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Montessori education is characterized by autonomous learning, whereas traditional education is often depicted by high structure and fewer choice opportunities. This study examined differences in beliefs of Montessori and traditional teachers in regard to effectiveness, normality, and ease of autonomy-supportive and controlling teaching, as well as differences in motivating styles. We analyzed the U.S. subset from an international study examining self-described motivation styles and beliefs. Our secondary analysis revealed both groups felt autonomy-supportive teaching was easy and effective, and that they found controlling teaching also to be easy, but ineffective. Montessori teachers were more likely to believe autonomy-supportive teaching was normal, whereas traditional teachers believed controlling teaching was more normal. Both groups described their teaching style as autonomy-supportive, but traditional teachers more often rated controlling scenarios as similar to their own practices. These differences, supported by large effect sizes, demonstrate more potential for controlling behavior in traditional classrooms and suggest the possibility of a cultural difference between Montessori and traditional teachers.

Objectives The aim of the study was to describe patient characteristics and outcomes among HIV-positive adults presenting to a Zambian tertiary care hospital with new-onset seizures. Methods From July 2011 to June 2013, adults with seizures and a known or probable diagnosis of HIV infection were screened for a cohort study. Demographic and clinical data were obtained, including information on engagement in HIV services and in-patient mortality. Analyses were conducted to identify characteristics associated with poor engagement in care and death. Results A total of 320 of 351 screened adults were HIV-positive, with 268 of 320 experiencing new-onset seizures. Of these, 114 of 268 (42.5%) were female, and their mean age was 36.8 years. Seventy-nine of the 268 patients (29.5%) were diagnosed with HIV infection during the index illness. Among those who were aware of their HIV-positive status, 59 of 156 (37.8%) had disengaged from care. Significant functional impairment ( Karnofsky score < 50) was evident in 44.0% of patients. Cerebrospinal fluid was not obtained in 108 of 268 (40.3%). In-patient mortality outcomes were available for 214 patients, and 47 of these 214 (22.0%) died during hospitalization. Patients with significant functional impairment were more likely to undergo lumbar puncture ( P = 0.046). Women and the functionally impaired were more likely to die ( P = 0.04 and < 0.001, respectively). Conclusions Despite the availability of care, less than half of HIV-infected people with new-onset seizures were actively engaged in care and in-patient mortality rates were high. In the absence of clinical contraindication, lumbar puncture should be performed to diagnose treatable conditions and reduce morbidity and mortality. Continued efforts are needed to expand community-based testing and improve HIV care retention rates. Qualitative studies are needed to elucidate factors contributing to lumbar puncture usage in this population. [ABSTRACT FROM AUTHOR]

Neural networks for processing language often are reorganized in patients with epilepsy. However, the extent and location of within and between hemisphere re-organization are not established. We studied 45 patients, all with a left hemisphere seizure focus (mean age 22.8, seizure onset 13.3), and 19 normal controls (mean age 24.8) with an fMRI word definition language paradigm to assess the location of language processing regions. Individual patient SPM maps were compared to the normal group in a voxel-wise comparison; a voxel was considered to be significant if its z-value exceeded mid R:2mid R:. Subsequently, we used principal component analysis with hierarchical clustering of variance patterns from individual difference maps to identify four patient sub-groups. One did not differ from normal controls; one had increased left temporal activation on the margin of regions activated in controls; two others had recruitment in right inferior frontal gyrus, middle frontal gyrus and temporal cortex. Right hemisphere activation in these two groups occurred in homologues of left hemisphere regions that sustained task activation. Our study used novel data driven methods to find evidence for constraints on inter-hemispheric reorganization of language in recruitment of right homologues, and, in a subpopulation of patients, evidence for intra-hemispheric reorganization of language limited to the margins of typical left temporal regional activation. These methods may be applied to investigate both normal and pathological variance in other developmental disorders and cognitive domains. [ABSTRACT FROM AUTHOR]

The interaction between primidone and phenytoin was studied in an epileptic patient treated with primidone only and primidone plus phenytoin for 3 months. Plasma and urine levels of drugs and metabolites were monitored daily by GC and GC-MS. The addition of phenytoin to the regimen increased steady-state plasma levels of phenobarbitone and phenylethylmalonamide (PEMA), metabolites of primidone, and decreased levels of primidone and unconjugated p- hydroxyphenobarbitone (p-OHPB), a metabolite of phenobarbitone. After withdrawal of phenytoin, plasma phenobarbitone and primidone levels slowly returned to previous steady-state levels, PEMA rapidly decreased to lower levels than before, and p-OHPB levels rose rapidly. Urinary excretion of primidone and its metabolites paralleled the changes in their plasma levels after the addition of phenytoin but the percentage of unconjugated p-OHPB in urine was unchanged during the course of the study. In conclusion phenytoin initially induces the conversion of primidone to PEMA and phenobarbitone, although each to a different extent, but it appears to inhibit the hydroxylation of phenobarbitone. Thus, two apparently contradictory phenomena seem to be involved in the primidone-phenytoin interaction. The net effect is an enhanced increase in plasma phenobarbitone levels. [ABSTRACT FROM AUTHOR]

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Functional connectivity (FC) refers to the activation correlation between different brain regions. FC networks as typically represented as graphs with brain regions of interest (ROIs) as nodes and functional correlation as edges. Graph neural networks (GNNs) are machine learning architectures used to analyze FC graphs. However, traditional GNNs are limited in their ability to characterize FC edge attributes because they typically emphasize the importance of ROI node-based brain activation data. Line GNNs convert the edges of the original graph to nodes in the transformed graph, thereby emphasizing the FC between brain regions. We hypothesize that line GNNs will outperform traditional GNNs in FC applications. We investigated the performance of two common GNN architectures (GraphSAGE and GCN) trained on line and traditional graphs predicting task-associated FC changes across two datasets. The first dataset was from the Human Connectome Project (HCP) with 205 participants, the second was a dataset with 12 participants. The HCP dataset detailed FC changes in participants during a story-listening task, while the second dataset included the FC changes in a different auditory language task. Our findings from the HCP dataset indicated that line GNNs achieved lower mean squared error compared to traditional GNNs, with the line GraphSAGE model outperforming the traditional GraphSAGE by 18% ( p  < 0.0001). When applying the same models to the second dataset, both line GNNs also showed statistically significant improvements over their traditional counterparts with little to no overfitting. We believe this shows that line GNN models demonstrate promising utility in FC studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Acker, Liang, Sinaii, Wingert, Kurosu, Rajan, Inati, Theodore and Biassou.)

Objective: A well-established bidirectional relationship exists between sleep and epilepsy. Patients with epilepsy tend to have less efficient sleep and shorter rapid eye movement (REM) sleep. Seizures are far more likely to arise from sleep transitions and non-REM sleep compared to REM sleep. Delay in REM onset or reduction in REM duration may have reciprocal interactions with seizure occurrence. Greater insight into the relationship between REM sleep and seizure occurrence is essential to our understanding of circadian patterns and predictability of seizure activity. We assessed a cohort of adults undergoing evaluation of drug-resistant epilepsy to examine whether REM sleep prior to or following seizures is delayed in latency or reduced in quantity., Methods: We used a spectrogram-guided approach to review the video-electroencephalograms of patients' epilepsy monitoring unit admissions for sleep scoring to determine sleep variables., Results: In our cohort of patients, we found group- and individual-level delay of REM latency and reduced REM duration when patients experienced a seizure before the primary sleep period (PSP) of interest or during the PSP of interest. A significant increase in REM latency and decrease in REM quantity were observed on nights where a seizure occurred within 4 h of sleep onset. No change in REM variables was found when investigating seizures that occurred the day after the PSP of interest. Our study is the first to provide insight about a perisleep period, which we defined as 4-h periods before and after the PSP., Significance: Our results demonstrate a significant relationship between seizures occurring prior to the PSP, during the PSP, and in the 4-h perisleep period and a delay in REM latency. These findings have implications for developing a biomarker of seizure detection as well as longer term seizure risk monitoring., (© 2024 International League Against Epilepsy.)

Objective: To determine the long-term outcomes, including mortality and recurrent seizures, among children living with HIV (CLWH) who present with new onset seizure., Methods: Zambian CLWH and new onset seizure were enrolled prospectively to determine the risk of and risk factors for recurrent seizures. Demographic data, clinical profiles, index seizure etiology, and 30-day mortality outcomes were previously reported. After discharge, children were followed quarterly to identify recurrent seizures and death. Given the high risk of early death, risk factors for recurrent seizure were evaluated using a model that adjusted for mortality., Results: Among 73 children enrolled, 28 died (38%), 22 within 30-days of the index seizure. Median follow-up was 533 days (IQR 18-957) with 5% (4/73) lost to follow-up. Seizure recurrence was 19% among the entire cohort. Among children surviving at least 30-days after the index seizure, 27% had a recurrent seizure. Median time from index seizure to recurrent seizure was 161 days (IQR 86-269). Central nervous system opportunistic infection (CNS OI), as the cause for the index seizure was protective against recurrent seizures and higher functional status was a risk factor for seizure recurrence., Significance: Among CLWH presenting with new onset seizure, mortality risks remain elevated beyond the acute illness period. Recurrent seizures are common and are more likely in children with higher level of functioning even after adjusting for the outcome of death. Newer antiseizure medications appropriate for co-usage with antiretroviral therapies are needed for the care of these children. CNS OI may represent a potentially reversible provocation for the index seizure, while seizures in high functioning CLWH without a CNS OI may be the result of a prior brain injury or susceptibility to seizures unrelated to HIV and thus represent an ongoing predisposition to seizures., Plain Language Summary: This study followed CLWH who experienced a new onset seizure to find out how many go on to have more seizures and identify any patient characteristics associated with having more seizures. The study found that mortality rates continue to be high beyond the acute clinical presentation with new onset seizure. Children with a CNS OI causing the new onset seizure had a lower risk of later seizures, possibly because the trigger for the seizure can be treated. In contrast, high functioning children without a CNS OI were at higher risk of future seizures., (© 2024 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Purpose of Review: Currently, an estimated 3.4 million people in the United States live with epilepsy. Previous studies have identified health disparities associated with race/ethnicity, socioeconomic status (SES), sex, insurance status, and age in this population. However, there has been a dearth of research addressing these disparities. We performed a literature review of articles published between 2010 and 2020 pertaining to health disparities in people with epilepsy (PWE), identified key factors that contribute to gaps in their care, and discussed possible solutions., Recent Findings: Health disparities in prevalence, treatment access, time to diagnosis, health care delivery and engagement, and clinical outcomes were identified among individuals who were either of low SES, rural-based, uninsured/underinsured, older patients, patients of color, or female sex., Summary: Disparities in care for PWE continue to persist. Greater priority should be placed on addressing these gaps intricately tied to sociodemographic factors. Reforms to mitigate health disparities in PWE are necessary for timely diagnosis, effective treatment, and positive long-term outcomes., Competing Interests: The authors report no relevant disclosures. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Background: Seizures are relatively common among children with HIV in low- and middle-income countries and are associated with significant morbidity and mortality. Early treatment with antiretroviral therapy (ART) may reduce this risk by decreasing rates of central nervous system infections and HIV encephalopathy., Methods: We conducted a prospective, unmatched case-control study. We enrolled children with new-onset seizure from University Teaching Hospital in Lusaka, Zambia and 2 regional hospitals in rural Zambia. Controls were children with HIV and no history of seizures. Recruitment took place from 2016 to 2019. Early treatment was defined as initiation of ART before 12 months of age, at a CD4 percentage >15% in children aged 12-60 months or a CD4 count >350 cells/mm 3 for children aged 60 months or older. Logistic regression models were used to evaluate the association between potential risk factors and seizures., Results: We identified 73 children with new-onset seizure and compared them with 254 control children with HIV but no seizures. Early treatment with ART was associated with a significant reduction in the odds of seizures [odds ratio (OR) 0.04, 95% confidence interval: 0.02 to 0.09; P < 0.001]. Having an undetectable viral load at the time of enrollment was strongly protective against seizures (OR 0.03, P < 0.001), whereas history of World Health Organization Stage 4 disease (OR 2.2, P = 0.05) or CD4 count <200 cells/mm 3 (OR 3.6, P < 0.001) increased risk of seizures., Conclusions: Early initiation of ART and successful viral suppression would likely reduce much of the excess seizure burden in children with HIV., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Interictal epileptiform discharges have been shown to propagate from focal epileptogenic sources as travelling waves or through more rapid white matter conduction. We hypothesize that both modes of propagation are necessary to explain interictal discharge timing delays. We propose a method that, for the first time, incorporates both propagation modes to identify unique potential sources of interictal activity. We retrospectively analysed 38 focal epilepsy patients who underwent intracranial EEG recordings and diffusion-weighted imaging for epilepsy surgery evaluation. Interictal discharges were detected and localized to the most likely source based on relative delays in time of arrival across electrodes, incorporating travelling waves and white matter propagation. We assessed the influence of white matter propagation on distance of spread, timing and clinical interpretation of interictal activity. To evaluate accuracy, we compared our source localization results to earliest spiking regions to predict seizure outcomes. White matter propagation helps to explain the timing delays observed in interictal discharge sequences, underlying rapid and distant propagation. Sources identified based on differences in time of receipt of interictal discharges are often distinct from the leading electrode location. Receipt of activity propagating rapidly via white matter can occur earlier than more local activity propagating via slower cortical travelling waves. In our cohort, our source localization approach was more accurate in predicting seizure outcomes than the leading electrode location. Inclusion of white matter in addition to travelling wave propagation in our model of discharge spread did not improve overall accuracy but allowed for identification of unique and at times distant potential sources of activity, particularly in patients with persistent postoperative seizures. Since distant white matter propagation can occur more rapidly than local travelling wave propagation, combined modes of propagation within an interictal discharge sequence can decouple the commonly assumed relationship between spike timing and distance from the source. Our findings thus highlight the clinical importance of recognizing the presence of dual modes of propagation during interictal discharges, as this may be a cause of clinical mislocalization., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)

Purpose: Non-invasive imaging studies play a critical role in the presurgical evaluation of patients with drug-resistant temporal lobe epilepsy (TLE), particularly in helping to lateralize the seizure focus. Arterial Spin Labeling (ASL) MRI has been widely used to non-invasively study cerebral blood flow (CBF), with somewhat variable interictal alterations reported in TLE. Here, we compare temporal lobe subregional interictal perfusion and symmetry in lesional (MRI+) and non-lesional (MRI-) TLE compared to healthy volunteers (HVs)., Methods: Twenty TLE patients (9 MRI+, 11 MRI-) and 14 HVs under went 3 T Pseudo-Continuous ASL MRI through an epilepsy imaging research protocol at the NIH Clinical Center. We compared normalized CBF and absolute asymmetry indices in multiple temporal lobe subregions., Results: Compared to HVs, both MRI+ and MRI- TLE groups demonstrated significant ipsilateral mesial and lateral temporal hypoperfusion, specifically in the hippocampal and anterior temporal neocortical subregions, with additional hypoperfusion in the ipsilateral parahippocampal gyrus in the MRI+ and contralateral hippocampus in the MRI- TLE groups. Contralateral to the seizure focus, there was significant relative hypoperfusion in multiple subregions in the MRI- compared to the MRI+ TLE groups. The MRI+ group therefore had significantly greater asymmetry across multiple temporal subregions compared to the MRI- TLE and HV groups. No significant differences in asymmetry were found between the MRI- TLE and HV groups., Conclusion: We found a similar extent of interictal ipsilateral temporal hypoperfusion in MRI+ and MRI- TLE. However, significantly increased asymmetries were found only in the MRI+ group due to differences in perfusion contralateral to the seizure focus between the patient groups. The lack of asymmetry in the MRI- group may negatively impact the utility of interictal ASL for seizure focus lateralization in this patient population., Competing Interests: Declarations of Competing Interest Dr. Abdennadher receives research support from the Simon Grinspoon Award and the Integrated Pilot Grant Award at Boston University for research not related to this study. The remaining authors have no conflicts of interest., (Published by Elsevier B.V.)

Objective: This study describes clinical profiles including human immunodeficiency virus (HIV) disease history and seizure etiology among children living with HIV presenting with new-onset seizure during the era of antiretroviral therapy (ART) in Zambia. 30-day mortality and cause of death are also reported., Methods: Children living with HIV (CLWHIV) with new-onset seizures were prospectively evaluated at one large urban teaching hospital and two non-urban healthcare facilities. Interviews with family members, review of medical records, and where needed, verbal autopsies were undertaken. Two clinicians who were not responsible for the patients' care independently reviewed all records and assigned seizure etiology and cause of death with adjudication as needed., Results: From April 2016 to June 2019, 73 children (49 urban, 24 rural) were identified. Median age was 6 years (IQR 2.2-10.0) and 39 (53%) were male children. Seizures were focal in 36 (49%) and were often severe, with 37% presenting with multiple recurrent seizures in the 24 hours before admission or in status epilepticus. Although 36 (49%) were on ART at enrollment, only 7 of 36 (19%) were virally suppressed. Seizure etiologies were infectious in over half (54%), with HIV encephalitis, bacterial meningitis, and tuberculous meningitis being the most common. Metabolic causes (19%) included renal failure and hypoglycemia. Structural lesions identified on imaging accounted for 10% of etiologies and included stroke and non-accidental trauma. No etiology could be identified in 12 (16%) children, most of whom died before the completion of clinical investigations. Twenty-two (30%) children died within 30 days of the index seizure., Significance: Despite widespread ART roll out in Zambia, new-onset seizure in CLWHIV occurs in the setting of advanced, active HIV disease. Seizure severity/burden is high as is early mortality. Enhanced programs to assure early ART initiation, improve adherence, and address ART failure are needed to reduce the burden of neurological injury and premature death in CLWHIV., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

We investigated the association between human herpesvirus 6 (HHV-6) and mesial temporal sclerosis (MTS) in 87 patients who had surgery for drug-resistant epilepsy. Fifty-four had MTS, 22 focal cortical dysplasia (FCD), four tumors, three vascular malformations, and three a history of encephalitis. We extracted DNA from fresh brain tissue immediately after surgery and performed viral detection with quantitative real-time polymerase chain reaction (PCR) or digital droplet PCR specific for HHV-6A and HHV-6B. Tissue was studied with standard clinical techniques, including hematoxylin and eosin, glial fibrillary acidic protein, and NeuN stains. Twenty-nine of 54 patients with MTS, six of 23 with focal cortical dysplasia (FCD), and one of three with a history of encephalitis were positive for HHV-6 (P < .02). Febrile seizure history was not associated with HHV-6 detection. Patients with MTS had significantly lower seizure onset age than those with other pathologies. Thirteen patients had positron emission tomography with [11C]PBR28, a marker for reactive astrocytes and activated microglia; there was a trend for HHV-6-positive patients to have higher binding in their seizure foci, suggesting inflammation. Our study supports a potential role for HHV-6 in the etiology of MTS., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background and Objectives: To explore efficacy/safety of natalizumab, a humanized monoclonal anti-α4-integrin antibody, as adjunctive therapy in adults with drug-resistant focal epilepsy., Methods: Participants with ≥6 seizures during the 6-week baseline period were randomized 1:1 to receive natalizumab 300 mg IV or placebo every 4 weeks for 24 weeks. Primary efficacy outcome was change from baseline in log-transformed seizure frequency, with a predefined threshold for therapeutic success of 31% relative reduction in seizure frequency over the placebo group. Countable seizure types were focal aware with motor signs, focal impaired awareness, and focal to bilateral tonic-clonic. Secondary efficacy endpoints/safety were also assessed., Results: Of 32 and 34 participants dosed in the natalizumab 300 mg and placebo groups, 30 (94%) and 31 (91%) completed the placebo-controlled treatment period, respectively (one participant was randomized to receive natalizumab but not dosed due to IV complications). Estimated relative change in seizure frequency of natalizumab over placebo was -14.4% (95% confidence interval [CI] -46.1%-36.1%; p = 0.51). The proportion of participants with ≥50% reduction from baseline in seizure frequency was 31.3% for natalizumab and 17.6% for placebo (odds ratio 2.09, 95% CI 0.64-6.85; p = 0.22). Adverse events were reported in 24 (75%) and 22 (65%) participants receiving natalizumab vs placebo., Discussion: Although the threshold to demonstrate efficacy was not met, there were no unexpected safety findings and further exploration of possible anti-inflammatory therapies for drug-resistant epilepsy is warranted., Trial Registration Information: The ClinicalTrials.gov registration number is NCT03283371., Classification of Evidence: This study provides Class I evidence that IV natalizumab every 4 weeks, compared to placebo, did not significantly change seizure frequency in adults with drug-resistant epilepsy. The study lacked the precision to exclude an important effect of natalizumab., (© 2021 American Academy of Neurology.)

We examined safety, tolerability, and efficacy of SGS-742, a γ-aminobutyric acid B (GABA-B) receptor antagonist, in patients with succinic semialdehyde dehydrogenase deficiency. This was a single-center randomized, double-blind crossover phase II clinical trial of SGS-742 versus placebo in patients with succinic semialdehyde dehydrogenase deficiency. Procedures included transcranial magnetic stimulation and the Adaptive Behavior Assessment Scale. Nineteen subjects were consented and enrolled; the mean age was 14.0 ± 7.5 years and 11 (58%) were female. We did not find a significant effect of SGS-742 on the Adaptive Behavior Assessment Scale score, motor threshold, and paired-pulse stimulation. The difference in recruitment curve slopes between treatment groups was 0.003 ( P = .09). There was no significant difference in incidence of adverse effects between drug and placebo arms. SGS-742 failed to produce improved cognition and normalization of cortical excitability as measured by the Adaptive Behavior Assessment Scale and transcranial magnetic stimulation. Our data do not support the current use of SGS-742 in succinic semialdehyde dehydrogenase deficiency.Trial registry number NCT02019667. Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency. https://clinicaltrials.gov/ct2/show/NCT02019667.

Purpose: Inflammation plays a crucial role in epileptogenesis. We analyzed inflammatory cytokines in plasma and saliva from children with seizures and healthy controls and measured their associations with HHV6 and EBV infection., Methods: We analyzed plasma from 36 children within 24 h of seizures (cases) and 43 healthy controls and saliva from 44 cases and 44 controls with a multiplex immunoassay. Saliva from all controls and 65 cases and blood from 26 controls and 35 cases were also analyzed by PCR for viral DNA. Primary outcome was cytokine levels in cases vs. controls. Secondary outcomes included detection of HHV-6 and EBV viral DNA in cases vs. controls and viral loads in cases vs. controls. Statistical analysis included the Wilcoxon Rank Sum test, Fisher's exact test, ANOVA, and Spearman correlation., Results: Compared to controls, patients had higher levels of CCL11 (p = 0.0018), CCL26 (p<0.001), IL10 (p = 0.044), IL6 (p<0.001), IL8 (p = 0.018), and MIP1β (p = 0.0012). CCL11 was higher with 3 or more seizures (p = 0.01), seizures longer than 10 min (p = 0.001), and when EEG showed focal slowing (p = 0.02). In saliva, febrile seizures had higher levels of IL-1β (n = 7, p = 0.04) and new onset seizures had higher IL-6 (n = 15, p = 0.02). Plasma and saliva cytokine levels did not show a correlation. The frequency of HHV-6 and EBV detection was similar across groups and not different than controls. We found no correlation between viral load and cytokine levels., Conclusions: We showed differential activation of neuroinflammatory pathways in plasma from different seizure etiologies compared to controls, unrelated to viral infection., (Copyright © 2021 British Epilepsy Association. All rights reserved.)

Onset of many forms of epilepsy occurs after an initial epileptogenic insult or as a result of an identified genetic defect. Given that the precipitating insult is known, these epilepsies are, in principle, amenable to secondary prevention. However, development of preventive treatments is difficult because only a subset of individuals will develop epilepsy and we cannot currently predict which individuals are at the highest risk. Biomarkers that enable identification of these individuals would facilitate clinical trials of potential anti-epileptogenic treatments, but no such prognostic biomarkers currently exist. Several putative molecular, imaging, electroencephalographic and behavioural biomarkers of epileptogenesis have been identified, but clinical translation has been hampered by fragmented and poorly coordinated efforts, issues with inter-model reproducibility, study design and statistical approaches, and difficulties with validation in patients. These challenges demand a strategic roadmap to facilitate the identification, characterization and clinical validation of biomarkers for epileptogenesis. In this Review, we summarize the state of the art with respect to biomarker research in epileptogenesis and propose a five-phase roadmap, adapted from those developed for cancer and Alzheimer disease, that provides a conceptual structure for biomarker research.

Despite extensive scholarship, several questions on the view of seizures and epilepsy in the Hippocratic collection have not been answered. The book 'On the Sacred Disease' contains descriptions of focal and generalized tonic-clonic seizures, understands the stigma attached to epilepsy, its association with depression, and probably describes auras. Remarkably, the collection presents a physiologic theory of 'mental' disease. Other parts of the collection suggest recognition of syndromes such as childhood febrile seizures. Non-motor seizures are not clearly described. There may be a distinction between 'acute symptomatic' and recurrent seizures or 'epilepsy.' Analysis of the relative occurrence of terms related to 'epilepsy' or 'spasms' in an online text collection shows a significant difference: 'epilepsy' terms are more frequent when seizures are described alone, while 'spasm' terms are more frequent in the context of systemic diseases or injuries. This dichotomy suggests, in contrast to previous accounts, possible understanding of the distinction between 'idiopathic' and 'symptomatic' seizure disorders., Competing Interests: Declaration of competing interest The author have no conflicts of interest to report., (Published by Elsevier Inc.)

Objective: Focal cortical dysplasias (FCDs) are a common cause of apparently non-lesional drug-resistant focal epilepsy. Visual detection of subtle FCDs on MRI is clinically important and often challenging. In this study, we implement a set of 3D local image filters adapted from computer vision applications to characterize the appearance of normal cortex surrounding the gray-white junction. We create a normative model to serve as the basis for a novel multivariate constrained outlier approach to automated FCD detection., Methods: Standardized MPRAGE, T 2 and FLAIR MR images were obtained in 15 patients with radiologically or histologically diagnosed FCDs and 30 healthy volunteers. Multiscale 3D local image filters were computed for each MR contrast then sampled onto the gray-white junction surface. Using an iterative Gaussianization procedure, we created a normative model of cortical variability in healthy volunteers, allowing for identification of outlier regions and estimates of similarity in normal cortex and FCD lesions. We used a constrained outlier approach following local normalization to automatically detect FCD lesions based on projection onto the mean FCD feature vector., Results: FCDs as well as some normal cortical regions such as primary sensorimotor and paralimbic regions appear as outliers. Regions such as the paralimbic regions and the anterior insula have similar features to FCDs. Our constrained outlier approach allows for automated FCD detection with 80% sensitivity and 70% specificity., Significance: A normative model using multiscale local image filters can be used to describe the normal cortical variability. Although FCDs appear similar to some cortical regions such as the anterior insula and paralimbic cortices, they can be identified using a constrained outlier detection approach. Our method for detecting outliers and estimating similarity is generic and could be extended to identification of other types of lesions or atypical cortical areas., (Published by Elsevier Inc.)

Objective: Interactions between enzyme-inducing anti-seizure medications (EI-ASMs) and antiretroviral drugs (ARVs) can lead to decreased ARV levels and may increase the likelihood of viral resistance. We conducted a study to determine if co-usage of ARVs and EI-ASMs is associated with ARV-resistant human immunodeficiency virus (HIV) among people living with HIV in Zambia., Methods: Eligible participants were ≥18 years of age and concurrently taking ASMs and ARVs for at least 1 month of the prior 6-month period. Data were obtained regarding medication and HIV history. CD4 counts, plasma viral loads (pVLs), and HIV genotype and resistance profile in participants with a pVL >1000 copies/mL were obtained. Pearson's test of independence was used to determine whether treatment with EI-ASM was associated with pVL >1000/mL copies., Results: Of 50 participants, 41 (82%) were taking carbamazepine (37 on monotherapy), and all had stable regimens in the prior 6 months. Among the 13 ARV regimens used, 68% had a tenofovir/lamivudine backbone. The majority (94%) were on a stable ARV regimen for >6 months. Median CD4 nadir was 205 cells/mm 3 (interquartile range [IQR] 88-389), and 60% of participants had commenced ARV treatment before advanced disease occurred. Mean CD4 count at enrollment was 464 cells/mm 3 (SD 226.3). Seven participants (14%) had a CD4 count <200 cells/mm 3 . Four (8%) had a pVL >1000 copies/mL; all were on carbamazepine. Three participants with elevated pVL had a CD4 count <200 cells/mm 3 . None had documented adherence concerns by providers; however, two had events concerning for clinical failure. HIV genotype testing showed mutations in three participants. Carbamazepine was not found to correlate with elevated pVL (P = .58)., Significance: EI-ASMs are commonly used in sub-Saharan Africa. Despite concurrent use of EI-ASMs and ARVs, the majority of participants showed CD4 counts >200 cells/mm 3 and were virally suppressed. Carbamazepine was not associated with an increased risk of virological failure or ARV-resistant HIV., (© 2020 International League Against Epilepsy.)

Objective: To study the effects of human herpes virus 6 (HHV-6) on the hippocampal volume in patients with mesial temporal sclerosis (MTS)., Background: HHV-6 may play an etiologic role in MTS. Previous studies found a possible association with febrile status epilepticus. Several investigators have reported a higher prevalence of HHV-6 in MTS resections compared to other epilepsy etiologies., Design/methods: We used FreeSurfer to segment cortical structures and obtain whole hippocampal and subfield volumes in 41 patients with intractable epilepsy. In addition, an investigator blinded to other data traced hippocampi manually on each slice. The main study outcome measure was the asymmetry index (AI) between hippocampal volumes ipsilateral and contralateral to seizure foci compared between HHV-6 positive and negative patients. Viral DNA was isolated from fresh brain tissue obtained at temporal lobectomy. For 25 patients, viral detection was performed using quantitative real-time PCR specific for HHV-6A and HHV-6B. For 16 patients, viral DNA detection was performed using digital droplet PCR specific for HHV-6A and HHV-6B., Results: Twenty-two patients were positive (14 of 25 tested with real-time PCR, and 8 of 16 with digital droplet PCR), and 19 negatives for HHV-6. HHV-6 negative patients had significantly greater AI and lower total hippocampal volume ipsilateral to seizure foci than HHV-6 positive patients. Epilepsy duration and age of onset did not affect results., Interpretation: Our data suggest multiple potential etiologies for MTS. HHV-6 may have a less severe effect on the hippocampus than other etiologies., (Published 2020. This article is a U.S Government work and is in the public domain in the USA. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

We compared resting state (RS) functional connectivity and task-based fMRI to lateralize language dominance in 30 epilepsy patients (mean age = 33; SD = 11; 12 female), a measure used for presurgical planning. Language laterality index (LI) was calculated from task fMRI in frontal, temporal, and frontal + temporal regional masks using LI bootstrap method from SPM12. RS language LI was assessed using two novel methods of calculating RS language LI from bilateral Broca's area seed based connectivity maps across regional masks and multiple thresholds (p < .05, p < .01, p < .001, top 10% connections). We compared LI from task and RS fMRI continuous values and dominance classifications. We found significant positive correlations between task LI and RS LI when functional connectivity thresholds were set to the top 10% of connections. Concordance of dominance classifications ranged from 20% to 30% for the intrahemispheric resting state LI method and 50% to 63% for the resting state LI intra- minus interhemispheric difference method. Approximately 40% of patients left dominant on task showed RS bilateral dominance. There was no difference in LI concordance between patients with right-sided and left-sided resections. Early seizure onset (<6 years old) was not associated with atypical language dominance during task-based or RS fMRI. While a relationship between task LI and RS LI exists in patients with epilepsy, language dominance is less lateralized on RS than task fMRI. Concordance of language dominance classifications between task and resting state fMRI depends on brain regions surveyed and RS LI calculation method., (Published [2020]. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: Seizure clusters are often encountered in people with poorly controlled epilepsy. Detection of seizure clusters is currently based on simple clinical rules, such as two seizures separated by four or fewer hours or multiple seizures in 24 h. Current definitions fail to distinguish between statistically significant clusters and those that may result from natural variation in the person's seizures. Ability to systematically define when a seizure cluster is significant for the individual carries major implications for treatment. However, there is no uniform consensus on how to define seizure clusters. This study proposes a principled statistical approach to defining seizure clusters that addresses these issues., Methods: A total of 533,968 clinical seizures from 1,748 people with epilepsy in the Seizure Tracker™ seizure diary database were used for algorithm development. We propose an algorithm for automated individualized seizure cluster identification combining cumulative sum change-point analysis with bootstrapping and aberration detection, which provides a new approach to personalized seizure cluster identification at user-specified levels of clinical significance. We develop a standalone user interface to make the proposed algorithm accessible for real-time seizure cluster identification (ClusterCalc™). Clinical impact of systematizing cluster identification is demonstrated by comparing empirically-defined clusters to those identified by routine seizure cluster definitions. We also demonstrate use of the Hurst exponent as a standardized measure of seizure clustering for comparison of seizure clustering burden within or across patients., Results: Seizure clustering was present in 26.7 % (95 % CI, 24.5-28.7 %) of people with epilepsy. Empirical tables were provided for standardizing inter- and intra-patient comparisons of seizure cluster tendency. Using the proposed algorithm, we found that 37.7-59.4 % of seizures identified as clusters based on routine definitions had high probability of occurring by chance. Several clusters identified by the algorithm were missed by conventional definitions. The utility of the ClusterCalc algorithm for individualized seizure cluster detection is demonstrated., Significance: This study proposes a principled statistical approach to individualized seizure cluster identification and demonstrates potential for real-time clinical usage through ClusterCalc. Using this approach accounts for individual variations in baseline seizure frequency and evaluates statistical significance. This new definition has the potential to improve individualized epilepsy treatment by systematizing identification of unrecognized seizure clusters and preventing unnecessary intervention for random events previously considered clusters., Competing Interests: Declaration of Competing Interest SC is the founder of EpilepsyAI, LLC. RM is the cofounder and owner of Seizure Tracker, LLC, cofounder of EpilepsyAI, LLC, and has received personal fees from Cyberonics, Courtagen, Engage Therapeutics, Brain Sentinel, Neurelis, UCB, and grants from the Tuberous Sclerosis Alliance. DG is on the medical advisory board of Magic Leap, and has received grant support from BIDMC and NIH T32NS048005. SH is on the Editorial Board of Epilepsy and Behavior. A patent application has been filed based on these results. The remaining authors have no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: We conducted clinical testing of an automated Bayesian machine learning algorithm (Epilepsy Seizure Assessment Tool [EpiSAT]) for outpatient seizure risk assessment using seizure counting data, and validated performance against specialized epilepsy clinician experts., Methods: We conducted a prospective longitudinal study of EpiSAT performance against 24 specialized clinician experts at three tertiary referral epilepsy centers in the United States. Accuracy, interrater reliability, and intra-rater reliability of EpiSAT for correctly identifying changes in seizure risk (improvements, worsening, or no change) were evaluated using 120 seizures from four synthetic seizure diaries (seizure risk known) and 120 seizures from four real seizure diaries (seizure risk unknown). The proportion of observed agreement between EpiSAT and clinicians was evaluated to assess compatibility of EpiSAT with clinical decision patterns by epilepsy experts., Results: EpiSAT exhibited substantial observed agreement (75.4%) with clinicians for assessing seizure risk. The mean accuracy of epilepsy providers for correctly assessing seizure risk was 74.7%. EpiSAT accurately identified seizure risk in 87.5% of seizure diary entries, corresponding to a significant improvement of 17.4% (P = .002). Clinicians exhibited low-to-moderate interrater reliability for seizure risk assessment (Krippendorff's α = 0.46) with good intrarater reliability across a 4- to 12-week evaluation period (Scott's π = 0.89)., Significance: These results validate the ability of EpiSAT to yield objective clinical recommendations on seizure risk which follow decision patterns similar to those from specialized epilepsy providers, but with improved accuracy and reproducibility. This algorithm may serve as a useful clinical decision support system for quantitative analysis of clinical seizure frequency in clinical epilepsy practice., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)