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1.
Epilepsia ; 65(6): 1568-1580, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38606600

RESUMO

OBJECTIVE: This study was undertaken to determine whether hippocampal T2 hyperintensity predicts sequelae of febrile status epilepticus, including hippocampal atrophy, sclerosis, and mesial temporal lobe epilepsy. METHODS: Acute magnetic resonance imaging (MRI) was obtained within a mean of 4.4 (SD = 5.5, median = 2.0) days after febrile status on >200 infants with follow-up MRI at approximately 1, 5, and 10 years. Hippocampal size, morphology, and T2 signal intensity were scored visually by neuroradiologists blinded to clinical details. Hippocampal volumetry provided quantitative measurement. Upon the occurrence of two or more unprovoked seizures, subjects were reassessed for epilepsy. Hippocampal volumes were normalized using total brain volumes. RESULTS: Fourteen of 22 subjects with acute hippocampal T2 hyperintensity returned for follow-up MRI, and 10 developed definite hippocampal sclerosis, which persisted through the 10-year follow-up. Hippocampi appearing normal initially remained normal on visual inspection. However, in subjects with normal-appearing hippocampi, volumetrics indicated that male, but not female, hippocampi were smaller than controls, but increasing hippocampal asymmetry was not seen following febrile status. Forty-four subjects developed epilepsy; six developed mesial temporal lobe epilepsy and, of the six, two had definite, two had equivocal, and two had no hippocampal sclerosis. Only one subject developed mesial temporal epilepsy without initial hyperintensity, and that subject had hippocampal malrotation. Ten-year cumulative incidence of all types of epilepsy, including mesial temporal epilepsy, was highest in subjects with initial T2 hyperintensity and lowest in those with normal signal and no other brain abnormalities. SIGNIFICANCE: Hippocampal T2 hyperintensity following febrile status epilepticus predicted hippocampal sclerosis and significant likelihood of mesial temporal lobe epilepsy. Normal hippocampal appearance in the acute postictal MRI was followed by maintained normal appearance, symmetric growth, and lower risk of epilepsy. Volumetric measurement detected mildly decreased hippocampal volume in males with febrile status.


Assuntos
Epilepsia do Lobo Temporal , Hipocampo , Imageamento por Ressonância Magnética , Esclerose , Convulsões Febris , Estado Epiléptico , Humanos , Hipocampo/patologia , Hipocampo/diagnóstico por imagem , Epilepsia do Lobo Temporal/diagnóstico por imagem , Epilepsia do Lobo Temporal/patologia , Masculino , Feminino , Esclerose/patologia , Estado Epiléptico/diagnóstico por imagem , Estado Epiléptico/patologia , Estado Epiléptico/etiologia , Convulsões Febris/patologia , Convulsões Febris/diagnóstico por imagem , Lactente , Pré-Escolar , Criança , Seguimentos , Atrofia/patologia , Esclerose Hipocampal
2.
Neuropathol Appl Neurobiol ; 48(1): e12746, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34164845

RESUMO

AIMS: Hippocampal findings are implicated in the pathogenesis of sudden unexplained death in childhood (SUDC), although some studies have identified similar findings in sudden explained death in childhood (SEDC) cases. We blindly reviewed hippocampal histology in SUDC and SEDC controls. METHODS: Hippocampal haematoxylin and eosin (H&E) slides (n = 67; 36 SUDC, 31 controls) from clinical and forensic collaborators were evaluated by nine blinded reviewers: three board-certified forensic pathologists, three neuropathologists and three dual-certified neuropathologists/forensic pathologists. RESULTS: Among nine reviewers, about 50% of hippocampal sections were rated as abnormal (52.5% SUDC, 53.0% controls), with no difference by cause of death (COD) (p = 0.16) or febrile seizure history (p = 0.90). There was little agreement among nine reviewers on whether a slide was within normal range (Fleiss' κ = 0.014, p = 0.47). Within reviewer groups, there were no findings more frequent in SUDC compared with controls, with variability in pyramidal neuron and dentate gyrus findings. Across reviewer groups, there was concordance for bilamination and granule cell loss. Neither SUDC (51.2%) nor control (55.9%) slides were considered contributory to determining COD (p = 0.41). CONCLUSIONS: The lack of an association of hippocampal findings in SUDC and controls, as well as inconsistency of observations by multiple blinded reviewers, indicates discrepancy with previous studies and an inability to reliably identify hippocampal maldevelopment associated with sudden death (HMASD). These findings underscore a need for larger studies to standardise evaluation of hippocampal findings, identifying the range of normal variation and changes unrelated to SUDC or febrile seizures. Molecular studies may help identify novel immunohistological markers that inform on COD.


Assuntos
Neuropatologia , Convulsões Febris , Encéfalo/patologia , Criança , Morte Súbita/patologia , Hipocampo/patologia , Humanos , Convulsões Febris/complicações , Convulsões Febris/patologia
3.
Acta Neuropathol ; 143(5): 585-599, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35333953

RESUMO

Sudden unexplained death in childhood (SUDC) is death of a child over 1 year of age that is unexplained after review of clinical history, circumstances of death, and complete autopsy with ancillary testing. Multiple etiologies may cause SUDC. SUDC and sudden unexpected death in epilepsy (SUDEP) share clinical and pathological features, suggesting some similarities in mechanism of death and possible abnormalities in hippocampus and cortex. To identify molecular signaling pathways, we performed label-free quantitative mass spectrometry on microdissected frontal cortex, hippocampal dentate gyrus (DG), and cornu ammonis (CA1-3) in SUDC (n = 19) and pediatric control cases (n = 19) with an explained cause of death. At a 5% false discovery rate (FDR), we found differential expression of 660 proteins in frontal cortex, 170 in DG, and 57 in CA1-3. Pathway analysis of altered proteins identified top signaling pathways associated with activated oxidative phosphorylation (p = 6.3 × 10-15, z = 4.08) and inhibited EIF2 signaling (p = 2.0 × 10-21, z = - 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 × 10-6, z = 2.65) and CA1-3 (p = 4.7 × 10-6, z = 2.00). Weighted gene correlation network analysis (WGCNA) of clinical history indicated that SUDC-positive post-mortem virology (n = 4/17) had the most significant module in each brain region, with the top most significant associated with decreased mRNA metabolic processes (p = 2.8 × 10-5) in frontal cortex. Additional modules were associated with clinical history, including fever within 24 h of death (top: increased mitochondrial fission in DG, p = 1.8 × 10-3) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 × 10-5) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 × 10-3). Overall, cortical and hippocampal protein changes were present in SUDC cases and some correlated with clinical features. Our studies support that proteomic studies of SUDC cohorts can advance our understanding of the pathogenesis of these tragedies and may inform the development of preventive strategies.


Assuntos
Proteômica , Convulsões Febris , Autopsia , Criança , Morte Súbita/etiologia , Morte Súbita/patologia , Hipocampo/patologia , Humanos , Convulsões Febris/complicações , Convulsões Febris/patologia
4.
BMC Med Genet ; 21(1): 10, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31914951

RESUMO

BACKGROUND: The role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene. CASE PRESENTATION: The proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T). CONCLUSIONS: This case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.


Assuntos
Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/genética , Esquizofrenia/genética , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Eletroencefalografia , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Fenótipo , Esquizofrenia/fisiopatologia , Convulsões Febris/genética , Convulsões Febris/patologia
5.
J Pharmacol Sci ; 144(4): 212-217, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070840

RESUMO

The hippocampus is a brain region well-known to exhibit structural and functional changes in temporal lobe epilepsy. Studies analyzing the brains of patients with epilepsy and those from animal models of epilepsy have revealed that microglia are excessively activated, especially in the hippocampus. These findings suggest that microglia may contribute to the onset and aggravation of epilepsy; however, direct evidence for microglial involvement or the underlying mechanisms by which this occurs remain to be fully discovered. To date, neuron-microglia interactions have been vigorously studied in adult epilepsy models; such studies have clarified microglial responses to excessive synchronous firing of neurons. In contrast, the role of microglia in the postnatal brain of patients with epileptic seizures remain largely unclear. Some early-life seizures, such as complex febrile seizures, have been shown to cause structural and functional changes in the brain, which is a risk factor for future development of epilepsy. Because brain structure and function are actively modulated by microglia in both health and disease, it is essential to clarify the role of microglia in early-life seizures and its impact on epileptogenesis.


Assuntos
Comunicação Celular , Epilepsia do Lobo Temporal/etiologia , Epilepsia do Lobo Temporal/patologia , Hipocampo/citologia , Hipocampo/patologia , Microglia/patologia , Microglia/fisiologia , Fatores Etários , Idade de Início , Animais , Giro Denteado/citologia , Giro Denteado/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Neurônios/fisiologia , Ratos , Fatores de Risco , Convulsões Febris/etiologia , Convulsões Febris/patologia , Sinapses/fisiologia
6.
Epilepsia ; 60(7): 1306-1316, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31166617

RESUMO

OBJECTIVE: To assess hippocampal signal changes on diffusion-weighted imaging (DWI) during the acute period after febrile status epilepticus (FSE) and to examine the relationship between DWI and subsequent epilepsy. METHODS: A prospective, multicenter study of children with a first episode of FSE was performed. The patients underwent magnetic resonance imaging (MRI) within 3 days of FSE, and signal intensity was evaluated on DWI. Electroencephalography studies within 3 days of FSE were also assessed. Nine to 13 years after FSE, information on subsequent epilepsy was obtained. RESULTS: Twenty-two children with FSE were evaluated. DWI showed unilateral hippocampal hyperintensity in six patients (27%). Three of six patients with hippocampal hyperintensity had ipsilateral thalamic hyperintensity. On EEG within 3 days of FSE, five of six patients with hippocampal hyperintensity had ipsilateral focal slowing, spikes, or attenuation. Nine to 13 years later, the outcomes could be determined in five patients with hippocampal hyperintensity and in 10 without. All 5 patients with hippocampal hyperintensity had hippocampal atrophy and developed focal epilepsy, whereas only 1 of 10 patients without hippocampal hyperintensity developed epilepsy (P = 0.002). Ictal semiology was concordant with temporal lobe seizures in all patients. Ipsilateral temporal epileptiform abnormalities were seen on EEG in four of five at last follow-up. SIGNIFICANCE: Acute DWI hippocampal hyperintensity was seen in 27% of patients with FSE. Acute DWI hyperintensity suggests cytotoxic edema caused by prolonged seizure activity. Hippocampal DWI hyperintensity is related to mesial temporal lobe epilepsy and can be a target of neuroprotective treatments to prevent the onset of epilepsy.


Assuntos
Epilepsia/patologia , Hipocampo/patologia , Convulsões Febris/patologia , Estado Epiléptico/patologia , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Neuroimagem , Estudos Prospectivos , Convulsões Febris/diagnóstico por imagem , Estado Epiléptico/diagnóstico por imagem
7.
Epilepsia ; 60(4): 585-592, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30854647

RESUMO

Febrile infection-related epilepsy syndrome (FIRES) is a rare severe epileptic syndrome occurring in previously healthy children and characterized by refractory status epilepticus (SE) following a febrile illness. Brain imaging findings in affected patients have been reported in few case series and some case reports. This article is a comprehensive review of the magnetic resonance imaging (MRI) characteristics in all reported patients with a diagnosis of FIRES, describing the findings in the acute and chronic phases of the disease, and discussing possible pathogenesis and radiologic differential diagnoses. Most of the patients had normal brain scans in the acute phase (61%) and about 25% of the patients reported in literature had abnormalities in the temporal lobes. Changes in the basal ganglia and rarely in thalami or brainstem have also been described, as well as diffuse cerebral edema in a minority of patients during the acute phase. The chronic phase of the disease was characterized by atrophic changes and evidence of mesiotemporal sclerosis. An understanding of these MRI abnormalities is necessary to support the diagnosis of FIRES and exclude mimics.


Assuntos
Epilepsia Resistente a Medicamentos/diagnóstico por imagem , Síndromes Epilépticas/diagnóstico por imagem , Neuroimagem/métodos , Convulsões Febris/diagnóstico por imagem , Estado Epiléptico/diagnóstico por imagem , Criança , Pré-Escolar , Epilepsia Resistente a Medicamentos/etiologia , Epilepsia Resistente a Medicamentos/patologia , Síndromes Epilépticas/etiologia , Síndromes Epilépticas/patologia , Feminino , Humanos , Infecções/complicações , Masculino , Convulsões Febris/patologia , Estado Epiléptico/etiologia , Estado Epiléptico/patologia
8.
Anal Chem ; 90(24): 14514-14520, 2018 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-30474971

RESUMO

Febrile seizure (FS), a frequently encountered seizure disorder in pediatric populations, can cause hippocampus damage. It has been elucidated that sulfur dioxide (SO2) content is overproduced during the development of FS and related brain injury. Thus, monitoring in situ the level of endogenous SO2 in FS-related models is helpful to estimate the pathogenesis of FS-induced brain injury, but the effect detection method remains to be explored. Herein, we developed a two-photon energy transfer cassette based on an acedan-anthocyanidin scaffold, TP-Ratio-SO2, allowing us to achieve this purpose. TP-Ratio-SO2 specifically responds to SO2 derivatives (HSO3-/SO32-) in an ultrafast fashion (less than 3 s), and HSO3-/SO32- can be sensitively determined with a detection limit of 26 nM. Moreover, it exhibits significant changes in two well-resolved fluorescence emissions (Δλ = 140 nm) by reacting with HSO3-/SO32-, behaving as a ratiometric fluorescent sensor. Importantly, ratiometric imaging of endogenous SO2 derivatives generation in hyperpyretic U251 cells and in a rat model of FS-treated hippocampus damage was successfully carried out by TP-Ratio-SO2, demonstrating that it may be a promising tool for studying the role of SO2 in FS-associated neurological diseases.


Assuntos
Transferência Ressonante de Energia de Fluorescência , Hipocampo/metabolismo , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Dióxido de Enxofre/análise , Animais , Antocianinas/química , Linhagem Celular Tumoral , Modelos Animais de Doenças , Corantes Fluorescentes/química , Hipocampo/química , Humanos , Limite de Detecção , Fígado/metabolismo , Fígado/patologia , Ratos , Convulsões Febris/metabolismo , Convulsões Febris/patologia , Espectrofotometria , Dióxido de Enxofre/química , Dióxido de Enxofre/metabolismo
9.
Biochem Biophys Res Commun ; 486(3): 706-711, 2017 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-28342868

RESUMO

Human herpesvirus 6B (HHV-6B) causes exanthema subitum in infants and is known to be mildly pathogenic. However, HHV-6B infection can induce febrile seizures in a high percentage of patients, and in rare cases, result in encephalitis. We detected higher levels of interleukin (IL)-1ß and basic fibroblast growth factor (bFGF) in the cerebrospinal fluid (CFS) of patients with HHV-6B encephalitis when compared to those in patients with non-HHV-6B-induced febrile seizures. In vitro, IL-1ß and bFGF enhanced HHV-6B gene expression in infected U373 astrocytes during the initial and maintenance phases of infection, respectively. These findings indicated that IL-1ß and bFGF contribute to HHV-6B growth and the onset of encephalitis.


Assuntos
DNA Viral/genética , Encefalite Viral/genética , Fatores de Crescimento de Fibroblastos/genética , Herpesvirus Humano 6/genética , Interleucina-1beta/genética , Convulsões Febris/genética , Astrócitos/metabolismo , Astrócitos/virologia , Estudos de Casos e Controles , Linhagem Celular , Pré-Escolar , DNA Viral/líquido cefalorraquidiano , Encefalite Viral/líquido cefalorraquidiano , Encefalite Viral/patologia , Encefalite Viral/virologia , Feminino , Fatores de Crescimento de Fibroblastos/líquido cefalorraquidiano , Expressão Gênica , Herpesvirus Humano 6/crescimento & desenvolvimento , Herpesvirus Humano 6/patogenicidade , Interações Hospedeiro-Patógeno , Humanos , Lactente , Interleucina-1beta/líquido cefalorraquidiano , Masculino , RNA Mensageiro/líquido cefalorraquidiano , RNA Mensageiro/genética , Convulsões Febris/líquido cefalorraquidiano , Convulsões Febris/patologia , Convulsões Febris/virologia
10.
Biochim Biophys Acta Mol Basis Dis ; 1863(9): 2120-2125, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28572006

RESUMO

Febrile seizures (FS) are convulsions associated with high body temperature. It has a high incidence in children from the age of 6months to 5years and may have adverse consequences in adulthood. The experimental model of FS could be induced in animals via hyperthermia. The present study was designed to investigate persistent electroencephalographic (EEG), neurochemical and behavioral alterations in adult animals that had experienced complex FS at their immature age. EEG signals were obtained from the cortex of both FS and control normothermic groups of animals. A spectrophotometric assay was carried out to determine oxidative stress parameters (malondialdehyde, nitric oxide, reduced glutathione) and acetylcholinesterase activity in the cortex and hippocampus of FS and control animals. Behavioral assessment of seizure threshold and severity were investigated via a sub-convulsive dose of nicotine in adult animals. Alterations in the oxidant/antioxidant system and AChE activity were obtained in the cortex and hippocampus of FS animals in comparison to control animals. EEG spectral analysis displayed significant changes in all EEG frequency bands. A decrease in seizure latency and an increase in seizure severity were also observed. The present study provides evidence for long-lasting abnormalities in the cortex and hippocampus of adult animals subjected to complex FS at their developmental age, which may be correlated to the underlying mechanism of epileptogenesis and its related co-morbidities.


Assuntos
Comportamento Animal , Eletrocardiografia , Hipocampo/fisiopatologia , Convulsões Febris/fisiopatologia , Acetilcolinesterase/metabolismo , Animais , Modelos Animais de Doenças , Proteínas Ligadas por GPI/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Nicotina/efeitos adversos , Nicotina/farmacologia , Ratos , Ratos Wistar , Convulsões Febris/induzido quimicamente , Convulsões Febris/metabolismo , Convulsões Febris/patologia , Fatores de Tempo
11.
Epilepsia ; 58(5): 772-780, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28332711

RESUMO

OBJECTIVE: Diffusion magnetic resonance imaging (MRI) studies have demonstrated acute white matter changes following prolonged febrile seizures (PFS), but their longer-term evolution is unknown. We investigated a population-based cohort to determine white matter diffusion properties 8 years after PFS. METHODS: We used diffusion tensor imaging (DTI) and applied Tract-Based Spatial Statistics for voxel-wise comparison of white matter microstructure between 26 children with PFS and 27 age-matched healthy controls. Age, gender, handedness, and hippocampal volumes were entered as covariates for voxel-wise analysis. RESULTS: Mean duration between the episode of PFS and follow-up was 8.2 years (range 6.7-9.6). All children were neurologically normal, and had normal conventional neuroimaging. On voxel-wise analysis, compared to controls, the PFS group had (1) increased fractional anisotropy in early maturing central white matter tracts, (2) increased mean and axial diffusivity in several peripheral white matter tracts and late-maturing central white matter tracts, and (3) increased radial diffusivity in peripheral white matter tracts. None of the tracts had reduced fractional anisotropy or diffusivity indices in the PFS group. SIGNIFICANCE: In this homogeneous, population-based sample, we found increased fractional anisotropy in early maturing central white matter tracts and increased mean and axial diffusivity with/without increased radial diffusivity in several late-maturing peripheral white matter tracts 8 years post-PFS. We propose disruption in white matter maturation secondary to seizure-induced axonal injury, with subsequent neuroplasticity and microstructural reorganization as a plausible explanation.


Assuntos
Encéfalo/patologia , Imagem de Difusão por Ressonância Magnética , Vias Neurais/patologia , Plasticidade Neuronal/fisiologia , Convulsões Febris/patologia , Substância Branca/patologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Imagem Ecoplanar , Feminino , Seguimentos , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento Tridimensional , Lactente , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/fisiopatologia , Tamanho do Órgão/fisiologia , Valores de Referência , Esclerose , Convulsões Febris/diagnóstico , Convulsões Febris/fisiopatologia , Lobo Temporal/patologia , Lobo Temporal/fisiopatologia , Substância Branca/fisiopatologia
12.
Neurobiol Dis ; 91: 10-20, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26875662

RESUMO

Atypical febrile seizures are considered a risk factor for epilepsy onset and cognitive impairments later in life. Patients with temporal lobe epilepsy and a history of atypical febrile seizures often carry a cortical malformation. This association has led to the hypothesis that the presence of a cortical dysplasia exacerbates febrile seizures in infancy, in turn increasing the risk for neurological sequelae. The mechanisms linking these events are currently poorly understood. Potassium-chloride cotransporter KCC2 affects several aspects of neuronal circuit development and function, by modulating GABAergic transmission and excitatory synapse formation. Recent data suggest that KCC2 downregulation contributes to seizure generation in the epileptic adult brain, but its role in the developing brain is still controversial. In a rodent model of atypical febrile seizures, combining a cortical dysplasia and hyperthermia-induced seizures (LHS rats), we found a premature and sustained increase in KCC2 protein levels, accompanied by a negative shift of the reversal potential of GABA. In parallel, we observed a significant reduction in dendritic spine size and mEPSC amplitude in CA1 pyramidal neurons, accompanied by spatial memory deficits. To investigate whether KCC2 premature overexpression plays a role in seizure susceptibility and synaptic alterations, we reduced KCC2 expression selectively in hippocampal pyramidal neurons by in utero electroporation of shRNA. Remarkably, KCC2 shRNA-electroporated LHS rats show reduced hyperthermia-induced seizure susceptibility, while dendritic spine size deficits were rescued. Our findings demonstrate that KCC2 overexpression in a compromised developing brain increases febrile seizure susceptibility and contribute to dendritic spine alterations.


Assuntos
Encéfalo/metabolismo , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/patologia , Convulsões Febris/patologia , Simportadores/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/crescimento & desenvolvimento , Suscetibilidade a Doenças/metabolismo , Epilepsia/fisiopatologia , Transtornos da Memória/metabolismo , Neurogênese/fisiologia , Células Piramidais/metabolismo , Ratos Sprague-Dawley , Convulsões Febris/metabolismo , Convulsões Febris/fisiopatologia , Cotransportadores de K e Cl-
13.
Am J Hum Genet ; 93(5): 967-75, 2013 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-24207121

RESUMO

Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and fever-sensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures.


Assuntos
Proteínas de Ligação a DNA/genética , Epilepsias Mioclônicas/genética , Animais , Criança , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Estudos de Coortes , Epilepsias Mioclônicas/patologia , Exoma , Feminino , Técnicas de Silenciamento de Genes , Haploinsuficiência , Humanos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Larva/genética , Masculino , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Fenótipo , Convulsões Febris/genética , Convulsões Febris/patologia , Adulto Jovem , Peixe-Zebra
14.
J Neurosci Res ; 94(9): 804-13, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26931373

RESUMO

Prolonged and focal febrile seizures (FSs) have been associated with the development of temporal lobe epilepsy (TLE), although the underlying mechanism and the contribution of predisposing risk factors are still poorly understood. Using a kainate model of TLE, we previously provided strong evidence that interruption of astrocyte gap junction-mediated intercellular communication represents a crucial event in epileptogenesis. To elucidate this aspect further, we induced seizures in immature mice by hyperthermia (HT) to study the consequences of FSs on the hippocampal astrocytic network. Changes in interastrocytic coupling were assessed by tracer diffusion studies in acute slices from mice 5 days after experimental FS induction. The results reveal that HT-induced FSs cause a pronounced reduction of astrocyte gap junctional coupling in the hippocampus by more than 50%. Western blot analysis indicated that reduced connexin43 protein expression and/or changes in the phosphorylation status account for this astrocyte dysfunction. Remarkably, uncoupling occurred in the absence of neuronal death and reactive gliosis. These data provide a mechanistic link between FSs and the subsequent development of TLE and further strengthen the emerging view that astrocytes have a central role in the pathogenesis of this disorder. © 2016 Wiley Periodicals, Inc.


Assuntos
Astrócitos/patologia , Sinapses Elétricas/patologia , Convulsões Febris/patologia , Animais , Morte Celular , Conexina 43/metabolismo , Epilepsia do Lobo Temporal/patologia , Febre/patologia , Gliose/patologia , Hipocampo/patologia , Ativação de Macrófagos , Camundongos , Fosforilação
15.
Epilepsia ; 57(5): 717-26, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27020476

RESUMO

OBJECTIVE: Febrile seizures (FS) are fever-associated convulsions, being the most common seizure disorder in early childhood. A subgroup of these children later develops epilepsy characterized by a hyperexcitable neuronal network in the hippocampus. Hippocampal excitability is regulated by the hippocampal dentate gyrus (DG) where postnatal neurogenesis occurs. Experimental FS increase the survival of newborn hippocampal dentate granule cells (DGCs), yet the significance of this neuronal subpopulation to the hippocampal network remains unclear. In the current study, we characterized the temporal maturation and structural integration of these post-FS born DGCs in the DG. METHODS: Experimental FS were induced in 10-day-old rat pups. The next day, retroviral particles coding for enhanced green fluorescent protein (eGFP) were stereotactically injected in the DG to label newborn cells. Histochemical analyses of eGFP expressing DGCs were performed one, 4, and 8 weeks later and consisted of the following: (1) colocalization with neurodevelopmental markers doublecortin, calretinin, and the mature neuronal marker NeuN; (2) quantification of dendritic complexity; and (3) quantification of spine density and morphology. RESULTS: At neither time point were neurodevelopmental markers differently expressed between FS animals and normothermia (NT) controls. One week after treatment, DGCs from FS animals showed dendrites that were 66% longer than those from NT controls. At 4 and 8 weeks, Sholl analysis of the outer 83% of the molecular layer showed 20-25% more intersections in FS animals than in NT controls (p < 0.01). Although overall spine density was not affected, an increase in mushroom-type spines was observed after 8 weeks. SIGNIFICANCE: Experimental FS increase dendritic complexity and the number of mushroom-type spines in post-FS born DGCs, demonstrating a more mature phenotype and suggesting increased incoming excitatory information. The consequences of this hyperconnectivity to signal processing in the DG and the output of the hippocampus remain to be studied.


Assuntos
Dendritos/fisiologia , Giro Denteado/patologia , Neurônios/ultraestrutura , Convulsões Febris/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Calbindina 2/metabolismo , Convulsivantes/toxicidade , Giro Denteado/crescimento & desenvolvimento , Modelos Animais de Doenças , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeos/metabolismo , Fosfopiruvato Hidratase/metabolismo , Polimetil Metacrilato/toxicidade , Ratos , Ratos Sprague-Dawley , Convulsões Febris/induzido quimicamente , Transdução Genética , Transfecção
16.
Neurochem Res ; 41(4): 933-42, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26700432

RESUMO

Accumulating data suggest that sodium-hydrogen exchangers (NHEs) play a key role in modulating seizure activity by regulating neuronal pH in the brain. Amiloride, an inhibitor of NHEs, has been demonstrated to be effective in many seizure models, although its efficacy for prolonged febrile seizures (FS) remains unclear. In this study, we investigated whether amiloride could produce neuroprotective effects in a prolonged FS model in which FS were induced in rat pups at postnatal day 10 using a heated air approach. Amiloride was administered by intraperitoneal injection at three different doses (0.65, 1.3 and 2.6 mg/kg). Pretreatment with amiloride significantly delayed the onset of the first episode of limbic seizures, whereas posttreatment with amiloride decreased escape latency in the Morris water maze test compared to post-FS treatment with saline. Amiloride also inhibited seizure-induced aberrant neurogenesis. In conclusion, this study demonstrated the antiseizure activity of amiloride. In particular, posttreatment with amiloride resulted in cognitive improvement; this finding provides crucial evidence of the neuroprotective function of amiloride and of the therapeutic potential of amiloride in FS.


Assuntos
Amilorida/uso terapêutico , Proteínas de Transporte de Cátions/antagonistas & inibidores , Transtornos Cognitivos/tratamento farmacológico , Convulsões Febris/tratamento farmacológico , Trocadores de Sódio-Hidrogênio/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Proteínas de Transporte de Cátions/metabolismo , Transtornos Cognitivos/psicologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Neurogênese , Neurônios/patologia , Ratos Sprague-Dawley , Convulsões Febris/patologia , Convulsões Febris/fisiopatologia , Convulsões Febris/psicologia , Trocador 1 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Fatores de Tempo
17.
Neuroimmunomodulation ; 23(5-6): 271-277, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28095390

RESUMO

OBJECTIVE: Hydrogen sulfide (H2S), as a novel gasotransmitter, plays important roles in a number of physiological and pathological processes. Its effectiveness has been demonstrated in different types of brain disorders but not in repetitive febrile seizure (febrile status epilepticus; FSE) models. This study aims to test whether a donor of H2S sodium sulfhydrate (NaHS) is also effective for FSE in rats. METHODS: FSE was induced in rat pups on postnatal day 10 in water at 45.0 ± 0.1°C for 10 consecutive days with or without preadministration of NaHS. Following evaluation of the latency and duration of hyperthermic seizures, impairment in learning and memory was measured by the Morris water maze test. Moreover, alterations of the microglial response and the production of proinflammatory cytokines IL-1ß and TNF-α were calculated in the hippocampus. RESULTS: We found that NaHS significantly increased the latency and decreased the duration of hyperthermic seizures. Furthermore, NaHS-treated pups showed less impairment in learning and memory. In addition, NaHS inhibited FSE-induced microglial responses and suppressed the production of IL-1ß and TNF-α in the hippocampus. CONCLUSION: NaHS appears to be effective for the treatment of FSE in infants and children, in part due to its anti-inflammatory action.


Assuntos
Citocinas/metabolismo , Gasotransmissores/uso terapêutico , Sulfeto de Hidrogênio/uso terapêutico , Deficiências da Aprendizagem/tratamento farmacológico , Deficiências da Aprendizagem/etiologia , Convulsões Febris/complicações , Animais , Animais Recém-Nascidos , Antígeno CD11b/genética , Antígeno CD11b/metabolismo , Citocinas/genética , Modelos Animais de Doenças , Eletroencefalografia , Feminino , Febre/complicações , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Gravidez , RNA Mensageiro/metabolismo , Ratos , Tempo de Reação/efeitos dos fármacos , Convulsões Febris/etiologia , Convulsões Febris/patologia
18.
Kathmandu Univ Med J (KUMJ) ; 14(56): 347-351, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-29336424

RESUMO

Background Seizure disorder is the most common childhood neurologic condition and a major public health concern. Identification of the underlying seizure etiology helps to identify appropriate treatment options and the prognosis for the child. Objective This study was conducted to investigate the clinical profile, causes and electroencephalogram findings in children with seizure presenting to a tertiary center in Kavre district. Method This was a hospital based prospective study carried out in the Department of Pediatrics, Dhulikhel Hospital, Kavre from 1st April 2015 to 31st March 2016. Variables collected were demographics, clinical presentations, laboratory tests, brain imaging studies, electroencephalography, diagnosis and outcome. Result Study included 120 (age 1 month to 16 years) children attending Dhulikhel Hospital. Majority of the patients were male (60.84%). Age at first seizure was less than 5 years in 75.83% of children. Seizure was generalized in 62.50%, focal in 31.67% and unclassified in 5.83%. Common causes of seizure were - Primary generalized epilepsy (26.66%), neurocysticercosis (10%) and hypoxic injury (6.6%) which was diagnosed in the perinatal period. Febrile seizure (26.66%) was the most common cause of seizure in children between 6 months to 5 years of age. Neurological examination, electroencephalography and Computed Tomography were abnormal in 71.66%, 68.92% and 58.14% cases respectively. Seizure was controlled by monotherapy in 69.16% cases and was resistant in 7.50% of the cases. Conclusion Primary generalized epilepsy and febrile seizure were the most common causes of seizures in children attending Dhulikhel Hospital. Electroencephalogram findings help to know the pattern of neuronal activity. Response to monotherapy was good and valproic acid was the most commonly used drug.


Assuntos
Convulsões/diagnóstico , Convulsões/patologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Eletroencefalografia , Feminino , Humanos , Lactente , Masculino , Prognóstico , Estudos Prospectivos , Convulsões/diagnóstico por imagem , Convulsões Febris/diagnóstico , Convulsões Febris/patologia , Fatores Sexuais , Fatores Socioeconômicos , Tomografia Computadorizada por Raios X
19.
J Neurosci ; 34(26): 8672-84, 2014 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-24966369

RESUMO

A significant proportion of temporal lobe epilepsy (TLE), a common, intractable brain disorder, arises in children with febrile status epilepticus (FSE). Preventative therapy development is hampered by our inability to identify early the FSE individuals who will develop TLE. In a naturalistic rat model of FSE, we used high-magnetic-field MRI and long-term video EEG to seek clinically relevant noninvasive markers of epileptogenesis and found that reduced amygdala T2 relaxation times in high-magnetic-field MRI hours after FSE predicted experimental TLE. Reduced T2 values likely represented paramagnetic susceptibility effects derived from increased unsaturated venous hemoglobin, suggesting augmented oxygen utilization after FSE termination. Indeed, T2 correlated with energy-demanding intracellular translocation of the injury-sensor high-mobility group box 1 (HMGB1), a trigger of inflammatory cascades implicated in epileptogenesis. Use of deoxyhemoglobin-sensitive MRI sequences enabled visualization of the predictive changes on lower-field, clinically relevant scanners. This novel MRI signature delineates the onset and suggests mechanisms of epileptogenesis that follow experimental FSE.


Assuntos
Encéfalo/fisiopatologia , Eletroencefalografia/métodos , Epilepsia/diagnóstico , Imageamento por Ressonância Magnética/métodos , Convulsões Febris/complicações , Estado Epiléptico/complicações , Animais , Biomarcadores , Encéfalo/patologia , Modelos Animais de Doenças , Epilepsia/etiologia , Epilepsia/patologia , Epilepsia/fisiopatologia , Ratos , Ratos Sprague-Dawley , Convulsões Febris/patologia , Convulsões Febris/fisiopatologia , Estado Epiléptico/patologia , Estado Epiléptico/fisiopatologia
20.
Neurobiol Dis ; 77: 62-70, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25731747

RESUMO

Childhood absence epilepsy (CAE) is one of the most common forms of epilepsy among children. The study of a large Australian family demonstrated that a point mutation in the gene encoding the gamma2 subunit of the GABA(A) receptor (G2R43Q) leads to an autosomal dominantly inherited form of CAE and febrile seizures (FS). In a transgenic mouse model carrying the gamma2 (R43Q) mutation heterozygous animals recapitulate the human phenotype. In-vitro experiments indicated that this point mutation impairs cortical inhibition and thus increases the likelihood of seizures. Here, using whole-cell (WC) and extracellular (EC) recordings as well as voltage-sensitive dye imaging (VSDI), we systematically searched for an in vivo correlate of cortical alterations caused by the G2R43Q mutation, as suggested by the mentioned in vitro results. We measured spontaneous and whisker-evoked activity in the primary somatosensory cortex and ventral posteriomedial nucleus of the thalamus (VPM) before and after intraperitoneal injection of the ictogenic substance pentylenetetrazol (PTZ) in urethane-anesthetized G2R43Q mice and controls in a blinded setting. Compared to wildtype controls in G2R43Q mice after PTZ injection we found 1.) Increased cortical spontaneous activity in layer 2/3 and layer 5/6 pyramidal neurons (increased standard deviation of the mean membrane potential in WC recordings), 2.) Increased variance of stimulus evoked cortical responses in VSDI experiments. 3.) The cortical effects are not due to increased strength or precision of thalamic output. In summary our findings support the hypothesis of a cortical pathology in this mouse model of human genetic absence epilepsy. Further study is needed to characterize underlying molecular mechanisms.


Assuntos
Córtex Cerebral/patologia , Epilepsia Tipo Ausência/patologia , Mutação/genética , Receptores de GABA-A/genética , Convulsões Febris/patologia , Potenciais de Ação/genética , Animais , Convulsivantes/toxicidade , Modelos Animais de Doenças , Epilepsia Tipo Ausência/induzido quimicamente , Epilepsia Tipo Ausência/genética , Potenciais Somatossensoriais Evocados/efeitos dos fármacos , Humanos , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Pentilenotetrazol/toxicidade , Convulsões Febris/induzido quimicamente , Convulsões Febris/genética , Estatísticas não Paramétricas , Vibrissas/inervação , Imagens com Corantes Sensíveis à Voltagem
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