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Up to 35% of individuals diagnosed with epilepsy continue to have seizures despite treatment, commonly referred to as drug-resistant epilepsy. Uncontrolled seizures can directly, or indirectly, negatively impact an individual's quality of life. To inform clinical management and life decisions, it is important to be able to predict the likelihood of seizure control. Those likely to achieve seizure control will be able to return sooner to their usual work and leisure activities and require less follow-up, whereas those with a poor prognosis will need more frequent clinical attendance and earlier consideration of epilepsy surgery. This is a systematic review aimed at identifying demographic, clinical, physiological (e.g., electroencephalographic), and imaging (e.g., magnetic resonance imaging) factors that may be predictive of treatment outcomes in patients with newly diagnosed epilepsy (NDE). MEDLINE and Embase were searched for prediction models of treatment outcomes in patients with NDE. Study characteristics were extracted and subjected to assessment of risk of bias (and applicability concerns) using the PROBAST (Prediction Model Risk of Bias Assessment Tool) tool. Baseline variables associated with treatment outcomes are reported as prognostic factors. After screening, 48 models were identified in 32 studies, which generally scored low for concerns of applicability, but universally scored high for susceptibility to bias. Outcomes reported fit broadly into four categories: drug resistance, short-term treatment response, seizure remission, and mortality. Prognostic factors were also heterogenous, but the predictors that were commonly significantly associated with outcomes were those related to seizure characteristics/types, epilepsy history, and age at onset. Antiseizure medication response was often included as a baseline variable, potentially obscuring other factor relationships at baseline. Currently, outcome prediction models for NDE demonstrate a high risk of bias. Model development could be improved with a stronger adherence to recommended TRIPOD (Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis) practices. Furthermore, we outline actionable changes to common practices that are intended to improve the overall quality of prediction model development in NDE., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Collaborative efforts between basic scientists, engineers, and clinicians are enabling translational epileptology. In this article, we summarize the recent advances presented at the International Conference for Technology and Analysis of Seizures (ICTALS 2022): (1) novel developments of structural magnetic resonance imaging; (2) latest electroencephalography signal-processing applications; (3) big data for the development of clinical tools; (4) the emerging field of hyperdimensional computing; (5) the new generation of artificial intelligence (AI)-enabled neuroprostheses; and (6) the use of collaborative platforms to facilitate epilepsy research translation. We highlight the promise of AI reported in recent investigations and the need for multicenter data-sharing initiatives., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Neurocysticercosis (NCC)-a parasitic CNS infection endemic to developing nations-has been called the leading global cause of acquired epilepsy yet remains understudied. It is currently unknown why a large proportion of patients develop recurrent seizures, often following the presentation of acute seizures. Furthermore, the presentation of NCC is heterogenous and the features that predispose to the development of an epileptogenic state remain uncertain. Perilesional factors (such as oedema and gliosis) have been implicated in NCC-related ictogenesis, but the effects of cystic factors, including lesion load and location, seem not to play a role in the development of habitual epilepsy. In addition, the cytotoxic consequences of the cyst's degenerative stages are varied and the majority of research, relying on retrospective data, lacks the necessary specificity to distinguish between acute symptomatic and unprovoked seizures. Previous research has established that epileptogenesis can be the consequence of abnormal network connectivity, and some imaging studies have suggested that a causative link may exist between NCC and aberrant network organisation. In wider epilepsy research, network approaches have been widely adopted; studies benefiting predominantly from the rich, multimodal data provided by advanced MRI methods are at the forefront of the field. Quantitative MRI approaches have the potential to elucidate the lesser-understood epileptogenic mechanisms of NCC. This review will summarise the current understanding of the relationship between NCC and epilepsy, with a focus on MRI methodologies. In addition, network neuroscience approaches with putative value will be highlighted, drawing from current imaging trends in epilepsy research., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: A first unprovoked seizure is a common presentation, reliably identifying those that will have recurrent seizures is a challenge. This study will be the first to explore the combined utility of serum biomarkers, quantitative electroencephalogram (EEG) and quantitative MRI to predict seizure recurrence. This will inform patient stratification for counselling and the inclusion of high-risk patients in clinical trials of disease-modifying agents in early epilepsy., Methods and Analysis: 100 patients with first unprovoked seizure will be recruited from a tertiary neuroscience centre and baseline assessments will include structural MRI, EEG and a blood sample. As part of a nested pilot study, a subset of 40 patients will have advanced MRI sequences performed that are usually reserved for patients with refractory chronic epilepsy. The remaining 60 patients will have standard clinical MRI sequences. Patients will be followed up every 6 months for a 24-month period to assess seizure recurrence. Connectivity and network-based analyses of EEG and MRI data will be carried out and examined in relation to seizure recurrence. Patient outcomes will also be investigated with respect to analysis of high-mobility group box-1 from blood serum samples., Ethics and Dissemination: This study was approved by North East-Tyne & Wear South Research Ethics Committee (20/NE/0078) and funded by an Association of British Neurologists and Guarantors of Brain clinical research training fellowship. Findings will be presented at national and international meetings published in peer-reviewed journals., Trial Registration Number: NIHR Clinical Research Network's (CRN) Central Portfolio Management System (CPMS)-44976., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objective: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features., Methods: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance., Results: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10 -16 ), age at onset (ρ = -.18, p = 9.82 × 10 -7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI., Significance: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features., (© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes., (© 2022. The Author(s).)

Purpose: Most techniques used for automatic segmentation of subcortical brain regions are developed for three-dimensional (3D) MR images. MRIs obtained in non-specialist hospitals may be non-isotropic and two-dimensional (2D). Automatic segmentation of 2D images may be challenging and represents a lost opportunity to perform quantitative image analysis. We determine the performance of a modified subcortical segmentation technique applied to 2D images in patients with idiopathic generalised epilepsy (IGE)., Methods: Volume estimates were derived from 2D (0.4 × 0.4 × 3 mm) and 3D (1 × 1x1mm) T1-weighted acquisitions in 31 patients with IGE and 39 healthy controls. 2D image segmentation was performed using a modified FSL FIRST (FMRIB Integrated Registration and Segmentation Tool) pipeline requiring additional image reorientation, cropping, interpolation and brain extraction prior to conventional FIRST segmentation. Consistency between segmentations was assessed using Dice coefficients and volumes across both approaches were compared between patients and controls. The influence of slice thickness on consistency was further assessed using 2D images with slice thickness increased to 6 mm., Results: All average Dice coefficients showed excellent agreement between 2 and 3D images across subcortical structures (0.86-0.96). Most 2D volumes were consistently slightly lower compared to 3D volumes. 2D images with increased slice thickness showed lower agreement with 3D images with lower Dice coefficients (0.55-0.83). Significant volume reduction of the left and right thalamus and putamen was observed in patients relative to controls across 2D and 3D images., Conclusion: Automated subcortical volume estimation of 2D images with a resolution of 0.4 × 0.4x3mm using a modified FIRST pipeline is consistent with volumes derived from 3D images, although this consistency decreases with an increased slice thickness. Thalamic and putamen atrophy has previously been reported in patients with IGE. Automated subcortical volume estimation from 2D images is feasible and most reliable at using in-plane acquisitions greater than 1 mm x 1 mm and provides an opportunity to perform quantitative image analysis studies in clinical trials., (© 2021. The Author(s).)

Neuromodulation is an increasingly utilized therapy for the treatment of people with drug-resistant epilepsy. To date, the most common and effective target has been the thalamus, which is known to play a key role in multiple forms of epilepsy. Neuroimaging has facilitated rapid developments in the understanding of functional targets, surgical and programming techniques, and the effects of thalamic stimulation. In this review, the role of neuroimaging in neuromodulation is explored. First, the structural and functional changes of the thalamus in common epilepsy syndromes are discussed as the rationale for neuromodulation of the thalamus. Next, methods for imaging different thalamic nuclei are presented, as well as rationale for the need of direct surgical targeting rather than reliance on traditional stereotactic coordinates. Lastly, we discuss the potential role of neuroimaging in assessing the effects of thalamic stimulation and as a potential biomarker for neuromodulation outcomes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis., Methods: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy., Results: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia., Conclusions: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control., (© 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Determining the anatomical basis of hemispheric language dominance (HLD) remains an important scientific endeavor. The Wada test remains the gold standard test for HLD and provides a unique opportunity to determine the relationship between HLD and hemispheric structural asymmetries on MRI. In this study, we applied a whole-brain voxel-based asymmetry (VBA) approach to determine the relationship between interhemispheric structural asymmetries and HLD in a large consecutive sample of Wada tested patients. Of 135 patients, 114 (84.4%) had left HLD, 10 (7.4%) right HLD, and 11 (8.2%) bilateral language representation. Fifty-four controls were also studied. Right-handed controls and right-handed patients with left HLD had comparable structural brain asymmetries in cortical, subcortical, and cerebellar regions that have previously been documented in healthy people. However, these patients and controls differed in structural asymmetry of the mesial temporal lobe and a circumscribed region in the superior temporal gyrus, suggesting that only asymmetries of these regions were due to brain alterations caused by epilepsy. Additional comparisons between patients with left and right HLD, matched for type and location of epilepsy, revealed that structural asymmetries of insula, pars triangularis, inferior temporal gyrus, orbitofrontal cortex, ventral temporo-occipital cortex, mesial somatosensory cortex, and mesial cerebellum were significantly associated with the side of HLD. Patients with right HLD and bilateral language representation were significantly less right-handed. These results suggest that structural asymmetries of an insular-fronto-temporal network may be related to HLD., (© 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.)

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed., (© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.)

The Wada test remains the traditional test for lateralizing language and memory function prior to epilepsy surgery. Functional imaging, particularly functional MRI (fMRI), has made progress in the language domain, but less so in the memory domain. Magnetoencephalography (MEG) has received less research attention, but shows promise, particularly for language lateralization. We recruited a consecutive sample of 19 patients with epilepsy who had completed presurgical work-up, including the Wada test, and compared fMRI (memory) and MEG (language and memory) with Wada test results. The main research question was the concordance between Wada and these two imaging techniques as preepilepsy surgery investigations. We were also interested in the acceptability of the three techniques to patients. Concordance rates (N=16) were nonsignificant (Cohen's Kappa) between fMRI and Wada test (memory) and between MEG and Wada test (memory and language). The Wada test was a well-established protocol used at several epilepsy surgery centers in the UK. Patients generally found the Wada test an odd, but not aversive procedure. Sixteen (84%) patients who were scanned reported some level of obtundation in MEG. We present these discordant findings in support of the position that functional imaging and the Wada test are distinctive procedures, with little in the way of overlapping mechanisms, and that patient's experience should be taken into account when procedures are selected and offered to them., (Copyright © 2017 Elsevier Inc. All rights reserved.)