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1.
PLoS One ; 15(8): e0238121, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32845893

RESUMO

Variants implicated in childhood epilepsy have been identified in all four voltage-gated sodium channels that initiate action potentials in the central nervous system. Previous research has focused on the functional effects of particular variants within the most studied of these channels (NaV1.1, NaV1.2 and NaV1.6); however, there have been few comparative studies across channels to infer the impact of mutations in patients with epilepsy. Here we compare patterns of variation in patient and public databases to test the hypothesis that regions of known functional significance within voltage-gated sodium (NaV) channels have an increased burden of deleterious variants. We assessed mutational burden in different regions of the Nav channels by (1) performing Fisher exact tests on odds ratios to infer excess variants in domains, segments, and loops of each channel in patient databases versus public "control" databases, and (2) comparing the cumulative distribution of variant sites along DNA sequences of each gene in patient and public databases (i.e., independent of protein structure). Patient variant density was concordant among channels in regions known to play a role in channel function, with statistically significant higher patient variant density in S4-S6 and DIII-DIV and an excess of public variants in SI-S3, DI-DII, DII-DIII. On the other hand, channel-specific patterns of patient burden were found in the NaV1.6 inactivation gate and NaV1.1 S5-S6 linkers, while NaV1.2 and NaV1.6 S4-S5 linkers and S5 segments shared patient variant patterns that contrasted with those in NaV1.1. These different patterns may reflect different roles played by the NaV1.6 inactivation gate in action potential propagation, and by NaV1.1 S5-S6 linkers in loss of function and haploinsufficiency. Interestingly, NaV1.2 and NaV1.6 both lack amino acid substitutions over significantly long stretches in both the patient and public databases suggesting that new mutations in these regions may cause embryonic lethality or a non-epileptic disease phenotype.


Assuntos
Epilepsia/patologia , Ativação do Canal Iônico/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Substituição de Aminoácidos/genética , Sequência de Bases , Encéfalo/fisiologia , Epilepsia/genética , Variação Genética/genética , Humanos , Potenciais da Membrana/genética , Mutação/genética , Técnicas de Patch-Clamp , Análise de Sequência de DNA
2.
Clin Chem ; 66(1): 199-206, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32609854

RESUMO

BACKGROUND: Exome sequencing has become a commonly used clinical diagnostic test. Multiple studies have examined the diagnostic utility and individual laboratory performance of exome testing; however, no previous study has surveyed and compared the data quality from multiple clinical laboratories. METHODS: We examined sequencing data from 36 clinical exome tests from 3 clinical laboratories. Exome data were compared in terms of overall characteristics and coverage of specific genes and nucleotide positions. The sets of genes examined included genes in Consensus Coding Sequence (CCDS) (n = 17723), a subset of genes clinically relevant to epilepsy (n = 108), and genes that are recommended for reporting of secondary findings (n = 57; excludes X-linked genes). RESULTS: The average exome nucleotide coverage (≥20×) of each laboratory varied at 96.49% (CV = 3%), 96.54% (CV = 1%), and 91.68% (CV = 4%), for laboratories A, B, and C, respectively. For CCDS genes, the average number of completely covered genes varied at 12184 (CV = 29%), 11687 (CV = 13%), and 5989 (CV = 37%), for laboratories A, B, and C, respectively. With smaller subsets of genes related to epilepsy and secondary findings, the CV revealed low consistency, with a maximum CV seen in laboratory C for both epilepsy genes (CV = 60%) and secondary findings genes (CV = 71%). CONCLUSIONS: Poor consistency in complete gene coverage was seen in the clinical exome laboratories surveyed. The degree of consistency varied widely between the laboratories.


Assuntos
Exoma/genética , Proteína BRCA1/genética , Epilepsia/genética , Epilepsia/patologia , Éxons , Guias como Assunto , Humanos , Laboratórios Hospitalares/normas , Proteína 1 Homóloga a MutL/genética , Sequenciamento Completo do Exoma
3.
Gene ; 754: 144847, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32531456

RESUMO

BACKGROUND: A 30-year-old man presented with intellectual disability associated with epilepsy. The epilepsy was initially treated with sodium valproate and since he was 28 years-old with lamotrigine. With the addition of lamotrigine, a pattern of Brugada syndrome appeared on the electrocardiogram. The family history was positive for epilepsy from the mothers side, who had never been treated with lamotrigine. OBJECTIVE: Determine the genetic cause of the intellectual disability, epilepsy and Brugada syndrome of the patient and try to establish a possible correlation between the genetic background and the Brugada syndrome pattern under lamotrigine treatment. METHODS: A standard karyotype, array comparative genomic hybridization and two different NGS panels have done to the index case to identify the genetic causes of the intellectual disability, epilepsy and Brugada syndrome pattern. RESULTS: Genetic analyses in the family identified a de novo duplication of 1.3 Mb in 8p21.3 as well as two novel heterozygous rare variants in SCN9A and AKAP9 genes, both inherited from the mother. CONCLUSION: We hypothesize that in this family the SCN9A variant was responsible for the epileptic syndrome. In addition, given that SCN9A is lightly expressed in the heart tissue, we postulate that this SCN9A variant, alone or in combination with AKAP9 variant, might be responsible for the Brugada pattern when challenged by lamotrigine.


Assuntos
Anticonvulsivantes/efeitos adversos , Síndrome de Brugada/patologia , Epilepsia/tratamento farmacológico , Duplicação Gênica , Lamotrigina/efeitos adversos , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Adulto , Síndrome de Brugada/induzido quimicamente , Síndrome de Brugada/genética , Epilepsia/genética , Epilepsia/patologia , Humanos , Masculino
4.
PLoS One ; 15(6): e0234095, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530968

RESUMO

BACKGROUND: Patients with epilepsy (PwE) have an increased risk of active and lifetime depression. Two in 10 patients experience depression. Lack of trained psychiatric staff in low- and middle-income countries (LMIC) creates a need for screening tools that enable detection of depression in PwE. We describe the translation, validity and reliability assessment of the Patient Health Questionnaire-9 (PHQ-9) as a screening tool for depression among PwE in Rwanda. METHOD: PHQ-9 was translated to Kinyarwanda using translation-back translation and validated by a discussion group. For validation, PwE of ≥15 years of age were administered the PHQ-9 and Hamilton Depression Rating Scale (HDRS) by trained psychiatry staff at Visit 1. A random sample of 20% repeated PHQ-9 and HDRS after 14 days to assess temporal stability and intra-rater reliability. Internal structure, reliability and external validity were assessed using confirmatory factor analysis, reliability coefficients and HDRS-correlation, respectively. Maximal Youden's index was considered for cut-offs. RESULTS: Four hundred and thirty-four PwE, mean age 30.5 years (SD ±13.3), were included of whom 33.6%, 37.9%, 13.4%, and 15.1% had no, mild, moderate and severe depression, respectively. PHQ-9 performed well on a one-factor model (unidimensional model), with factor loadings of 0.63-0.86. Reliability coefficients above 0.80 indicated strong internal consistency. Good temporal stability was observed (0.79 [95% CI: 0.68-0.87]). A strong correlation (R = 0.66, p = 0.01) between PHQ-9 and HDRS summed scores demonstrated robust external validity. The optimal cut-off for the PHQ-9 was similar (≥5) for mild and moderate depression and ≥7 for severe depression. CONCLUSION: PHQ-9 validation in Kinyarwanda creates the capacity to screen PwE in Rwanda at scores of ≥5 for mild or moderate and ≥7 for severe depression. The availability of validated tools for screening and diagnosis for depression is a forward step for holistic care in a resource-limited environment.


Assuntos
Depressão/diagnóstico , Epilepsia/patologia , Questionário de Saúde do Paciente , Adolescente , Adulto , Área Sob a Curva , Depressão/etiologia , Epilepsia/complicações , Feminino , Humanos , Masculino , Psicometria/métodos , Curva ROC , Reprodutibilidade dos Testes , Ruanda , Índice de Gravidade de Doença , Tradução , Adulto Jovem
5.
PLoS One ; 15(5): e0230141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32413036

RESUMO

Comparative severity assessment of animal models and experimental interventions is of utmost relevance for harm-benefit analysis during ethical evaluation, an animal welfare-based model prioritization as well as the validation of refinement measures. Unfortunately, there is a lack of evidence-based approaches to grade an animal's burden in a sensitive, robust, precise, and objective manner. Particular challenges need to be considered in the context of animal-based neuroscientific research because models of neurological disorders can be characterized by relevant changes in the affective state of an animal. Here, we report about an approach for parameter selection and development of a composite measure scheme designed for precise analysis of the distress of animals in a specific model category. Data sets from the analysis of several behavioral and biochemical parameters in three different epilepsy models were subjected to a principal component analysis to select the most informative parameters. The top-ranking parameters included burrowing, open field locomotion, social interaction, and saccharin preference. These were combined to create a composite measure scheme (CMS). CMS data were subjected to cluster analysis enabling the allocation of severity levels to individual animals. The results provided information for a direct comparison between models indicating a comparable severity of the electrical and chemical post-status epilepticus models, and a lower severity of the kindling model. The new CMS can be directly applied for comparison of other rat models with seizure activity or for assessment of novel refinement approaches in the respective research field. The respective online tool for direct application of the CMS or for creating a new CMS based on other parameters from different models is available at https://github.com/mytalbot/cms. However, the robustness and generalizability needs to be further assessed in future studies. More importantly, our concept of parameter selection can serve as a practice example providing the basis for comparable approaches applicable to the development and validation of CMS for all kinds of disease models or interventions.


Assuntos
Modelos Animais de Doenças , Epilepsia/fisiopatologia , Software , Animais , Variação Biológica da População , Epilepsia/patologia , Feminino , Excitação Neurológica , Locomoção , Ratos , Ratos Sprague-Dawley , Comportamento Social , Comportamento Espacial
6.
BMC Med Genet ; 21(1): 96, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32381069

RESUMO

BACKGROUND: Joubert syndrome (JBTS) is a genetically heterogeneous group of neurodevelopmental syndromes caused by primary cilia dysfunction. Usually the neurological presentation starts with abnormal neonatal breathing followed by muscular hypotonia, psychomotor delay, and cerebellar ataxia. Cerebral MRI shows mid- and hindbrain anomalies including the molar tooth sign. We report a male patient with atypical presentation of Joubert syndrome type 23, thus expanding the phenotype. CASE PRESENTATION: Clinical features were consistent with JBTS already from infancy, yet the syndrome was not suspected before cerebral MRI later in childhood showed the characteristic molar tooth sign and ectopic neurohypophysis. From age 11 years seizures developed and after few years became increasingly difficult to treat, also related to inadequate compliance to therapy. He died at 23 years of sudden unexpected death in epilepsy (SUDEP). The genetic diagnosis remained elusive for many years, despite extensive genetic testing. We reached the genetic diagnosis by performing whole genome sequencing of the family trio and analyzing the data with the combination of one analysis pipeline for single nucleotide variants (SNVs)/indels and one for structural variants (SVs). This lead to the identification of the most common variant detected in patients with JBTS23 (OMIM# 616490), rs534542684, in compound heterozygosity with a 8.3 kb deletion in KIAA0586, not previously reported. CONCLUSIONS: We describe for the first time ectopic neurohypophysis and SUDEP in JBTS23, expanding the phenotype of this condition and raising the attention on the possible severity of the epilepsy in this disease. We also highlight the diagnostic power of WGS, which efficiently detects SNVs/indels and in addition allows the identification of SVs.


Assuntos
Anormalidades Múltiplas/genética , Proteínas de Ciclo Celular/genética , Cerebelo/anormalidades , Morte Súbita/patologia , Epilepsia/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Retina/anormalidades , Anormalidades Múltiplas/mortalidade , Anormalidades Múltiplas/patologia , Adulto , Cerebelo/patologia , Criança , Morte Súbita/epidemiologia , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/mortalidade , Deficiências do Desenvolvimento/patologia , Epilepsia/mortalidade , Epilepsia/patologia , Anormalidades do Olho/mortalidade , Anormalidades do Olho/patologia , Feminino , Heterozigoto , Humanos , Mutação INDEL , Doenças Renais Císticas/mortalidade , Doenças Renais Císticas/patologia , Masculino , Neuro-Hipófise/metabolismo , Neuro-Hipófise/patologia , Retina/patologia , Sequenciamento Completo do Genoma , Adulto Jovem
7.
Proc Natl Acad Sci U S A ; 117(19): 10155-10164, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32327603

RESUMO

Myeloperoxidase (MPO)-mediated oxidative stress has been suggested to play an important role in the pathological dysfunction of epileptic brains. However, there is currently no robust brain-imaging tool to detect real-time endogenous hypochlorite (HClO) generation by MPO or a fluorescent probe for rapid high-throughput screening of antiepileptic agents that control the MPO-mediated chlorination stress. Herein, we report an efficient two-photon fluorescence probe (named HCP) for the real-time detection of endogenous HClO signals generated by MPO in the brain of kainic acid (KA)-induced epileptic mice, where HClO-dependent chlorination of quinolone fluorophore gives the enhanced fluorescence response. With this probe, we visualized directly the endogenous HClO fluxes generated by the overexpression of MPO activity in vivo and ex vivo in mouse brains with epileptic behaviors. Notably, by using HCP, we have also constructed a high-throughput screening approach to rapidly screen the potential antiepileptic agents to control MPO-mediated oxidative stress. Moreover, from this screen, we identified that the flavonoid compound apigenin can relieve the MPO-mediated oxidative stress and inhibit the ferroptosis of neuronal cells. Overall, this work provides a versatile fluorescence tool for elucidating the role of HClO generation by MPO in the pathology of epileptic seizures and for rapidly discovering additional antiepileptic agents to prevent and treat epilepsy.


Assuntos
Apigenina/farmacologia , Encéfalo/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Ferroptose , Ácido Hipocloroso/metabolismo , Estresse Oxidativo , Peroxidase/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Mapeamento Encefálico/métodos , Epilepsia/metabolismo , Epilepsia/patologia , Corantes Fluorescentes/química , Camundongos , Neuroimagem/métodos , Fármacos Neuroprotetores/farmacologia
8.
Isr Med Assoc J ; 22(3): 178-184, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32147984

RESUMO

BACKGROUND: The authors reviewed the two most common current uses of brain 18F-labeled fluoro-2-deoxyglucose positron emission tomography (FDG-PET) at a large academic medical center. For epilepsy patients considering surgical management, FDG-PET can help localize epileptogenic lesions, discriminate between multiple or discordant EEG or MRI findings, and predict prognosis for post-surgical seizure control. In elderly patients with cognitive impairment, FDG-PET often demonstrates lobar-specific patterns of hypometabolism that suggest particular underlying neurodegenerative pathologies, such as Alzheimer's disease. FDG-PET of the brain can be a key diagnostic modality and contribute to improved patient care.


Assuntos
Encéfalo/diagnóstico por imagem , Demência/diagnóstico por imagem , Epilepsia/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/patologia , Demência/patologia , Epilepsia/patologia , Humanos
9.
PLoS One ; 15(3): e0229953, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32168507

RESUMO

Epilepsy is a complex neurological disorder characterized by sudden and recurrent seizures, which are caused by various factors, including genetic abnormalities. Several animal models of epilepsy mimic the different symptoms of this disorder. In particular, the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) animals exhibit sound-induced seizures similar to the generalized tonic seizures observed in epileptic patients. However, the genetic alterations underlying the audiogenic seizure susceptibility of the GASH/Sal model remain unknown. In addition, gene variations in the GASH/Sal might have a close resemblance with those described in humans with epilepsy, which is a prerequisite for any new preclinical studies that target genetic abnormalities. Here, we performed whole exome sequencing (WES) in GASH/Sal animals and their corresponding controls to identify and characterize the mutational landscape of the GASH/Sal strain. After filtering the results, moderate- and high-impact variants were validated by Sanger sequencing, assessing the possible impact of the mutations by "in silico" reconstruction of the encoded proteins and analyzing their corresponding biological pathways. Lastly, we quantified gene expression levels by RT-qPCR. In the GASH/Sal model, WES showed the presence of 342 variations, in which 21 were classified as high-impact mutations. After a full bioinformatics analysis to highlight the high quality and reliable variants, the presence of 3 high-impact and 15 moderate-impact variants were identified. Gene expression analysis of the high-impact variants of Asb14 (ankyrin repeat and SOCS Box Containing 14), Msh3 (MutS Homolog 3) and Arhgef38 (Rho Guanine Nucleotide Exchange Factor 38) genes showed a higher expression in the GASH/Sal than in control hamsters. In silico analysis of the functional consequences indicated that those mutations in the three encoded proteins would have severe functional alterations. By functional analysis of the variants, we detected 44 significantly enriched pathways, including the glutamatergic synapse pathway. The data show three high-impact mutations with a major impact on the function of the proteins encoded by these genes, although no mutation in these three genes has been associated with some type of epilepsy until now. Furthermore, GASH/Sal animals also showed gene variants associated with different types of epilepsy that has been extensively documented, as well as mutations in other genes that encode proteins with functions related to neuronal excitability, which could be implied in the phenotype of the GASH/Sal. Our findings provide valuable genetic and biological pathway data associated to the genetic burden of the audiogenic seizure susceptibility and reinforce the need to validate the role of each key mutation in the phenotype of the GASH/Sal model.


Assuntos
Biologia Computacional , Epilepsia Reflexa/epidemiologia , Epilepsia/epidemiologia , Convulsões/epidemiologia , Estimulação Acústica , Animais , Cricetinae , Modelos Animais de Doenças , Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/patologia , Epilepsia Reflexa/tratamento farmacológico , Epilepsia Reflexa/genética , Epilepsia Reflexa/patologia , Feminino , Regulação da Expressão Gênica/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Proteína 3 Homóloga a MutS/genética , Mutação/genética , Convulsões/tratamento farmacológico , Convulsões/genética , Convulsões/patologia , Sequenciamento Completo do Exoma
10.
Hum Genet ; 139(4): 545-555, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32020363

RESUMO

Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.


Assuntos
Potenciais de Ação , Encéfalo , Epilepsia , Proteínas de Membrana , Mutação de Sentido Incorreto , Rede Nervosa , Neurotransmissores/metabolismo , Potenciais Sinápticos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Rede Nervosa/metabolismo , Rede Nervosa/patologia
11.
PLoS One ; 15(2): e0228284, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32023286

RESUMO

INTRODUCTION: The relationships between family history, sex, age at onset, and migraine occurrence have been documented. However, the associations between these factors across different sexes and subgroups of patients have yet to be elucidated. This study evaluated the association between family history and migraine in male and female patients experiencing episodic and chronic migraine with and without aura. METHODS: This cross-sectional, case-control study included 299 headache-free controls and 885 patients receiving outpatient treatment for migraine. Participants were classified into episodic (1-14 days/month) and chronic (≥15 days/month) migraine groups. RESULTS: Positive family history was significantly more frequently observed in the episodic group than in the chronic group (49.5% vs. 26%; P < 0.001) in male patients, particularly in male patients without aura (50.3% vs. 21.9%; P = 0.003); it was less frequently observed (58.7% vs. 73.7%; P = 0.048) in female patients with aura. Family history was correlated with an earlier age at onset (20.7 years vs. 22.8 years; P = 0.002), particularly in patients without aura (21 years vs. 23.7 years; P = 0.002), who were women (20.9 years vs. 23.9 years; P = 0.002). CONCLUSIONS: Different patterns of association between family history and migraine can be observed between men and women. A positive family history of migraine is correlated with an earlier age at onset, particularly among female patients without aura.


Assuntos
Epilepsia/patologia , Transtornos de Enxaqueca/patologia , Adulto , Idade de Início , Estudos de Casos e Controles , Estudos Transversais , Epilepsia/complicações , Família , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Enxaqueca/complicações , Razão de Chances , Q-Sort , Fatores de Risco , Fatores Sexuais , Adulto Jovem
12.
Epilepsia ; 61(3): 433-444, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32065673

RESUMO

OBJECTIVE: Focal cortical dysplasia (FCD) lesion detection and subtyping remain challenging on conventional MRI. New diffusion models such as the spherical mean technique (SMT) and neurite orientation dispersion and density imaging (NODDI) provide measurements that potentially produce more specific maps of abnormal tissue microstructure. This study aims to assess the SMT and NODDI maps for computational and radiological lesion characterization compared to standard fractional anisotropy (FA) and mean diffusivity (MD). METHODS: SMT, NODDI, FA, and MD maps were calculated for 33 pediatric patients with suspected FCD (18 histologically confirmed). Two neuroradiologists scored lesion visibility on clinical images and diffusion maps. Signal profile changes within lesions and homologous regions were quantified using a surface-based approach. Diffusion parameter changes at multiple cortical depths were statistically compared between FCD type IIa and type IIb. RESULTS: Compared to fluid-attenuated inversion recovery (FLAIR) or T1-weighted imaging, lesions conspicuity on NODDI intracellular volume fraction (ICVF) maps was better/equal/worse in 5/14/14 patients, respectively, while on SMT intra-neurite volume fraction (INVF) in 3/3/27. Compared to FA or MD, lesion conspicuity on the ICVF was better/equal/worse in 27/4/2, while on the INVF in 20/7/6. Quantitative signal profiling demonstrated significant ICVF and INVF reductions in the lesions, whereas SMT microscopic mean, radial, and axial diffusivities were significantly increased. FCD type IIb exhibited greater changes than FCD type IIa. No changes were detected on FA or MD profiles. SIGNIFICANCE: FCD lesion-specific signal changes were found in ICVF and INVF but not in FA and MD maps. ICVF and INVF showed greater contrast than FLAIR in some cases and had consistent signal changes specific to FCD, suggesting that they could improve current presurgical pediatric epilepsy imaging protocols and can provide features useful for automated lesion detection.


Assuntos
Imagem de Difusão por Ressonância Magnética/métodos , Epilepsia/diagnóstico por imagem , Espaço Extracelular/diagnóstico por imagem , Espaço Intracelular/diagnóstico por imagem , Malformações do Desenvolvimento Cortical do Grupo I/diagnóstico por imagem , Adolescente , Anisotropia , Criança , Pré-Escolar , Imagem de Tensor de Difusão , Epilepsia/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical do Grupo I/patologia , Neuritos/patologia , Adulto Jovem
13.
Epilepsia ; 61(3): 421-432, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32080846

RESUMO

OBJECTIVE: The microscopic review of hematoxylin-eosin-stained images of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex remains challenging. Both entities are distinct subtypes of human malformations of cortical development that share histopathological features consisting of neuronal dyslamination with dysmorphic neurons and balloon cells. We trained a convolutional neural network (CNN) to classify both entities and visualize the results. Additionally, we propose a new Web-based deep learning application as proof of concept of how deep learning could enter the pathologic routine. METHODS: A digital processing pipeline was developed for a series of 56 cases of focal cortical dysplasia type IIb and cortical tuber of tuberous sclerosis complex to obtain 4000 regions of interest and 200 000 subsamples with different zoom and rotation angles to train a neural network. Guided gradient-weighted class activation maps (Guided Grad-CAMs) were generated to visualize morphological features used by the CNN to distinguish both entities. RESULTS: Our best-performing network achieved 91% accuracy and 0.88 area under the receiver operating characteristic curve at the tile level for an unseen test set. Novel histopathologic patterns were found through the visualized Guided Grad-CAMs. These patterns were assembled into a classification score to augment decision-making in routine histopathology workup. This score was successfully validated by 11 expert neuropathologists and 12 nonexperts, boosting nonexperts to expert level performance. SIGNIFICANCE: Our newly developed Web application combines the visualization of whole slide images with the possibility of deep learning-aided classification between focal cortical dysplasia IIb and tuberous sclerosis complex. This approach will help to introduce deep learning applications and visualization for the histopathologic diagnosis of rare and difficult-to-classify brain lesions.


Assuntos
Córtex Cerebral/patologia , Aprendizado Profundo , Epilepsia/patologia , Malformações do Desenvolvimento Cortical do Grupo I/patologia , Neurônios/patologia , Esclerose Tuberosa/patologia , Algoritmos , Área Sob a Curva , Diagnóstico por Computador , Epilepsia/diagnóstico , Humanos , Internet , Malformações do Desenvolvimento Cortical do Grupo I/diagnóstico , Redes Neurais de Computação , Neuropatologia , Estudo de Prova de Conceito , Curva ROC , Reprodutibilidade dos Testes , Esclerose Tuberosa/diagnóstico
14.
PLoS One ; 15(1): e0227854, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31971965

RESUMO

BACKGROUND: Common mental illness has a substantial impact on seizure control and negatively affects the overall quality of life among individuals with epilepsy. However, there is a dearth of studies that examined the associated factors of common mental illness among epilepsy patients in Ethiopia, particularly in the study area. This study aimed to assess the magnitude and factors associated with common mental disorders in epilepsy patients who attended government health institutions in Bahir Dar city, Ethiopia. METHOD: Health institution based cross-sectional study was conducted using a systematic sampling technique among people living with epilepsy in Bahir Dar City Administration. Common mental illness was assessed using a self-reporting questionnaire and a semi-structured questionnaire was employed to collect data on socio-demographic and clinical related characteristics. Data were analyzed using descriptive statistics, univariate logistic regression, and multivariable logistic regression. RESULTS: The magnitude of comorbid common mental illness among people living with epilepsy was found 35.4%. High magnitude of common mental illness was reported among females (39.9%) when compared to males (32.3%). The most prevalent common mental disorders symptoms include being worried, unhappy feeling, trouble thinking clearly, and difficult to enjoy daily activities. Family history of epilepsy, frequent seizures attacks, side effects of antiepileptic drugs, lack of social support and not adherent to antiepileptic drugs were factors associated with common mental illness. CONCLUSIONS: Common mental illness was found to be prevalent among people living with epilepsy. Therefore, it is recommended that great attention should be given to mental illness besides controlling seizure attacks.


Assuntos
Epilepsia/epidemiologia , Transtornos Mentais/epidemiologia , Convulsões/epidemiologia , Adulto , Anticonvulsivantes/efeitos adversos , Epilepsia/complicações , Epilepsia/tratamento farmacológico , Epilepsia/patologia , Etiópia/epidemiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Transtornos Mentais/complicações , Transtornos Mentais/tratamento farmacológico , Transtornos Mentais/patologia , Pessoa de Meia-Idade , Qualidade de Vida , Convulsões/complicações , Convulsões/tratamento farmacológico , Convulsões/patologia , Caracteres Sexuais , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto Jovem
15.
PLoS One ; 15(1): e0228204, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978189

RESUMO

OBJECTIVE: To clarify the complex mechanism underlying epileptogeneis, a novel animal model was generated. METHODS: In our previous research, we have generated a melanocyte-lineage mTOR hyperactivation mouse model (Mitf-M-Cre Tsc2 KO mice; cKO mice) to investigate mTOR pathway in melanogenesis regulation, markedly reduced skin pigmentation was observed. Very unexpectedly, spontaneous recurrent epilepsy was also developed in this mouse model. RESULTS: Compared with control littermates, no change was found in either brain size or brain mass in cKO mice. Hematoxylin staining revealed no obvious aberrant histologic features in the whole brains of cKO mice. Histoimmunofluorescence staining and electron microscopy examination revealed markedly increased mTOR signaling and hyperproliferation of mitochondria in cKO mice, especially in the hippocampus. Furthermore, rapamycin treatment reversed these abnormalities. CONCLUSIONS: This study suggests that our melanocyte-lineage mTOR hyperactivation mouse is a novel animal model of epilepsy, which may promote the progress of both epilepsy and neurophysiology research.


Assuntos
Epilepsia/patologia , Serina-Treonina Quinases TOR/metabolismo , Animais , Encéfalo/patologia , Encéfalo/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia/tratamento farmacológico , Epilepsia/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/patologia , Melanócitos/citologia , Melanócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Proteína 2 do Complexo Esclerose Tuberosa/deficiência , Proteína 2 do Complexo Esclerose Tuberosa/genética
16.
BMC Vet Res ; 16(1): 18, 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959173

RESUMO

BACKGROUND: Cumulating evidence from rodent models points to a pathophysiological role of inflammatory signaling in the epileptic brain with Toll-like receptor-4 signaling acting as one key factor. However, there is an apparent lack of information about expression alterations affecting this pathway in canine patients with epilepsy. Therefore, we have analyzed the expression pattern of Toll-like receptor 4 and its ligands in brain tissue of canine patients with structural or idiopathic epilepsy in comparison with tissue from laboratory dogs or from owner-kept dogs without neurological diseases. RESULTS: The analysis revealed an overexpression of Toll-like receptor-4 in the CA3 region of dogs with structural epilepsy. Further analysis provided evidence for an upregulation of Toll-like receptor-4 ligands with high mobility group box-1 exhibiting increased expression levels in the CA1 region of dogs with idiopathic and structural epilepsy, and heat shock protein 70 exhibiting increased expression levels in the piriform lobe of dogs with idiopathic epilepsy. In further brain regions, receptor and ligand expression rates proved to be either in the control range or reduced below control levels. CONCLUSIONS: Our study reveals complex molecular alterations affecting the Toll-like receptor signaling cascade, which differ between epilepsy types and between brain regions. Taken together, the data indicate that multi-targeting approaches modulating Toll-like receptor-4 signaling might be of interest for management of canine epilepsy. Further studies are recommended to explore respective molecular alterations in more detail in dogs with different etiologies and to confirm the role of the pro-inflammatory signaling cascade as a putative target.


Assuntos
Encéfalo/patologia , Doenças do Cão/patologia , Epilepsia/veterinária , Receptor 4 Toll-Like/metabolismo , Animais , Encéfalo/metabolismo , Doenças do Cão/metabolismo , Cães , Epilepsia/patologia , Proteínas de Choque Térmico HSP70/metabolismo , Inflamação , Transdução de Sinais
17.
Cell Mol Life Sci ; 77(17): 3279-3291, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31974655

RESUMO

Deep brain stimulation is used to alleviate symptoms of neurological and psychiatric disorders including Parkinson's disease, epilepsy, and obsessive-compulsive-disorder. Electrically stimulating limbic structures has been of great interest, and in particular, the region of the fornix. We conducted a systematic search for studies that reported clinical and preclinical outcomes of deep brain stimulation within the fornix up to July 2019. We identified 13 studies (7 clinical, 6 preclinical) that examined the effects of fornix stimulation in Alzheimer's disease (n = 9), traumatic brain injury (n = 2), Rett syndrome (n = 1), and temporal lobe epilepsy (n = 1). Overall, fornix stimulation can lead to decreased rates of cognitive decline (in humans), enhanced memory (in humans and animals), visuo-spatial memorization (in humans and animals), and improving verbal recollection (in humans). While the exact mechanisms of action are not completely understood, studies suggest fornix DBS to be involved with increased functional connectivity and neurotransmitter levels, as well as enhanced neuroplasticity.


Assuntos
Doença de Alzheimer/patologia , Lesões Encefálicas Traumáticas/patologia , Estimulação Encefálica Profunda , Epilepsia/patologia , Fórnice/fisiologia , Síndrome de Rett/patologia , Animais , Humanos , Memória , Transtornos da Memória/patologia
18.
Support Care Cancer ; 28(3): 1405-1409, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31267278

RESUMO

BACKGROUND: Tumor-related epilepsy (TRE) is the most common cause of hospitalizations in patients with malignant gliomas leading to increased distress and decreased quality of life (QOL) for patients and caregivers. PURPOSE: We sought to determine the feasibility of incorporating a structured TRE-specific education intervention into clinical practice while assessing effect on distress and TRE knowledge. METHODS: We prospectively enrolled glioma patients and their caregivers on an IRB-approved study. Subjects underwent a pre-test to assess baseline knowledge regarding seizure management. A neuro-oncology provider guided subjects through a presentation focused on safety and home management of seizures. Seizure-related distress was measured before and after the educational intervention using a distress thermometer. A post-test was completed. At 2 and 6 months, distress was re-assessed and post-tests were repeated. Subject satisfaction was assessed. RESULTS: Fifty subjects (23 patients, 27 caregivers) were enrolled. Median age was 59. Fifty-seven percent of patients had TRE. Median time to completion was 21.5 min. Median baseline distress scores were 2/10 for patients and 5/10 for caregivers. Distress scores decreased by a mean of 1.5 points and TRE knowledge increased by 2 points for all subjects between the initial and 2-month visit. Ninety-eight percent of subjects strongly agreed that the education was helpful and informative. Caregivers reported more distress despite better baseline seizure knowledge than patients. CONCLUSION: Structured TRE education is feasible in patients with gliomas and their caregivers and may be effective in reducing distress. Further prospective studies are warranted to assess effects on hospitalizations, cost, and QOL.


Assuntos
Cuidadores/educação , Epilepsia/patologia , Glioma/patologia , Educação de Pacientes como Assunto/métodos , Convulsões/terapia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Participação do Paciente/métodos , Estudos Prospectivos , Qualidade de Vida/psicologia , Convulsões/fisiopatologia
19.
Cell Mol Life Sci ; 77(2): 267-274, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31432233

RESUMO

Epilepsy is one of the most common brain disorders, which can be caused by abnormal synaptic transmissions. Many epilepsy-related mutations have been identified in synaptic ion channels, which are main targets for current antiepileptic drugs. One of the novel potential targets for therapy of epilepsy is a class of non-ion channel-type epilepsy-related proteins. The leucine-rich repeat glioma-inactivated protein 1 (LGI1) is a neuronal secreted protein, and has been extensively studied as a product of a causative gene for autosomal dominant lateral temporal lobe epilepsy (ADLTE; also known as autosomal dominant partial epilepsy with auditory features [ADPEAF]). At least 43 mutations of LGI1 have been found in ADLTE families. Additionally, autoantibodies against LGI1 in limbic encephalitis are associated with amnesia, seizures, and cognitive dysfunction. Although the relationship of LGI1 with synaptic transmission and synaptic disorders has been studied genetically, biochemically, and clinically, the structural mechanism of LGI1 remained largely unknown until recently. In this review, we introduce insights into pathogenic mechanisms of LGI1 from recent structural studies on LGI1 and its receptor, ADAM22. We also discuss the mechanism for pathogenesis of autoantibodies against LGI1, and the potential of chemical correctors as novel drugs for epilepsy, with structural aspects of LGI1-ADAM22.


Assuntos
Proteínas ADAM/genética , Epilepsia/genética , Epilepsia/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Animais , Autoanticorpos/metabolismo , Humanos , Mutação/genética
20.
Eur J Paediatr Neurol ; 24: 24-29, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31875834

RESUMO

There has been a traditional conceptual partition between the so-called non-lesional genetic epilepsies and the genetically determined interposed epileptogenic structural abnormalities. In this review, we summarise how growing evidence acquired through neuroimaging and neurobiology modelling is demonstrating that a distinction between lesional and functional (or non-lesional) epileptogenesis is less obvious than previously thought, particularly for epileptogenic neurodevelopmental disorders, but also for most genetically determined epilepsies.


Assuntos
Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/patologia , Epilepsia/genética , Epilepsia/patologia , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/diagnóstico , Epilepsia/complicações , Epilepsia/diagnóstico , Humanos
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