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

AIMS: The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. METHODS: Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. RESULTS: We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. CONCLUSIONS: These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Structural brain abnormalities in the common epilepsies assessed in a worldwide ENIGMA study.

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed.

Cortical Neuroprosthesis Merges Visible and Invisible Light Without Impairing Native Sensory Function.

Adult rats equipped with a sensory prosthesis, which transduced infrared (IR) signals into electrical signals delivered to somatosensory cortex (S1), took approximately 4 d to learn a four-choice IR discrimination task. Here, we show that when such IR signals are projected to the primary visual cortex (V1), rats that are pretrained in a visual-discrimination task typically learn the same IR discrimination task on their first day of training. However, without prior training on a visual discrimination task, the learning rates for S1- and V1-implanted animals converged, suggesting there is no intrinsic difference in learning rate between the two areas. We also discovered that animals were able to integrate IR information into the ongoing visual processing stream in V1, performing a visual-IR integration task in which they had to combine IR and visual information. Furthermore, when the IR prosthesis was implanted in S1, rats showed no impairment in their ability to use their whiskers to perform a tactile discrimination task. Instead, in some rats, this ability was actually enhanced. Cumulatively, these findings suggest that cortical sensory neuroprostheses can rapidly augment the representational scope of primary sensory areas, integrating novel sources of information into ongoing processing while incurring minimal loss of native function.

Late onset temporal lobe epilepsy due to cerebral hypoperfusion: case report / Epilepsia de lobo temporal de início tardio decorrente de hipoperfusão cerebral: relato de caso / Epilepsia de lóbulo temporal de inicio tardío debido a hipoperfusión cerebral: relato de caso

Temporal lobe epilepsy is the most common form of focal epilepsy. The main pathological substrate of refractory TLE is hippocampal sclerosis (HS). HS has been associated with prolonged febrile and recurrent seizures. Other known causes for hippocampal injury are head trauma, ischemia, stroke and Alzheimer's disease. The exact causes of HS remain unknown, although they are probably diverse and multifactorial. The patient with TLE had no risk factors for epilepsy. His first seizure occurred immediately after an abdominal surgery complicated by profuse bleeding and hypotension during the procedure. The MRI showed hippocampal atrophy, probably due to hippocampal hypoperfusion, given the temporal relationship between the seizures and surgery. The etiology of hippocampal infarcts is discussed in this article. In a study with animal model, cerebral hypoperfusion led to a pattern of epileptiform activity similar to that found in the human hippocampus.

A epilepsia de lobo temporal (ELT) é a forma mais comum de epilepsia focal. O principal substrato patológico da ELT refratária é a esclerose hipocampal (EH). A EH tem sido associada a crises febris prolongadas e convulsões recorrentes. Outras causas conhecidas de dano hipocampal são: traumatismo cranioencefálico, isquemia, acidente vascular cerebral e doença de Alzheimer. As causas exatas da EH permanecem desconhecidas, apesar de serem provavelmente diversas e multifatoriais. O paciente com ELT não tinha fatores de risco de epilepsia. O paciente apresentou a primeira crise epiléptica no pós-operatório imediato de uma cirurgia abdominal complicada por sangramento profuso e hipotensão durante o procedimento. A RM evidenciou atrofia hipocampal, provavelmente decorrente da hipoperfusão hipocampal, dada a relação temporal das crises com o procedimento cirúrgico. A etiologia dos infartos hipocampais é abordada neste artigo. Em um estudo com modelo animal, o hipofluxo cerebral levou a um padrão de atividade epileptiforme semelhante ao encontrado no hipocampo humano.

La epilepsia de lóbulo temporal (ELT) es la forma más común de epilepsia focal. El principal sustrato patológico de la ELT refractaria es la esclerosis hipocampal (EH). La EH ha sido asociada a crisis febriles prolongadas y convulsiones recurrentes. Otras causas conocidas de daño hipocampal son: traumatismo craneoencefálico, isquemia, accidente vascular cerebral y enfermedad de Alzheimer. Las causas exactas de la EH permanecen desconocidas, a pesar de ser probablemente diversas y multifactoriales. El paciente con ELT no tenía factores de riesgo de epilepsia. El paciente presentó la primera crisis epiléptica en el postoperatorio inmediato de una cirugía abdominal complicada por sangrado profuso e hipotensión durante el procedimiento. La RM evidenció atrofia hipocampal, probablemente debido a la hipoperfusión hipocampal, dada la relación temporal de las crisis con el procedimiento quirúrgico. La etiología de los infartos hipocampales es abordada en este artículo. En un estudio con modelo animal, el hipoflujo cerebral llevó a un estándar de actividad epileptiforme semejante al encontrado en el hipocampo humano.

Late diagnosis of limbic encephalitis associated with LGI1 antibodies leading to relapses / Diagnóstico tardio de encefalite límbica associada a anticorpos LGI1 que levam a recidivas / Diagnóstico tardío de encefalitis límbica asociada a anticuerpos LGI1 que llevan a recidivas

Autoimmune encephalitis has been a subject of research in the past few years; most of the cases are non-paraneoplastic and associated with an antibody to a surface protein of neurons. Studies have shown that VGKC complex is indeed represented by three proteins, and LGI1 is the most prevalent in limbic encephalitis. This entity is characterized by monophasic presentation with acute or subacute onset, memory loss, confusion, seizures and psychiatric symptoms. The presentation of anti-LGI1 antibodies in serum or CSF confirms the diagnosis. The treatment consists of immunotherapy with good clinical response, which is a criterion for diagnosis. We report a case of a patient with diagnosis confirmed six months after the symptoms onset, improvement after immunotherapy, but with episodes of relapse.

A encefalite autoimune tem sido assunto de pesquisa nos últimos anos, a maioria dos casos é não paraneoplásica e associada ao anticorpo para uma proteína de superfície dos neurônios. Estudos têm mostrado que o complexo VGKC é efetivamente representado por três proteínas, e a LGI1 é a mais prevalente na encefalite límbica. Essa entidade é caracterizada por apresentação monofásica com início agudo ou subagudo, perda de memória, confusão mental, crises convulsivas e sintomas psiquiátricos. A apresentação de anticorpos anti-LGI1 no soro ou no LCE confirma o diagnóstico. O tratamento consiste em imunoterapia com boa resposta clínica, que é um critério diagnóstico. Relatamos o caso de um paciente com diagnóstico confirmado seis meses após o início dos sintomas, com melhora após imunoterapia, porém com episódios de recaídas.

La encefalitis autoinmune ha sido asunto de investigación en los últimos años; la mayoría de los casos es no paraneoplásica y asociada al anticuerpo para una proteína de superficie de las neuronas. Estudios han mostrado que el complejo VGKC es efectivamente representado por tres proteínas, y la LGI1 es la más prevalente en la encefalitis límbica. Esa entidad es caracterizada por presentación monofásica con inicio agudo o subagudo, pérdida de memoria, confusión mental, crisis convulsivas y síntomas psiquiátricos. La presentación de anticuerpos anti-LGI1 en el suero o en el LCE confirma el diagnóstico. El tratamiento consiste en inmunoterapia con buena respuesta clínica, que es un criterio diagnóstico. Relatamos el caso de un paciente con diagnóstico confirmado seis meses después del inicio de los síntomas, con mejora después de inmunoterapia, aunque con episodios de recaídas.

Fragile X Syndrome and Epilepsy: case report / Síndrome do X Frágil e Epilepsia: relato de caso

Introduction: Learning disabilities is defined by intelligence quotient of less than or equal to 70 associated with limited learning functions such as cognition, language, motor function and social skills activities. Epilepsy is more common in individuals with learning disabilities and its frequency increases progressively considering severe intellectual impairment. Fragile X syndrome is the most common genetic cause of learning disability and 10-20% of these children have epilepsy. Methods: We describe a patient with fragile X syndrome, who had febrile seizures leading to temporal lobe epilepsy. Results: Male patient, 36 years old. He had several episodes of febrile seizures from one to seven years old and at the age of 27 he started with spontaneous dyscognitive seizures with possible temporal lobe origin. His brother, who also has the diagnosis of fragile X syndrome, presented a single afebrile seizure as a child. Patient's MRI showed left hippocampal atrophy. Conclusion: The relationship between febrile seizure and temporal lobe epilepsy in the context of fragile X syndrome is discussed in this article. Fragile X syndrome turns patients morevulnerable to have any kind of seizures. Therefore, we have to prevent febrile seizures in these patients...

Introdução: O déficit de aprendizagem é definido por quociente de inteligência inferior ou igual a 70 associado às funções limitadas de aprendizagem, tais como a cognição, a linguagem, a função motora e as habilidades sociais. Epilepsia é mais comum em indivíduos com dificuldades de aprendizagem e sua incidência aumenta progressivamente em pacientes com deficiência intelectual grave. Síndrome do X Fragil é a causa genética mais comum de deficiência de aprendizado e 10-20% destas crianças têm epilepsia. Métodos: Nós descrevemos um paciente com síndrome do X frágil, que teve convulsões febris e evoluiu com epilepsia do lobo temporal. Resultados: O paciente apresentou dois episódios de convulsão febril durante a infância e, com 27 anos, iniciou crises discognitivas típicas de lobo temporal. Seu irmão, que também tem síndrome do X frágil, apresentou crise afebril única na infância. A RM do paciente mostrou atrofia hipocampal à esquerda. Conclusão: A relação entre a convulsão febril e epilepsia do lobo temporal no contexto da síndrome do X frágil é discutida neste artigo. Pacientes com síndrome do X frágil são mais suscetíveis a ter qualquer tipo de crise epiléptica. Portanto, temos que tentar evitar crise febril prolongada nestes pacientes...

Análise da ação da Himatanthus drasticus na progressão do câncer de pulmão induzido por uretana em camundongos / Analysis of the action of Himatanthus drasticus in progression of urethane-induced lung cancer in mice

Objective: To evaluate the effect of janaguba in inhibiting the development of lung cancer in an experimental urethane-induced model. Methods: a total of 3 mg/kg urethane was injected in 51 Balb-C mice aged 7-13 weeks of life. Janaguba was administered orally daily in two doses: 0.04 mL (Group 2, G2) and 0.06 mL (Group 3, G3), for 20 weeks. After this period, the mice were sacrificed and the number of lesions counted. Results: The mean weight of Group 2 was lower than that of Group 3, and that of Group 1 (Control, G1) (G1 = 35.533 g; G2 = 33.359 g; G3 = 37.125 g). The number of nodules did not differ between groups (mean G1 = G2 = G3 = 1; p = 0.88). Conclusion: Janaguba had an effect on the growth of mice, but had no influence on the progression of lung cancer in this model.

Objetivo: Avaliar a ação da janaguba na inibição do desenvolvimento de câncer de pulmão em modelo experimental induzido por uretana. Métodos: Foram injetados 3mg/kg de uretana em 51 camundongos Balb-C , com 7 a 13 semanas de vida. Janaguba foi administrada via oral diariamente em duas doses: 0,04 mL (Grupo 2, G2) e 0,06 mL(Grupo 3,G3), por 20 semanas. Após esse período, os camundongos foram sacrificados e o número de lesões, contado. Resultados: A média de peso do Grupo 2 foi menor que a do Grupo 3, e que a do Grupo 1 (Controle, G1) (G1 = 35,533 g; G2 = 33,359 g; G3 = 37,125 g). O número de nódulos não diferiu entre os grupos (média G1 = G2 = G3 = 1; p = 0,88). Conclusão: A janaguba apresentou um efeito no crescimento dos camundongos, mas não apresentou influência na progressão do câncer de pulmão neste modelo.

Analysis of the action of Himatanthus drasticus in progression of urethane-induced lung cancer in mice.

OBJECTIVE: To evaluate the effect of janaguba in inhibiting the development of lung cancer in an experimental urethane-induced model. METHODS: a total of 3mg/kg urethane was injected in 51 Balb-C mice aged 7-13 weeks of life. Janaguba was administered orally daily in two doses: 0.04 mL (Group 2, G2) and 0.06 mL (Group 3, G3), for 20 weeks. After this period, the mice were sacrificed and the number of lesions counted. RESULTS: The mean weight of Group 2 was lower than that of Group 3, and that of Group 1 (Control, G1) (G1 = 35.533 g; G2 = 33.359 g; G3 = 37.125 g). The number of nodules did not differ between groups (mean G1 = G2 = G3 = 1; p = 0.88). CONCLUSION: Janaguba had an effect on the growth of mice, but had no influence on the progression of lung cancer in this model.