Publications by authors named "Fernando Cendes"

356 Publications

ResectVol: A tool to automatically segment and characterize lacunas in brain images.

Epilepsia Open 2021 Oct 5. Epub 2021 Oct 5.

Neuroimaging Laboratory, Department of Neurology, University of Campinas, Campinas, Brazil.

Objective: To assess and validate the performance of a new tool developed for segmenting and characterizing lacunas in postoperative MR images of epilepsy patients.

Methods: A MATLAB-based pipeline was implemented using SPM12 to produce the 3D mask of the surgical lacuna and estimate its volume. To validate its performance, we compared the manual and automatic lacuna segmentations obtained from 51 MRI scans of epilepsy patients who underwent temporal lobe resections.

Results: The code is consolidated as a tool named ResectVol, which can be run via a graphical user interface or command line. The automatic and manual segmentation comparison resulted in a median Dice similarity coefficient of 0.77 (interquartile range: 0.71-0.81).

Significance: Epilepsy surgery is the treatment of choice for pharmacoresistant focal epilepsies, and despite the extensive literature on the subject, we still cannot predict surgical outcomes accurately. As the volume and location of the resected tissue are fundamentally relevant to this prediction, researchers commonly perform a manual segmentation of the lacuna, which presents human bias and does not provide detailed information about the structures removed. In this study, we introduce ResectVol, a user-friendly, fully automatic tool to accomplish these tasks. This capability enables more advanced analytical techniques applied to surgical outcomes prediction, such as machine-learning algorithms, by facilitating coregistration of the resected area and preoperative findings with other imaging modalities such as PET, SPECT, and functional MRI ResectVol is freely available at https://www.lniunicamp.com/resectvol.
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http://dx.doi.org/10.1002/epi4.12546DOI Listing
October 2021

Measurement of retina/choroid complex perfusion with magnetic resonance imaging in eyes with acute primary angle-closure.

Arq Bras Oftalmol 2021 Sep 10. Epub 2021 Sep 10.

Department de Ophthalmology, University of Campinas, Campinas, Brazil.

Purpose: To measure retina/choroid complex perfusion with magnetic resonance imaging in eyes with acute primary angle-closure (APAC).

Methods: Three sequences of magnetic resonance imaging, two anatomical and one perfusional using gadolinium, were acquired in patients who were diagnosed with acute primary angle-closure. Regions of interest were drawn on the perfusional sequence and overlaid to the anatomical sequence. The relative blood volume measured during the first 2 s was considered as the baseline value and the change during the subsequent 28 s was analyzed.

Results: Five eyes of 5 patients with acute primary angle-closure were included (3 with unilateral and 2 with bilateral acute primary angle-closure). Three contralateral eyes and 2 eyes of 2 healthy patients, paired for age and sex, were included in the control group. Acute primary angle-closure patients included 4 (80%) women, with an average age of 65.8 ± 12.37 y, mean intraocular pressure of 56.2 ± 14.67 mmHg, mean arterial pressure of 113.4 ± 8.17 mmHg, and average ocular perfusion pressure of 57.2 ± 13.46 mmHg. In the control group, the mean intraocular pressure was 15.6 ± 2.61 mmHg (p=0.0625), the mean arterial pressure was 107.4 ± 6.57 mmHg (p=1.00), and the average ocular perfusion pressure was 91.8 ± 6.72 mmHg (p=0.0625). The relative blood volume of the retina/choroid complex was -0.127 ± 0.048 in acute primary angle-closure patients and -0.213 ± 0.116 in the controls (p=0.3125).

Conclusion: The magnetic resonance imaging sequence with gadolinium did not show a change in the retina/choroid complex perfusion in the eyes of patients with acute primary angle-closure.
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http://dx.doi.org/10.5935/0004-2749.20220034DOI Listing
September 2021

ILAE Neuroimaging Task Force Highlight: harnessing optimized imaging protocols for drug-resistant childhood epilepsy.

Epileptic Disord 2021 Oct;23(5):675-681

BC Children's Hospital, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.

The ILAE Neuroimaging Task Force aims to publish educational case reports highlighting basic aspects related to neuroimaging in epilepsy consistent with the educational mission of the ILAE. Previous quantitative MRI studies have established important imaging markers of epilepsy-related pathology, including features sensitive to hippocampal cell loss and reactive astrogliosis. Here, we review the case of a female with pediatric drug-resistant epilepsy. Throughout her course of treatment, she had seven MRI investigations at several centers; the first three did not follow optimized epilepsy imaging protocols whereas the remaining four adhered to HARNESS-MRI protocols ( har monized n euroimaging of e pilepsy s tructural s equences). Visual inspection of a set of HARNESS-MR images revealed conspicuous left hippocampal hyperintensity which may have been initially overlooked on non-optimized MR images. Quantitative analysis of these multimodal imaging data along hippocampal subfields provided clear evidence of hippocampal sclerosis, with increased atrophy, increased mean diffusivity, increased T2-FLAIR signal, and lower qT1 values observed in the anterior portions of the left, compared to the right hippocampus. The patient underwent a left anterior temporal lobectomy with amygdalohippocampectomy at age 16 years. Histopathology of the resected specimen also confirmed hippocampal sclerosis with widespread gliosis and focal neuronal loss in the hippocampal subfields overlapping with regions of multimodal quantitative alterations. The patient remains seizure-free one year after surgery. Collectively, this case highlights the need for optimized data acquisition protocols early in the treatment of epilepsy and supports quantitative analysis of MRI contrasts to enhance personalized diagnosis and prognosis of drug-resistant patients with epilepsy.
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http://dx.doi.org/10.1684/epd.2021.1312DOI Listing
October 2021

Multicenter Validation of a Deep Learning Detection Algorithm for Focal Cortical Dysplasia.

Neurology 2021 Oct 14;97(16):e1571-e1582. Epub 2021 Sep 14.

From the Neuroimaging of Epilepsy Laboratory (R.S.G., H.-M.L., B.C., S.-J.H., N.B., A.B.), Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; Pediatric Neurology Unit and Laboratories (C.B., M.L., R.G.), Children's Hospital A. Meyer-University of Florence, Italy; Epilepsy Unit (F.D.) and Neuroradiology (L.D.), Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy; Department of Neurology (V.C.M.C., F.C.), University of Campinas, Brazil; The Florey Institute of Neuroscience and Mental Health and The University of Melbourne (M.S., G.J.), Victoria, Australia; Department of Pediatrics (D.V.S.), British Columbia Children's Hospital, Vancouver, Canada; Aix Marseille University (F.B.), INSERM UMR 1106, Institut de Neurosciences des Systèmes; Aix Marseille University (M.G.), CNRS, CRMBM UMR 7339, Marseille, France; Freiburg Epilepsy Center (A.S.-B., H.U.), Universitätsklinikum Freiburg, Germany; Department of Neurology (K.H.C.), Yonsei University College of Medicine, Seoul, Korea; and Department of Neurology (R.E.H.), Washington University School of Medicine, St. Louis, MO.

Background And Objective: To test the hypothesis that a multicenter-validated computer deep learning algorithm detects MRI-negative focal cortical dysplasia (FCD).

Methods: We used clinically acquired 3-dimensional (3D) T1-weighted and 3D fluid-attenuated inversion recovery MRI of 148 patients (median age 23 years [range 2-55 years]; 47% female) with histologically verified FCD at 9 centers to train a deep convolutional neural network (CNN) classifier. Images were initially deemed MRI-negative in 51% of patients, in whom intracranial EEG determined the focus. For risk stratification, the CNN incorporated bayesian uncertainty estimation as a measure of confidence. To evaluate performance, detection maps were compared to expert FCD manual labels. Sensitivity was tested in an independent cohort of 23 cases with FCD (13 ± 10 years). Applying the algorithm to 42 healthy controls and 89 controls with temporal lobe epilepsy disease tested specificity.

Results: Overall sensitivity was 93% (137 of 148 FCD detected) using a leave-one-site-out cross-validation, with an average of 6 false positives per patient. Sensitivity in MRI-negative FCD was 85%. In 73% of patients, the FCD was among the clusters with the highest confidence; in half, it ranked the highest. Sensitivity in the independent cohort was 83% (19 of 23; average of 5 false positives per patient). Specificity was 89% in healthy and disease controls.

Discussion: This first multicenter-validated deep learning detection algorithm yields the highest sensitivity to date in MRI-negative FCD. By pairing predictions with risk stratification, this classifier may assist clinicians in adjusting hypotheses relative to other tests, increasing diagnostic confidence. Moreover, generalizability across age and MRI hardware makes this approach ideal for presurgical evaluation of MRI-negative epilepsy.

Classification Of Evidence: This study provides Class III evidence that deep learning on multimodal MRI accurately identifies FCD in patients with epilepsy initially diagnosed as MRI negative.
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http://dx.doi.org/10.1212/WNL.0000000000012698DOI Listing
October 2021

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

Front Neurol 2021 5;12:690847. Epub 2021 Aug 5.

Department of Translational Medicine, University of Campinas, Campinas, Brazil.

We aimed to investigate the role of interleukin-1 beta (IL-1β) 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 gene; (ii) quantification of the transcript in the hippocampal tissue of patients with refractory seizures; and (iii) quantification of the IL-1β protein in the plasma. We found a genetic association signal for two SNPs, rs2708928 and rs3730364C in the gene, regardless of the presence of FS (adjusted = 9.62e-11 and 5.14e-07, respectively). We found no difference between transcript levels when comparing sclerotic hippocampal tissue from patients with MTLE+HS, without FS, and hippocampi from autopsy controls ( > 0.05). Nevertheless, we found increased IL-1β in the plasma of patients with MTLE+HS with FS compared with controls ( = 0.0195). Our results support the hypothesis of a genetic association between MTLE+HS and the gene.
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http://dx.doi.org/10.3389/fneur.2021.690847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375265PMC
August 2021

Incorporation of quantitative MRI in a model to predict temporal lobe epilepsy surgery outcome.

Brain Commun 2021 16;3(3):fcab164. Epub 2021 Jul 16.

Department of Neurology, Epilepsy Center, Cleveland Clinic, Cleveland, OH, USA.

Quantitative volumetric brain MRI measurement is important in research applications, but translating it into patient care is challenging. We explore the incorporation of clinical automated quantitative MRI measurements in statistical models predicting outcomes of surgery for temporal lobe epilepsy. Four hundred and thirty-five patients with drug-resistant epilepsy who underwent temporal lobe surgery at Cleveland Clinic, Mayo Clinic and University of Campinas were studied. We obtained volumetric measurements from the pre-operative T1-weighted MRI using NeuroQuant, a Food and Drug Administration approved software package. We created sets of statistical models to predict the probability of complete seizure-freedom or an Engel score of I at the last follow-up. The cohort was randomly split into training and testing sets, with a ratio of 7:3. Model discrimination was assessed using the concordance statistic (C-statistic). We compared four sets of models and selected the one with the highest concordance index. Volumetric differences in pre-surgical MRI located predominantly in the frontocentral and temporal regions were associated with poorer outcomes. The addition of volumetric measurements to the model with clinical variables alone increased the model's C-statistic from 0.58 to 0.70 (right-sided surgery) and from 0.61 to 0.66 (left-sided surgery) for complete seizure freedom and from 0.62 to 0.67 (right-sided surgery) and from 0.68 to 0.73 (left-sided surgery) for an Engel I outcome score. 57% of patients with extra-temporal abnormalities were seizure-free at last follow-up, compared to 68% of those with no such abnormalities (-value = 0.02). Adding quantitative MRI data increases the performance of a model developed to predict post-operative seizure outcomes. The distribution of the regions of interest included in the final model supports the notion that focal epilepsies are network disorders and that subtle cortical volume loss outside the surgical site influences seizure outcome.
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http://dx.doi.org/10.1093/braincomms/fcab164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361423PMC
July 2021

A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.

Neuropathol Appl Neurobiol 2021 Aug 13. Epub 2021 Aug 13.

Neuroscience Research Center, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.

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.
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http://dx.doi.org/10.1111/nan.12758DOI Listing
August 2021

Artificial intelligence for classification of temporal lobe epilepsy with ROI-level MRI data: A worldwide ENIGMA-Epilepsy study.

Neuroimage Clin 2021 24;31:102765. Epub 2021 Jul 24.

Institute for Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany; Institute for Diagnostic and Interventional Radiology, Pediatric and Neuroradiology, University Medical Centre Rostock, Rostock, Germany.

Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with ("lesional") and without ("non-lesional") radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68-75%) compared to models to lateralize the side of TLE (56-73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67-75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68-76%) than models that stratified non-lesional patients (53-62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.
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http://dx.doi.org/10.1016/j.nicl.2021.102765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346685PMC
September 2021

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

Epilepsia 2021 Oct 2;62(10):2439-2450. Epub 2021 Aug 2.

Epilepsy Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

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.
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http://dx.doi.org/10.1111/epi.17024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8488002PMC
October 2021

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

Epilepsia 2021 Oct 31;62(10):2385-2394. Epub 2021 Jul 31.

University of Campinas, Campinas, Brazil.

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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http://dx.doi.org/10.1111/epi.17023DOI Listing
October 2021

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

Front Genet 2021 8;12:672304. Epub 2021 Jul 8.

Department of Translational Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.

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; -values <3.55e). 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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http://dx.doi.org/10.3389/fgene.2021.672304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297412PMC
July 2021

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

Mov Disord 2021 Jul 20. Epub 2021 Jul 20.

Neuroimaging Laboratory, Department of Neurology, University of Campinas, Campinas, Brazil.

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 (d  = -0.20, d  = -0.09). The bilateral putamen (d  = -0.14, d  = -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.
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http://dx.doi.org/10.1002/mds.28706DOI Listing
July 2021

Axonal dysfunction is associated with interferon-γ levels in childhood-onset systemic lupus erythematosus: a multivoxel magnetic resonance spectroscopy study.

Rheumatology (Oxford) 2021 Jul 20. Epub 2021 Jul 20.

Rheumatology Lab, School of Medical Sciences, University of Campinas.

Objective: Axonal/neuronal damage has been shown to be a pathological finding that precedes neuropsychiatric manifestations in systemic lupus erythematosus (SLE). Therefore, the objective of this study was to determine the presence of axonal dysfunction in childhood-onset SLE patients (cSLE) and to determine clinical, immunological, and treatment features associated with its occurrence.

Methods: We included 86 consecutive cSLE patients [median age 17 years (range 5-28)] and 71 controls [median age 18 years (5-28)]. We performed Proton Magnetic Resonance Spectroscopic Imaging (1H-MRSI) using point resolved spectroscopy sequence (PRESS) over the superior-posterior region of the corpus callosum and signals from N-acetylaspartate compounds (NAA), choline-based compounds (CHO); creatine containing compounds (Cr), myo-inositol (mI), lactate (Lac), glutamate (Glu), glutamine (Gln) and lactate (Lac) were measured and metabolites/Cr ratios were determined. Complete clinical, laboratory and neurological evaluations were performed in all subjects. Sera IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, TNF- α, INF- γ cytokines levels, antiribosomal P protein antibodies (anti-P) and S100β were measured by enzyme-linked immunosorbent assay (ELISA) using commercial kits. Data were compared by non-parametric tests.

Results: NAA/Cr ratios (p= 0.035) and Lac/Cr ratios (p= 0.019) levels were significantly decreased in cSLE patients when compared with controls. In multivariate analysis, interferon (IFN) gamma (γ) levels (OR = 4.1; 95% 2.01-7.9) and depressive symptoms (OR = 1.9; 95%CI = 1.1-3.2) were associated with NAA/Cr ratio. Increased Cho/Cr was associated with the presence of cognitive impairment (OR = 3.4; p< 0.001; 95%CI = 2.034-5.078). mI/Cr ratio correlated with cumulative glucocorticoids dosage (r = 0.361; p= 0.014).

Conclusion: NAA and CHO ratios may be useful as biomarkers in neuropsychiatric cSLE. Longitudinal studies are necessary to determine whether they predict structural damage.
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http://dx.doi.org/10.1093/rheumatology/keab530DOI Listing
July 2021

Differences in structural and functional default mode network connectivity in amyloid positive mild cognitive impairment: a longitudinal study.

Neuroradiology 2021 Jul 19. Epub 2021 Jul 19.

Laboratory of Neuroimaging, Department of Neurology - Medical Sciences School, University of Campinas (UNICAMP), Rua Tessália Vieira de Camargo 126, Campinas, SP, 13083-887, Brazil.

Purpose: Default mode network (DMN) has emerged as a potential biomarker of Alzheimer's disease (AD); however, it is not clear whether it can differentiate amnestic mild cognitive impairment with altered amyloid (aMCI-Aβ +) who will evolve to AD. We evaluated if structural and functional connectivity (FC), hippocampal volumes (HV), and cerebrospinal fluid biomarkers (CSF-Aβ, p-Tau, and t-Tau) can differentiate aMCI-Aβ + converters from non-converters.

Methods: Forty-eight individuals (18 normal controls and 30 aMCI subjects in the AD continuum - with altered Aβ in the CSF) were followed up for an average of 13 months. We used MultiAtlas, UFC, and Freesurfer software to evaluate diffusion tensor imaging, FC, and HV, respectively, INNOTEST® kits to measure CSF proteins, and neuropsychological tests. Besides, we performed different MANOVAs with further univariate analyses to differentiate groups.

Results: During follow-up, 8/30 aMCI-Aβ + converted (26.6%) to AD dementia. There were no differences in multivariate analysis between groups in CSF biomarkers (p = 0.092) or at DMN functional connectivity (p = 0.814). aMCI-Aβ + converters had smaller right HV than controls (p = 0.013), and greater right cingulum parahippocampal bundle radial diffusivity than controls (p < 0.001) and non-converters (p = 0.036).

Conclusion: In this exploratory study, structural, but not functional, DMN connectivity alterations may differentiate aMCI-Aβ + subjects who converted to AD dementia.
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http://dx.doi.org/10.1007/s00234-021-02760-5DOI Listing
July 2021

Brain Structural Signature of RFC1-Related Disorder.

Mov Disord 2021 Jul 9. Epub 2021 Jul 9.

Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.

Background: The cerebellar ataxia, neuropathy, and vestibular areflexia syndrome was initially described in the early 1990s as a late-onset slowly progressive condition. Its underlying genetic cause was recently mapped to the RFC1 gene, and additional reports have expanded on the phenotypic manifestations related to RFC1, although little is known about the pattern and extent of structural brain abnormalities in this condition.

Objective: The aim is to characterize the structural signature of brain damage in RFC1-related disorder, correlating the findings with clinical symptoms and normal brain RFC1 expression.

Methods: We recruited 22 individuals with molecular confirmation of RFC1 expansions and submitted them to high-resolution 3T magnetic resonance imaging scans. We performed multimodal analyses to assess separately cerebral and cerebellar abnormalities within gray and white matter (WM). The results were compared with a group of 22 age- and sex-matched controls.

Results: The mean age and disease duration of patients were 62.8 and 10.9 years, respectively. Ataxia, sensory neuronopathy, and vestibular areflexia were the most frequent manifestations, but parkinsonism and pyramidal signs were also noticed. We found that RFC1-related disorder is characterized by widespread and relatively symmetric cerebellar and basal ganglia atrophy. There is brainstem volumetric reduction along all its segments. Cerebral WM is also involved-mostly the corpus callosum and deep tracts, but cerebral cortical damage is rather restricted.

Conclusion: This study adds new relevant insights into the pathophysiological mechanisms of RFC1-related disorder. It should no longer be considered a purely cerebellar and sensory pathway disorder. Basal ganglia and deep cerebral WM are additional targets of damage. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28711DOI Listing
July 2021

Toward a refined genotype-phenotype classification scheme for the international consensus classification of Focal Cortical Dysplasia.

Brain Pathol 2021 07;31(4):e12956

Epilepsy Center, Cleveland Clinic Foundation, Cleveland, OH, USA.

Focal Cortical Dysplasia (FCD) is the most common cause of drug-resistant focal epilepsy in children and young adults. The diagnosis of currently defined FCD subtypes relies on a histopathological assessment of surgical brain tissue. The many ongoing challenges in the diagnosis of FCD and their various subtypes mandate, however, continuous research and consensus agreement to develop a reliable classification scheme. Advanced neuroimaging and genetic studies have proven to augment the diagnosis of FCD subtypes and should be considered for an integrated clinico-pathological and molecular classification. In this review, we will discuss the histopathological foundation of the current FCD classification and potential advancements when using genetic analysis of somatic brain mutations in neurosurgically resected brain specimens and postprocessing of presurgical neuroimaging data. Combining clinical, imaging, histopathology, and molecular studies will help to define the disease spectrum better and finally unveil FCD-specific treatment options.
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http://dx.doi.org/10.1111/bpa.12956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8412090PMC
July 2021

Cerebral Structure and Function in Stroke-free Patients with Atrial Fibrillation.

J Stroke Cerebrovasc Dis 2021 Aug 5;30(8):105887. Epub 2021 Jun 5.

Neuroimaging Laboratory, Department of Neurology, University of Campinas, UNICAMP, Campinas, SP, Brazil; Brazilian Institute of Neuroscience and Neurotechnology, BRAINN, at UNICAMP, Campinas, SP, Brazil. Electronic address:

Objectives: Atrial fibrillation (AF) is associated with high risk of dementia and brain atrophy in stroke-free patients, but the mechanisms underlying this association remain unclear. We aimed to examine the brain volume and connectivity of paramount cognitive brain networks in stroke-free patients with AF without dementia.

Materials And Methods: Twenty-six stroke-free patients with AF and 26 age and sex-matched subjects without AF were submitted to a 3-tesla brain structural and functional MRI. An extensive clinical evaluation excluded stroke, dementia, low cardiac output, carotid stenosis and metabolic diseases without optimal therapy. We used CHADS-VASc score to classify the cardiovascular risk factor burden and a broad neuropsychological battery to assess the cognitive performance. Voxel based morphometry analysis of. structural MRI defined whole-brain gray and white matter volumes. Finally, we used eco-plannar MRI images to compare the differences of functional connectivity of 7 large-scale resting-state networks between AF patients and controls.

Results: Taking into account the history of hypertension and heart failure, AF was associated to volume decrease of the right basal frontal lobe and right inferior cerebellum. Decreased connectivity of the ventral Default Mode Network (vDMN) was observed in the AF group. No disruption of connectivity was observed in the executive, visuospatial and salience networks.

Conclusion: Individuals with AF without stroke or dementia have subtle reduction of gray and white matter, restricted to frontal areas and cerebellum. These patients show decreased vDMN connectivity, without other large-scale brain network disruption.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105887DOI Listing
August 2021

Toward a better definition of focal cortical dysplasia: An iterative histopathological and genetic agreement trial.

Epilepsia 2021 06 5;62(6):1416-1428. Epub 2021 May 5.

Department of Neuropathology, Institute of Neurology, University College London, London, UK.

Objective: Focal cortical dysplasia (FCD) is a major cause of difficult-to-treat epilepsy in children and young adults, and the diagnosis is currently based on microscopic review of surgical brain tissue using the International League Against Epilepsy classification scheme of 2011. We developed an iterative histopathological agreement trial with genetic testing to identify areas of diagnostic challenges in this widely used classification scheme.

Methods: Four web-based digital pathology trials were completed by 20 neuropathologists from 15 countries using a consecutive series of 196 surgical tissue blocks obtained from 22 epilepsy patients at a single center. Five independent genetic laboratories performed screening or validation sequencing of FCD-relevant genes in paired brain and blood samples from the same 22 epilepsy patients.

Results: Histopathology agreement based solely on hematoxylin and eosin stainings was low in Round 1, and gradually increased by adding a panel of immunostainings in Round 2 and the Delphi consensus method in Round 3. Interobserver agreement was good in Round 4 (kappa = .65), when the results of genetic tests were disclosed, namely, MTOR, AKT3, and SLC35A2 brain somatic mutations in five cases and germline mutations in DEPDC5 and NPRL3 in two cases.

Significance: The diagnoses of FCD 1 and 3 subtypes remained most challenging and were often difficult to differentiate from a normal homotypic or heterotypic cortical architecture. Immunohistochemistry was helpful, however, to confirm the diagnosis of FCD or no lesion. We observed a genotype-phenotype association for brain somatic mutations in SLC35A2 in two cases with mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy. Our results suggest that the current FCD classification should recognize a panel of immunohistochemical stainings for a better histopathological workup and definition of FCD subtypes. We also propose adding the level of genetic findings to obtain a comprehensive, reliable, and integrative genotype-phenotype diagnosis in the near future.
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http://dx.doi.org/10.1111/epi.16899DOI Listing
June 2021

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

Epilepsia 2021 06 22;62(6):1429-1441. Epub 2021 Apr 22.

Department of Neurology, University of Campinas, Campinas, São Paulo, Brazil.

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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http://dx.doi.org/10.1111/epi.16907DOI Listing
June 2021

Automatic MR image quality evaluation using a Deep CNN: A reference-free method to rate motion artifacts in neuroimaging.

Comput Med Imaging Graph 2021 06 11;90:101897. Epub 2021 Mar 11.

MICLab - Medical Image Computing Laboratory, School of Electrical and Computer Engineering, University of Campinas (UNICAMP), Brazil.

Motion artifacts on magnetic resonance (MR) images degrade image quality and thus negatively affect clinical and research scanning. Considering the difficulty in preventing patient motion during MR examinations, the identification of motion artifact has attracted significant attention from researchers. We propose an automatic method for the evaluation of motion corrupted images using a deep convolutional neural network (CNN). Deep CNNs has been used widely in image classification tasks. While such methods require a significant amount of annotated training data, a scarce resource in medical imaging, the transfer learning and fine-tuning approaches allow us to use a smaller amount of data. Here we selected four renowned architectures, initially trained on Imagenet contest dataset, to fine-tune. The models were fine-tuned using patches from an annotated dataset composed of 68 T1-weighted volumetric acquisitions from healthy volunteers. For training and validation 48 images were used, while the remaining 20 images were used for testing. Each architecture was fine-tuned for each MR axis, detecting the motion artifact per patches from the three orthogonal MR acquisition axes. The overall average accuracy for the twelve models (three axes for each of four architecture) was 86.3%. As our goal was to detect fine-grained corruption in the image, we performed an extensive search on lower layers from each of the four architectures, since they filter small regions in the original input. Experiments showed that architectures with fewer layers than the original ones reported the better results for image patches with an overall average accuracy of 90.4%. The accuracies per architecture were similar so we decided to explore all four architectures performing a result consensus. Also, to determine the probability of motion artifacts presence on the whole acquisition a combination of the three axes were performed. The final architecture consists of an artificial neural network (ANN) classifier combining all models from the four shallower architectures, which overall acquisition-based accuracy was 100.0%. The proposed method generalization was tested using three different MR data: (1) MR image acquired in epilepsy patients (93 acquisitions); (2) MR image presenting susceptibility artifact (22 acquisitions); and (3) MR image acquired from different scanner vendor (20 acquisitions). The achieved acquisition-based accuracy on generalization tests (1) 90.3%, (2) 63.6%, and (3) 75.0%) suggests that domain adaptation is necessary. Our proposed method can be rapidly applied to large amounts of image data, providing a motion probability p∈[0,1] per acquisition. This method output can be used as a scale to identify the motion corrupted images from the dataset, thus minimizing the time spent on visual quality control.
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http://dx.doi.org/10.1016/j.compmedimag.2021.101897DOI Listing
June 2021

Epilepsy care in China and its relevance for other countries.

Authors:
Fernando Cendes

Lancet Neurol 2021 05 23;20(5):333-334. Epub 2021 Mar 23.

Department of Neurology, University of Campinas, Campinas, São Paulo 13083-887, Brazil. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(21)00096-XDOI Listing
May 2021

Automated analysis of cortical volume loss predicts seizure outcomes after frontal lobectomy.

Epilepsia 2021 05 23;62(5):1074-1084. Epub 2021 Mar 23.

Cleveland Clinic Epilepsy Center, Cleveland Clinic Foundation, Cleveland, OH, USA.

Objective: Patients undergoing frontal lobectomy demonstrate lower seizure-freedom rates than patients undergoing temporal lobectomy and several other resective interventions. We attempted to utilize automated preoperative quantitative analysis of focal and global cortical volume loss to develop predictive volumetric indicators of seizure outcome after frontal lobectomy.

Methods: Ninety patients who underwent frontal lobectomy were stratified based on seizure freedom at a mean follow-up time of 3.5 (standard deviation [SD] 2.5) years. Automated quantitative analysis of cortical volume loss organized by distinct brain region and laterality was performed on preoperative T1-weighted magnetic resonance imaging (MRI) studies. Univariate statistical analysis was used to select potential predictors of seizure freedom. Backward variable selection and multivariate logistical regression were used to develop models to predict seizure freedom.

Results: Forty-eight of 90 (53.3%) patients were seizure-free at the last follow-up. Several frontal and extrafrontal brain regions demonstrated statistically significant differences in both volumetric cortical volume loss and volumetric asymmetry between the left and right sides in the seizure-free and non-seizure-free cohorts. A final multivariate logistic model utilizing only preoperative quantitative MRI data to predict seizure outcome was developed with a c-statistic of 0.846. Using both preoperative quantitative MRI data and previously validated clinical predictors of seizure outcomes, we developed a model with a c-statistic of 0.897.

Significance: This study demonstrates that preoperative cortical volume loss in both frontal and extrafrontal regions can be predictive of seizure outcome after frontal lobectomy, and models can be developed with excellent predictive capabilities using preoperative MRI data. Automated quantitative MRI analysis can be quickly and reliably performed in patients with frontal lobe epilepsy, and further studies may be developed for integration into preoperative risk stratification.
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http://dx.doi.org/10.1111/epi.16877DOI Listing
May 2021

Clinical variables that help in predicting the presence of autoantibodies in patients with acute encephalitis.

Seizure 2021 Aug 24;90:117-122. Epub 2021 Feb 24.

Department of Neurology, FCM, University of Campinas (UNICAMP), and the Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, SP, Brazil. Electronic address:

Objective: To identify clinical variables that could predict the presence of autoantibodies in patients with acute encephalitis.

Methods: An observational, retrospective study from May 2011 to May 2017. Clinical, EEG, brain MRI data, and antibodies against human neuronal antigens (NMDAR, GABAR, AMPAR, LGI1, CASPR2, and GAD) from 158 patients with criteria for possible autoimmune encephalitis were analyzed to create a predictive model for this disease.

Results: We analyzed 158 samples, of which 18 cases were positive for anti-NMDAR, 2 for anti-LGI1, and 2 for anti-GAD. Seven of the 18 positive NMDAR patients were children, and 12 were female. Behavioral disorder, epileptic seizures, movement disorder, and altered level of consciousness were the frequent symptoms with >75 % sensitivity in positive anti-NMDAR patients. Other symptoms, such as language disorder, psychosis, hypoventilation, altered wake and sleep cycle, and cognitive impairment, had a sensitivity >55 %. Abnormal EEG findings had a high sensitivity (99.4 %). Brain MRI suggestive of encephalitis was observed in 7 of the positive cases for NMDAR. Abnormal CSF findings were reported in 12 patients positive for this receptor (sensitivity 70.6 %). With 7 of these symptoms, we obtained a sensitivity of 70 % and specificity of 81 % for the presence of anti-NMDAR antibodies (ROC Area 82 %). However, to predict that a patient with subacute encephalitis may have an autoimmune cause, the patient should include clinical manifestations such as movement disorder, behavioral disorder, hypoventilation, dysautonomia, and alteration of the wake and sleep cycle. Children were significantly more likely than adults with autoimmune encephalitis to experience chorea and status epilepticus (p < 0.05).

Conclusions: Anti-NMDAR encephalitis was more frequent in females and children. The repertoire of autoimmune encephalitis in children is different from adults. The presence of subacute behavioral changes, epileptic seizures, movement disorders, altered consciousness, hypoventilation, dysautonomia, and altered wake and sleep cycle predicted autoimmune encephalitis in our series.
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http://dx.doi.org/10.1016/j.seizure.2021.02.023DOI Listing
August 2021

Longitudinal analysis of interictal electroencephalograms in patients with temporal lobe epilepsy with hippocampal sclerosis.

Seizure 2021 Aug 12;90:141-144. Epub 2021 Feb 12.

Department of Neurology, University of Campinas (UNICAMP), Campinas, SP, Brazil. Electronic address:

Background: While studies have shown the progression of atrophy in temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS), little is known about the long-term dynamics of interictal epileptiform discharges (IEDs).

Objectives: To investigate long-term IEDs distribution in routine EEGs.

Methods: We evaluated 314 patients with TLE and MRI signs of HS (TLE-HS). Six had bilateral, 163 had left, and 145 had right HS. We analyzed 3655 routine EEGs (average 11.6 EEGs/patient). The EEGs were classified into four groups: (i) ipsilateral-IEDs (n = 1485), EEGs with only IEDs ipsilateral to the HS; (ii) bilateral-IEDs (n = 390); (iii) contralateral-IEDs (n = 186); and (iv) normal-EEGs (n = 1594). The duration of epilepsy at the time of the EEG (average 27.9 years) was divided into four groups: (a) <8 years (n = 140), (b) 9-17 years (n = 505), (c) 18-29 years (n = 1165), and (d) >30 years (n = 1845). We performed ANOVA with Tukey's pairwise comparisons and linear regression analysis between the duration of epilepsy and the EEG groups.

Results: The ANOVA showed a difference in the distribution of IEDs over time (p < 0.0001). While there were no significant changes in the relative numbers of bilateral and contralateral-IEDs combined, there was a significant increase in ipsilateral-IEDs (p < 0.0001) and a decrease in normal-EEGs (p < 0.0001) over time. The linear regression analysis confirmed that the proportion of ipsilateral-IEDs (p < 0.0001), and to a lesser extent, bilateral-IEDs (p = 0.0002), increased over time, while contralateral-IEDs were unchanged (p = 0.923).

Conclusions: Contrary to our expectations, contralateral-IEDs remained stable over time, whereas normal-EEGs decreased and ipsilateral-IEDs increased. Contralateral-IEDs may reflect early abnormalities and not epilepsy progression.
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http://dx.doi.org/10.1016/j.seizure.2021.02.008DOI Listing
August 2021

Brain Damage and Gene Expression Across Hereditary Spastic Paraplegia Subtypes.

Mov Disord 2021 07 11;36(7):1644-1653. Epub 2021 Feb 11.

Department of Neurology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil.

Background: Spinal cord has been considered the main target of damage in hereditary spastic paraplegias (HSPs), but mounting evidence indicates that the brain is also affected. Despite this, little is known about the brain signature of HSPs, in particular regarding stratification for specific genetic subtypes.

Objective: We aimed to characterize cerebral and cerebellar damage in five HSP subtypes (9 SPG3A, 27 SPG4, 10 SPG7, 9 SPG8, and 29 SPG11) and to uncover the clinical and gene expression correlates.

Methods: We obtained high-resolution brain T1 and diffusion tensor image (DTI) datasets in this cross-sectional case-control study (n = 84). The MRICloud, FreeSurfer, and CERES-SUIT pipelines were employed to assess cerebral gray (GM) and white matter (WM) as well as the cerebellum.

Results: Brain abnormalities were found in all but one HSP group (SPG3A), but the patterns were gene-specific: basal ganglia, thalamic, and posterior WM involvement in SPG4; diffuse WM and cerebellar involvement in SPG7; cortical thinning at the motor cortices and pallidal atrophy in SPG8; and widespread GM, WM, and deep cerebellar nuclei damage in SPG11. Abnormal regions in SPG4 and SPG8 matched those with higher SPAST and WASHC5 expression, whereas in SPG7 and SPG11 this concordance was only noticed in the cerebellum.

Conclusions: Brain damage is a conspicuous feature of HSPs (even for pure subtypes), but the pattern of abnormalities is genotype-specific. Correlation between brain structural damage and gene expression maps is different for autosomal dominant and recessive HSPs, pointing to distinct pathophysiological mechanisms underlying brain damage in these subgroups of the disease. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28519DOI Listing
July 2021

Transsylvian amygdalohippocampectomy for mesial temporal lobe epilepsy: Comparison of three different approaches.

Epilepsia 2021 02 15;62(2):439-449. Epub 2021 Jan 15.

Neuroimaging Laboratory, University of Campinas, Campinas, Brazil.

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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http://dx.doi.org/10.1111/epi.16816DOI Listing
February 2021

Comparative analysis of the safety and tolerability of eslicarbazepine acetate in older (≥60 years) and younger (18-59 years) adults.

Epilepsy Res 2021 01 10;169:106478. Epub 2020 Oct 10.

Sunovion Pharmaceuticals Inc., Marlborough, MA, USA. Electronic address:

Objective: To investigate the safety and tolerability of eslicarbazepine acetate (ESL), a once-daily oral anti-seizure drug (ASD), in older and younger adult patient populations.

Methods: Two post-hoc pooled data analyses were performed: one from three Phase III studies in patients with focal (partial-onset) seizures who were taking 1-3 concomitant ASDs; the other from five Phase II studies in patients from non-epilepsy populations not taking other ASDs chronically and/or at a clinically-effective anti-seizure dose. The frequencies of treatment-emergent adverse events (TEAEs) were calculated for the older (≥60 years) and younger (18-59 years) adults separately.

Results: In the focal seizures study pool, 4.1 % of patients (58/1431) were aged ≥60 years. The overall frequency of TEAEs was 77.5 % in older ESL-treated patients and 72.6 % in younger ESL-treated patients (p = 0.495). For patients who received placebo, the overall frequency of TEAEs was 50.0 % in the older adults and 57.5 % in the younger adults (p = 0.531). The overall placebo-adjusted frequency of TEAEs was 27.5 % in older adults and 15.1 % in younger adults. The placebo-adjusted frequencies of the TEAEs dizziness, somnolence, headache, nausea, diplopia, blurred vision, and ataxia were ≥5 % higher, and frequencies of vomiting and vertigo were ≥2 % higher in older than younger adults. The overall frequency of TEAEs leading to discontinuation was 15.0 % in older ESL-treated patients and 17.6 % in younger ESL-treated patients (p = 0.647); the frequency increased with increasing ESL dose. For patients who received placebo, the overall frequency of TEAEs leading to discontinuation was 5.6 % in older adults and 6.6 % in younger adults (p = 0.847). In the non-epilepsy study pool, 30.2 % of patients (515/1705) were aged ≥60 years. The overall frequency of TEAEs was 56.9 % in older ESL-treated patients and 58.8 % in younger ESL-treated patients. The placebo-adjusted frequencies were 14.9 % in older and 15.1 % in younger ESL-treated patients. The placebo-adjusted frequencies of the TEAEs nausea, vomiting, fatigue, and vertigo were ≥2 % higher in older adults, whereas somnolence was ≥2 % higher in younger adults. The overall frequency of TEAEs leading to discontinuation was 18.3 % in older ESL-treated patients and 12.1 % in younger ESL-treated patients (p = 0.003); frequencies were not related to ESL dose. For patients who received placebo, the overall frequency of TEAEs leading to discontinuation was 8.0 % in older adults and 5.6 % in younger adults (p = 0.407).

Conclusion: Analyses of adverse event data support the safety and tolerability of ESL in adults aged ≥60 years. In the limited number of older patients with focal seizures taking ESL plus concomitant ASDs (n = 40), the frequency of TEAEs was generally higher than in younger adults. However, in the non-epilepsy patient group (in which the number of older patients was ten times larger; 427 patients taking ESL without concomitant ASDs), no marked age-related TEAE differences were observed, suggesting that increased ASD load associated with adjunctive therapy may complicate treatment selection in older patients, due to risk of increased adverse events. As is common practice for all ASDs, balancing clinical response and tolerability is needed in this vulnerable group of patients.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106478DOI Listing
January 2021

Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study.

Sci Adv 2020 Nov 18;6(47). Epub 2020 Nov 18.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia.

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.
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http://dx.doi.org/10.1126/sciadv.abc6457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673818PMC
November 2020

Revisiting the clinical impact of variants in EFHC1 in patients with different phenotypes of genetic generalized epilepsy.

Epilepsy Behav 2020 11 29;112:107469. Epub 2020 Sep 29.

Department of Medical Genetics and Genomic Medicine, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brazil; The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), Campinas, SP, Brazil. Electronic address:

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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http://dx.doi.org/10.1016/j.yebeh.2020.107469DOI Listing
November 2020

Right Temporoparietal Junction Underlies Avoidance of Moral Transgression in Autism Spectrum Disorder.

J Neurosci 2021 02 6;41(8):1699-1715. Epub 2020 Nov 6.

Institut des Sciences Cognitives Marc Jeannerod, CNRS, Neuroeconomics Lab 69675 Bron, France

Autism spectrum disorder (ASD) is characterized by a core difference in theory-of-mind (ToM) ability, which extends to alterations in moral judgment and decision-making. Although the function of the right temporoparietal junction (rTPJ), a key neural marker of ToM and morality, is known to be atypical in autistic individuals, the neurocomputational mechanisms underlying its specific changes in moral decision-making remain unclear. Here, we addressed this question by using a novel fMRI task together with computational modeling and representational similarity analysis (RSA). ASD participants and healthy control subjects (HCs) decided in public or private whether to incur a personal cost for funding a morally good cause (Good Context) or receive a personal gain for benefiting a morally bad cause (Bad Context). Compared with HC, individuals with ASD were much more likely to reject the opportunity to earn ill gotten money by supporting a bad cause than were HCs. Computational modeling revealed that this resulted from heavily weighing benefits for themselves and the bad cause, suggesting that ASD participants apply a rule of refusing to serve a bad cause because they evaluate the negative consequences of their actions more severely. Moreover, RSA revealed a reduced rTPJ representation of the information specific to moral contexts in ASD participants. Together, these findings indicate the contribution of rTPJ in representing information concerning moral rules and provide new insights for the neurobiological basis underpinning moral behaviors illustrated by a specific difference of rTPJ in ASD participants. Previous investigations have found an altered pattern of moral behaviors in individuals with autism spectrum disorder (ASD), which is closely associated with functional changes in the right temporoparietal junction (rTPJ). However, the specific neurocomputational mechanisms at play that drive the altered function of the rTPJ in moral decision-making remain unclear. Here, we show that ASD individuals are more inflexible when following a moral rule although an immoral action can benefit themselves, and experience an increased concern about their ill-gotten gains and the moral cost. Moreover, a selectively reduced rTPJ representation of information concerning moral rules was observed in ASD participants. These findings deepen our understanding of the neurobiological roots that underlie atypical moral behaviors in ASD individuals.
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http://dx.doi.org/10.1523/JNEUROSCI.1237-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115877PMC
February 2021
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