RESUMEN
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.
Asunto(s)
Epilepsia del Lóbulo Temporal , Hipocampo , Imagen por Resonancia Magnética , Esclerosis , Convulsiones Febriles , Estado Epiléptico , Humanos , Hipocampo/patología , Hipocampo/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/patología , Masculino , Femenino , Esclerosis/patología , Estado Epiléptico/diagnóstico por imagen , Estado Epiléptico/patología , Estado Epiléptico/etiología , Convulsiones Febriles/patología , Convulsiones Febriles/diagnóstico por imagen , Lactante , Preescolar , Niño , Estudios de Seguimiento , Atrofia/patología , Esclerosis del HipocampoRESUMEN
PURPOSE: We investigated the volumetric differences in cortical and subcortical structures between patients with complex febrile seizure (FS) and recurrent simple FS. We aimed to identify the brain morphological patterns of children with complex FS. METHODS: Twenty-five patients with complex FS and age- and sex-matched 25 patients with recurrent simple FS with structural magnetic resonance imaging (MRI) scans were studied. Cortical volumetric analysis was performed using a voxel-based morphometry method with the CAT12 toolbox within SPM12. FSL-FIRST was used to obtain volume measures of subcortical deep grey matter structures (amygdala, caudate nucleus, thalamus, nucleus accumbens, putamen, globus pallidus, and hippocampus). The volumetric asymmetry index (AI) and laterality index (LI) were calculated for each subcortical structure. RESULTS: Compared with recurrent simple FS, complex FS demonstrated lower volume in the left putamen (p = .003) and right nucleus accumbens (p = .001). Additionally, patients with complex FS presented a higher magnitude of AI of the nucleus accumbens (p < .001) compared with recurrent simple FS. CONCLUSIONS: The findings indicate that volumetric analysis may be a useful marker for the detection of FS-induced changes that reflect microstructural alterations. This study is the first to report on alterations in the putamen and nucleus accumbens in FS.
Asunto(s)
Convulsiones Febriles , Niño , Humanos , Convulsiones Febriles/diagnóstico por imagen , Convulsiones Febriles/patología , Imagen por Resonancia Magnética/métodos , Tálamo/patología , Globo Pálido/patología , HipocampoRESUMEN
Febrile seizure (FS), which occurs as a response to fever, is the most common seizure that occurs in infants and young children. FS is usually accompanied by diverse neuropsychiatric symptoms, including impaired social behaviors; however, research on neuropsychiatric disorders and hippocampal inflammatory changes following febrile seizure occurrences is very limited. Here, we provide evidence linking FS occurrence with ASD pathogenesis in rats. We developed an FS juvenile rats model and found ASD-like abnormal behaviors including deficits in social novelty, repetitive behaviors, and hyperlocomotion. In addition, FS model juvenile rats showed enhanced levels of gliosis and inflammation in the hippocampal CA2 region and cerebellum. Furthermore, abnormal levels of social and repetitive behaviors persisted in adults FS model rats. These findings suggest that the inflammatory response triggered by febrile seizures in young children could potentially serve as a mediator of social cognitive impairments.
Asunto(s)
Convulsiones Febriles , Humanos , Niño , Ratas , Animales , Preescolar , Convulsiones Febriles/complicaciones , Convulsiones Febriles/patología , Región CA2 Hipocampal/patología , Ratas Sprague-Dawley , Citocinas , Gliosis/complicacionesRESUMEN
PURPOSE: To investigate the characteristics of patients with MRI-negative temporal lobe epilepsy (TLE) (1.5 T brain MRI) in comparison with: (i) patients with hippocampal sclerosis (HS)-TLE; (ii) persons with non-HS structural TLE; and (iii) patients with dual pathology. METHODS: This was a retrospective study. All patients with an electro-clinical diagnosis of TLE were studied at the outpatient epilepsy clinic at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2020. RESULTS: Six hundred and forty-one patients were studied [273 (42.6%) HS, 154 (24.0%) non-HS structural TLE, 174 (27.1%) MRI-negative TLE, and 40 (6.2%) dual pathology]. The groups differed significantly. Important dissimilarities included: (i) compared with HS-TLE group, patients with MRI-negative TLE more often had a family history of epilepsy and less often had a history of febrile convulsion; (ii) compared with non-HS structural TLE group, patients with MRI-negative TLE more often had focal to bilateral tonic-clonic seizures, less often had focal seizures with impaired awareness, and more often had a family history of epilepsy; (iii) compared with the dual pathology group, patients with MRI-negative TLE less often were male and less often had a history of febrile convulsion. CONCLUSION: Patients with MRI-negative TLE are not a homogenous group of people and it is not necessarily a distinct entity from other forms of TLE either. With the emergence of advanced imaging technologies, the underlying pathologies of MRI-negative TLE may be revealed.
Asunto(s)
Epilepsia del Lóbulo Temporal , Convulsiones Febriles , Humanos , Masculino , Femenino , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/patología , Convulsiones Febriles/patología , Estudios Retrospectivos , Hipocampo/patología , Esclerosis/diagnóstico por imagen , Esclerosis/patología , Imagen por Resonancia Magnética/métodos , ConvulsionesRESUMEN
Febrile seizure (FS) is a common type of seizure occurring in human during infancy and childhood. Although an epileptic seizure is associated with psychiatric disorders and comorbid diseases such as depression, anxiety, autism spectrum disorders, sleep disorders, attention deficits, cognitive impairment, and migraine, the causal relationship between FS and psychiatric disorders is poorly understood. The objective of the current study was to investigate the relationship of FS occurrence in childhood with the pathogenesis of anxiety disorder and depression using an FS rat model. We induced febrile seizures in infantile rats (11 days postnatal) using a mercury vapor lamp. At 3 weeks and 12 weeks after FS induction, we examined behaviors and recorded local field potentials (LFPs) to assess anxiety and depression disorder. Interestingly, after FS induction in infantile rats, anxiogenic behaviors and depression-like phenotypes were found in both adult and juvenile FS rats. The analysis of LFPs revealed that 4-7 Hz hippocampal theta rhythm, a neural oscillatory marker for anxiety disorder, was significantly increased in FS rats compared with their wild-type littermates. Taken together, our findings suggest that FS occurrence in infants is causally related to increased levels of anxiety-related behaviors and depression-like symptoms in juvenile and adult rodents.
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Mercurio , Convulsiones Febriles , Humanos , Adulto , Lactante , Ratas , Animales , Convulsiones Febriles/inducido químicamente , Convulsiones Febriles/patología , Depresión/complicaciones , Hipocampo/patología , Ansiedad/complicacionesRESUMEN
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.
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Proteómica , Convulsiones Febriles , Autopsia , Niño , Muerte Súbita/etiología , Muerte Súbita/patología , Hipocampo/patología , Humanos , Convulsiones Febriles/complicaciones , Convulsiones Febriles/patologíaRESUMEN
Complex febrile seizures (CFS), a subset of paediatric febrile seizures (FS), have been studied for their prognosis, epileptogenic potential and neurocognitive outcome. We evaluated their functional connectivity differences with simple febrile seizures (SFS) in children with recent-onset FS. Resting-state fMRI (rs-fMRI) datasets of 24 children with recently diagnosed FS (SFS-n = 11; CFS-n = 13) were analysed. Functional connectivity (FC) was estimated using time series correlation of seed region-to-whole-brain-voxels and network topology was assessed using graph theory measures. Regional connectivity differences were correlated with clinical characteristics (FDR corrected p < 0.05). CFS patients demonstrated increased FC of the bilateral middle temporal pole (MTP), and bilateral thalami when compared to SFS. Network topology study revealed increased clustering coefficient and decreased participation coefficient in basal ganglia and thalamus suggesting an inefficient-unbalanced network topology in patients with CFS. The number of seizure recurrences negatively correlated with the integration of Left Thalamus (r = - 0.58) and FC of Left MTP to 'Right Supplementary Motor and left Precentral' gyrus (r = - 0.53). The FC of Right MTP to Left Amygdala, Putamen, Parahippocampal, and Orbital Frontal Cortex (r = 0.61) and FC of Left Thalamus to left Putamen, Pallidum, Caudate, Thalamus Hippocampus and Insula (r 0.55) showed a positive correlation to the duration of the longest seizure. The findings of the current study report altered connectivity in children with CFS proportional to the seizure recurrence and duration. Regardless of the causal/consequential nature, such observations demonstrate the imprint of these disease-defining variables of febrile seizures on the developing brain.
Asunto(s)
Encéfalo/patología , Convulsiones Febriles/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Mapeo Encefálico , Niño , Humanos , Imagen por Resonancia Magnética , Convulsiones Febriles/patologíaRESUMEN
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.
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Neuropatología , Convulsiones Febriles , Encéfalo/patología , Niño , Muerte Súbita/patología , Hipocampo/patología , Humanos , Convulsiones Febriles/complicaciones , Convulsiones Febriles/patologíaRESUMEN
Febrile seizures (FSs) are common neurological disorders in both infants and children, although the precise underlying mechanism remains to be explored, especially in the expression pattern and function of microRNAs (miRNAs). In this report, we aimed to screen new potential miRNAs and examine the role of miR-148a-3p in hippocampal neurons in FS rats via Synaptojanin-1 (SYNJ1). Thirty rats were randomly divided into the normal and FS model groups, which were investigated by miRNA array. This process identified 31 differentially expressed (20 upregulated and 11 downregulated) miRNAs and potential miRNA target genes. In addition, hippocampal neurons were assigned into five groups for different transfections. Apoptosis was detected by TUNEL and flow cytometry. SYNJ1 was identified as a target gene of miR-148-3p. In vitro experiments revealed that inhibition of miR-148a-3p decreased neuronal cell apoptosis. Moreover, overexpression of miR-148a-3p resulted in activation of PI3K/Akt signaling pathway and the apoptosis of hippocampal neurons. MiR-148a-3p inhibitor could reverse the above events. Taken together, our data demonstrated that the hippocampal miRNA expression profiles of a rat model of FS provide a large database of candidate miRNAs and neuron-related target genes. Furthermore, miR-148a-3p acted as a apoptosis enhcaner via the activation of the SYNJ1/PI3K/Akt signaling pathway, highlighting a potential therapeutic target in the treatment of infants with hyperthermia-induced brain injury.
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Apoptosis , MicroARNs/biosíntesis , Convulsiones Febriles/metabolismo , Transducción de Señal , Animales , Perfilación de la Expresión Génica , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfatidilinositol 3-Quinasas/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Sprague-Dawley , Convulsiones Febriles/patologíaRESUMEN
Complex febrile seizures (FSs) lead to a high risk of intractable temporal lobe epilepsy during adulthood, yet the pathological process of complex FSs is largely unknown. Here, we demonstrate that activated microglia extensively associated with glutamatergic neuronal soma displace surrounding GABAergic presynapses in complex FSs. Patch-clamp electrophysiology establishes that the microglial displacement of GABAergic presynapses abrogates a complex-FS-induced increase in GABAergic neurotransmission and neuronal excitability, whereas GABA exerts an excitatory action in this immature stage. Pharmacological inhibition of microglial displacement of GABAergic presynapses or selective ablation of microglia in CD11bDTR mice promotes the generation of complex FSs. Blocking or deleting the P2Y12 receptor (P2Y12R) reduces microglial displacement of GABAergic presynapses and shortens the latency of complex FSs. Together, microglial displacement of GABAergic presynapses, regulated by P2Y12R, reduces neuronal excitability to mitigate the generation of complex FSs. Microglial displacement is a protective event during the pathological process of complex FSs.
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Microglía/patología , Convulsiones Febriles/patología , Sinapsis/patología , Ácido gamma-Aminobutírico/metabolismo , Animales , Corteza Cerebral/patología , Susceptibilidad a Enfermedades , Imagenología Tridimensional , Ratones Endogámicos C57BL , Neuronas/patología , Fagocitosis , Terminales Presinápticos/metabolismo , Receptores Purinérgicos P2Y12/metabolismo , Transmisión SinápticaRESUMEN
Adipokines, including leptin, visfatin, adiponectin, and interleukin-6 (IL)-6, play multiple roles in the pathophysiology of epilepsy and febrile seizures (FS). We aimed to investigate the associations among plasma adipokines, mainly leptin, visfatin, adiponectin, or IL-6, and the prognosis of FS. This prospective cross-sectional study was conducted from January 2017 to December 2018 at the Wuxi Second People' Hospital China. The levels of serum leptin, visfatin, adiponectin, and IL-6 in 55 children with FS (FS group) were compared with 42 febrile children without seizure (FC group) and 48 healthy children (HC group) in an acute phase. The correlation with clinical indicators was determined by logistic regression analysis. Serum adiponectin and IL-6 levels were significantly higher in the FS group than in the FC and HC groups (p < 0.05), but there was no statistical difference between the FC and HC groups. In addition, logistic regression analysis showed that high concentrations of adiponectin and IL-6 were significantly associated with the occurrence of FS. For leptin and visfatin, they were significantly lower in the FS and FC groups than in the normal control group, but there was no statistical difference between the FS and FC groups. Our results suggest that higher plasma levels of IL-6 and adiponectin may serve as an additional biomarker in the early treatment or follow-up of the FS children.
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Adiponectina/sangre , Biomarcadores/sangre , Citocinas/sangre , Interleucina-6/sangre , Leptina/sangre , Nicotinamida Fosforribosiltransferasa/sangre , Convulsiones Febriles/patología , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Masculino , Pronóstico , Estudios Prospectivos , Convulsiones Febriles/sangreRESUMEN
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.
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Comunicación Celular , Epilepsia del Lóbulo Temporal/etiología , Epilepsia del Lóbulo Temporal/patología , Hipocampo/citología , Hipocampo/patología , Microglía/patología , Microglía/fisiología , Factores de Edad , Edad de Inicio , Animales , Giro Dentado/citología , Giro Dentado/patología , Modelos Animales de Enfermedad , Humanos , Ratones , Neuronas/fisiología , Ratas , Factores de Riesgo , Convulsiones Febriles/etiología , Convulsiones Febriles/patología , Sinapsis/fisiologíaRESUMEN
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.
Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Proteínas de Unión al ADN/genética , Esquizofrenia/genética , Encéfalo/metabolismo , Encéfalo/patología , Niño , Cromatina/genética , Ensamble y Desensamble de Cromatina/genética , Electroencefalografía , Femenino , Heterocigoto , Humanos , Masculino , Mutación , Fenotipo , Esquizofrenia/fisiopatología , Convulsiones Febriles/genética , Convulsiones Febriles/patologíaRESUMEN
BACKGROUND: The pathogenesis of acute encephalopathy (AE) remains unclear, and a biomarker has not been identified. METHODS: Levels of 49 cytokines and chemokines, including osteopontin (OPN), were measured in serum and cerebrospinal fluid (CSF) of children with AE (n = 17) or febrile convulsion (FC; n = 8; control group). The AE group included acute necrotizing encephalopathy (n = 1), acute encephalopathy with biphasic seizures and late reduced diffusion (AESD; n = 3), clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS; n = 4), and unclassified acute encephalopathy (UCAE; n = 9) that does not meet the criteria of syndrome classification. Five individuals with AE had neurological sequelae or death (poor prognosis), whereas 12 were alive without neurological sequelae (good prognosis). RESULTS: The CSF:serum ratios of OPN, CC chemokine ligand (CCL)4, and interleukin (IL)-10 were significantly higher in AE than in FC. The CSF levels of macrophage inhibitory factor (MIF) and leukemia inhibitory factor (LIF) were significantly higher in the poor-prognosis group than in the good-prognosis group. The CSF:serum ratios of OPN were significantly higher in AESD and in MERS than in FC. The CSF:serum ratios of MIF and OPN were higher in MERS than in UCAE or FC. CONCLUSION: Our results suggest that microglia-related cytokines and chemokines such as OPN, MIF, and LIF could be novel biomarkers of AE, in addition to the previously reported IL-10 and CCL4, and that MIF and LIF may be markers of poor prognosis.
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Encefalopatías/inmunología , Encefalopatías/patología , Citocinas/análisis , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Quimiocinas/análisis , Quimiocinas/sangre , Quimiocinas/líquido cefalorraquídeo , Preescolar , Citocinas/sangre , Citocinas/líquido cefalorraquídeo , Encefalitis/líquido cefalorraquídeo , Femenino , Humanos , Lactante , Oxidorreductasas Intramoleculares/sangre , Oxidorreductasas Intramoleculares/líquido cefalorraquídeo , Factor Inhibidor de Leucemia/sangre , Factor Inhibidor de Leucemia/líquido cefalorraquídeo , Factores Inhibidores de la Migración de Macrófagos/sangre , Factores Inhibidores de la Migración de Macrófagos/líquido cefalorraquídeo , Masculino , Osteopontina/sangre , Osteopontina/líquido cefalorraquídeo , Convulsiones/etiología , Convulsiones Febriles/complicaciones , Convulsiones Febriles/inmunología , Convulsiones Febriles/patologíaRESUMEN
The present study aimed at exploring a potentially neuroprotective effect of topiramate (TPM), one of the most commonly used newer-generation, broad-spectrum, antiepileptic drugs against ultrastructural damage of hippocampal synaptic endings in the experimental model of febrile seizures (FS). The study used male young Wistar rats aged 22-30 days, divided into three experimental groups and the control group. Brain maturity in such animals corresponds to that of 1- or 2-year-old children. Hyperthermic stress was evoked by placing animals in a 45°C water bath for four consecutive days. TPM at a dose of 80 mg/kg b.m. was administered with an intragastric tube before and immediately after FS. Specimens (1 mm3) collected from the hippocampal CA1 and CA3 sectors, fixed via transcardial perfusion with a solution of paraformaldehyde and glutaraldehyde, were routinely processed for transmission-electron microscopic analysis. Advanced ultrastructural changes induced by hyperthermic stress were manifested by distinct swelling of hippocampal pre- and post-synaptic axodendritic and axospinal endings, including their vacuolization and disintegration. The axoplasm of the presynaptic boutons contained a markedly decreased number of synaptic vesicles and their abnormal accumulation in the active synaptic region. The synaptic junctions showed a dilated synaptic cleft and a decreased synaptic active zone. TPM used directly after FS was ineffective in the prevention of hyperthermia-induced injury of synaptic endings in hippocampal CA1 and CA3 sectors. However, "prophylactic" administration of TPM, prior to FS induction, demonstrated a neuroprotective effect against synaptic damage in approximately 25% of the synaptic endings in the hippocampal sectors, more frequently located in perivascular zones. It was manifested by smaller oedema of both presynaptic and postsynaptic parts, containing well-preserved mitochondria, increased number and regular distribution of synaptic vesicles within the axoplasm, and increased synaptic active zone. Our current and previous findings suggest that TPM administered "prophylactically", before FS, could exert a favourable effect on some synapses, indirectly, via the vascular factor, i.e. protecting blood-brain barrier components and through better blood supply of the hippocampal CA1 and CA3 sectors, which may have practical implications.
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Anticonvulsivantes/farmacología , Región CA1 Hipocampal/efectos de los fármacos , Región CA3 Hipocampal/efectos de los fármacos , Terminales Presinápticos/efectos de los fármacos , Convulsiones Febriles/patología , Topiramato/farmacología , Animales , Región CA1 Hipocampal/ultraestructura , Región CA3 Hipocampal/ultraestructura , Modelos Animales de Enfermedad , Masculino , Microscopía Electrónica de Transmisión , Fármacos Neuroprotectores/farmacología , Terminales Presinápticos/ultraestructura , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Epilepsia/patología , Hipocampo/patología , Convulsiones Febriles/patología , Estado Epiléptico/patología , Preescolar , Imagen de Difusión por Resonancia Magnética , Electroencefalografía , Epilepsia/diagnóstico por imagen , Femenino , Hipocampo/diagnóstico por imagen , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Estudios Prospectivos , Convulsiones Febriles/diagnóstico por imagen , Estado Epiléptico/diagnóstico por imagenAsunto(s)
Epilepsia Refractaria/patología , Síndromes Epilépticos/patología , Convulsiones Febriles/patología , Adulto , Epilepsia Refractaria/diagnóstico por imagen , Epilepsia Refractaria/fisiopatología , Síndromes Epilépticos/diagnóstico por imagen , Síndromes Epilépticos/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Convulsiones Febriles/diagnóstico por imagen , Convulsiones Febriles/fisiopatología , Estado Epiléptico/diagnóstico por imagen , Estado Epiléptico/patología , Estado Epiléptico/fisiopatologíaRESUMEN
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.
Asunto(s)
Epilepsia Refractaria/diagnóstico por imagen , Síndromes Epilépticos/diagnóstico por imagen , Neuroimagen/métodos , Convulsiones Febriles/diagnóstico por imagen , Estado Epiléptico/diagnóstico por imagen , Niño , Preescolar , Epilepsia Refractaria/etiología , Epilepsia Refractaria/patología , Síndromes Epilépticos/etiología , Síndromes Epilépticos/patología , Femenino , Humanos , Infecciones/complicaciones , Masculino , Convulsiones Febriles/patología , Estado Epiléptico/etiología , Estado Epiléptico/patologíaRESUMEN
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.
Asunto(s)
Transferencia Resonante de Energía de Fluorescencia , Hipocampo/metabolismo , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Dióxido de Azufre/análisis , Animales , Antocianinas/química , Línea Celular Tumoral , Modelos Animales de Enfermedad , Colorantes Fluorescentes/química , Hipocampo/química , Humanos , Límite de Detección , Hígado/metabolismo , Hígado/patología , Ratas , Convulsiones Febriles/metabolismo , Convulsiones Febriles/patología , Espectrofotometría , Dióxido de Azufre/química , Dióxido de Azufre/metabolismoRESUMEN
Background: Fangjing decoction is a Traditional Chinese Medicine that exhibits anticonvulsive effects in treating febrile seizures (FS). Its action mechanism and the regulation on Akt/mammalian target of rapamycin (mTOR) pathway were revealed in the present study.Methods: FS model was established in Sprague-Dawley rats with or without Fangjing decoction treatment. On day 5, following initiation of drug treatment, seizures were monitored. Hippocampal neuron apoptosis was assessed using terminal dUTP nick end-labeling method. The levels of Bax, protein kinase B (Akt), phospho-Akt (p-Akt), mTOR, and p-mTOR proteins were analyzed using Western blotting. The content of hippocampal γ-aminobutyric acid (GABA) was measured by using ELISA assay.Results: Compared with the control group (n=8), Fangjing decoction effectively prolonged the latency but shortened the duration of FS in rats (n=8). Concomitantly, the apoptosis of hippocampal neurons, as well as Bax protein levels were also decreased in FS rats which were treated with Fangjing decoction. In addition, the Akt/mTOR signaling was found to be activated in rat hippocampus following FS, as evidenced by increased p-Akt and p-mTOR, while Fangjing decoction could inhibit the activation of Akt/mTOR signaling. Furthermore, the low GABA content in rat hippocampus following FS was significantly elevated by Fangjing decoction treatment. More importantly, SC79, a specific activator for Akt, apparently attenuated the protective effects of Fangjing decoction on FS rats.Conclusion: These results suggest that Fangjing decoction protects the hippocampal neurons from apoptosis by inactivating Akt/mTOR pathway, which may contribute to mitigating FS-induced brain injury.