BACKGROUND AND PURPOSE:This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle-specific kinase antibodies and were receiving standard-of-care therapy. METHODS:Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard-of-care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. RESULTS:Twenty-nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. CONCLUSION:Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial.

肌张力障碍是一种多动性运动障碍,其特征在于不受控制的过度运动性肌肉收缩,导致重复扭转运动和异常姿势,可影响四肢、躯干、颈部和面部[1].遗传缺陷在肌张力障碍的发生中起重要作用.由于新一代测序技术的出现,从发现DYT1 (TOR1A)[2]开始,肌张力障碍相关基因的范围不断扩大[3].2016年,两个研究小组独立确定KMT2B的突变是儿童期全身性肌张力障碍的重要原因[4-5].KMT2B编码一种特定的赖氨酸甲基转移酶,在正常人类发育中起关键作用[6-7].迄今为止,已经报道了78例KMT2B变异的患者[4-5,8-22] ,其中有9例来自中国[11,13,15].现报道1例本院收治的KMT2B基因新突变导致的肌张力障碍,以提高对该病的认识.

多发性硬化(multiple sclerosis,MS)是好发于年轻人的最常见的神经系统疾病之一,疾病修正疗法(DMT)是MS患者缓解期的标准治疗.由于MS是终生性神经退行性疾病,患者需要长期有效且耐受性良好的治疗,因此DMT药物的长期安全性问题值得关注.Ⅲ期TOWER核心+延长试验显示,在特立氟胺14 mg/d最长应用达7.22年期间,治疗有效且安全性和耐受性良好,无新发病变或非预期安全性问题,与Ⅲ期TOWER核心研究结果一致,提示特立氟胺长期治疗的安全性和有效性.

Multiple sclerosis (MS) is a chronic and progressive disease. Patients with MS experience symptoms that result in a decline in physical and psychological function, which has a negative and serious impact on their quality of life (QoL). QoL, which provides a broad and subjective measure of the disease as well as treatment impact, is one of the frequently used patient reported outcome (PRO) measurements. The Teri-PRO study investigated the overall satisfaction of patients with MS treated with teriflunomide by using the Treatment Satisfaction Questionnaire. The results showed that greater patient satisfaction was reported when converting injectable disease modifying therapy (DMT) to oral treatment with teriflunomide. The introduction of QoL assessment into MS research in China enables neurologists to comprehensively understand the clinical efficacy of DMT and the subjective evaluation, and provides a valuable perspective for regulatory authorities to evaluate MS medication.

BACKGROUND:In the phase 3 TOWER core study (NCT00751881), the efficacy and safety of teriflunomide compared with placebo were demonstrated in patients with relapsing forms of multiple sclerosis (RMS). Here, the long-term safety and efficacy outcomes from the TOWER extension study (NCT00751881) are reported. METHODS:All patients who entered the extension (N = 751) were assigned to teriflunomide 14 mg and assessed for long-term safety and efficacy. RESULTS:Of 751 patients in the TOWER extension study, 253, 265, and 233 patients received placebo/teriflunomide 14 mg, teriflunomide 7 mg/14 mg, and teriflunomide 14 mg/14 mg, respectively. Median teriflunomide exposure was 4.25 years (maximum 6.3 years). The overall frequency of adverse events (AEs) was comparable across treatment groups, but a higher proportion of patients in the teriflunomide 7 mg/14 mg (12.4%) and 14 mg/14 mg (12.4%) groups had serious AEs compared with the placebo/teriflunomide 14 mg group (6.4%). Alanine aminotransferase increase and hair thinning occurred at a higher frequency in the placebo/teriflunomide 14 mg group (11.2% and 14.3%, respectively) compared with the teriflunomide 7 mg/14 mg (3.0% and 4.5%, respectively) and 14 mg/14 mg groups (5.2% and 4.3%, respectively). The incidences of AEs of interest (hematologic and hepatic effects, peripheral neuropathy, hypertension, and malignancy) were low and comparable across treatment arms. Disability worsening and adjusted annualized relapse rates were low and stable over time, and mean Expanded Disability Status Scale scores were unchanged over time, for all treatment groups. CONCLUSION:In the TOWER extension study, the efficacy of teriflunomide 14 mg was maintained in patients with RMS. No new or unexpected AEs were observed with teriflunomide treatment, supporting a safety profile in the extension that was consistent with the core trial. These findings support the positive benefit:risk profile of teriflunomide as a long-term immunomodulatory therapy.

The number of patients who had BAEP inspected was 59.The number of patients with abnormal BAEP was 10.The number of patients with 3-5 wave elongation was 9.

Background Myasthenia gravis (MG), a chronic neuromuscular disorder, can adversely affect patients’ health-related quality of life (HRQoL), especially in women. The study aimed to evaluate the difference in HRQoL of women and men MG patients and explore the factors that mediate the relationship between gender and HRQoL. Methods A cross-sectional study was conducted among 1815 patients with MG in China. The revised 15-item MG quality of life scale (MG-QOL15r) was used to access patients’ HRQoL in overall, physical, social and emotional domains. Socio-demographic information, diagnosis and treatment history, comorbidities, social support, active lifestyle and the MG activities of daily living scale (MG-ADL) were recorded and compared between women and men using the Student’s t-test and Pearson’s Chi-square test. Multivariable regression analyses were conducted to identify independent contributors to HRQoL, especially those affecting different gender. Results On average, female patients with MG reported a lower MG-QOL15r score than the males (44.49 ± 29.10 vs 49.32 ± 29.18). The association between gender and patients’ HRQoL interacted with the number of comorbidities across the overall, physical and social domains of patients. As the number of comorbidities increased, the scores of HRQoL decreased and it was faster among females than the males ( p < 0.05). Moreover, unemployment, exacerbation of the disease, and active lifestyle contributed to the patients’ HRQoL across all domains. Unemployment (β = − 4.99 [95%CI, − 7.80 to − 2.18], p < 0.001) and exacerbations (β = − 8.49 [95%CI, − 11.43 to − 5.54], p < 0.001) were correlated with poorer HRQoL; while an active lifestyle had a positive impact on HRQoL (β = 0.28 [95%CI, 0.16 to 0.40], p < 0.001). Conclusions The results indicate that the HRQoL of women MG patients was lower than that of men. The relationship between gender and HRQoL is modulated by the number of comorbidities. Thus, to improve the HRQoL of women MG patients, symptomatic treatments might not be enough, their comorbid conditions should be considered as well. Additionally, employment status, MG exacerbations, and an active lifestyle have been found as determining factors of the patients’ HRQoL, which suggests future interventions should cope with these factors to improve their quality of life.

In the phase 3 TOWER (NCT00751881) study, teriflunomide 14 mg significantly reduced annualized relapse rate (ARR) and risk of 12-week confirmed disability worsening (12-w CDW) vs placebo in patients with relapsing forms of MS (RMS). The TOWER population included an appreciable proportion of Asian patients. Reductions in ARR and 12-w CDW associated with teriflunomide 14 mg were comparable between the Asian and overall populations, as were the rates for adverse events and serious adverse events, with no new or unexpected safety findings. These observations provide further evidence to support the clinical benefits and safety profile of teriflunomide in a broad range of patients with RMS. (C) 2018 The Authors. Published by Elsevier Ltd.

Holmes-Adie syndrome (HAS) is a clinical syndrome mainly characterized by tonic pupil and disappearance of tendon reflex. It is mostly idiopathic and can also be seen in cerebral diseases, such as trauma, infection and tumors. However, it is rarely reported to be accompanied with myasthenia gravis (MG). We report a case of MG and HAS, whose clinical manifestations were fluctuation of limb weakness, breathing difficulties, right ptosis. Her pupils were unequal: the left pupil was 3 mm, the right pupil was 2 mm, direct and indirect light reflex was slow in left pupil, and right pupil was sensitive to light reflex. The left eye pupil shrank to 2 mm after dripped pilocarpine diluent for 10 minutes, while the right pupil was still 2 mm. Chest CT examination revealed thymoma. After treatment with thymectomy, glucocorticoid, immunoglobulins and tacrolimus, her symptoms of MG were improved, but the left pupil diameter and light reflex were not changed. Combined with the patient's symptoms, physical signs and examinations, this patient was diagnosed as MG accompanied with HAS.

BACKGROUND:Disease-modifying therapy is the standard treatment for patients with multiple sclerosis (MS) in remission. The primary objective of the current analysis was to assess the efficacy and safety of two teriflunomide doses (7 mg and 14 mg) in the subgroup of Chinese patients with relapsing MS included in the TOWER study. METHODS:TOWER was a multicenter, multinational, randomized, double-blind, parallel-group (three groups), placebo-controlled study. This subgroup analysis includes 148 Chinese patients randomized to receive either teriflunomide 7 mg (n = 51), teriflunomide 14 mg (n = 43), or placebo (n = 54). RESULTS:Of the 148 patients in the intent-to-treat population, adjusted annualized relapse rates were 0.63 (95% confidence interval [CI]: 0.44, 0.92) in the placebo group, 0.48 (95% CI: 0.33, 0.70) in the teriflunomide 7 mg group, and 0.18 (95% CI: 0.09, 0.36) in the teriflunomide 14 mg group; this corresponded to a significant relative risk reduction in the teriflunomide 14 mg group versus placebo (-71.2%, P = 0.0012). Teriflunomide 14 mg also tended to reduce 12-week confirmed disability worsening by 68.1% compared with placebo (hazard ratio: 0.319, P = 0.1194). There were no differences across all treatment groups in the proportion of patients with treatment-emergent adverse events (TEAEs; 72.2% in the placebo group, 74.5% in the teriflunomide 7 mg group, and 69.8% in the teriflunomide 14 mg group); corresponding proportions for serious adverse events were 11.1%, 3.9%, and 11.6%, respectively. The most frequently reported TEAEs with teriflunomide versus placebo were neutropenia, increased alanine aminotransferase, and hair thinning. CONCLUSIONS:Teriflunomide was as effective and safe in the Chinese subpopulation as it was in the overall population of patients in the TOWER trial. Teriflunomide has the potential to meet unmet medical needs for MS patients in China. TRIAL REGISTRATION:ClinicalTrials.gov, NCT00751881; https://clinicaltrials.gov/ct2/show/NCT00751881?term=NCT00751881&rank=1.

中国神经免疫学自20世纪三、四十年代起萌芽、成长、发展、壮大,至今已是集临床、科研、教学与学术交流为一体的相对完整体系,也是中国医学体系中的重要一支.80多年的发展历程中,中国神经免疫工作者在国家各级机构和同行的支持与陪伴下,学习、成长、开拓进取,取得了目前令人瞩目的成就.

Thymectomy is routinely carried out in patients with myasthenia gravis (MG) and thymomas. However, there is still a dispute as to whether MG patients with thymic hyperplasia should undergo thymectomy. We aimed to investigate the pathological findings in the thymus in patients with co-existing MG and thymic hyperplasia or thymomas treated with thymectomy, as well as effects of immunosuppression. Thirty-three patients with MG were selected and grouped accordingly: patients with no thymic abnormalities, patients with thymic hyperplasia, and patients with thymomas. All patients were treated with methylprednisolone alongside immunosuppression. A separate cohort of 24 MG patients with thymic hyperplasia or thymomas and treated with thymectomy were selected. As controls, 5 patients with thymomas or thymic carcinoma without MG were selected. Expression of CD5, extracellular regulated protein kinases1/2 mitogen activated protein kinase (ERK1/2MAPKs) and CD95 ligand (FasL) in the thymus was examined. Methylprednisolone and immunosuppressive therapy are highly effective in MG patients with normal thymus tissue and MG patients with thymic hyperplasia compared to MG patients with thymomas alone. CD5 expression was highest in MG patients with thymic hyperplasia, correlating with expression of ERK1/2MAPKs. FasL expression was similar across all groups. Thymomas may be distinguished from thymic hyperplasia by expression of CD5 and ERK1/2MAPKs. Thymectomy is the preferred treatment for MG patients with thymomas but may not be necessary in MG patients with thymic hyperplasia who are treated with immunosuppressive therapy.

重症肌无力（myasthenia gravis，MG）是一种累及外周神经-肌肉接头处的自身免疫性疾病，其以体液免疫为主，主要由乙酰胆碱受体（acetyl choline receptor, AchR）抗体侵袭神经-肌肉接头突触后膜上的乙酰胆碱受体而致病。视神经脊髓炎（neuromyelitis optica, NMO）是一种表现为视神经和脊髓相继或同时受累的急性或亚急性中枢神经系统白质脱髓鞘性疾病。MG与NMO同时发生于同一患者十分罕见，故在此报道我院住院的1例MG并发NMO患者的病历资料。

多发性硬化（MS）是中枢神经系统（CNS）自身免疫性、炎性、白质多灶性、脱髓鞘性疾病[1-2]。其临床表现一般由CNS病损所致[3]。

Objective _ To analyze the predictive value of electrophysiological results on generalized myasthenia gravis (gMG ) progression in patients with ocular myasthenia gravis (oMG ) and assess related influencing factors of generalized transformation. Methods_ A retrospective analysis of clinical data of 76 oMG patients hospitalized from May 2006 to May 2009 in Department of Neurology ,Beijing hospital ,whose symptoms were still confined to the extraocular muscles after at least three months of the onset was performed.According to test results of repetitive nerve stimulation (RNS ) and Single Fiber Electromyography (SFEMG ) during hospitalization ,patients were divided into the electrophysiological testing negative and positive groups. We followed up all patients for 5‐10 years , analyzed their clinical characteristics , therapeutic interventions (thymectomy and/or immunosuppressive therapy) situation and prognostic outcome during hospitalization ,and related influencing factors of transformation were further analyzed in patients transformed into gMG. Results_17 of 76 patients (22.37% ) were ultimately transformed into gMG ,and the percentage of gMG transformation in the electrophysiological positive group was significantly higher than that of the electrophysiological negative group (33.33% vs. 6.45% ;χ2 = 7.638 , P< 0.01) . The transformation time:6 cases in 2 years ,10 cases in 2‐5 years ,only one case after 5 years. The percentage of abnormal thymus (thymic hyperplasia or thymoma) (94.11% vs. 64.41% ;χ2 =4.312 , P<0.05) and age of onset [ (44.24 ± 24.43) vs. (31.08 ± 25.03) years old;t= - 1.927 , P < 0.05 ] in patients converted to gMG were significantly higher than those of the untransformed group (oMG group ) . Whether the electrophysiological results were positive or not , early&nbsp;therapeutic interventions (thymectomy and/or immunotherapy) showed no significant effect on clinical outcome. Conclusions_Only a few of oMG patients will transfer to gMG and the electrophysiological results are more commonly positive. Transformation time is mostly within 5 years. Early therapeutic interventions (thymectomy and/or immunotherapy) showed no significant effect on clinical outcome. Abnormal thymus (thymic hyperplasia or thymoma) and old age of onset are also risk factors for generalized transformation.

目的 评价短程大剂量糖皮质激素(GCS)冲击联合其他免疫抑制剂治疗重症肌无力(MG)的疗效及安全性.方法 回顾性分析作者医院2003-11-2011-2期间住院的40例应用短程大剂量GCS冲击联合其他免疫抑制剂治疗MG患者的疗效和不良反应,比较不同治疗时段、性别、起病年龄、临床类型、免疫抑制剂的疗效.结果 与治疗前比较,所有病例在短程大剂量GCS冲击联合其他免疫抑制剂治疗4周时临床绝对评分显著改善(6.88±6.97 vs.24.50±10.78,P＜0.01),治疗12个月时与治疗4周时临床绝对评分无统计学差异(7.22±10.39 vs.6.88±6.97,P＞0.05);治疗4周时的相对评分69.00％±27.53％、有效率92.50％,治疗12个月时的相对评分70.00％±39.35％、有效率87.50％.其治疗4周时与治疗12个月时的有效率在不同性别、起病年龄、眼肌型/全身型的比较中均无统计学差异(P＞0.05).治疗4周时环孢素组的有效率优于硫唑嘌呤组(P＜0.05),治疗12个月时此2组有效率无统计学差异(P＞0.05).结论 短程大剂量GCS冲击联合免疫抑制剂治疗可显著改善MG患者临床表现.

Neuromyelitis optica spectrum disorders (NMOSDs) include classic neuromyelitis optica (NMO), opticospinal multiple sclerosis (OSMS), limited form of NMO and isolated optic neuritis or myelitis accompanied by either systemic autoimmune diseases or typical MRI findings of NMO. The common neuro-ophthalmic features of NMOSDs include simultaneous or consecutive bilateral optic neuritis, more commonly seen optic disk edema and surrounding exudate, poor visual recovery, steroid responsiveness and dependency. Combined with serum aquaporin 4 (AQP4) antibody and brain MRI examination, these clinical features can be helpful to the early differential diagnosis between NMOSDs and MS. Some types of eye movement abnormalities have been reported in patients with NMOSDs, but further investigation needs to be done before the specificity of these features are confirmed. doi: 10.3969/j.issn.1672-6731.2014.10.003

In 19th century, neuromyelitis optica (NMO) indicated optic neuritis and myelitis with simultaneous onset of both sides. Later studies proposed that the onset of right or left side optic neuritis could be separated by weeks, months even years. The revolutionary discovery of aquaporin 4 (AQP4) antibody in 2004 by Vanda A Lennon challenged and changed the old concept of NMO. The concept of neuromyelitis optica spectrum disorders (NMOSDs) was proposed in 2007. Since then, a series of different terms have been proposed, including opticospinal multiple sclerosis (OSMS), NMOSDs, spectrum of NMO, expanded spectrum of NMO, etc. Through a summary of different concepts of NMO, this paper will make a comprehensive review on the evolution history of NMO study from 19th to 21st century, and the prospective targets of study will also be proposed. doi: 10.3969/j.issn.1672-6731.2014.09.002

Delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) is a syndrome constituted by acute dementia, psychiatric symptoms, pyramidal and extrapyramidal symptoms, which can be developed after the original clinical symptoms of carbon monoxide poisoning recovered. Lots of studies have been done to explain the mechanisms of DEACMP, and more and more researches have demonstrated that the immunological mechanism may be involved in or play an important role on the pathogenesis of the process. This article will review the researches of immunological mechanism of DEACMP in recent years and give some prompts to clinical study in the future. doi: 10.3969/j.issn.1672-6731.2014.10.006

Objective Multiple sclerosis (MS) is a mainly cell-mediated autoimmune demyelinating disease in central nervous system (CNS), characterized by inflammatory demyelinating and infiltration of mononuclear cells around microvessels in CNS. It has been shown that MS is caused by the imbalance between T helper cell 1 (Th1) and Th2 or between inflammatory cytokines and anti-inflammatory cytokines. However, the profile of cytokine according to the published data is contradictory. This study is to evaluate the status of cytokines from mononuclear T cells in MS patients and try to provide clues for clinical diagnosis and treatment. Methods Enzyme-linked immunospot assay (ELISPOT) was used to test the spontaneous and antigen-specific [concanavalin A (ConA), myelin basic protein (MBP) and acetyleholine receptor (AChR)] Th1-related cytokine interferon-γ (IFN-γ) and Th2-related cytokines interleukin-4 (IL-4), IL-10 in the peripheral blood mononuclear cells in MS patients, who had not received any immunological treatment over the last 3 months. Results Compared with normal controls and patients with non-immune neurological diseases, MBP specific IL-4, IL-10 and IFN-γ of MS patients increased significantly (P = 0.000, for all). In addition, MBP specific IFN-γ level of MS patients increased signicantly in acute or exacerbating phase when compared with that in stable phase (P = 0.002), while MBP specific IL-4 and IL-10 levels did not differ significantly (P > 0.05, for all). Conclusions The examinations of IL-4, IL-10 and IFN-γ cytokines using ELISPOT are helpful for the differential diagnosis and the disease course of MS. doi: 10.3969/j.issn.1672-6731.2014.10.008