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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.
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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.
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Displasia Cortical Focal , Malformações do Desenvolvimento Cortical do Grupo I , Humanos , Gliose , NeurogliaRESUMO
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.
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COVID-19 , Miocardite , Humanos , Miocardite/diagnóstico , Autoimunidade , Anticorpos , MiocárdioRESUMO
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.
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Epilepsia do Lobo Temporal , Humanos , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/cirurgia , Epilepsia do Lobo Temporal/patologia , Transcriptoma/genética , Hipocampo/metabolismo , RNA Mensageiro/metabolismo , Imageamento por Ressonância MagnéticaRESUMO
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.
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Epilepsia do Lobo Temporal , Malformações do Desenvolvimento Cortical , Substância Branca , Atrofia/patologia , Imagem de Tensor de Difusão/métodos , Hipocampo/patologia , Humanos , Imageamento por Ressonância Magnética , Malformações do Desenvolvimento Cortical/patologia , Esclerose/patologia , Substância Branca/patologiaRESUMO
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.
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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.
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Epilepsia do Lobo Temporal , Epilepsia , Animais , Benchmarking , Modelos Animais de Doenças , Epilepsia/patologia , Epilepsia do Lobo Temporal/patologia , Humanos , Proteoma , Proteômica , EscleroseRESUMO
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.
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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.
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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.
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Citocinas , Epilepsia , Fator Neurotrófico Derivado do Encéfalo , Fator Neurotrófico Ciliar , Citocinas/metabolismo , Epilepsia/etiologia , Epilepsia/metabolismo , Epilepsia/patologia , Fator Neurotrófico Derivado de Linhagem de Célula Glial , Humanos , Inflamação/metabolismo , Interferon gama , Interleucina-10 , Interleucina-17 , Interleucina-2 , Interleucina-4 , Interleucina-6 , Fator de Crescimento Neural , Convulsões , Fator de Necrose Tumoral alfaRESUMO
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.
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Epilepsia do Lobo Frontal/diagnóstico por imagem , Epilepsia do Lobo Frontal/patologia , Malformações do Desenvolvimento Cortical/diagnóstico por imagem , Oligodendroglia/patologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Epilepsia Resistente a Medicamentos/patologia , Epilepsia Resistente a Medicamentos/cirurgia , Eletroencefalografia , Epilepsia do Lobo Frontal/cirurgia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical/cirurgia , Pessoa de Meia-Idade , Neurônios/patologia , Procedimentos Neurocirúrgicos , Tomografia por Emissão de Pósitrons , Resultado do Tratamento , Adulto JovemRESUMO
OBJECTIVE: This study's objective was to compare the transinsular (TI-AH), transuncus (TU-AH), and temporopolar (TP-AH) amygdalohippocampectomy approaches regarding seizure control, temporal stem (TS) damage, and neurocognitive decline. METHODS: We included 114 consecutive patients with unilateral hippocampal sclerosis (HS) who underwent TI-AH, TU-AH, or TP-AH between 2002 and 2017. We evaluated seizure control using Engel classification. We used diffusion tensor imaging and postoperative Humphrey perimetry to assess the damage of the TS. We also performed pre- and postoperative memory performance and intelligence quotient (IQ). RESULTS: There were no significant differences in the proportion of patients free of disabling seizures (Engel IA+IB) among the three surgical approaches in the survival analysis. However, more patients were free of disabling seizures (Engel IA+IB) at 2 years of postsurgical follow-up with TP-AH (69.5%) and TI-AH (76.7%) as compared to the TU-AH (43.5%) approach (p = .03). The number of fibers of the inferior fronto-occipital fasciculus postoperatively was reduced in the TI-AH group compared with the TU-AH and TP-AH groups (p = .001). The rate of visual field defects was significantly higher with TI-AH (14/19, 74%) in comparison to the TU-AH (5/15, 33%) and TP-AH (13/40, 32.5%) approaches (p = .008). Finally, there was a significant postoperative decline in verbal memory in left-sided surgeries (p = .019) and delayed recall for both sides (p < .001) regardless of the surgical approach. However, TP-AH was the only group that showed a significant improvement in visual memory (p < .001) and IQ (p < .001) for both right- and left-sided surgeries. SIGNIFICANCE: The TP-AH group had better short-term seizure control than TU-AH, a lower rate of visual field defects than TI-AH, and improved visual memory and IQ compared to the other groups. Our findings suggest that TP-AH is a better surgical approach for temporal lobe epilepsy with HS than TI-AH and TU-AH.
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Tonsila do Cerebelo/cirurgia , Epilepsia Resistente a Medicamentos/cirurgia , Epilepsia do Lobo Temporal/cirurgia , Hipocampo/cirurgia , Procedimentos Neurocirúrgicos/métodos , Complicações Cognitivas Pós-Operatórias/epidemiologia , Adulto , Lobectomia Temporal Anterior , Córtex Cerebral , Imagem de Tensor de Difusão , Feminino , Hipocampo/patologia , Humanos , Testes de Inteligência , Masculino , Memória , Pessoa de Meia-Idade , Giro Para-Hipocampal , Complicações Cognitivas Pós-Operatórias/fisiopatologia , Estudos Prospectivos , Esclerose , Lobo Temporal , Resultado do Tratamento , Campos VisuaisRESUMO
The most common form of genetic generalized epilepsy (GGE) is juvenile myoclonic epilepsy (JME), which accounts for 5 to 10% of all epilepsy cases. The gene EFHC1 has been implicated as a putative cause of JME. However, it remains debatable whether testing for EFHC1 mutations should be included in the diagnostic epilepsy gene panels. To investigate the clinical utility of EFHC1 testing, we studied 125 individuals: 100 with JME and 25 with other GGEs. We amplified and sequenced all EFHC1 coding exons. Then, we predicted the pathogenicity or benign impact of the variants using the analyses proposed by the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP). Mutation screening revealed 11 missense variants in 44 probands with JME (44%) and one of the seven individuals with generalized tonic-clonic seizures on awakening (14%). Six of the 11 variants (54%) were classified as 'benign,' and the remaining variants were considered variants of uncertain significance (VUS). There is currently a limitation to test for genes that predispose an individual to complex, nonmonogenic phenotypes. Thus, we show suggestive evidence that EFHC1 testing lacks a scientific foundation based on the disputed nature of the gene-disease relationship and should be currently limited to research purposes.
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Epilepsia Generalizada , Epilepsia Mioclônica Juvenil , Proteínas de Ligação ao Cálcio/genética , Epilepsia Generalizada/genética , Humanos , Epilepsia Mioclônica Juvenil/genética , Linhagem , FenótipoRESUMO
OBJECTIVE: To evaluate the interactions of metabolic neuronal-glial changes with the presence and hemispheric-side of hippocampal sclerosis (HS) and its potential role in predicting pharmacoresistance in temporal lobe epilepsy (TLE). METHODS: We included structural magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1 H-MRS) metabolic data for 91 patients with unilateral TLE and 50 healthy controls. We measured the values of total N-acetyl aspartate/total creatine (tNAA/tCr), glutamate/tCr (Glu/tCr), and myo-inositol/tCr (mIns/tCr). To assess the influence of the pharmacoresponse and hemispheric-side of HS on metabolic data, the relationship between clinical and MRI data, and the predictive value of NAA/Cr, we used analysis of variance/covariance and built a logistic regression model. We used bootstrap simulations to evaluate reproducibility. RESULTS: Bilateral tNAA/tCr reduction was associated with pharmacoresistance and with left HS, a decrease of Glu/tCr ipsilateral to the seizure focus was associated with pharmacoresistance, and ipsilateral mIns/tCr increase was related to pharmacoresistance and the presence of left HS. The logistic regression model containing clinical and 1 H-MRS data discriminated pharmacoresistance (area under the curve [AUC] = 0.78). However, the reduction of tNAA/tCr was the main predictor, with the odds 2.48 greater for pharmacoresistance. SIGNIFICANCE: Our study revealed a spectrum of neuronal-glial changes in TLE, which was associated with pharmacoresistance, being more severe in left-sided HS and less severe in MRI-negative TLE. These noninvasive, in vivo biomarkers provide valuable additional information about the interhemispheric differences in metabolic dysfunction, seizure burden, and HS, and may help to predict pharmacoresistance.
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Anticonvulsivantes/uso terapêutico , Epilepsia Resistente a Medicamentos/patologia , Epilepsia do Lobo Temporal/tratamento farmacológico , Hipocampo/patologia , Neuroglia/patologia , Neurônios/patologia , Adulto , Biomarcadores , Estudos de Casos e Controles , Creatina/metabolismo , Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/metabolismo , Epilepsia do Lobo Temporal/patologia , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/diagnóstico por imagem , Humanos , Inositol/metabolismo , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , N-Metilaspartato/metabolismo , Neuroimagem , Espectroscopia de Prótons por Ressonância Magnética , Esclerose , Resultado do Tratamento , Adulto JovemRESUMO
Neurocysticercosis (NC) is the most common parasitic infection of the central nervous system (CNS). Several studies have reported an association between NC and mesial temporal lobe epilepsy (MTLE). We intended to evaluate the frequency of hippocampal atrophy (HA), clinical evolution and imaging findings in patients with calcified neurocysticercotic lesions (CNLs). Methods: One hundred and eighty-one subjects (70 cases and 111 controls) were evaluated for the presence or absence of HA. We assessed the imaging findings, and the evolution of patients with NC treated or not with anthelmintics for NC. Results: Hippocampal volumes were different between cases and controls (p < 0.001). Seventy percent of the cases presented HA. 52.2% of the patients without a history of anthelmintic treatment for NC had reports of epileptic seizures. There was an association between non-treatment and the later occurrence of epileptic seizures (p = 0.006). There was an association between perilesional edema on MRI and the presence of uncontrolled epileptic seizures (p = 0.004). Conclusions: Hippocampal atrophy is frequent in patients with NCC. There was an association between no anthelmintic treatment in the acute phase of NC, perilesional edema, more pronounced hippocampal atrophy, and the occurrence of refractory seizures.
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OBJECTIVE: To analyze the lifetime trajectories in genetic generalized epilepsies (GGEs) and investigate the impact of symptoms of anxiety and depression on resting state functional connectivity (FC). METHODS: Seventy-four GGE patients were classified according to the pharmacological response as seizure-free (12 patients), pharmacoresistant (PhR; 14 patients), and fluctuating (FL; 48 patients). Fifty-four subjects completed both the Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI), and 38 also underwent 3-T resting state functional magnetic resonance imaging. These 38 patients were subdivided into a positive group (13 patients with concurrent symptoms of depression and anxiety) and a negative group (21 asymptomatic patients and four with mild anxiety or depression symptoms). For FC analysis of resting state networks, we matched 38 healthy asymptomatic volunteers and used the UF2C toolbox running on MATLAB2017/SPM12. RESULTS: The PhR group presented shorter duration of epilepsy (P = 0.016) and follow-up (P < 0.001) compared to the FL group. The PhR group showed higher levels (median = 20) on the BAI and BDI. Myoclonic seizures were the most difficult to control, as 50% of subjects persisted with them at last appointment, compared to generalized tonic-clonic seizures and absence seizures (<40%). Patients with concurrent anxiety and depression symptoms were 7.7 times more likely to exhibit pharmacoresistant seizures, although an increase of 1 year of epilepsy duration was associated with a decrease in the odds of presenting pharmacoresistance by a factor of 0.9. Overall, FC was altered between default mode network (DMN) and visuospatial/dorsal attention. However, only the positive group displayed abnormal FC between DMN and left executive control network, and between salience and visuospatial/dorsal attention. SIGNIFICANCE: Our findings may help clinicians to have a better understanding of GGE clinical course and increase attention to the potential relationship of psychopathologies and brain connectivity.
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Ansiedade/fisiopatologia , Encéfalo/fisiopatologia , Depressão/fisiopatologia , Epilepsia Generalizada/fisiopatologia , Epilepsia Generalizada/psicologia , Adolescente , Adulto , Ansiedade/complicações , Criança , Depressão/complicações , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Vias Neurais/fisiopatologia , Adulto JovemRESUMO
PURPOSE: Visualizing a brain in its native space plays an essential role during neurosurgical planning because it allows the superficial cerebral veins and surrounding regions to be preserved. This paper describes the use of a visualization tool in which single gadolinium contrast-enhanced T1-weighted magnetic resonance imaging was applied in nondefective and nonresective skulls to promote visualization of important structures. METHODS: A curvilinear reformatting tool was applied on the supratentorial compartment to peel the tissues to the depth of the dura mater and thereby revealing cortical and vascular spatial relationships. The major advantage of our proposed tool is that it does not require coregistration of anatomical and vascular volumes. RESULTS: The reliability of this technique was supported by comparisons between preoperative images and digital photographs of the brain cortical surface obtained after the dura mater was removed in 20 patients who underwent surgery in the Clinics Hospital of the University of Campinas from January 2017 to April 2018. CONCLUSION: Single fat-suppressed GAD contrast-enhanced T1-weighted magnetic resonance scans provide accurate preoperative 3D views of cortical and vascular relationships similar to neurosurgeons' intraoperative views. In developing countries with limited access to state-of-the-art health technologies, this imaging approach may improve the safety of complex neurosurgeries.
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Neoplasias Encefálicas/diagnóstico , Encéfalo/cirurgia , Artérias Cerebrais/diagnóstico por imagem , Veias Cerebrais/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Procedimentos Neurocirúrgicos/métodos , Interface Usuário-Computador , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Encéfalo/diagnóstico por imagem , Neoplasias Encefálicas/cirurgia , Criança , Feminino , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Reprodutibilidade dos Testes , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: Focal cortical dysplasias (FCDs) are an important cause of drug-resistant epilepsy. In this work, we aimed to investigate whether abnormal gene regulation, mediated by microRNA, could be involved in FCD type II. METHODS: We used total RNA from the brain tissue of 16 patients with FCD type II and 28 controls. MicroRNA expression was initially assessed by microarray. Quantitative polymerase chain reaction, in situ hybridization, luciferase reporter assays, and deep sequencing for genes in the mTOR pathway were performed to validate and further explore our initial study. RESULTS: hsa-let-7f (p = 0.039), hsa-miR-31 (p = 0.0078), and hsa-miR34a (p = 0.021) were downregulated in FCD type II, whereas a transcription factor involved in neuronal and glial fate specification, NEUROG2 (p < 0.05), was upregulated. We also found that the RND2 gene, a NEUROG2-target, is upregulated (p < 0.001). In vitro experiments showed that hsa-miR-34a downregulates NEUROG2 by binding to its 5'-untranslated region. Moreover, we observed strong nuclear expression of NEUROG2 in balloon cells and dysmorphic neurons and found that 28.5% of our patients presented brain somatic mutations in genes of the mTOR pathway. INTERPRETATION: Our findings suggest a new molecular mechanism, in which NEUROG2 has a pivotal and central role in the pathogenesis of FCD type II. In this way, we found that the downregulation of hsa-miR-34a leads to upregulation of NEUROG2, and consequently to overexpression of the RND2 gene. These findings indicate that a faulty coupling in neuronal differentiation and migration mechanisms may explain the presence of aberrant cells and complete dyslamination in FCD type II. Ann Neurol 2018;83:623-635.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Epilepsia/metabolismo , Hipoplasia Dérmica Focal/metabolismo , Malformações do Desenvolvimento Cortical/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/genética , Epilepsia/tratamento farmacológico , Epilepsia/genética , Feminino , Hipoplasia Dérmica Focal/genética , Humanos , Lactente , Masculino , Neurônios/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fatores de Transcrição/genética , Adulto Jovem , Proteínas rho de Ligação ao GTP/metabolismoRESUMO
OBJECTIVE: To compare surgical outcome in mesial temporal lobe epilepsy (MTLE) patients with unilateral hippocampal sclerosis (MTLE-HS) who had or did not have preoperative video-electroencephalographic monitoring (VEEG). METHODS: A prospective study was undertaken with 166 consecutive pharmacoresistant unilateral MTLE-HS patients. All patients were investigated with detailed seizure semiology, serial routine outpatient EEG, magnetic resonance imaging, neuropsychological evaluation, and if necessary, other examinations. Postoperative follow-up ranged between 2 and 16 years. Patients were divided into: (1) patients operated on based on routine outpatient EEG information, with >80% of EEGs with unilateral interictal epileptiform discharges (IEDs) ipsilateral to HS or ictal events (n = 71); and (2) patients submitted to preoperative VEEG (n = 95). To avoid the bias generated by ictal recordings, we performed a subanalysis of: (1) patients without preoperatively ictal recordings (n = 80) and (2) patients with ictal recordings in VEEG or routine outpatient EEG (n = 86). RESULTS: Groups were similar regarding gender, age at surgery, seizure onset, preoperative seizure frequency, and duration of follow-up. Overall, 136/166 (81.92%) were classified as Engel I seizure outcome, with no difference between groups; 76.84% and 88.73% of patients with and without VEEG, respectively, had Engel I postoperative seizure outcome (P = .77). The time lag until surgery was shorter in the group without VEEG (80 vs 38 months; P = .01). Considering ictal recordings, 76.74% of patients with seizures recorded and 87.50% without ictal recordings had Engel I outcome (P = .11). SIGNIFICANCE: We performed the first prospective study in a tertiary epilepsy center comparing surgical outcomes in unilateral MTLE-HS patients investigated preoperatively with and without VEEG. Based on the surgical outcome, VEEG is not imperative in patients with unilateral MTLE-HS who have compatible semiology and clearly ipsilateralized IEDs evaluated by a multidisciplinary and experienced epilepsy group.