A WORLDWIDE ENIGMA STUDY ON EPILEPSY-RELATED GRAY AND WHITE MATTER COMPROMISE ACROSS THE ADULT LIFESPAN.

Objectives: Temporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments. Methods: We studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves. Results: In TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions. Conclusions: This study highlights the profound impact of TLE on lifespan changes in grey and white matter structures, with an acceleration of aging-related processes in later decades of life. Our findings motivate future longitudinal studies across the lifespan and emphasize the importance of prompt diagnosis as well as intervention in patients.

Evidence of brain metabolism redistribution from neocortex to primitive brain structures in early acute COVID-19 respiratory syndrome.

BACKGROUND: Neuropsychiatric sequelae of COVID-19 have been widely documented in patients with severe neurological symptoms during the chronic or subacute phase of the disease. However, it remains unclear whether subclinical changes in brain metabolism can occur early in the acute phase of the disease. The aim of this study was to identify and quantify changes in brain metabolism in patients hospitalized for acute respiratory syndrome due to COVID-19 with no or mild neurological symptoms. RESULTS: Twenty-three non-intubated patients (13 women; mean age 55.5 ± 12.1 years) hospitalized with positive nasopharyngeal swab test (RT-PCR) for COVID-19, requiring supplemental oxygen and no or mild neurological symptoms were studied. Serum C-reactive protein measured at admission ranged from 6.43 to 189.0 mg/L (mean: 96.9 ± 54.2 mg/L). The mean supplemental oxygen demand was 2.9 ± 1.4 L/min. [18F]FDG PET/CT images were acquired with a median of 12 (4-20) days of symptoms. After visual interpretation of the images, semiquantitative analysis of [18F]FDG uptake in multiple brain regions was evaluated using dedicated software and the standard deviation (SD) of brain uptake in each region was automatically calculated in comparison with reference values of a normal database. Evolutionarily ancient structures showed positive SD mean values of [18F]FDG uptake. Lenticular nuclei were bilaterally hypermetabolic (> 2 SD) in 21/23 (91.3%) patients, and thalamus in 16/23 (69.6%), bilaterally in 11/23 (47.8%). About half of patients showed hypermetabolism in brainstems, 40% in hippocampi, and 30% in cerebellums. In contrast, neocortical regions (frontal, parietal, temporal and occipital lobes) presented negative SD mean values of [18F]FDG uptake and hypometabolism (< 2 SD) was observed in up to a third of patients. Associations were found between hypoxia, inflammation, coagulation markers, and [18F]FDG uptake in various brain structures. CONCLUSIONS: Brain metabolism is clearly affected during the acute phase of COVID-19 respiratory syndrome in neurologically asymptomatic or oligosymptomatic patients. The most frequent finding is marked hypermetabolism in evolutionary ancient structures such as lenticular nucleus and thalami. Neocortical metabolism was reduced in up to one third of patients, suggesting a redistribution of brain metabolism from the neocortex to evolutionary ancient brain structures in these patients.

Role of the glymphatic system and perivascular spaces as a potential biomarker for post-stroke epilepsy.

Stroke is one of the most common causes of acquired epilepsy, which can also result in disability and increased mortality rates particularly in elderly patients. No preventive treatment for post-stroke epilepsy is currently available. Development of such treatments has been greatly limited by the lack of biomarkers to reliably identify high-risk patients. The glymphatic system, including perivascular spaces (PVS), is the brain's waste clearance system, and enlargement or asymmetry of PVS (ePVS) is hypothesized to play a significant role in the pathogenesis of several neurological conditions. In this article, we discuss potential mechanisms for the role of perivascular spaces in the development of post-stroke epilepsy. Using advanced MR-imaging techniques, it has been shown that there is asymmetry and impairment of glymphatic function in the setting of ischemic stroke. Furthermore, studies have described a dysfunction of PVS in patients with different focal and generalized epilepsy syndromes. It is thought that inflammatory processes involving PVS and the blood-brain barrier, impairment of waste clearance, and sustained hypertension affecting the glymphatic system during a seizure may play a crucial role in epileptogenesis post-stroke. We hypothesize that impairment of the glymphatic system and asymmetry and dynamics of ePVS in the course of a stroke contribute to the development of PSE. Automated ePVS detection in stroke patients might thus assist in the identification of high-risk patients for post-stroke epilepsy trials. PLAIN LANGUAGE SUMMARY: Stroke often leads to epilepsy and is one of the main causes of epilepsy in elderly patients, with no preventative treatment available. The brain's waste removal system, called the glymphatic system which consists of perivascular spaces, may be involved. Enlargement or asymmetry of perivascular spaces could play a role in this and can be visualised with advanced brain imaging after a stroke. Detecting enlarged perivascular spaces in stroke patients could help identify those at risk for post-stroke epilepsy.

Clinical characteristics and outcomes of patients with post-stroke epilepsy: protocol for an individual patient data meta-analysis from the International Post-stroke Epilepsy Research Repository (IPSERR).

INTRODUCTION: Despite significant advances in managing acute stroke and reducing stroke mortality, preventing complications like post-stroke epilepsy (PSE) has seen limited progress. PSE research has been scattered worldwide with varying methodologies and data reporting. To address this, we established the International Post-stroke Epilepsy Research Consortium (IPSERC) to integrate global PSE research efforts. This protocol outlines an individual patient data meta-analysis (IPD-MA) to determine outcomes in patients with post-stroke seizures (PSS) and develop/validate PSE prediction models, comparing them with existing models. This protocol informs about creating the International Post-stroke Epilepsy Research Repository (IPSERR) to support future collaborative research. METHODS AND ANALYSIS: We utilised a comprehensive search strategy and searched MEDLINE, Embase, PsycInfo, Cochrane, and Web of Science databases until 30 January 2023. We extracted observational studies of stroke patients aged ≥18 years, presenting early or late PSS with data on patient outcome measures, and conducted the risk of bias assessment. We did not apply any restriction based on the date or language of publication. We will invite these study authors and the IPSERC collaborators to contribute IPD to IPSERR. We will review the IPD lodged within IPSERR to identify patients who developed epileptic seizures and those who did not. We will merge the IPD files of individual data and standardise the variables where possible for consistency. We will conduct an IPD-MA to estimate the prognostic value of clinical characteristics in predicting PSE. ETHICS AND DISSEMINATION: Ethics approval is not required for this study. The results will be published in peer-reviewed journals. This study will contribute to IPSERR, which will be available to researchers for future PSE research projects. It will also serve as a platform to anchor future clinical trials. TRIAL REGISTRATION NUMBER: NCT06108102.

Identifying cellular markers of focal cortical dysplasia type II with cell-type deconvolution and single-cell signatures.

Focal cortical dysplasia (FCD) is a brain malformation that causes medically refractory epilepsy. FCD is classified into three categories based on structural and cellular abnormalities, with FCD type II being the most common and characterized by disrupted organization of the cortex and abnormal neuronal development. In this study, we employed cell-type deconvolution and single-cell signatures to analyze bulk RNA-seq from multiple transcriptomic studies, aiming to characterize the cellular composition of brain lesions in patients with FCD IIa and IIb subtypes. Our deconvolution analyses revealed specific cellular changes in FCD IIb, including neuronal loss and an increase in reactive astrocytes (astrogliosis) when compared to FCD IIa. Astrogliosis in FCD IIb was further supported by a gene signature analysis and histologically confirmed by glial fibrillary acidic protein (GFAP) immunostaining. Overall, our findings demonstrate that FCD II subtypes exhibit differential neuronal and glial compositions, with astrogliosis emerging as a hallmark of FCD IIb. These observations, validated in independent patient cohorts and confirmed using immunohistochemistry, offer novel insights into the involvement of glial cells in FCD type II pathophysiology and may contribute to the development of targeted therapies for this condition.

Revealing the spatiotemporal requirements for accurate subject identification with resting-state functional connectivity: a simultaneous fNIRS-fMRI study.

Significance: Brain fingerprinting refers to identifying participants based on their functional patterns. Despite its success with functional magnetic resonance imaging (fMRI), brain fingerprinting with functional near-infrared spectroscopy (fNIRS) still lacks adequate validation. Aim: We investigated how fNIRS-specific acquisition features (limited spatial information and nonneural contributions) influence resting-state functional connectivity (rsFC) patterns at the intra-subject level and, therefore, brain fingerprinting. Approach: We performed multiple simultaneous fNIRS and fMRI measurements in 29 healthy participants at rest. Data were preprocessed following the best practices, including the removal of motion artifacts and global physiology. The rsFC maps were extracted with the Pearson correlation coefficient. Brain fingerprinting was tested with pairwise metrics and a simple linear classifier. Results: Our results show that average classification accuracy with fNIRS ranges from 75% to 98%, depending on the number of runs and brain regions used for classification. Under the right conditions, brain fingerprinting with fNIRS is close to the 99.9% accuracy found with fMRI. Overall, the classification accuracy is more impacted by the number of runs and the spatial coverage than the choice of the classification algorithm. Conclusions: This work provides evidence that brain fingerprinting with fNIRS is robust and reliable for extracting unique individual features at the intra-subject level once relevant spatiotemporal constraints are correctly employed.

Gene expression profile suggests different mechanisms underlying sporadic and familial mesial temporal lobe epilepsy.

Most patients with pharmacoresistant mesial temporal lobe epilepsy (MTLE) have hippocampal sclerosis on the postoperative histopathological examination. Although most patients with MTLE do not refer to a family history of the disease, familial forms of MTLE have been reported. We studied surgical specimens from patients with MTLE who had epilepsy surgery for medically intractable seizures. We assessed and compared gene expression profiles of the tissue lesion found in patients with familial MTLE (n = 3) and sporadic MTLE (n = 5). In addition, we used data from control hippocampi obtained from a public database (n = 7). We obtained expression profiles using the Human Genome U133 Plus 2.0 (Affymetrix) microarray platform. Overall, the molecular profile identified in familial MTLE differed from that in sporadic MTLE. In the tissue of patients with familial MTLE, we found an over-representation of the biological pathways related to protein response, mRNA processing, and synaptic plasticity and function. In sporadic MTLE, the gene expression profile suggests that the inflammatory response is highly activated. In addition, we found enrichment of gene sets involved in inflammatory cytokines and mediators and chemokine receptor pathways in both groups. However, in sporadic MTLE, we also found enrichment of epidermal growth factor signaling, prostaglandin synthesis and regulation, and microglia pathogen phagocytosis pathways. Furthermore, based on the gene expression signatures, we identified different potential compounds to treat patients with familial and sporadic MTLE. To our knowledge, this is the first study assessing the mRNA profile in surgical tissue obtained from patients with familial MTLE and comparing it with sporadic MTLE. Our results clearly show that, despite phenotypic similarities, both forms of MTLE present distinct molecular signatures, thus suggesting different underlying molecular mechanisms that may require distinct therapeutic approaches.

Structural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression.

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.

Superficial and deep white matter diffusion abnormalities in focal epilepsies.

OBJECTIVE: This study was undertaken to evaluate superficial-white matter (WM) and deep-WM magnetic resonance imaging diffusion tensor imaging (DTI) metrics and identify distinctive patterns of microstructural abnormalities in focal epilepsies of diverse etiology, localization, and response to antiseizure medication (ASM). METHODS: We examined DTI data for 113 healthy controls and 113 patients with focal epilepsies: 51 patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) refractory to ASM, 27 with pharmacoresponsive TLE-HS, 15 with temporal lobe focal cortical dysplasia (FCD), and 20 with frontal lobe FCD. To assess WM microstructure, we used a multicontrast multiatlas parcellation of DTI. We evaluated fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD), and assessed within-group differences ipsilateral and contralateral to the epileptogenic lesion, as well as between-group differences, in regions of interest (ROIs). RESULTS: The TLE-HS groups presented more widespread superficial- and deep-WM diffusion abnormalities than both FCD groups. Concerning superficial WM, TLE-HS groups showed multilobar ipsilateral and contralateral abnormalities, with less extensive distribution in pharmacoresponsive patients. Both the refractory TLE-HS and pharmacoresponsive TLE-HS groups also presented pronounced changes in ipsilateral frontotemporal ROIs (decreased FA and increased MD, RD, and AD). Conversely, FCD patients showed diffusion changes almost exclusively adjacent to epileptogenic areas. SIGNIFICANCE: Our findings add further evidence of widespread abnormalities in WM diffusion metrics in patients with TLE-HS compared to other focal epilepsies. Notably, superficial-WM microstructural damage in patients with FCD is more restricted around the epileptogenic lesion, whereas TLE-HS groups showed diffuse WM damage with ipsilateral frontotemporal predominance. These findings suggest the potential of superficial-WM analysis for better understanding the biological mechanisms of focal epilepsies, and identifying dysfunctional networks and their relationship with the clinical-pathological phenotype. In addition, lobar superficial-WM abnormalities may aid in the diagnosis of subtle FCDs.

Circulating Metabolites as Biomarkers of Disease in Patients with Mesial Temporal Lobe Epilepsy.

A major challenge in the clinical management of patients with mesial temporal lobe epilepsy (MTLE) is identifying those who do not respond to antiseizure medication (ASM), allowing for the timely pursuit of alternative treatments such as epilepsy surgery. Here, we investigated changes in plasma metabolites as biomarkers of disease in patients with MTLE. Furthermore, we used the metabolomics data to gain insights into the mechanisms underlying MTLE and response to ASM. We performed an untargeted metabolomic method using magnetic resonance spectroscopy and multi- and univariate statistical analyses to compare data obtained from plasma samples of 28 patients with MTLE compared to 28 controls. The patients were further divided according to response to ASM for a supplementary and preliminary comparison: 20 patients were refractory to treatment, and eight were responsive to ASM. We only included patients using carbamazepine in combination with clobazam. We analyzed the group of patients and controls and found that the profiles of glucose (p = 0.01), saturated lipids (p = 0.0002), isoleucine (p = 0.0001), ß-hydroxybutyrate (p = 0.0003), and proline (p = 0.02) were different in patients compared to controls (p < 0.05). In addition, we found some suggestive metabolites (without enough predictability) by multivariate analysis (VIP scores > 2), such as lipoproteins, lactate, glucose, unsaturated lipids, isoleucine, and proline, that might be relevant to the process of pharmacoresistance in the comparison between patients with refractory and responsive MTLE. The identified metabolites for the comparison between MTLE patients and controls were linked to different biological pathways related to cell-energy metabolism and pathways related to inflammatory processes and the modulation of neurotransmitter release and activity in MTLE. In conclusion, in addition to insights into the mechanisms underlying MTLE, our results suggest that plasma metabolites may be used as disease biomarkers. These findings warrant further studies exploring the clinical use of metabolites to assist in decision-making when treating patients with MTLE.

Benchmarking the proteomic profile of animal models of mesial temporal epilepsy.

OBJECTIVES: We compared the proteomic signatures of the hippocampal lesion induced in three different animal models of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS): the systemic pilocarpine model (PILO), the intracerebroventricular kainic acid model (KA), and the perforant pathway stimulation model (PPS). METHODS: We used shotgun proteomics to analyze the proteomes and find enriched biological pathways of the dorsal and ventral dentate gyrus (DG) isolated from the hippocampi of the three animal models. We also compared the proteomes obtained in the animal models to that from the DG of patients with pharmacoresistant MTLE+HS. RESULTS: We found that each animal model presents specific profiles of proteomic changes. The PILO model showed responses predominantly related to neuronal excitatory imbalance. The KA model revealed alterations mainly in synaptic activity. The PPS model displayed abnormalities in metabolism and oxidative stress. We also identified common biological pathways enriched in all three models, such as inflammation and immune response, which were also observed in tissue from patients. However, none of the models could recapitulate the profile of molecular changes observed in tissue from patients. SIGNIFICANCE: Our results indicate that each model has its own set of biological responses leading to epilepsy. Thus, it seems that only using a combination of the three models may one replicate more closely the mechanisms underlying MTLE+HS as seen in patients.

Junctional instability in neuroepithelium and network hyperexcitability in a focal cortical dysplasia human model.

Focal cortical dysplasia is a highly epileptogenic cortical malformation with few treatment options. Here, we generated human cortical organoids from patients with focal cortical dysplasia type II. Using this human model, we mimicked some focal cortical dysplasia hallmarks, such as impaired cell proliferation, the presence of dysmorphic neurons and balloon cells, and neuronal network hyperexcitability. Furthermore, we observed alterations in the adherens junctions zonula occludens-1 and partitioning defective 3, reduced polarization of the actin cytoskeleton, and fewer synaptic puncta. Focal cortical dysplasia cortical organoids showed downregulation of the small GTPase RHOA, a finding that was confirmed in brain tissue resected from these patients. Functionally, both spontaneous and optogenetically-evoked electrical activity revealed hyperexcitability and enhanced network connectivity in focal cortical dysplasia organoids. Taken together, our findings suggest a ventricular zone instability in tissue cohesion of neuroepithelial cells, leading to a maturational arrest of progenitors or newborn neurons, which may predispose to cellular and functional immaturity and compromise the formation of neural networks in focal cortical dysplasia.

Improving the prediction of epilepsy surgery outcomes using basic scalp EEG findings.

OBJECTIVE: This study aims to evaluate the role of scalp electroencephalography (EEG; ictal and interictal patterns) in predicting resective epilepsy surgery outcomes. We use the data to further develop a nomogram to predict seizure freedom. METHODS: We retrospectively reviewed the scalp EEG findings and clinical data of patients who underwent surgical resection at three epilepsy centers. Using both EEG and clinical variables categorized into 13 isolated candidate predictors and 6 interaction terms, we built a multivariable Cox proportional hazards model to predict seizure freedom 2 years after surgery. Harrell's step-down procedure was used to sequentially eliminate the least-informative variables from the model until the change in the concordance index (c-index) with variable removal was less than 0.01. We created a separate model using only clinical variables. Discrimination of the two models was compared to evaluate the role of scalp EEG in seizure-freedom prediction. RESULTS: Four hundred seventy patient records were analyzed. Following internal validation, the full Clinical + EEG model achieved an optimism-corrected c-index of 0.65, whereas the c-index of the model without EEG data was 0.59. The presence of focal to bilateral tonic-clonic seizures (FBTCS), high preoperative seizure frequency, absence of hippocampal sclerosis, and presence of nonlocalizable seizures predicted worse outcome. The presence of FBTCS had the largest impact for predicting outcome. The analysis of the models' interactions showed that in patients with unilateral interictal epileptiform discharges (IEDs), temporal lobe surgery cases had a better outcome. In cases with bilateral IEDs, abnormal magnetic resonance imaging (MRI) predicted worse outcomes, and in cases without IEDs, patients with extratemporal epilepsy and abnormal MRI had better outcomes. SIGNIFICANCE: This study highlights the value of scalp EEG, particularly the significance of IEDs, in predicting surgical outcome. The nomogram delivers an individualized prediction of postoperative outcome, and provides a unique assessment of the relationship between the outcome and preoperative findings.

Multidimensional Approach Assessing the Role of Interleukin 1 Beta in Mesial Temporal Lobe Epilepsy.

We aimed to investigate the role of interleukin-1 beta (IL-1ß) in the mechanisms underlying mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE+HS). We assessed a cohort of 194 patients with MTLE+HS and 199 healthy controls. Patients were divided into those with positive and negative antecedent febrile seizures (FS). We used a multidimensional approach, including (i) genetic association with single nucleotide polymorphisms (SNPs) in the IL1B gene; (ii) quantification of the IL1B transcript in the hippocampal tissue of patients with refractory seizures; and (iii) quantification of the IL-1ß protein in the plasma. We found a genetic association signal for two SNPs, rs2708928 and rs3730364*C in the IL1B gene, regardless of the presence of FS (adjusted p = 9.62e-11 and 5.14e-07, respectively). We found no difference between IL1B transcript levels when comparing sclerotic hippocampal tissue from patients with MTLE+HS, without FS, and hippocampi from autopsy controls (p > 0.05). Nevertheless, we found increased IL-1ß in the plasma of patients with MTLE+HS with FS compared with controls (p = 0.0195). Our results support the hypothesis of a genetic association between MTLE+HS and the IL1B gene.

Association Analysis of Candidate Variants in Admixed Brazilian Patients With Genetic Generalized Epilepsies.

Genetic generalized epilepsies (GGEs) include well-established epilepsy syndromes with generalized onset seizures: childhood absence epilepsy, juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), myoclonic absence epilepsy, epilepsy with eyelid myoclonia (Jeavons syndrome), generalized tonic-clonic seizures, and generalized tonic-clonic seizures alone. Genome-wide association studies (GWASs) and exome sequencing have identified 48 single-nucleotide polymorphisms (SNPs) associated with GGE. However, these studies were mainly based on non-admixed, European, and Asian populations. Thus, it remains unclear whether these results apply to patients of other origins. This study aims to evaluate whether these previous results could be replicated in a cohort of admixed Brazilian patients with GGE. We obtained SNP-array data from 87 patients with GGE, compared with 340 controls from the BIPMed public dataset. We could directly access genotypes of 17 candidate SNPs, available in the SNP array, and the remaining 31 SNPs were imputed using the BEAGLE v5.1 software. We performed an association test by logistic regression analysis, including the first five principal components as covariates. Furthermore, to expand the analysis of the candidate regions, we also interrogated 14,047 SNPs that flank the candidate SNPs (1 Mb). The statistical power was evaluated in terms of odds ratio and minor allele frequency (MAF) by the genpwr package. Differences in SNP frequencies between Brazilian and Europeans, sub-Saharan African, and Native Americans were evaluated by a two-proportion Z-test. We identified nine flanking SNPs, located on eight candidate regions, which presented association signals that passed the Bonferroni correction (rs12726617; rs9428842; rs1915992; rs1464634; rs6459526; rs2510087; rs9551042; rs9888879; and rs8133217; p-values <3.55e-06). In addition, the two-proportion Z-test indicates that the lack of association of the remaining candidate SNPs could be due to different genomic backgrounds observed in admixed Brazilians. This is the first time that candidate SNPs for GGE are analyzed in an admixed Brazilian population, and we could successfully replicate the association signals in eight candidate regions. In addition, our results provide new insights on how we can account for population structure to improve risk stratification estimation in admixed individuals.

Inflammatory and neurotrophic factor plasma levels are related to epilepsy independently of etiology.

OBJECTIVE: Inflammation plays an essential role in epilepsy. Studies indicate that cytokines and neurotrophic factors can act in neuroexcitability and epileptogenesis. We aimed to investigate the association between plasma inflammatory and neurotrophic markers, seizure frequency, and chronic epilepsy subtypes. METHODS: We studied 446 patients with epilepsy and 166 healthy controls. We classified patients according to etiology and seizure frequency. We measured plasma levels of interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-10, IL-17, interferon-γ (IFNγ), tumor necrosis factor α (TNFα), soluble TNF receptor 1 (sTNFr1), sTNFr2, brain-derived neurotrophic factor (BDNF), neurotrophic factor 3 (NT3), NT4/5, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF), and glial cell line-derived neurotrophic factor (GDNF) by enzyme-linked immunosorbent assay or cytometric bead array. RESULTS: The plasma levels of BDNF, NT3, NGF, and sTNFr2 were higher, whereas IL-2, IL-4, IL-6, IL-10, IL-17, IFNγ, TNFα, CNTF, and sTNFr1 were lower in patients than controls. IL1, GDNF, and NT4/5 were similar between groups. These markers did not correlate with age, sex, and epilepsy duration. The molecule sTNFr2 was the best marker to discriminate patients from controls (area under the curve = .857), also differing between patients with frequent and infrequent seizures. SIGNIFICANCE: This large cohort confirmed that patients with epilepsy have abnormal levels of plasma inflammatory and neurotrophic markers independent of the underlying etiology. Plasma level of sTNFr2 was related to seizure frequency and discriminated people with or without epilepsy with good accuracy, making it a potential biomarker for epilepsy and seizure burden.

International Multicenter Analysis of Brain Structure Across Clinical Stages of Parkinson's Disease.

BACKGROUND: Brain structure abnormalities throughout the course of Parkinson's disease have yet to be fully elucidated. OBJECTIVE: Using a multicenter approach and harmonized analysis methods, we aimed to shed light on Parkinson's disease stage-specific profiles of pathology, as suggested by in vivo neuroimaging. METHODS: Individual brain MRI and clinical data from 2357 Parkinson's disease patients and 1182 healthy controls were collected from 19 sources. We analyzed regional cortical thickness, cortical surface area, and subcortical volume using mixed-effects models. Patients grouped according to Hoehn and Yahr stage were compared with age- and sex-matched controls. Within the patient sample, we investigated associations with Montreal Cognitive Assessment score. RESULTS: Overall, patients showed a thinner cortex in 38 of 68 regions compared with controls (dmax  = -0.20, dmin  = -0.09). The bilateral putamen (dleft  = -0.14, dright  = -0.14) and left amygdala (d = -0.13) were smaller in patients, whereas the left thalamus was larger (d = 0.13). Analysis of staging demonstrated an initial presentation of thinner occipital, parietal, and temporal cortices, extending toward rostrally located cortical regions with increased disease severity. From stage 2 and onward, the bilateral putamen and amygdala were consistently smaller with larger differences denoting each increment. Poorer cognition was associated with widespread cortical thinning and lower volumes of core limbic structures. CONCLUSIONS: Our findings offer robust and novel imaging signatures that are generally incremental across but in certain regions specific to disease stages. Our findings highlight the importance of adequately powered multicenter collaborations. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Magnetic resonance imaging findings and clinical characteristics in mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy in a predominantly adult cohort.

OBJECTIVE: We aimed to better characterize the magnetic resonance imaging (MRI) findings of mild malformation of cortical development with oligodendroglial hyperplasia (MOGHE), a rare clinicopathological entity associated with pharmacoresistance recently described in patients with frontal lobe epilepsy. METHODS: We studied 12 patients who underwent epilepsy surgery and whose surgical specimens showed histopathological findings of MOGHE, characterized by preserved cortical lamination, blurred gray-white matter interface due to increased number of oligodendrocytes, and heterotopic neurons in the white matter. The age at MRI evaluation ranged from 11 to 58 years, except for one 4.5-year-old patient. RESULTS: Following a detailed MRI analysis using an in-house protocol, we found abnormalities in all cases. The lesion was circumscribed in the frontal lobe in six (50%) and in the temporal lobe in three (25%) patients. In the remaining three patients (25%), the lesion was multilobar (frontotemporal and temporoparieto-occipital). Cortical thickening was mild in all patients, except in the 4.5-year-old patient, who had pronounced cortical thickening and white matter blurring. We also identified cortical/subcortical hyperintense T2/fluid-attenuated inversion recovery signal associated with gray/white matter blurring in all but one patient. When present, cleft cortical dimple, and deep sulci aided in localizing the lesion. Overall, the MRI findings were like those in focal cortical dysplasia (FCD) Type IIa. Surgical outcome was excellent in five patients (Engel Class I in 25% and II in 17%). The remaining seven patients (58%) had worthwhile seizure reduction (Engle Class III). Incomplete lesion resection was significantly associated with worse outcomes. SIGNIFICANCE: MRI findings associated with MOGHE are similar to those described in FCD Type IIa. Although more frequent in the frontal lobe, MOGHE also occurred in the temporal lobe or involved multiple lobes. Multilobar or extensive MOGHE MRI lesions are associated with less favorable surgical outcomes. Because this is a rare condition, multicenter studies are necessary to characterize MOGHE further.