement for these projects. All funds go to the institution. None of the other authors have conflicts to disclose. 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.

Objective: Acute encephalopathy may occur in COVID-19-infected patients. We investigated whether medically indicated EEGs performed in acutely ill patients under investigation (PUIs) for COVID-19 report epileptiform abnormalities and whether these are more prevalent in COVID-19 positive than negative patients., Methods: In this retrospective case series, adult COVID-19 inpatient PUIs underwent EEGs for acute encephalopathy and/or seizure-like events. PUIs had 8-channel headband EEGs (Ceribell; 20 COVID-19 positive, 6 COVID-19 negative); 2 more COVID-19 patients had routine EEGs. Overall, 26 Ceribell EEGs, 4 routine and 7 continuous EEG studies were reviewed. EEGs were interpreted by board-certified clinical neurophysiologists (n = 16). EEG findings were correlated with demographic data, clinical presentation and history, and medication usage. Fisher's exact test was used., Results: We included 28 COVID-19 PUIs (30-83 years old), of whom 22 tested positive (63.6% males) and 6 tested negative (33.3% male). The most common indications for EEG, among COVID-19-positive vs COVID-19-negative patients, respectively, were new onset encephalopathy (68.2% vs 33.3%) and seizure-like events (14/22, 63.6%; 2/6, 33.3%), even among patients without prior history of seizures (11/17, 64.7%; 2/6, 33.3%). Sporadic epileptiform discharges (EDs) were present in 40.9% of COVID-19-positive and 16.7% of COVID-19-negative patients; frontal sharp waves were reported in 8/9 (88.9%) of COVID-19-positive patients with EDs and in 1/1 of COVID-19-negative patient with EDs. No electrographic seizures were captured, but 19/22 COVID-19-positive and 6/6 COVID-19-negative patients were given antiseizure medications and/or sedatives before the EEG., Significance: This is the first preliminary report of EDs in the EEG of acutely ill COVID-19-positive patients with encephalopathy or suspected clinical seizures. EDs are relatively common in this cohort and typically appear as frontal sharp waves. Further studies are needed to confirm these findings and evaluate the potential direct or indirect effects of COVID-19 on activating epileptic activity., Competing Interests: AS Galanopoulou is co‐Editor in Chief of Epilepsia Open and has received royalties for publications from Elsevier and Morgan & Claypool publishers. AD Legatt serves on the editorial board of Journal of Clinical Neurophysiology and has received royalties for a publication from Springer Publishing. He has received consultant’s fees from Brain Sentinel. SR Haut serves on the editorial board of Epilepsy and Behavior. SL Moshé is serving as Associate Editor of Neurobiology of Disease and is on the editorial board of Brain and Development, Pediatric Neurology and Physiological Research. He receives from Elsevier an annual compensation for his work as Associate Editor in Neurobiology of Disease and royalties from two books he co‐edited. He has received consultant's fees from UCB and Pfizer. AB Boro is site PI for clinical trials sponsored clinical trials sponsored by Biogen, SK Life Science, Neurelis and UCB. He receives no salary support or other reimbursement for these projects. All funds go to the institution. None of the other authors have conflicts to disclose. 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. 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., (© 2020 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Despite the advances in imaging, EEG remains a critical test for the diagnosis of epilepsy. Not only can it confirm the diagnosis, but it can also clarify the type of epilepsy. There are many different types of EEG recordings depending on duration, the presence of video, and inpatient or outpatient setting, each with its pros and cons. Interictal epileptiform abnormalities are very specific to epilepsy, but they can be over-interpreted by inexperienced readers. In addition to diagnosis of epilepsy, EEG also has a role in the decision to discontinue treatment in seizure-free patients, and in assessing critically ill patients for possible status epilepticus and encephalopathies. EEG reports should be relatively standardized and clear to the clinician who requested the EEG.

Objective: The use of the Internet for health-related questions is increasing, but it is not clear whether individuals can understand the information available online. Most health organizations recommend that health educational materials (HEMs) be written below the sixth grade reading level. This study was designed to evaluate the readability level of available online HEMs pertaining to traumatic brain injury (TBI), epilepsy, and posttraumatic epilepsy (PTE)., Methods: This cross-sectional readability assessment included HEMs from TBI and epilepsy stakeholder organizations and those obtained from four Internet searches. The search strategy was designed to replicate a nonmedical individual's keyword searches. Each HEM was assessed with an online automated readability tool using three indices (Flesch Reading Ease Score, Flesch-Kincaid Grade Level, and Simple Measure of Gobbledygook). Findings were compared as a function of organization type (journalistic news or health organization), targeted medical condition (TBI, epilepsy, or PTE), or content topic (patient health education, clinical research education, or both)., Results: Readability analysis of 405 identified HEMs revealed scores above the sixth grade reading level recommendation. Only 6.2% of individual HEMs met the sixth grade recommendation. Journalistic news organizations' HEMs had similar readability levels to health organizations' HEMs. PTE-related HEMs required the highest readability level, >11th grade (P < .001). There were significant differences in the readability scores (P < .01 for all indices) among HEMs with information on health education, research education, or both topics. The highest required readability level (>12 grade level) was for HEMs that included both health and research education., Significance: The majority of TBI-, epilepsy-, and PTE-related online HEMs do not meet the sixth grade reading recommendation. Improving the readability of HEMs may advance health literacy around TBI, epilepsy, and PTE, leading to more effective participant recruitment/retention strategies for future antiepileptogenesis trials in persons with TBI and perhaps better patient-centered outcomes., (Wiley Periodicals, Inc. © 2020 International League Against Epilepsy.)

This review aims to highlight the historical hallmarks in the development of the concepts of seizures and epilepsy. It begins with a discussion of seizure semiology and terminology, followed by the pathophysiology of seizures. We then discuss the definition of epilepsy, its etiologies, and ultimately classification schemes. Each section starts with our current views and subsequently transports the reader back in time to understand how these views evolved and came to be what they are today. People living as early as in the prehistoric times may have been aware of the existence of seizures, and descriptions and terminology have been provided as early as 2500 BC. While names have been revised and updated through time, the meanings are seemingly unchanged. However, it is clearly evident that we have come a long way in understanding the pathophysiology and etiology of seizures and epilepsy, thus leading to our current classification schemes. No classification scheme will be perfect yet, until our understanding is advanced enough to create one based predominantly on scientific grounds. The goal is that it is relevant to clinical practice, leading to a more precise diagnosis to guide targeted treatments., Competing Interests: Dr Moshé is serving as Associate Editor of Neurobiology of Disease and is on the editorial board of Brain and Development, Pediatric Neurology and Physiological Research. He receives from Elsevier an annual compensation for his work as Associate Editor in Neurobiology of Disease and royalties from 2 books he coedited. He has received consultant's fees from UCB, Mallinckrodt, and Pfizer. Dr Patel has no 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., (© 2019 The Authors. Epilepsia Open published by Wiley Periodicals Inc. on behalf of International League Against Epilepsy.)

Competing Interests: Declaration of competing interest Dr. Molinero has no disclosures. Dr. Galanopoulou is co-Editor in Chief of Epilepsia Open and has received royalties for publications from Elsevier and Morgan and Claypool publishers. She has received a one-time honorarium for participation in an Eisai scientific advisory board. Dr. Moshé is serving as Associate Editor of Neurobiology of Disease and is on the editorial board of Brain and Development, Pediatric Neurology and Physiological Research. He receives from Elsevier an annual compensation for his work as Associate Editor in Neurobiology of Disease and royalties from 2 books he co-edited. He has received consultant's fees from UCB, Mallinckrodt and Pfizer.