An increasing number of studies have focused on the role of NEDD4-2 in regulating neuronal excitability and the mechanism of epilepsy. However, the exact mechanism has not yet been elucidated. Here, we explored the roles of NEDD4-2 and the CLC-2 channel in regulating neuronal excitability and mesial temporal lobe epilepsy (MTLE) pathogenesis. First, chronic MTLE models were induced by lithium-pilocarpine in developmental rats. Coimmunoprecipitation analysis revealed that the interaction between CLC-2 and NEDD4-2. Western blot analyses indicated that NEDD4-2 expression was downregulated, while phosphorylated (P-) NEDD4-2 and CLC-2 expression was upregulated in adult MTLE rats. Then, the primary hippocampal neuronal cells were isolated and cultured, and the NEDD4-2 was knocked down by shRNA vector, resulting in decreased protein levels of CLC-2. While CLC-2 absence caused increased NEDD4-2 in cells. Next, in an epileptic cell model induced by a Mg2+-free culture, whole-cell current-clamp recording demonstrated that NEDD4-2 deficiency inhibited the spontaneous action potentials of cells, and CLC-2 absence caused more significant decrease in the spontaneous action potentials of cells. In conclusion, we herein revealed that NEDD4-2 regulates the expression of CLC-2, which is involved in neuronal excitability, and participates in the pathogenesis of MTLE.

Objective To report the clinical manifestations, EEG characteristics, diagnosis and treatment of 3 children with "benign epileptic discharge", and analyze the causes of misdiagnosis and treatment. Methods and Results The clinical data of 3 children with centrotemporal spikes (CTS) in EEG treated in Peking Union Medical College Hospital, Chinese Academy of Medical Sciences from December 2008 to October 2020 were retrospectively analyzed. Case 1 presented with non-epileptic seizure, which was misdiagnosed as "epilepsy" due to episodic events and CTS, and was eventually diagnosed as night fright based on clinical manifestations and EEG. Case 2 did not have clinical seizures, but was misdiagnosed as "epilepsy" due to CTS, and took antiepileptic drugs (AEDs) for several years. Although benign childhood epilepsy with central-temporal spikes (BECTS) was diagnosed in Case 3, the dosage and types of AEDs were increased even when the clinical seizures were well controlled. After diagnosis, AEDs was not performed in Case 1, AEDs were gradually stopped in Cases 2 and Case 3, and no epileptic seizure was observed. Conclusions "Benign epileptic discharge" is common in children's EEG examination. It is the key point to avoid the misdiagnosis and mismanagement to determine whether there is a causal relationship between EEG abnormalities and clinical seizures. For children with "benign epileptic discharge", the antiepileptic therapy is aimed at controlling clinical seizures rather than eliminating EEG abnormalities.

SummaryObjectiveTo assess the efficacy, safety, and tolerability of adjunctive levetiracetam (LEV) in Chinese and Japanese adults with generalized tonic–clonic (GTC) seizures (N01159; NCT01228747).MethodsThis double‐blind, randomized, placebo‐controlled, multicenter phase III trial comprised: 4‐week retrospective and 4‐week prospective baseline, 12‐week dose‐adjustment, and 16‐week evaluation periods. Chinese and Japanese patients ≥16 years old with idiopathic generalized, symptomatic generalized, or undetermined epilepsy with GTC seizures received a single‐blind placebo during the prospective baseline, and then were randomized 1:1 to placebo or LEV 1,000 mg/day administered twice daily. Patients reporting GTC seizures up to week 8 had the LEV dosage increased to 3,000 mg/day. The primary efficacy variable was percent reduction from combined baseline in GTC seizures/week during the 28‐week treatment period.ResultsOverall, 251 patients were randomized (208 from China; 43 from Japan); 141 (56.2%) completed the 28‐week treatment period. Least‐squares mean percent reduction from combined baseline in GTC seizures/week (treatment period) was placebo 12.6% versus LEV 68.8% (95% confidence interval, 44.0–68.2; p < 0.0001). GTC seizure frequency reduction occurred in both patients with idiopathic and symptomatic generalized epilepsy. The 50% responder rate (treatment period) was placebo 28.4% versus LEV 77.8%. Freedom from GTC seizures (evaluation period) was placebo 3.1% versus LEV 29.6%. Incidence of treatment‐emergent adverse events (TEAEs; treatment period) was placebo 52.0% versus LEV 57.1%; most frequently nasopharyngitis, protein in urine, decreased platelet count, and pyrexia. Incidence of TEAEs leading to discontinuation was 4.8% versus 3.2%; incidence of serious TEAEs was 3.2% versus 0.8% for placebo and LEV, respectively; 3 patients taking placebo died versus none taking LEV.SignificanceIn this trial, adjunctive LEV 1,000–3,000 mg/day was effective in reducing GTC seizure frequency in Chinese and Japanese patients ≥16 years old with GTC seizures. Seizure reduction occurred in both patients with idiopathic and symptomatic generalized epilepsy. LEV was well tolerated in this population.

Objective To find out whether conversation analysis helps to differentiate psychogenic nonepileptic seizure (PNES) from epileptic seizure in Chinese patients.Methods Twelve unselected patients from Peking Union Medical College Hospital during 2014 to 2016 with diagnostic uncertainty were included.Interactions following standard protocol were carried out.A linguist blinded to all medical data and a neurologist studied videos and transcripts of the interactions.Using a diagnostic scoring aid which includes 17 conversation features summarized from previous researches, they attempted to predict the medical diagnosis of those patients independently.Results Accurate diagnosis was predicted in 10/12 patients by both raters.Average scores of patients with epileptic seizures were 8.00 (linguist) and 6.75 (neurologist), while average scores of paitents with PNES were-5.75 (linguist) and-7.88 (neurologist).Both raters agreed on most individual items (81.86%, 167/204).To demonstrate different features between these two groups, a case comparison was made between one patient with frontal lobe epilepsy and one patient with PNES.Conclusion In Chinese patients, conversation analysis can help differentiate between epileptic seizure and PNES.

朊蛋白病可为散发或遗传性[1],致病原为可传播的朊蛋白.临床上以克雅氏病(Creutzfeldt-Jacob disease,CJD)最常见,CJD又称可传播性海绵样脑病,为中枢神经系统弥漫变性病变,主要在中年以上发病.临床特征为进行性痴呆、运动障碍和肌阵挛[2].脑电图(EEG)特征性的周期性图形对本病具有诊断意义[3].本文介绍一例CJD患者的诊治经过,探讨EEG在诊断中的应用问题.

The glutamate transporter GLT-1 is critical for the maintenance of low interstitial glutamate concentrations. Loss of GLT-1 is commonly observed in neurological disorders, including temporal lobe epilepsy (TLE). Despite the hypothesis that targeting the mechanisms of GLT-1 deficiency may be a novel strategy for treating drug-resistant epilepsy, the underlying molecular cascade remains largely unknown. Here, we show that Hsp90β is up-regulated in reactive astrocytes of the epileptic hippocampus in patients with TLE and mouse models of epilepsy. Inhibition of Hsp90, but not Hsp70, increased GLT-1 levels. Mechanistically, Hsp90β recruits GLT-1 to the 20S proteasome, thereby promoting GLT-1 degradation. Hsp90 inhibitor prevents GLT-1 degradation by disrupting the association between Hsp90β and GLT-1. Using a model of TLE, we demonstrated that long-term systemic administration of 17AAG dramatically suppressed spontaneous recurrent seizures and ameliorated astrogliosis. Overall, these results suggest that up-regulation of GLT-1 by inhibiting Hsp90β in reactive astrocytes may be a potential therapeutic target for the treatment of epilepsy and excitotoxicity.

Objective To investigate the lateralizing value of ictal face wiping（FW）in patients with refractory mesial temporal lobe epilepsy（MTLE）.Methods Presurgical video types were retrospectively reviewed among 96 patients who were seizure-free for at least 3 years after temporal lobectomy between 1997 and 2012.Attention was

病历摘要 患者 女,14岁.因“反复发作性头脑反应慢、记忆力下降2.5年”入院.据患者母亲回忆,自入院前2年半起,常发现患者在白天清醒状态时,不明原因出现“头脑反应慢,双眼无神”,呈发作性,每次约持续l0min～l.5 h;发作起始及结束均较隐袭,其母亲基本不能判断出何时出现及结束发作(不能准确到数分钟之内).在发作期间,患者或对问话不做答,或可进行简单对答,但发应较平时慢,回答切题或不切题;可听懂并执行简单命令.例如,在听到“到里屋去拿自己的杯子”后,能自己走到屋内,但进屋后却想不起来要做什么.事后患者基本不能回忆发作过程,偶有零散且基本符合事实的记忆.

Although the pathogenesis and epileptogenesis of mesial temporal lobe epilepsy (MTLE) have been studied for years, many questions remain. The ubiquitin–proteasome system (UPS) is one factor that might regulate ion channels, inflammation and neuron excitability. Nedd4-2 is an E3 ubiquitin ligase linked with ion channels and synaptic vesicle recycling. Here, we explore the role of the UPS and its E3 ligase Nedd4-2 in the pathogenesis of MTLE. Our western blot results revealed that ubiquitin and Nedd4-2 were expressed differentially in different stages of MTLE. Co-immunoprecipitation and double immunostaining results indicated that Nedd4-2 was the substrate protein of ubiquitin both in vivo and in vitro. Inhibition of the UPS aggravated the epileptogenesis of MTLE, causing early and frequent spontaneous seizures, more obvious neuron loss and aberrant mossy fiber sprouting. Inhibition of ubiquitin also enhanced the activation of Nedd4-2, and switched ion channel α-ENaC downstream. Our study is the first to report that the UPS participates in the pathogenesis of MTLE, inhibition of UPS could aggravate the epileptogenesis, and that Nedd4-2 is a critical E3 ligase involved in this process.

OBJECTIVE:To explore the relation between parahippocampal structures, such as the amygdala and the entorhinal cortex (EC), with verbal and nonverbal memory in patients with medial temporal lobe epilepsy (MTLE) with visually normal MR imaging findings by volumetric measurements using magnetic resonance imaging (MRI). METHODS:Thirty-six consecutive patients with MTLE presenting a non-sclerotic hippocampus though visual inspection were assessed by MRI to measure the volumes of the hippocampus, amygdale and EC, and by using the clinical memory scale (CMS), a test battery for verbal and nonverbal memory, where summation of all CMS subscale scores equals the memory quotient (MQ). The correlations between MRI volumetric data (Z scores or asymmetry indexes (AI; (L-R)/(L+R)), "L" and "R" refer to the left and right volumes of each structure, respectively), clinical variables and memory scale scores were analyzed using a principal component regression model. RESULTS:Volumetric MRI revealed significant differences between the volumes of the hippocampus, EC, and right amygdala, but no differences in the volume of the left amygdala between the controls and the patients group. The patients group performed significantly worse in MQ (p < 0.01), the associate memory test (p < 0.01), directed memory test (p < 0.05), and the nonsense graphical recognition test (p < 0.05) compared to the control group. The asymmetry of the amygdala negatively correlated to verbal paired associates' recall and nonsense graphical recognition. The direct memory was positively related to the volume of the EC. CONCLUSION:The volumetric asymmetry of the amygdala contributes to either verbal or nonverbal memory impairment in MTLE patients. Verbal memory may correlate with the volume of the EC.

Purpose: The comorbidity of depression in patients with epilepsy is common and treatment is still controversial. This pilot study was aimed at evaluating the efficacy and safety of Xylaria nigripes for treating depressive symptoms in patients with epilepsy during 12 weeks of treatment.Methods: A multicenter, double-blind, placebo-controlled, randomized superiority study was performed. A total of 104 patients with epilepsy who fulfilled the study criteria were randomized 1:1 to receive Xylaria nigripes (the Wu Ling group) or placebo (the placebo group) treatment in the 12-week period of study. The participants were visited on weeks 0, 2, 4, 8, and 12 of the treatment course.Results: Eighty-one patients finished all of the visits. The primary efficacy endpoint in this study was the total effective rate for depression, which was significantly greater in the Wu Ling group (51.3%, n = 39) than in the placebo group (35.7%, n = 42, 0.51-0.36 = 0.15, 95% CI -0.06 to 0.37, U= 2.83, P = 0.002) after 12 weeks of treatment. No differences in seizure frequency or changes in severity were found between the Wu Ling and the placebo groups. In addition, the quality of life and seizure worry subscale scores in patients with epilepsy were also improved more notably in the Wu Ling group than in the placebo group (P < 0.05). Most of the adverse effects (AEs) in this study were mild and had no differences between the Wu Ling and the placebo groups.Conclusion: Xylaria nigripes could alleviate depressive symptoms within 12 weeks treatment and was well tolerated in patients with epilepsy. (C) 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Mesial temporal lobe epilepsy (mTLE) is the main type and most common medically intractable form of epilepsy. Severity of disease-based stratified samples may help identify new disease-associated mutant genes. We analyzed mRNA expression profiles from patient hippocampal tissue. Three of the seven patients had severe mTLE with generalized-onset convulsions and consciousness loss that occurred over many years. We found that compared with other groups, patients with severe mTLE were classified into a distinct group. Whole-exome sequencing and Sanger sequencing validation in all seven patients identified three novel SUN domain-containing ossification factor (SUCO) mutations in severely affected patients. Furthermore, SUCO knock down significantly reduced dendritic length in vitro. Our results indicate that mTLE defects may affect neuronal development, and suggest that neurons have abnormal development due to lack of SUCO, which may be a generalized-onset epilepsy-related gene.

Objective: To explore the involvement of medial temporal lobe structures such as the hippocampus, amygdala, and entorhinal cortex (EC) in memory consolidation by volumetric magnetic resonance imaging (MRI).Methods: Sixty-two consecutive patients with medial temporal lobe epilepsy (MMTLE) were assessed using the Clinical Memory Scale (CMS) and MRI to measure the volumes of the hippocampus, amygdala, and EC. Participants were grouped according to MRI findings into 3 groups: left MRI-positive (abnormal hippocampal formation on the left side; n=17), right MRI-positive (abnormal hippocampal formation on the left side; n=9), and MRI-negative (normal hippocampal formation; n=36). One-way analysis of variance (ANOVA) was used to assess group differences for all volumetric data (Z scores or asymmetry indexes (Al)), memory scale scores, and clinical parameters. Post hoc analyses were done with Fisher's least significant difference (LSD) tests. Al = 100 x (L-R)/(L + R). "L" and "R" refer to the left and right volumes of each structure, respectively.Results: The nonsense graphical recognition tests and the facial memory tests were significantly different between the three groups. Post hoc analyses showed that the right MRI-positive group performed significantly worse than the MRI-negative group on nonsense graphical recognition tests (P=0.008) and the left MRI-positive group had significantly lower scores than the MRI-negative group on facial memory tests (P=0.023).Conclusions: Nonverbal memory was correlated with the status of the right hippocampus. (C) 2014 Elsevier B.V. All rights reserved.

So far, only two mutations in the CHRNA4 gene (in three studies) and one mutation in the CHRNB2 gene had been identified in the patients with sporadic nocturnal frontal lobe epilepsy (NFLE). The absence of mutations in the candidate genes in the majority of sporadic NFLE patients suggest that they are rare loci for the disease, but the necessity of performing genetic testing for sporadic cases should not be neglected. We designed mutation screening of exon 5 of CHRNA4, exon 5 of CHRNB2, and exon 6 of CHRNA2 in a group of 56 Chinese sporadic NFLE cases. A de novo missense mutation in the transmembrane domain M2 segment of the α4 subunit of the neuronal nicotinic acetylcholine receptor, c.823A > T, was found in a 15 year-old right-handed male, but was not observed in his parents and 400 control chromosomes. The mutation decreased the surrounding hydrophobicity and slightly altered secondary structure of the protein. No mutations were found in CHRNB2 and CHRNA2.

Aim To evaluate the efficacy and tolerability of pregabalin(PBG) as add-on therapy in patients with refractory partial seizures. Methods In this multicenter, double-blind, randomized, placebo-controlled trial, 225 patients diagnosed with partialonset seizures were randomly divided into a PBG therapy group and a placebo group. All patients entered a 6-week baseline period followed by an 8-week titration interval and an 8-week maintenance period. The starting dose of PBG group was 150 mg·d-1, and target dose was 400 mg·d-1. The main outcome was 28-day seizure responses ratio. The secondary outcomes points included 28-day seizure response ratio of all seizure types, 28-day seizure reduction rate, clinical seizure frequency evaluation, percentage of patients with reduction of secondary generalized tonic clonic seizures(SGTC), percentage of patients with seizure free or more than 50% seizure reduction, Clinical Global Impression(CGI) rating scales, and adverse events. Results The 28-day seizure response ratio of PBG group was(-40.24±37.88), and the placebo group was(-22.84 ± 37.61)%(F=15.063 9,P=0.000 1). The rate of adverse event of PBG and placebo group was 60.53% and 47.75% respectively without statistical significance. However, the adverse effect rate of PBG group was higher than that of placebo group(45.61% vs 23.42%, P=0.000 7). Commonly reported adverse effects were dizziness, sleepiness, blurred vision and fatigue. Conclusion Pregabalin treatment was generally well tolerated and was associated with significant reductions in seizure frequency as adjunctive treatment for partial-onset seizures.

Objective To investigate the lateralizing value of head deviation(HD) during complex partial seizures (CPS) in patients with refractory mesial temporal lobe epilepsy (mTLE).Methods Presurgical videotypes of 43 patients who were seizure-free for at least one year after temporal lobectomy were retrospectively reviewed.Attention was paid to the relationship between time and type of HD and the side of epileptogenic zone.Results HD was seen in 88 CPS from 43 patients who had total 206 CPS with or without secondary generalization.Both versive and non-versive HD displayed high positive predictive value (83％ (33/40) and 88％ (22/25)) for localization of an ipsilateral and contralateral seizure onset,respectively.Conclusion Both non-versive HD and versive HID during CPS in patients with mTLE are reliable lateralizing signs that can complement other diagnostic modalities in presurgical evaluation.

OBJECTIVE:To explore the lateralizing value of dystonic posturing (DP) of upper limb in patients with refractory mesial temporal lobe epilepsy (MTLE).METHODS:Presurgical videotypes of 89 patients staying seizure-free for at least 2 years after temporal lobectomy were retrospectively reviewed. Attention was paid to temporal correlation between occurrence of DP and seizure and the relationship of DP to side of epileptogenic zone (resected side).RESULTS:DP was observed in 92 complex partial seizure (CPS) from 37 (41.6%) patients among 89 patients with a total of 424 CPS. DP was not an initial symptom in the course of CPS and its onset occurred mostly in the middle third of ictus. DP displayed a high positive predictive value of 93.9% for lateralizing a contralateral seizure onset.CONCLUSION:DP is a reliable lateralizing sign in patients with MTLE.

Objective To study the clinical features,diagnosis and immunotherapy response of leucine-rich glioma inactivated-1 (LGi1)-antibody positive limbic encephalitis (LE).Methods A case of anti-LGi1 LE in a 68-year-old male was reported.The related literature was reviewed and clinical features were summarized.Results Anti-LGi1 LE is characterized by subacute development of amnesia,frequent,brief,and drug-resistant faciobrachial dystonic seizures,refractory hyponatremia,mesial temporal lobe abnormalities on magnetic resonance imaging and positron emission tomography,and a good response to intravenous immunoglobulin therapy.Conclusion Early recognition and appropriate immunotherapy for patients with LE associated with anti-LGi1 antibody may prevent irreversible injury to limbic function.

Notch signaling in the nervous system is often regarded as a developmental pathway. However, recent studies have suggested that Notch is associated with neuronal discharges. Here, focusing on temporal lobe epilepsy, we found that Notch signaling was activated in the kainic acid (KA)-induced epilepsy model and in human epileptogenic tissues. Using an acute model of seizures, we showed that DAPT, an inhibitor of Notch, inhibited ictal activity. In contrast, pretreatment with exogenous Jagged1 to elevate Notch signaling before KA application had proconvulsant effects. In vivo, we demonstrated that the impacts of activated Notch signaling on seizures can in part be attributed to the regulatory role of Notch signaling on excitatory synaptic activity in CA1 pyramidal neurons. In vitro, we found that DAPT treatment impaired synaptic vesicle endocytosis in cultured hippocampal neurons. Taken together, our findings suggest a correlation between aberrant Notch signaling and epileptic seizures. Notch signaling is up-regulated in response to seizure activity, and its activation further promotes neuronal excitation of CA1 pyramidal neurons in acute seizures.