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Despite improved ancillary investigations in epilepsy care, patients' narratives remain indispensable for diagnosing and treatment monitoring. This wealth of information is typically stored in electronic health records and accumulated in medical journals in an unstructured manner, thereby restricting complete utilization in clinical decision-making. To this end, clinical researchers increasing apply natural language processing (NLP) - a branch of artificial intelligence - as it removes ambiguity, derives context and imbues standardized meaning from free-narrative clinical texts. This systematic review presents an overview of the current NLP applications in epilepsy and discusses the opportunities and drawbacks of NLP alongside its future implications. We searched the PubMed and Embase databases with a "natural language processing" and "epilepsy" query (March 4

This cross-sectional study evaluates the existence and timing of trial registration for randomized clinical trials (RCTs) published from 2002 to 2017 as well as substantive changes to the primary outcomes entered into registry information after those studies started.

Abnormalities of the brain network organization in focal epilepsy have been extensively quantified. However, the extent and directionality of abnormalities are highly variable and subtype insensitive. We conducted meta-analyses to obtain a more accurate and epilepsy type-specific quantification of the interictal global brain network organization in focal epilepsy. By using random-effects models, we estimated differences in average clustering coefficient, average path length, and modularity between patients with focal epilepsy and controls, based on 45 studies with a total sample size of 1,468 patients and 1,021 controls. Structural networks had a significant lower level of integration in patients with epilepsy as compared to controls, with a standardized mean difference of -0.334 (95 % confidence interval -0.631 to -0.038; p-value 0.027). Functional networks did not differ between patients and controls, except for the beta band clustering coefficient. Our meta-analyses show that differences in the brain network organization are not as well defined as individual studies often propose. We discuss potential pitfalls and suggestions to enhance the yield and clinical value of network studies.

BackgroundDespite improvements in acute stroke therapies and rehabilitation strategies, many stroke patients are left with long-term upper limb motor impairment. We assessed whether an inhibitory repetitive transcranial magnetic stimulation (rTMS) treatment paradigm started within three weeks after stroke onset promotes upper limb motor recovery.MethodsPatients with ischemic stroke or intracerebral hemorrhage and unilateral upper limb motor impairment admitted to a single rehabilitation center were randomized to ten daily sessions of active or sham continuous theta burst stimulation (cTBS) of the contralesional primary motor cortex (M1) combined with standard upper limb therapy, started within three weeks after stroke onset. The primary outcome was the change in the Action Research Arm Test (ARAT) score from baseline (pre-treatment) at three months after stroke. Secondary outcomes included the score on the modified Rankin Scale (mRS) at three months and the length of stay (LOS) at the rehabilitation center. Statistical analyses were performed using mixed models for repeated measures.ResultsWe enrolled 60 patients between April, 2017 and February, 2021, of whom 29 were randomized to active cTBS and 31 to sham cTBS. One patient randomized to active cTBS withdrew consent before the intervention and was excluded from the analyses. The mean difference in the change in ARAT score from baseline at three months post-stroke was 9.6 points (95%CI 1.2-17.9; p 0.0244) in favor of active cTBS. Active cTBS was associated with better scores on the mRS at three months (OR 0.2; 95%CI 0.1-0.8; p 0.0225) and with an 18 days shorter length of stay at the rehabilitation center than sham cTBS (95%CI 0.0-36.4; p 0.0494). There were no serious adverse events.ConclusionsTen daily sessions of cTBS of the contralesional M1 combined with upper limb training, started within three weeks after stroke onset, promote recovery of the upper limb, reduce disability and dependence and leads to earlier discharge from the rehabilitation center.Trial registrationThe trial was registered at the international clinical trials registry platform (https://trialsearch.who.int/) with unique identifier: NTR6133.

Background and ObjectivesTo identify predictors of postoperative intelligence and developmental quotients (IQ/DQ) and develop and validate clinically applicable IQ/DQ prediction models.MethodsWe retrospectively analyzed neuropsychological outcomes and their possible determinants for children treated in Bethel and Utrecht since 1990. We performed separate analyses for patients with IQ and those with only DQ available. We developed prediction models based on presurgical determinants to predict dichotomized levels of performance (IQ ≥85, IQ ≥70, DQ ≥50).ResultsIQ/DQ data before and 2 years after surgery were available for 492 patients (IQ n = 365, DQ n = 127). At a cutoff level ±10 points, the chance of improvement was considerably higher than the chance of deterioration (IQ 37.3% vs 6.6% and DQ 31.5% vs 15.0%, respectively). Presurgical IQ/DQ was the strongest predictor of postoperative cognition (IQ r = 0.85, p r = 0.57, p DiscussionAfter epilepsy surgery in children, the risk of cognitive deterioration is very low. Presurgical development has a strong effect on the postoperative trajectory. The presented models can improve presurgical counseling of patients and parents by reliably predicting cognitive outcomes.Classification of EvidenceThis study provides Class II evidence that for children undergoing epilepsy surgery presurgical IQ/DQ was the strongest predictor of postoperative cognition.

BackgroundChoosing candidates for antiseizure medication (ASM) withdrawal in well- controlled epilepsy is challenging. We evaluated 1) the correlation between neurologists’ seizure risk estimation (“clinician predictions”) versus calculated predictions, 2) how viewing calculated predictions influenced recommendations, and 3) barriers to using risk calculation.MethodsWe asked neurologists to predict two-year seizure risk after ASM withdrawal for hypothetical vignettes. We compared withdrawal recommendations ASMs before versus after viewing calculated predictions using generalized linear models.ResultsThree-hundred forty-six responded. There was moderate correlation between clinician and calculated predictions (Spearman coefficient 0.42). Clinician predictions varied widely, e.g., predictions ranged 5%-100% for a two-year seizure-free adult without epileptiform abnormalities. Mean clinician predictions exceeded calculated predictions for vignettes with epileptiform abnormalities (e.g., childhood absence epilepsy: clinician 65%, 95% confidence interval [CI] 57%-74%; calculated 46%) and surgical vignettes (e.g., focal cortical dysplasia six-months seizure-free mean clinician 56%, 95% CI 52%-60%; calculated 28%). Clinicians overestimated the influence of epileptiform EEG findings on withdrawal risk (26%, 95% CI 24%-28%) compared with calculators (14%, 95% 13%-14%). Viewing calculated predictions slightly reduced willingness to withdraw (−0.8/10 change, 95% CI -1.0 to -0.7), particularly without epileptiform abnormalities. The greatest barrier to calculator use was doubting its accuracy (44%).ConclusionsClinicians overestimated the influence of abnormal EEGs particularly for low-risk patients and overestimated risk and the influence of seizure-free duration for surgical patients, compared with calculators. These data may question widespread ordering of EEGs or time-based seizure-free thresholds for surgical patients. Viewing calculated predictions reduced willingness to withdraw particularly without epileptiform abnormalities.What is already known on this topicFor the two-thirds of patients with epilepsy who become seizure-free on antiseizure medications (ASMs), a key question is whether ASMs are necessary indefinitely after attaining seizure-freedom. An individualized post-withdrawal seizure risk calculator exists,[1,2] which has demonstrated moderate external validity, and one 1993 study suggested that viewing results from an older version of such a calculator slightly reduced patients’ willingness to withdraw.What this study addsBefore our study, it was unknown how closely clinicians’ intuitive estimates of post-withdrawal seizure risk (“clinician predictions”) align with model (“calculated”) predictions, and no study had previously evaluated the influence of viewing calculated risk on clinician recommendations. We found 1) moderate correlation between clinician and calculated predictions (Spearman coefficient 0.42), 2) clinician predictions and recommendations varied widely, 3) clinicians tended to overestimate risk compared with calculators for vignettes with epileptiform abnormalities and surgical cases, 4) viewing calculated predictions slightly reduced willingness to withdraw particularly without epileptiform abnormalities, and 5) the greatest endorsed barrier to calculator use was doubting its accuracy.How this study might affect research, practice or policyOur study suggests patient scenarios in which viewing calculator results may be most useful or be most likely to change clinical practice. These data may also question widespread ordering of EEGs or time-based seizure-free thresholds for surgical patients given calculated risk differences were smaller than clinician predictions. We also provide preliminary data guiding future work to improve calculator implementation such as targeting educational efforts to improve knowledge of its development, improving its accuracy, and integrating it into the electronic medical record.

Background. Recovery of motor function after stroke appears to be related to the integrity of axonal connections in the corticospinal tract (CST) and corpus callosum, which may both be affected after cortical stroke. Objective. In the present study, we aimed to elucidate the relationship of changes in measures of the CST and transcallosal tract integrity, with the interhemispheric functional connectivity and sensorimotor performance after experimental cortical stroke. Methods. We conducted in vivo diffusion magnetic resonance imaging (MRI), resting-state functional MRI, and behavior testing in twenty-five male Sprague Dawley rats recovering from unilateral photothrombotic stroke in the sensorimotor cortex. Twenty-three healthy rats served as controls. Results. A reduction in the number of reconstructed fibers, a lower fractional anisotropy, and higher radial diffusivity in the ipsilesional but intact CST, reflected remote white matter degeneration. In contrast, transcallosal tract integrity remained preserved. Functional connectivity between the ipsi- and contralesional forelimb regions of the primary somatosensory cortex significantly reduced at week 8 post-stroke. Comparably, usage of the stroke-affected forelimb was normal at week 28, following significant initial impairment between day 1 and week 8 post-stroke. Conclusions. Our study shows that post-stroke motor recovery is possible despite degeneration in the CST and may be supported by intact neuronal communication between hemispheres.

BackgroundWe determined the prevalence, incidence, and risk factors for epilepsy in Nigeria.MethodsWe conducted a door-to-door survey to identify cases of epilepsy in 3 regions. We estimated age-standardized prevalence adjusted for nonresponse and sensitivity and the 1-year retrospective incidence for active epilepsy. To assess potential risk factors, we conducted a case-control study by collecting sociodemographic and risk factor data. We estimated odds ratios using logistic regression analysis and corresponding population attributable fractions (PAFs).ResultsWe screened 42,427 persons (age ≥6 years), of whom 254 had confirmed active epilepsy. The pooled prevalence of active epilepsy per 1,000 was 9.8 (95% confidence interval [CI] 8.6–11.1), 17.7 (14.2–20.6) in Gwandu, 4.8 (3.4–6.6) in Afikpo, and 3.3 (2.0–5.1) in Ijebu-Jesa. The pooled incidence per 100,000 was 101.3 (95% CI 57.9–167.6), 201.2 (105.0–358.9) in Gwandu, 27.6 (3.3–128.0) in Afikpo, and 23.9 (3.2–157.0) in Ijebu-Jesa. Children's significant risk factors included febrile seizures, meningitis, poor perinatal care, open defecation, measles, and family history in first-degree relatives. In adults, head injury, poor perinatal care, febrile seizures, family history in second-degree relatives, and consanguinity were significant. Gwandu had more significant risk factors. The PAF for the important factors in children was 74.0% (71.0%–76.0%) and in adults was 79.0% (75.0%–81.0%).ConclusionThis work suggests varied epidemiologic numbers, which may be explained by differences in risk factors and population structure in the different regions. These variations should differentially determine and drive prevention and health care responses.

Antiseizure medication may have long-term effects on the neurodevelopment of children. We aimed to investigate the association between cumulative antiseizure medication load and intelligence quotient (IQ) in relation to brain volume and cortical thickness.A retrospective analysis of children with focal epilepsy who underwent neuropsychological assessment and MRI between the ages of 5-12 years in a tertiary epilepsy centre was performed. Cumulative medication load was presented in medication years. We studied the association between total medication load and IQ with multivariable linear regression, corrected for epilepsy-related confounders: age at first treatment, aetiology, maximum seizure frequency, duration of active epilepsy, history of secondary generalized seizures, history of status epilepticus, and the number of antiseizure medications used at time of neuropsychological assessment.We included 59 children. Median medication load was 5.3 medication-years (interquartile range: 2.0 – 11.1) and mean total IQ (± standard deviation) was 77.4±18.9. A significant negative relation between medication load and total IQ was found with a decrease of 1.2 IQ-points per medication-year (95% confidence interval: -2.0 to -0.3) after correcting for confounders. Medication load and IQ were both not significantly associated with brain volume or cortical thickness.Higher cumulative medication load is associated with lower total IQ after adjusting for epilepsy-related confounders. We found no evidence to support the hypothesis that the medication-related IQ decrease was mediated by volumetric brain changes. However, these results should be interpreted with caution, and prospective, longitudinal confirmation of these findings is required. Lastly, it should be stressed that effective seizure prevention often outweighs the potential negative effects of antiseizure medication.

More than half of adults with epilepsy undergoing resective epilepsy surgery achieve long-term seizure freedom and might consider withdrawing antiseizure medications. We aimed to identify predictors of seizure recurrence after starting postoperative antiseizure medication withdrawal and develop and validate predictive models. We performed an international multicentre observational cohort study in nine tertiary epilepsy referral centres. We included 850 adults who started antiseizure medication withdrawal following resective epilepsy surgery and were free of seizures other than focal non-motor aware seizures before starting antiseizure medication withdrawal. We developed a model predicting recurrent seizures, other than focal non-motor aware seizures, using Cox proportional hazards regression in a derivation cohort (n = 231). Independent predictors of seizure recurrence, other than focal non-motor aware seizures, following the start of antiseizure medication withdrawal were focal non-motor aware seizures after surgery and before withdrawal [adjusted hazard ratio (aHR) 5.5, 95% confidence interval (CI) 2.7–11.1], history of focal to bilateral tonic-clonic seizures before surgery (aHR 1.6, 95% CI 0.9–2.8), time from surgery to the start of antiseizure medication withdrawal (aHR 0.9, 95% CI 0.8–0.9) and number of antiseizure medications at time of surgery (aHR 1.2, 95% CI 0.9–1.6). Model discrimination showed a concordance statistic of 0.67 (95% CI 0.63–0.71) in the external validation cohorts (n = 500). A secondary model predicting recurrence of any seizures (including focal non-motor aware seizures) was developed and validated in a subgroup that did not have focal non-motor aware seizures before withdrawal (n = 639), showing a concordance statistic of 0.68 (95% CI 0.64–0.72). Calibration plots indicated high agreement of predicted and observed outcomes for both models. We show that simple algorithms, available as graphical nomograms and online tools (predictepilepsy.github.io), can provide probabilities of seizure outcomes after starting postoperative antiseizure medication withdrawal. These multicentre-validated models may assist clinicians when discussing antiseizure medication withdrawal after surgery with their patients.

Eating disorders and obesity form a major health problem in Western Society. To be able to provide adequate treatment and prevention, it is necessary to understand the neural mechanisms underlying the development of eating disorders and obesity. Specific brain networks have been shown to be involved in feeding behavior. We therefore hypothesized that functional connectivity in neural networks involved in feeding behavior is dependent on the status of homeostatic energy balance, thus on being hungry or satiated. To test our hypothesis, we measured functional connectivity and amplitudes of neural signals within neural networks in relation to food intake and sucrose tasting in rats. Therefore, 16 male Wistar rats, of which eight were food-restricted and eight were satiated, underwent resting-state functional magnetic resonance imaging (rs-fMRI) at 9.4 T. Subsequently, half of these animals underwent a sucrose tasting procedure followed by a second rs-fMRI scan. Functional connectivity and amplitude of low-frequency signal fluctuations were statistically analyzed in a linear mixed model. Although we did not detect a significant effect of food intake on functional connectivity before sucrose tasting, there was a trend toward interaction between group (satiated vs. hungry) and treatment (sucrose tasting). Functional connectivity between feeding-related regions tended to decrease stronger upon sucrose tasting in satiated rats as compared to food-restricted rats. Furthermore, rs-fMRI signal amplitudes decreased stronger upon sucrose tasting in satiated rats, as compared to food-restricted rats. These findings indicate that food intake and sucrose tasting can affect functional network organization, which may explain the specific patterns in feeding behavior.

Task-free functional connectivity in animal models provides an experimental framework to examine connectivity phenomena under controlled conditions and allows comparison with invasive or terminal procedures. To date, animal acquisitions are performed with varying protocols and analyses that hamper result comparison and integration. We introduce StandardRat, a consensus rat functional MRI acquisition protocol tested across 20 centers. To develop this protocol with optimized acquisition and processing parameters, we initially aggregated 65 functional imaging datasets acquired in rats from 46 centers. We developed a reproducible pipeline for the analysis of rat data acquired with diverse protocols and determined experimental and processing parameters associated with a more robust functional connectivity detection. We show that the standardized protocol enhances biologically plausible functional connectivity patterns, relative to pre-existing acquisitions. The protocol and processing pipeline described here are openly shared with the neuroimaging community to promote interoperability and cooperation towards tackling the most important challenges in neuroscience.

Objective The 1991 Medical Research Council (MRC) Study compared seizure relapse for seizure-free patients randomized to withdraw vs continue of antiseizure medications (ASMs). We re-analyzed this trial to account for crossover between arms using contamination-adjusted intention to treat (CA ITT) methods, to explore dose-response curves, and to validate predictions against external data. ITT assesses the effect of being randomized to withdraw, as-treated analysis assesses the confounded effect of withdrawing, but CA ITT assesses the unconfounded effect of actually withdrawing. Methods CA ITT involves two stages. First, we used randomized arm to predict whether patients withdrew their ASM (logistic) or total daily ASM dose (linear). Second, we used those values to predict seizure occurrence (logistic). Results The trial randomized 503 patients to withdraw and 501 patients to continue ASMs. We found that 316 of 376 patients (88%) who were randomized to withdraw decreased their dose at every pre-seizure visit, compared with 35 of 424 (8%) who were randomized to continue (p < .01). Adjusted odds ratios of a 2-year seizure for those who withdrew vs those who did not was 1.3 (95% confidence interval [CI] 0.9–1.9) in the as-treated analysis, 2.5 (95% CI 1.9–3.4) comparing those randomized to withdraw vs continue for ITT, and 3.1 (95% CI 2.1–4.5) for CA ITT. Probabilities (withdrawal vs continue) were 28% vs 24% (as-treated), 40% vs 22% (ITT), and 43% vs 21% (CA ITT). Differences between ITT and CA ITT were greater when varying the predictor (reaching zero ASMs) or outcome (1-year seizures). As-treated dose-response curves demonstrated little to no effects, but larger effects in CA ITT analysis. MRC data overpredicted risk in Lossius data, with moderate discrimination (areas under the curve ~0.70). Significance CA ITT results (the effect of actually withdrawing ASMs on seizures) were slightly greater than ITT effects (the effect of recommend withdrawing ASMs on seizures). How these findings affect clinical practice must be individualized.

Obsessive-compulsive disorder (OCD) is increasingly considered to be a neurodevelopmental disorder. However, despite insights in neural substrates of OCD in adults, less is known about mechanisms underlying compulsivity during brain development in children and adolescents. Therefore, we developed an adolescent rat model of compulsive checking behavior and investigated developmental changes in structural and functional measures in the frontostriatal circuitry. Five-weeks old Sprague Dawley rats were subcutaneously injected with quinpirole (n = 21) or saline (n = 20) twice a week for five weeks. Each injection was followed by placement in the middle of an open field table, and compulsive behavior was quantified as repeated checking behavior. Anatomical, resting-state functional and diffusion MRI at 4.7T were conducted before the first and after the last quinpirole/saline injection to measure regional volumes, functional connectivity and structural integrity in the brain, respectively. After consecutive quinpirole injections, adolescent rats demonstrated clear checking behavior and repeated travelling between two open-field zones. MRI measurements revealed an increase of regional volumes within the frontostriatal circuits and an increase in fractional anisotropy (FA) in white matter areas during maturation in both experimental groups. Quinpirole-injected rats showed a larger developmental increase in FA values in the internal capsule and forceps minor compared to control rats. Our study points toward a link between development of compulsive behavior and altered white matter maturation in quinpirole-injected adolescent rats, in line with observations in pediatric patients with compulsive phenotypes. This novel animal model provides opportunities to investigate novel treatments and underlying mechanisms for patients with early-onset OCD specifically.

MRI and intraoperative electrocorticography are often used in tandem to delineate epileptogenic tissue in resective surgery for focal epilepsy. Both the resection of the MRI lesion and tissue with high rates of electrographic discharges on electrocorticography, e.g. spikes and high-frequency oscillations (80–500 Hz), lead to a better surgical outcome. How MRI and electrographic markers are related, however, is currently unknown. The aim of this study was to find the spatial relationship between MRI lesions and spikes/high-frequency oscillations. We retrospectively included 33 paediatric and adult patients with lesional neocortical epilepsy who underwent electrocorticography-tailored surgery (14 females, median age = 13.4 years, range = 0.6–47.0 years). Mesiotemporal lesions were excluded. We used univariable linear regression to find correlations between pre-resection spike/high-frequency oscillation rates on an electrode and its distance to the MRI lesion. We tested straight lines to the centre and the edge of the MRI lesion, and the distance along the cortical surface to determine which of these distances best reflects the occurrence of spikes/high-frequency oscillations. We conducted a moderator analysis to investigate the influence of the underlying pathology type and lesion volume on our results. We found spike and high-frequency oscillation rates to be spatially linked to the edge of the MRI lesion. The underlying pathology type influenced the spatial relationship between spike/high-frequency oscillation rates and the MRI lesion (Pspikes < 0.0001, Pripples < 0.0001), while the lesion volume did not (Pspikes = 0.64, Pripples = 0.89). A higher spike rate was associated with a shorter distance to the edge of the lesion for cavernomas [F(1,64) = −1.37, P < 0.0001, η2 = 0.22], focal cortical dysplasias [F(1,570) = −0.25, P < 0.0001, η2 = 0.05] and pleomorphic xanthoastrocytomas [F(1,66) = −0.18, P = 0.01, η2 = 0.09]. In focal cortical dysplasias, a higher ripple rate was associated with a shorter distance [F(1,570) = −0.35, P < 0.0001, η2 = 0.05]. Conversely, low-grade gliomas showed a positive correlation; the further an electrode was away from the lesion, the higher the rate of spikes [F(1,75) = 0.65, P < 0.0001, η2 = 0.37] and ripples [F(1,75) = 2.67, P < 0.0001, η2 = 0.22]. Pathophysiological processes specific to certain pathology types determine the spatial relationship between the MRI lesion and electrocorticography results. In our analyses, non-tumourous lesions (focal cortical dysplasias and cavernomas) seemed to intrinsically generate spikes and high-frequency oscillations, particularly at the border of the lesion. This advocates for a resection of this tissue. Low-grade gliomas caused epileptogenicity in the peritumoural tissue. Whether a resection of this tissue leads to a better outcome is unclear. Our results suggest that the underlying pathology type should be considered when intraoperative electrocorticography is interpreted.

Background: It remains unclear whether revascularization of moyamoya vasculopathy (MMV) has a positive effect on cognitive function. In this prospective, single-center study, we investigated the effect of revascularization on cognitive function in patients with MMV. We report clinical and radiological outcome parameters and the associations between clinical determinants and change in neurocognitive functioning. Methods: We consecutively included all MMV patients at a Dutch tertiary referral hospital who underwent pre- and postoperative standardized neuropsychological evaluation, [15O]H2O-PET (including cerebrovascular reactivity (CVR)), MRI, cerebral angiography, and completed standardized questionnaires on clinical outcome and quality of life (QOL). To explore the association between patient characteristics, imaging findings, and change in the z-scores of the cognitive domains, we used multivariable linear- and Bayesian regression analysis. Results: We included 40 patients of whom 35 (27 females, 21 children) were treated surgically. One patient died after surgery, and two withdrew from the study. TIA- and headache frequency and modified Rankin scale (mRS) improved (resp. p = 0.001, 0.019, 0.039). Eleven patients (seven children) developed a new infarct during follow-up (31%), five of which were symptomatic. CVR-scores improved significantly (p < 0.0005). The language domain improved (p = 0.029); other domains remained stable. In adults, there was an improvement in QOL. We could not find an association between change in imaging and cognitive scores. Conclusion: In this cohort of Western MMV patients, TIA frequency, headache, CVR, and mRS improved significantly after revascularization. The language domain significantly improved, while others remained stable. We could not find an association between changes in CVR and cognitive scores.

Background: A third of people with juvenile myoclonic epilepsy (JME) are drug-resistant. Three-quarters have a seizure relapse when attempting to withdraw anti-seizure medication (ASM) after achieving seizure-freedom. It is currently impossible to predict who is likely to become drug-resistant and safely withdraw treatment. We aimed to identify predictors of drug resistance and seizure recurrence to allow for individualised prediction of treatment outcomes in people with JME. Methods: We performed an individual participant data (IPD) meta-analysis based on a systematic search in EMBASE and PubMed – last updated on March 11, 2021 – including prospective and retrospective observational studies reporting on treatment outcomes of people diagnosed with JME and available seizure outcome data after a minimum one-year follow-up. We invited authors to share standardised IPD to identify predictors of drug resistance using multivariable logistic regression. We excluded pseudo-resistant individuals. A subset who attempted to withdraw ASM was included in a multivariable proportional hazards analysis on seizure recurrence after ASM withdrawal. The study was registered at the Open Science Framework (OSF; https://osf.io/b9zjc/). Findings: Our search yielded 1641 articles; 53 were eligible, of which the authors of 24 studies agreed to collaborate by sharing IPD. Using data from 2518 people with JME, we found nine independent predictors of drug resistance: three seizure types, psychiatric comorbidities, catamenial epilepsy, epileptiform focality, ethnicity, history of CAE, family history of epilepsy, status epilepticus, and febrile seizures. Internal-external cross-validation of our multivariable model showed an area under the receiver operating characteristic curve of 0·70 (95%CI 0·68–0·72). Recurrence of seizures after ASM withdrawal (n = 368) was predicted by an earlier age at the start of withdrawal, shorter seizure-free interval and more currently used ASMs, resulting in an average internal-external cross-validation concordance-statistic of 0·70 (95%CI 0·68–0·73). Interpretation: We were able to predict and validate clinically relevant personalised treatment outcomes for people with JME. Individualised predictions are accessible as nomograms and web-based tools. Funding: MING fonds.

Background and ObjectivesTo describe neurologist practice patterns, challenges, and decision support needs pertaining to withdrawal of antiseizure medications (ASMs) in patients with well-controlled epilepsy.MethodsWe sent an electronic survey to (1) US and (2) European physician members of the American Academy of Neurology and (3) members of EpiCARE, a European Reference Network for rare and complex epilepsies. Analyses included frequencies and percentages, and we showed distributions through histograms and violin plots.ResultsWe sent the survey to 4,923 individuals; 463 consented, 411 passed eligibility questions, and 287 responded to at least 1 of these questions. Most respondents indicated that they might ever consider ASM withdrawal, with respondents treating mostly children being more likely ever to consider withdrawal (e.g., medical monotherapy: children 96% vs adults 81%;p< 0.05). The most important factors when making decisions included seizure probability (83%), consequences of seizures (73%), and driving (74%). The top challenges when making decisions included unclear seizure probability (81%), inadequate guidelines (50%), and difficulty communicating probabilities (45%). Respondents would consider withdrawal after a median of 2-year seizure freedom, but also responded that they would begin withdrawal on average only when the postwithdrawal seizure relapse risk in the coming 2 years was less than 15%–30%. Wide variation existed in the use of words or numbers in respondents' counsel methods, for example, percentages vs frequencies or probability of seizure freedom vs seizure. The most highly rated point-of-care methods to inform providers of calculated risk were Kaplan-Meier curves and showing percentages only, rather than pictographs or text recommendations alone.DiscussionMost surveyed neurologists would consider withdrawing ASMs in seizure-free individuals. Seizure probability was the largest factor driving decisions, yet estimating seizure probabilities was the greatest challenge. Respondents on average indicated that they may withdraw ASM after a minimum seizure-free duration of 2 years, yet also on average were willing to withdraw when seizure risk decreased below 15%–30%, which is lower than most patients' postwithdrawal risk at 2-year seizure freedom and lower than the equivalent even of a first seizure of life. These findings will inform future efforts at developing decision support tools aimed at optimizing ASM withdrawal decisions.

We outline a Bayesian model-averaged (BMA) meta-analysis for standardized mean differences in order to quantify evidence for both treatment effectiveness δ and across-study heterogeneity 𝜏. We construct four competing models by orthogonally combining two present-absent assumptions, one for the treatment effect and one for across-study heterogeneity. To inform the choice of prior distributions for the model parameters, we used 50% of the Cochrane Database of Systematic Reviews to specify rival prior distributions for δ and 𝜏. The relative predictive performance of the competing models and rival prior distributions was assessed using the remaining 50% of the Cochrane Database. On average, ℋ 𝑟1—the model that assumes the presence of a treatment effect as well as across-study heterogeneity—outpredicted the other models, but not by a large margin. Within ℋ 𝑟1, predictive adequacy was relatively constant across the rival prior distributions. We propose specific empirical prior distributions, both for the field in general and for each of 46 specific medical subdisciplines. An example from oral health demonstrates how the proposed prior distributions can be used to conduct a BMA meta-analysis in the open-source software R and JASP. The preregistered analysis plan is available at https://osf.io/zs3df/.

Intraoperative electrocorticography is used to tailor epilepsy surgery by analysing interictal spikes or spike patterns that can delineate epileptogenic tissue. High-frequency oscillations (HFOs) on intraoperative electrocorticography have been proposed as a new biomarker of epileptogenic tissue, with higher specificity than spikes. We prospectively tested the non-inferiority of HFO-guided tailoring of epilepsy surgery to spike-guided tailoring on seizure freedom at 1 year.The HFO trial was a randomised, single-blind, adaptive non-inferiority trial at an epilepsy surgery centre (UMC Utrecht) in the Netherlands. We recruited children and adults (no age limits) who had been referred for intraoperative electrocorticography-tailored epilepsy surgery. Participants were randomly allocated (1:1) to either HFO-guided or spike-guided tailoring, using an online randomisation scheme with permuted blocks generated by an independent data manager, stratified by epilepsy type. Treatment allocation was masked to participants and clinicians who documented seizure outcome, but not to the study team or neurosurgeon. Ictiform spike patterns were always considered in surgical decision making. The primary endpoint was seizure outcome after 1 year (dichotomised as seizure freedom [defined as Engel 1A-B] vs seizure recurrence [Engel 1C-4]). We predefined a non-inferiority margin of 10% risk difference. Analysis was by intention to treat, with prespecified subgroup analyses by epilepsy type and for confounders. This completed trial is registered with the Dutch Trial Register, Toetsingonline ABR.NL44527.041.13, and ClinicalTrials.gov, NCT02207673.Between Oct 10, 2014, and Jan 31, 2020, 78 individuals were enrolled to the study and randomly assigned (39 to HFO-guided tailoring and 39 to spike-guided tailoring). There was no loss to follow-up. Seizure freedom at 1 year occurred in 26 (67%) of 39 participants in the HFO-guided group and 35 (90%) of 39 in the spike-guided group (risk difference -23·5%, 90% CI -39·1 to -7·9; for the 48 patients with temporal lobe epilepsy, the risk difference was -25·5%, -45·1 to -6·0, and for the 30 patients with extratemporal lobe epilepsy it was -20·3%, -46·0 to 5·4). Pathology associated with poor prognosis was identified as a confounding factor, with an adjusted risk difference of -7·9% (90% CI -20·7 to 4·9; adjusted risk difference -12·5%, -31·0 to 5·9, for temporal lobe epilepsy and 5·8%, -7·7 to 19·5, for extratemporal lobe epilepsy). We recorded eight serious adverse events (five in the HFO-guided group and three in the spike-guided group) requiring hospitalisation. No patients died.HFO-guided tailoring of epilepsy surgery was not non-inferior to spike-guided tailoring on intraoperative electrocorticography. After adjustment for confounders, HFOs show non-inferiority in extratemporal lobe epilepsy. This trial challenges the clinical value of HFOs as an epilepsy biomarker, especially in temporal lobe epilepsy. Further research is needed to establish whether HFO-guided intraoperative electrocorticography holds promise in extratemporal lobe epilepsy.UMCU Alexandre Suerman, EpilepsieNL, RMI Talent Fellowship, European Research Council, and MING Fund.

Compulsivity often develops during childhood and is associated with elevated glutamate levels within the frontostriatal system. This suggests that anti-glutamatergic drugs, like memantine, may be an effective treatment.Our goal was to characterize the acute and chronic effect of memantine treatment on compulsive behavior and frontostriatal network structure and function in an adolescent rat model of compulsivity.Juvenile Sprague-Dawley rats received repeated quinpirole, resulting in compulsive checking behavior (n = 32; compulsive) or saline injections (n = 32; control). Eight compulsive and control rats received chronic memantine treatment, and eight compulsive and control rats received saline treatment for seven consecutive days between the 10th and 12th quinpirole/saline injection. Compulsive checking behavior was assessed, and structural and functional brain connectivity was measured with diffusion MRI and resting-state fMRI before and after treatment. The other rats received an acute single memantine (compulsive: n = 12; control: n = 12) or saline injection (compulsive: n = 4; control: n = 4) during pharmacological MRI after the 12th quinpirole/saline injection. An additional group of rats received a single memantine injection after a single quinpirole injection (n = 8).Memantine treatment did not affect compulsive checking nor frontostriatal structural and functional connectivity in the quinpirole-induced adolescent rat model. While memantine activated the frontal cortex in control rats, no significant activation responses were measured after single or repeated quinpirole injections.The lack of a memantine treatment effect in quinpirole-induced compulsive adolescent rats may be partly explained by the interaction between glutamatergic and dopaminergic receptors in the brain, which can be evaluated with functional MRI.

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique implicated as a promising adjunct therapy to improve motor function through the neuromodulation of brain networks. Particularly bilateral tDCS, which affects both hemispheres, may yield stronger effects on motor learning than unilateral stimulation. Therefore, the aim of this exploratory study was to develop an experimental model for simultaneous magnetic resonance imaging (MRI) and bilateral tDCS in rats, to measure instant and resultant effects of tDCS on network activity and connectivity. Naïve, male Sprague‐Dawley rats were divided into a tDCS (n = 7) and sham stimulation group (n = 6). Functional MRI data were collected during concurrent bilateral tDCS over the sensorimotor cortex, while resting‐state functional MRI and perfusion MRI were acquired directly before and after stimulation. Bilateral tDCS induced a hemodynamic activation response, reflected by a bilateral increase in blood oxygenation level‐dependent signal in different cortical areas, including the sensorimotor regions. Resting‐state functional connectivity within the cortical sensorimotor network decreased after a first stimulation session but increased after a second session, suggesting an interaction between multiple tDCS sessions. Perfusion MRI revealed no significant changes in cerebral blood flow after tDCS. Our exploratory study demonstrates successful application of an MRI‐compatible bilateral tDCS setup in an animal model. Our results indicate that bilateral tDCS can locally modulate neuronal activity and connectivity, which may underlie its therapeutic potential., Our study demonstrates that simultaneous functional magnetic resonance imaging (MRI) and transcranial direct current stimulation (tDCS) in rats is feasible with an MRI‐compatible electrode montage. We found that bilateral tDCS can locally modulate neural activity and functional connectivity in rat brain, while cortical functional connectivity is differentially affected under the tDCS cathode and anode.

The power of language to modify the reader’s perception of interpreting biomedical results cannot be underestimated. Misreporting and misinterpretation are pressing problems in randomized controlled trials (RCT) output. This may be partially related to the statistical significance paradigm used in clinical trials centered around a P value below 0.05 cutoff. Strict use of this P value may lead to strategies of clinical researchers to describe their clinical results with P values approaching but not reaching the threshold to be “almost significant.” The question is how phrases expressing nonsignificant results have been reported in RCTs over the past 30 years. To this end, we conducted a quantitative analysis of English full texts containing 567,758 RCTs recorded in PubMed between 1990 and 2020 (81.5% of all published RCTs in PubMed). We determined the exact presence of 505 predefined phrases denoting results that approach but do not cross the line of formal statistical significance (P < 0.05). We modeled temporal trends in phrase data with Bayesian linear regression. Evidence for temporal change was obtained through Bayes factor (BF) analysis. In a randomly sampled subset, the associated P values were manually extracted. We identified 61,741 phrases in 49,134 RCTs indicating almost significant results (8.65%; 95% confidence interval (CI): 8.58% to 8.73%). The overall prevalence of these phrases remained stable over time, with the most prevalent phrases being “marginally significant” (in 7,735 RCTs), “all but significant” (7,015), “a nonsignificant trend” (3,442), “failed to reach statistical significance” (2,578), and “a strong trend” (1,700). The strongest evidence for an increased temporal prevalence was found for “a numerical trend,” “a positive trend,” “an increasing trend,” and “nominally significant.” In contrast, the phrases “all but significant,” “approaches statistical significance,” “did not quite reach statistical significance,” “difference was apparent,” “failed to reach statistical significance,” and “not quite significant” decreased over time. In a random sampled subset of 29,000 phrases, the manually identified and corresponding 11,926 P values, 68,1% ranged between 0.05 and 0.15 (CI: 67. to 69.0; median 0.06). Our results show that RCT reports regularly contain specific phrases describing marginally nonsignificant results to report P values close to but above the dominant 0.05 cutoff. The fact that the prevalence of the phrases remained stable over time indicates that this practice of broadly interpreting P values close to a predefined threshold remains prevalent. To enhance responsible and transparent interpretation of RCT results, researchers, clinicians, reviewers, and editors may reduce the focus on formal statistical significance thresholds and stimulate reporting of P values with corresponding effect sizes and CIs and focus on the clinical relevance of the statistical difference found in RCTs.

Many randomized controlled trials (RCTs) are biased and difficult to reproduce due to methodological flaws and poor reporting. There is increasing attention for responsible research practices and implementation of reporting guidelines, but whether these efforts have improved the methodological quality of RCTs (e.g., lower risk of bias) is unknown. We, therefore, mapped risk-of-bias trends over time in RCT publications in relation to journal and author characteristics. Meta-information of 176,620 RCTs published between 1966 and 2018 was extracted. The risk-of-bias probability (random sequence generation, allocation concealment, blinding of patients/personnel, and blinding of outcome assessment) was assessed using a risk-of-bias machine learning tool. This tool was simultaneously validated using 63,327 human risk-of-bias assessments obtained from 17,394 RCTs evaluated in the Cochrane Database of Systematic Reviews (CDSR). Moreover, RCT registration and CONSORT Statement reporting were assessed using automated searches. Publication characteristics included the number of authors, journal impact factor (JIF), and medical discipline. The annual number of published RCTs substantially increased over 4 decades, accompanied by increases in authors (5.2 to 7.8) and institutions (2.9 to 4.8). The risk of bias remained present in most RCTs but decreased over time for allocation concealment (63% to 51%), random sequence generation (57% to 36%), and blinding of outcome assessment (58% to 52%). Trial registration (37% to 47%) and the use of the CONSORT Statement (1% to 20%) also rapidly increased. In journals with a higher impact factor (>10), the risk of bias was consistently lower with higher levels of RCT registration and the use of the CONSORT Statement. Automated risk-of-bias predictions had accuracies above 70% for allocation concealment (70.7%), random sequence generation (72.1%), and blinding of patients/personnel (79.8%), but not for blinding of outcome assessment (62.7%). In conclusion, the likelihood of bias in RCTs has generally decreased over the last decades. This optimistic trend may be driven by increased knowledge augmented by mandatory trial registration and more stringent reporting guidelines and journal requirements. Nevertheless, relatively high probabilities of bias remain, particularly in journals with lower impact factors. This emphasizes that further improvement of RCT registration, conduct, and reporting is still urgently needed., Many randomized controlled trials (RCTs) are biased and difficult to reproduce due to methodological flaws and poor reporting. Analysis of 176,620 RCTs published between 1966 and 2018 reveals that the risk of bias in RCTs generally decreased. Nevertheless, relatively high probabilities of bias remain, showing that further improvement of RCT registration, conduct, and reporting is still urgently needed.

Objective To quantitatively map how non-significant outcomes are reported in randomised controlled trials (RCTs) over the last thirty years. Design Quantitative analysis of English full-texts containing 567,758 RCTs recorded in PubMed (81.5% of all published RCTs). Methods We determined the exact presence of 505 pre-defined phrases denoting results that do not reach formal statistical significance (P Results We identified 61,741 phrases indicating close to significant results in 49,134 (8.65%; 95% confidence interval (CI): 8.58–8.73) RCTs. The overall prevalence of these phrases remained stable over time, with the most prevalent phrases being ‘marginally significant’ (in 7,735 RCTs), ‘all but significant’ (7,015), ‘a nonsignificant trend’ (3,442), ‘failed to reach statistical significance’ (2,578) and ‘a strong trend’ (1,700). The strongest evidence for a temporal prevalence increase was found for ‘a numerical trend’, ‘a positive trend’, ‘an increasing trend’ and ‘nominally significant’. The phrases ‘all but significant’, ‘approaches statistical significance’, ‘did not quite reach statistical significance’, ‘difference was apparent’, ‘failed to reach statistical significance’ and ‘not quite significant’ decreased over time. In the random sampled subset, the 11,926 identified P values ranged between 0.05 and 0.15 (68.1%; CI: 67.3–69.0; median 0.06). Conclusions Our results demonstrate that phrases describing marginally significant results are regularly used in RCTs to report P values close to but above the dominant 0.05 cut-off. The phrase prevalence remained stable over time, despite all efforts to change the focus from P < 0.05 to reporting effect sizes and corresponding confidence intervals. To improve transparency and enhance responsible interpretation of RCT results, researchers, clinicians, reviewers, and editors need to abandon the focus on formal statistical significance thresholds and stimulate reporting of exact P values with corresponding effect sizes and confidence intervals. Significance statement The power of language to modify the reader’s perception of how to interpret biomedical results cannot be underestimated. Misreporting and misinterpretation are urgent problems in RCT output. This may be at least partially related to the statistical paradigm of the 0.05 significance threshold. Sometimes, creativity and inventive strategies of clinical researchers may be used – describing their clinical results to be ‘almost significant’ – to get their data published. This phrasing may convince readers about the value of their work. Since 2005 there is an increasing concern that most current published research findings are false and it has been generally advised to switch from null hypothesis significance testing to using effect sizes, estimation, and cumulation of evidence. If this ‘new statistics’ approach has worked out well should be reflected in the phases describing non-significance results of RCTs. In particular in changing patterns describing P values just above 0.05 value. More than five hundred phrases potentially suited to report or discuss non-significant results were searched in over half a million published RCTs. A stable overall prevalence of these phrases (10.87%, CI: 10.79–10.96; N: 61,741), with associated P values close to 0.05, was found in the last three decades, with strong increases or decreases in individual phrases describing these near-significant results. The pressure to pass scientific peer-review barrier may function as an incentive to use effective phrases to mask non-significant results in RCTs. However, this keeps the researcher’s pre-occupied with hypothesis testing rather than presenting outcome estimations with uncertainty. The effect of language on getting RCT results published should ideally be minimal to steer evidence-based medicine away from overselling of research results, unsubstantiated claims about the efficacy of certain RCTs and to prevent an over-reliance on P value cutoffs. Our exhaustive search suggests that presenting RCT findings remains a struggle when P values approach the carved-in-stone threshold of 0.05.

This population-based cross-sectional survey with a follow-up case-control study assessed the prevalence, incidence, and risk factors for epilepsy in a rural health district in the North-West Region of Cameroon. Community-based epilepsy screening targeted all inhabitants, six years and older, in all 16 health areas in the Batibo Health District. During door-to-door visits, trained fieldworkers used a validated questionnaire to interview consenting household heads to screen for epilepsy in eligible residents. Trained physicians subsequently assessed people with suspected seizures. After clinical assessment, they confirmed or refuted the diagnosis and estimated the date of epilepsy onset. A trained nurse interviewed people with epilepsy and randomly selected healthy individuals, obtaining relevant demographic details and information on exposure to risk factors for epilepsy. Out of 36,282 residents screened, 524 had active epilepsy. The age-standardized prevalence of active epilepsy was 33.9/1,000 (95% CI: 31.0-37.1/1,000). We estimated the one-year age-standardized epilepsy incidence at 171/100,000 (95%CI: 114.0-254.6). Active epilepsy prevalence varied widely between health areas, ranging between 12 and 75 per 1,000. The peak age-specific prevalence was in the 25-34 age group. In adults, multivariate analysis showed that having a relative with epilepsy was positively associated with epilepsy. Epilepsy characteristics in this population, geographical heterogeneity, and the age-specific prevalence pattern suggest that endemic neurocysticercosis and onchocerciasis may be implicated. Further investigations are warranted to establish the full range of risk factors for epilepsy in this population.