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  • 机译 关于网络的一切
    • 作者:Jerry J. Shih
    • 刊名:Epilepsy Currents
    • 2019年第3期
    摘要:Interictal stereotactic-EEG functional connectivity in refractory focal epilepsies Lagarde S, Roehri N, Lambert I, et al. Brain. 2018;141(10):2966-2980.Drug-refractory focal epilepsies are network diseases associated with functional connectivity alterations both during ictal and interictal periods. A large majority of studies on the interictal/resting state have focused on functional magnetic resonance imaging (MRI)-based functional connectivity. Few studies have used electrophysiology, despite its high-temporal capacities. In particular, stereotactic-electroencephalogram (EEG) is highly suitable to study functional connectivity because it permits direct intracranial electrophysiological recordings with relative large-scale sampling. Most previous studies in stereotactic-EEG have been directed toward temporal lobe epilepsy, which does not represent the whole spectrum of drug-refractory epilepsies. The present study aims at filling this gap, investigating interictal functional connectivity alterations behind cortical epileptic organization and its association with postsurgical prognosis. To this purpose, we studied a large cohort of 59 patients with malformation of cortical development explored by stereotactic-EEG with a wide spatial sampling (76 distinct brain areas were recorded, median of 13.2 per patient). We computed functional connectivity using nonlinear correlation. We focused on 3 zones defined by stereotactic-EEG ictal activity: the epileptogenic zone (EZ), the propagation zone (PZ), and the noninvolved zone. First, we compared within-zone and between-zones functional connectivity. Second, we analyzed the directionality of functional connectivity between these zones. Third, we measured the associations between functional connectivity measures and clinical variables, especially postsurgical prognosis. Our study confirms that functional connectivity differs according to the zone under investigation. We found: (1) a gradual decrease in the within-zone functional connectivity with higher values for EZ and PZ, and lower for noninvolved zones; (2) preferential coupling between structures of the EZ; (3) preferential coupling between EZ and PZ; and (4) poorer postsurgical outcome in patients with higher functional connectivity of non-involved zone (within-noninvolved zone, between noninvolved zone, and PZ functional connectivity). Our work suggests that, even during the interictal state, functional connectivity is reinforced within epileptic cortices (EZ and PZ) with a gradual organization. Moreover, larger functional connectivity alterations, suggesting more diffuse disease, are associated with poorer postsurgical prognosis. This is consistent with computational studies suggesting that connectivity is crucial in order to model the spatiotemporal dynamics of seizures. Dynamic brain network states in human generalized spike-wave discharges Tangwiriyasakul C, Perani S, Centeno M, et al. Brain. 2018;141(10):2981-2994.Generalized spike-wave discharges in idiopathic generalized epilepsy are conventionally assumed to have abrupt onset and offset. However, in rodent models, discharges emerge during a dynamic evolution of brain network states, extending several seconds before and after the discharge. In human idiopathic generalized epilepsy, simultaneous EEG and functional MRI shows cortical regions may be active before discharges, and network connectivity around discharges may not be normal. Here, in human idiopathic generalized epilepsy, we investigated whether generalized spike-wave discharges emerge during a dynamic evolution of brain network states. Using EEG-functional MRI, we studied 43 patients and 34 healthy control subjects. We obtained 95 discharges from 20 patients. We compared data from patients with discharges with data from patients without discharges and healthy controls. Changes in MRI (blood oxygenation level dependent) signal amplitude in discharge epochs were observed only at and after EEG onset, involving a sequence of parietal and frontal cortical regions then thalamus (P < .01, across all regions and measurement time points). Examining MRI signal phase synchrony as a measure of functional connectivity between each pair of 90 brain regions, we found significant connections (P < .01, across all connections and measurement time points) involving frontal, parietal and occipital cortex during discharges, and for 20 seconds after EEG offset. This network prominent during discharges showed significantly low synchrony (below 99% confidence interval for synchrony in this network in nondischarge epochs in patients) from 16 seconds to 10 seconds before discharges, then ramped up steeply to a significantly high level of synchrony 2 seconds before discharge onset. Significant connections were seen in a sensorimotor network in the minute before discharge onset. This network also showed elevated synchrony in patients without discharges compared to healthy controls (P = .004). During 6 seconds prior to discharges, additional significant connections to this sensorimotor network were observed, involving prefrontal, and precuneus regions. In healthy subjects, significant connections involved a posterior cortical network. In patients with discharges, this posterior network showed significantly low synchrony during the minute prior to discharge onset. In patients without discharges, this network showed the same level of synchrony as in healthy controls. Our findings suggest persistently high sensorimotor network synchrony, coupled with transiently (at least 1 minute) low posterior network synchrony, may be a state predisposing to generalized spike-wave discharge onset. Our findings also show that EEG onset and associated MRI signal amplitude change is embedded in a considerably longer period of evolving brain network states before and after discharge events.
  • 机译 难治性癫痫持续状态的心脏骤停患者的好结果:积极治疗或脑电分类的结果
    • 作者:Jong Woo Lee
    • 刊名:Epilepsy Currents
    • 2019年第3期
    摘要:Neurologic outcome of postanoxic refractory status epilepticus after aggressive treatment. Beretta S, Coppo A, Bianchi E, et al. Neurology. 2018;91(23):e2153-e2162. doi:10.1212/WNL.0000000000006615. Epub October 31, 2018.Objective:To investigate neurologic outcome of patients with cardiac arrest with refractory status epilepticus (RSE) treated with a standardized aggressive protocol with antiepileptic drugs and anesthetics compared to patients with other electroencephalogram (EEG) patterns.
  • 机译 原因不明的小儿痉挛:谁能有好的结果?
    • 作者:
    • 刊名:Epilepsy Currents
    • 2019年第3期
    摘要:Infantile spasms of unknown cause: predictors of outcome and genotype-phenotype correlation Yuskaitis CJ, Ruzhnikov MRZ, Howell KB, et al. Pediatr Neurol. 2018;87:48–56. doi:10.1016/j.pediatrneurol.2018.04.012. Epub 2018 May 7.Background:No large-scale studies have specifically evaluated the outcomes of infantile spasms (IS) of unknown cause, previously known as cryptogenic or idiopathic. The Epilepsy Phenome/Genome Project (EPGP) aimed to characterize IS of unknown cause by phenotype and genotype analysis.
  • 机译 寻找最佳结合点:微调DBS参数以治疗癫痫发作,同时避免精神病并发症
    摘要:Reversible Psychiatric Adverse Effects Related to Deep Brain Stimulation of the Anterior Thalamus in Patients With Refractory Epilepsy Järvenpää S, Peltola J, Rainesalo S, et al. Epilepsy Behav. 2018;88:373-379.Objective:Anterior nucleus of thalamus (ANT) deep brain stimulation (DBS) is becoming a more common treatment for drug-resistant epilepsy. Epilepsy and depression display a bidirectional association. Anterior nucleus of thalamus has connections to anterior cingulate cortex and orbitomedial prefrontal cortex, hence, a possible role in emotional and executive functions, and thus, ANT DBS might exert psychiatric adverse effects. Our aim was to evaluate previous and current psychiatric symptoms in patients with epilepsy undergoing ANT DBS surgery and assess the predictability of psychiatric adverse effects. Programming-related psychiatric adverse effects are also reported.
  • 机译 屋顶漏水,狂风暴雨肆虐:在对抗癫痫病中修复血脑屏障
    摘要:A large body of evidence that has accumulated over the past decade strongly supports the role of both blood–brain barrier (BBB) dysfunction and perivascular inflammation in the pathophysiology of epilepsy. Recent preclinical studies indicate that prolonged seizure- or brain injury-induced BBB dysfunction and subsequent perivascular inflammation may play an important role in post-traumatic epileptogenesis. In turn, perivascular inflammation can further sustain BBB dysfunction. In genetic epilepsies, such as tuberous sclerosis complex and other related epileptogenic developmental pathologies, there is an association between the underlying gene mutation, BBB dysfunction, and perivascular inflammation, but evidence for a causal link to epilepsy is lacking. Future neuroimaging studies might shed light on the role of BBB function in different epilepsies and address the potential for disease modification by targeting both the BBB and perivascular inflammation in acquired and genetic epilepsies.
  • 机译 研发抗癫痫药物发现的新方法
    摘要:Srivastava PK, van Eyll J, Godard P, Mazzuferi M, Delahaye-Duriez A, Steenwinckel JV, et al. A systems-level framework for drug discovery identifies Csf1R as an anti-epileptic drug target. Nat Commun. 2018;9(1):3561. doi:10.1038/s41467-018-06008-4.The identification of drug targets is highly challenging, particularly for diseases of the brain. To address this problem, we developed and experimentally validated a general computational framework for drug target discovery that combines gene regulatory information with causal reasoning (“Causal Reasoning Analytical Framework for Target discovery”-CRAFT). Using a systems genetics approach and starting from gene expression data from the target tissue, CRAFT provides a predictive framework for identifying cell membrane receptors with a direction-specified influence over disease-related gene expression profiles. As proof of concept, we applied CRAFT to epilepsy and predicted the tyrosine kinase receptor Csf1R as a potential therapeutic target. The predicted effect of Csf1R blockade in attenuating epilepsy seizures was validated in 3 preclinical models of epilepsy. These results highlight CRAFT as a systems-level framework for target discovery and suggest Csf1R blockade as a novel therapeutic strategy in epilepsy. The CRAFT is applicable to disease settings other than epilepsy.
  • 机译 刻板印象的低频事件中的高频活动可能有助于识别癫痫发作区
    摘要:Stereotyped high-frequency oscillations discriminate seizure onset zones and critical functional cortex in focal epilepsy.Liu S, Gurses C, Sha Z, Quach MM, Sencer A, Bebek N, et al. Brain. 2018;141(3):713-730. doi:10.1093/brain/awx374. PMID: .High-frequency oscillations in local field potentials recorded with intracranial electroencephalogram are putative biomarkers of seizure-onset zones in epileptic brain. However, localized 80- to 500-Hz oscillations can also be recorded from normal and nonepileptic cerebral structures. When defined only by rate or frequency, physiological high-frequency oscillations are indistinguishable from pathological ones that limit their application in epilepsy presurgical planning. We hypothesized that pathological high-frequency oscillations occur in a repetitive fashion with a similar waveform morphology that specifically indicates seizure onset zones. We investigated the waveform patterns of automatically detected high-frequency oscillations in 13 patients with epilepsy and 5 control subjects, with an average of 73 subdural and intracerebral electrodes recorded per patient. The repetitive oscillatory waveforms were identified using a pipeline of unsupervised machine learning techniques and were then correlated with independently clinician-defined seizure onset zones. Consistently in all patients, the stereotypical high-frequency oscillations with the highest degree of waveform similarity were localized within the seizure onset zones only, whereas the channels generating high-frequency oscillations embedded in random waveforms were found in the functional regions independent of the epileptogenic locations. The repetitive waveform pattern was more evident in fast ripples compared to ripples, suggesting a potential association between waveform repetition and the underlying pathological network. Our findings provided a new tool for the interpretation of pathological high-frequency oscillations that can be efficiently applied to distinguish seizure onset zones from functionally important sites, which is a critical step toward the translation of these signature events into valid clinical biomarkers.
  • 机译 抑制作用产生新的KAR气味
    摘要:Ionotropic and metabotropic kainate receptor signaling regulates Cl homeostasis and GABAergic inhibition Garand D, Mahadevan V, Woodin MA. J Physiol. 2018. doi:10.1113/JP276901Potassium chloride cotransporter 2 (KCC2) plays a critical role in the regulation of chloride (Cl) homeostasis within mature neurons. The KCC2 is a secondarily active transporter that extrudes Cl from the neuron, which maintains a low intracellular Clconcentration [Cl]. This results in a hyperpolarized reversal potential of GABA (EGABA), which is required for fast synaptic inhibition in the mature central nervous system. Potassium chloride cotransporter 2 also plays a structural role in dendritic spines and at excitatory synapses and interacts with “excitatory” proteins, including the GluK2 subunit of kainate receptors (KARs). Kainate receptors are glutamate receptors that display both ionotropic and metabotropic signaling. We show that activating KARs in the hippocampus hyperpolarizes EGABA, thus strengthening inhibition. This hyperpolarization occurs via both ionotropic and metabotropic KAR signaling in the CA3 region, whereas it is absent in the GluK1/2−/− mouse, and is independent of zinc release from mossy fiber terminals. The metabotropic signaling mechanism is dependent on KCC2, although the ionotropic signaling mechanism produces a hyperpolarization of EGABA even in the absence of KCC2 transporter function. These results demonstrate a novel functional interaction between a glutamate receptor and KCC2, a transporter critical for maintaining inhibition, suggesting that the KAR:KCC2 complex may play an important role in excitatory:inhibitory balance in the hippocampus. Additionally, the ability of KARs to regulate chloride homeostasis independently of KCC2 suggests that KAR signaling can regulate inhibition via multiple mechanisms. Activation of kainate-type glutamate receptors could serve as an important mechanism for increasing the strength of inhibition during periods of strong glutamatergic activity.
  • 机译 小胶质细胞抓住了与众不同的机会
    摘要:Human microglia regional heterogeneity and phenotypes determined by multiplexed single-cell mass cytometry Böttcher C, Schlickeiser S, Sneeboer MAM, et al. Nat Neurosci. 2019;22(1):78-90.Microglia, the specialized innate immune cells of the central nervous system, play crucial roles in neural development and function. Different phenotypes and functions have been ascribed to rodent microglia, but little is known about human microglia (huMG) heterogeneity. Difficulties in procuring huMG and their susceptibility to cryopreservation damage have limited large-scale studies. Here we applied multiplexed mass cytometry for a comprehensive characterization of postmortem huMG (103-104 cells). We determined expression levels of 57 markers on huMG isolated from up to 5 different brain regions of 9 donors. We identified the phenotypic signature of huMG, which was distinct from peripheral myeloid cells but was comparable to fresh huMG. We detected microglia regional heterogeneity using a hybrid workflow combining Cytobank and R/Bioconductor for multidimensional data analysis. Together, these methodologies allowed us to perform high-dimensional, large-scale Immunophenotyping of huMG at the single-cell level, which facilitates their unambiguous profiling in health and disease.
  • 机译 靶向补偿性离子通道基因表达是Dravet综合征的可行治疗策略吗?
    • 作者:Lori L. Isom
    • 刊名:Epilepsy Currents
    • 2019年第3期
    摘要:Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome Ritter-Makinson S, Clemente-Perez A, Higashikubo B, Cho FS, Holden SS, Bennett E, Chkhaidze A, Eelkman Rooda OHJ, Cornet MC, Hoebeek FE, Yamakawa K, Cilio MR, Delord B, Paz JT. Cell Rep. 2019;26(1):54-64.e6. doi:10.1016/j.celrep.2018.12.018.Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the nonconvulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote nonconvulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.
  • 机译 星形胶质细胞受体重生
    摘要:Conditional Knockout of mGluR5 From Astrocytes During Epilepsy Development Impairs High-Frequency Glutamate Uptake Umpierre AD, West PJ, White JA, et al. J Neurosci. 2019;39(4):727-742. doi:10.1523/JNEUROSCI.1148-18.2018Astrocyte expression of metabotropic glutamate receptor 5 (mGluR5) is consistently observed in resected tissue from patients with epilepsy and is equally prevalent in animal models of epilepsy. However, little is known about the functional signaling properties or downstream consequences of astrocyte mGluR5 activation during epilepsy development. In the rodent brain, astrocyte mGluR5 expression is developmentally regulated and confined in expression/function to the first weeks of life, with similar observations made in human control tissue. Herein, we demonstrate that mGluR5 expression and function dramatically increase in a mouse model of temporal lobe epilepsy. Interestingly, in both male and female mice, mGluR5 function persists in the astrocyte throughout the process of epileptogenesis following status epilepticus. However, mGluR5 expression and function are transient in animals that do not develop epilepsy over an equivalent time period, suggesting that patterns of mGluR5expression may signify continuing epilepsy development or its resolution. We demonstrate that, during epileptogenesis, astrocytes reacquire mGluR5-dependent calcium transients following agonist application or synaptic glutamate release, a feature of astrocyte–neuron communication absent since early development. Finally, we find that the selective and conditional knockout of mGluR5 signaling from astrocytes during epilepsy development slows the rate of glutamate clearance through astrocyte glutamate transporters under high-frequency stimulation conditions, a feature that suggests astrocyte mGluR5 expression during epileptogenesis may recapitulate earlier developmental roles in regulating glutamate transporter function.
  • 机译 癫痫的钙通道功能异常:CACNA1E的增益。
    摘要:De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy With Contractures, Macrocephaly, and Dyskinesias Helbig KL, Lauerer RJ, Bahr JC, et al. Am J Hum Genet. 2019;104(3):562.Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on electroencephalogram (EEG), and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high-voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all 4 S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the antiepileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
  • 机译 酒精中毒发作亚急性脑病:非惊厥性状态癫痫的一种亚型。
    摘要:A recent assessment of the classification of nonconvulsive status epilepticus (NCSE) has incorporated the specific electroencephalographic (EEG) patterns on a syndromic basis. Such a clinical EEG syndromic approach may enable more accurate and expedited diagnosis of particular subtypes of NCSE so as to improve therapy. Herein, we review the characteristics of subacute encephalopathy with seizures in alcoholics syndrome, a subtype of focal NCSE occurring in chronic alcoholism with specific features, including encephalopathy, lateralized periodic discharges on the EEG, chronic microvascular ischemia on neuroimaging studies, and possible recurrence when chronic antiseizure treatment is stopped.
  • 机译 使用8种抗癫痫药对主要先天性畸形的比较风险:EURAP注册中心的前瞻性队列研究
    摘要:Teratogenesis of 8 Antiepileptic Drugs in Multinational Experience Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, Perucca E, Sabers A, Thomas SV, Vajda F for the EURAP Study Group. Lancet Neurol. 2018;17(6):530-538.Background:Evidence for the comparative teratogenic risk of antiepileptic drugs is insufficient, particularly in relation to the dosage used. Therefore, we aimed to compare the occurrence of major congenital malformations following prenatal exposure to the 8 most commonly used antiepileptic drugs in monotherapy.
  • 机译 灭火的新软管?
    摘要:Tocilizumab Treatment for New Onset Refractory Status Epilepticus Jun JS, Lee ST, Kim R, Chu K, Lee SK. Ann Neurol. 2018;84(6):940-945. doi:10.1002/ana.25374.We investigated the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in 7 patients with new-onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n = 5) or without rituximab (n = 2). Status epilepticus (SE) was terminated after 1 or 2 doses of tocilizumab in 6 patients with a median interval of 3 days from the initiation. They had no recurrence of SE during the observation. However, 2 patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE.
  • 机译 第二次发作的费用:对治疗决定的重新思考
    • 作者:Edward Faught
    • 刊名:Epilepsy Currents
    • 2019年第2期
    摘要:Antiepileptic Drug Treatment After an Unprovoked First Seizure: A Decision Analysis Bao EL, Chao LY, Ni P, et al. Neurology. 2018;91(15):e1429-e1439. doi:10.1212/WNL.0000000000006319Objective:To compare the expected quality-adjusted life-years (QALYs) in adult patients undergoing immediate versus deferred antiepileptic drug (AED) treatment after a first unprovoked seizure.
  • 机译 癫痫手术中快速纹波的模棱两可性质
    摘要:Removing High-Frequency Oscillations: A Prospective Multicenter Study on Seizure Outcome Jacobs J, Wu JY, Perucca P, et al. Neurology. 2018;91(11):e1040-e1052.Objective:To evaluate the use of interictal high-frequency oscillations (HFOs) in epilepsy surgery for prediction of postsurgical seizure outcome in a prospective multicenter trial.
  • 机译 不要害怕冷藏柜-植物性大麻二酚作为治疗癫痫病的证据
    摘要:Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome Devinsky O, Patel AD, Cross JH, et al; GWPCARE3 Study Group. N Engl J Med. 2018;378:1888-1897.
  • 机译 在癫痫症中作出皮疹的决定:评估抗癫痫药物的超敏反应
    摘要:The Frequency and Clinical Features of Hypersensitivity Reactions to Antiepileptic Drugs in Children: A Prospective Study Guvenir H, Dibek Misirlioglu E, Civelek E. J Allergy Clin Immunol Pract. 2018;6(6):2043-2050.
  • 机译 当癫痫症长大时…
    • 作者:Katrina Boyer
    • 刊名:Epilepsy Currents
    • 2019年第2期
    摘要:Neurocognition in Childhood Epilepsy: Impact on Mortality and Complete Seizure Remission 50 Years Later Sillanpää M, Saarinen MM, Karrasch M, Schmidt D, Hermann BP. Epilepsia. 2019;60(1):131-138. doi:10.1111/epi.14606. Epub 2018 Nov 22.Objective:To study associations of the severity of impairment in childhood neurocognition (NC) with long-term mortality and complete seizure remission.

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