视神经脊髓炎谱系疾病遗传易感基因的研究进展

正视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorders,NMOSD)是一组主要由体液免疫参与的抗原-抗体介导的中枢神经系统(CNS)炎性脱髓鞘疾病谱系。其中包括传统意义的视神经脊髓炎(NMO)及尚不能满足2006年NMO诊断标准,伴随或不伴随AQP4-IgG阳性的形式局限的脱髓鞘疾病。许多研究资料表明,视神经脊髓炎同多发性硬化(multiple sclerosis,MS)一样具有遗传异质性。近几年,为进一步探索NMO/NMOSD的发病机制、治疗手段,在分子生     

T淋巴细胞亚群在视神经脊髓炎谱系疾病急性期中的作用

<正>视神经脊髓炎(neuromyelitis optica,NMO),又称Devic病,是一种具有高复发率及高致残率的中枢神经系统脱髓鞘疾病,临床上常表现为视神经炎(optic neuritis,ON)及长节段横贯性脊髓炎(longitudinally extensive transverse myelitis,LETM)。自2004年发现抗水通道蛋白4的Ig G抗体(Aquaporin 4-IgG,AQP4-IgG)以来,NMO逐渐被大多数学者认为是独立于多发性硬化存在的一种疾病实体^[1]。2015年,国际NMO诊断小组提出了视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorder,NMOSD)的概念,     

AQP4-IgG阳性与AQP4-IgG阴性NMOSD的临床学比较研究

目的 比较AQP4-IgG阳性与AQP4-IgG阴性视神经脊髓炎谱系疾病(NMOSD)患者的临床学特点.方法 收集2015年9月至2019年9月在郑州大学第一附属医院住院的345例NMOSD患者的临床资料,根据AQP4-IgG血清学状态,将NMOSD患者分为AQP4-IgG阳性组与AQP4-IgG阴性组.结果 AQP4...     

2015年视神经脊髓炎谱系疾病诊断标准国际共识解读

（aquaporin-4,AQP4）抗体的发现,加深了人们对 NMO 的认识,并扩展了 NMO 谱系疾sclerosis,MS）的一种中枢神经系统特发性炎性疾病。NMO 高度特异性的水通道蛋白4视神经脊髓炎（neuromyelitis optica,NMO）是不同于多发性硬化（multiple （International Panel for NMO Diagnosis,IPND）对 NMOSD 诊断标准进行了修订,并达病（neuromyelitis optica spectrum disorders,NMOSD）的定义。NMO 诊断国际专家组成2015年 NMOSD 诊断标准国际共识。该诊断标准取消了 NMO 的个别定义,而将 NMO归入 NMOSD。同时,根据 AQP4抗体表达状态,分为 AQP4抗体阳性和 AQP4抗体阴性NMOSD。AQP4抗体阳性 NMOSD 的诊断要求具备6项核心症状之一;AQP4抗体阴性或无法进行 AQP4抗体检测的 NMOSD 的诊断,要求则更为严格,必须有特征性的 MRI 表现。本文即对2015年 NMOSD 诊断标准国际共识中的要点进行解读和评论。     

水通道蛋白4抗体的研究进展

水通道蛋白4抗体(anti-aquaporin 4antibody,AQP4-IgG)是能与细胞膜表面的水通道蛋白4(aquaporin 4,AQP4)特异性结合的抗体,是由LENNON等[1]于2005年在视神经脊髓炎(neuromyelitis optica,NMO)患者的血清中首次发现。AQP4抗体对NMO诊断的高度特异性,也使其成为了一种独立的疾病,并在此基础上延伸出了视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorders,NMOSD)这一概念。但并非所有的NMOSD患者都合并AQP4抗体,并且该抗体也可能参与了其他类型中枢神经系统脱髓鞘疾病的发病,如多发性硬化(multiple sclerosis,MS)及Balo同心圆硬化(Balo’s concentric sclerosis,BCS),本文围绕AQP4抗体的致病机制,检测方法以及与这些疾病的关系作以综述。     

首次检测水通道蛋白-4抗体阴性视神经脊髓炎谱系疾病的临床转归

目的分析水通道蛋白-4抗体(aquaporin-4 immunoglobulin G antibodies,AQP4-IgG)阴性的视神经脊髓炎谱系疾病(neuro myelitis optica spectrum disorder,NMOSD)患者临床特征、抗体演变以及转归。方法纳入中山大学附属第三医院神经科首次检测AQP4-IgG阴性的NMOSD患者15例,定期门诊随访,收集临床及实验室检查资料,分析其临床转归。结果 15例AQP4-IgG阴性患者平均随诊67个月,以视神经炎(optic neuritis,ON)症状起病最多见(8例)。动态复查血清AQP4-IgG,其中4例(27%)由阴性转为阳性,2例血清不稀释处理时显示极低滴度(滴度为1:1)阳性,9例持续阴性。随访中,1例患者最终修正诊断为多发性硬化,4例诊断为AQP4-IgG阳性NMOSD。AQP4-IgG从阴性转变为阳性的时间节点临床可无复发(1例),但持续阴性患者也出现临床复发(3例)。结论 AQP4-IgG阴性NMOSD患者最常累及视神经;临床随访中AQP4-IgG可能发生血清学转变,患者诊断及转归不同。     

新诊断标准下视神经脊髓炎谱系疾病与多发性硬化的 临床特点分析

目的 研究视神经脊髓炎谱系疾病（NMOSD）的一般临床特点及与多发性硬化（MS）的区 别。方法 收集2016 年1 月—2017 年12 月于宣武医院神经内科住院的中枢神经系统脱髓鞘疾病患者， 依据2015 年NMOSD 诊断标准及2017 年McDonald 诊断标准进行筛选，对NMOSD 及MS 患者临床资料进 行回顾性分析，并比较NMOSD 及MS 患者临床特点。结果 纳入NMOSD 患者233 例，MS 患者125 例， 平均发病年龄分别为（43.0±14.7）岁、（38.1±11.2）岁，男女比例分别为1∶4.5、1∶2.6。NMOSD 多以视 神经受损症状起病，顽固性瘙痒、恶心、呕吐可能是其特征性临床特征；MS 则多以脑损伤起病。大多 数NMOSD 和MS 患者的首次发病无明显诱因，可能的诱因有上呼吸道感染、劳累、疫苗接种、产后等。 NMOSD 及MS 脑脊液压力方面无明显区别，相比MS 患者，NMOSD 患者脑脊液白细胞计数高于正常。血 水通道蛋白4 抗体（AQP4-Ab）与脑脊液寡克隆区带（OB）为鉴别二者重要生物标志物。结论 NMOSD 最 多被误诊的疾病是MS，尤其是疾病初期及对于AQP4-IgG 抗体测试阴性的NMOSD 患者。顽固性瘙痒、 恶心、呕吐可能是NMOSD 的一个被低估的特征。血AQP4-Ab 与脑脊液OB 分别为NMOSD 及MS 重要的 生物标志物，对鉴别两种疾病意义重大。     

视神经脊髓炎谱系疾病治疗后血清AQP4-IgG转换二例

正视神经脊髓炎(neuromyelitis optica,NMO)及其谱系疾病(neuromyelitis optica spectrum disorder,NMOSD)是免疫介导的中枢神经系统炎性脱髓鞘疾病。水通道蛋白4(aquaporin4,AQP4)-IgG是其相对特异性的血清学生物标记物,体外细胞实验和动物模型已初步证实AQP4-IgG的部分致病作用~([1-4])。在精准医疗时代,AQP4-IgG的临床检测受到神经科医生的高度重视。     

AQP4-IgG阳性视神经脊髓炎谱系疾病的脑脊液细胞学特点

目的探讨水通道蛋白4抗体(AQP4-IgG)阳性的视神经脊髓炎谱系疾病(neuromyelitis optica spectrum disorders,NMOSD)的脑脊液细胞学特点。方法回顾性收集AQP4-IgG阳性的NMOSD患者的脑脊液细胞学、脑脊液常规、生化及寡克隆区带结果,并分析其特点。结果共收集237例AQP4-IgG阳性的NMOSD患者的脑脊液细胞学资料。女∶男=7.8∶1。120例(50.6%)患者脑脊液细胞学可见炎性反应,炎性反应程度为轻、中、重度者分别为63、43、14例。95例为淋巴细胞性炎性反应,20例为淋巴细胞与中性粒细胞性炎性反应,4例为淋巴细胞与嗜酸性粒细胞性炎性反应,1例为淋巴细胞、中性粒细胞与嗜酸性粒细胞性炎性反应。71例(30.0%)患者可见激活淋巴细胞,11例(4.6%)可见激活单核细胞,15例(6.3%)可见浆细胞。176例患者行寡克隆区带检测,其中脑脊液特异性寡克隆区带阳性47例(26.7%)。结论达1/2的AQP4-IgG阳性NMOSD患者脑脊液细胞学可见炎性反应,以淋巴细胞性炎性反应为主,也可见中性粒细胞与嗜酸性粒细胞参与;部分患者脑脊液细胞学可见激活淋巴细胞、激活单核细胞和浆细胞;AQP4-IgG阳性NMOSD患者脑脊液特异性寡克隆区带阳性率较多发性硬化低。上述脑脊液特点有助于NMOSD的诊断和鉴别。     

视神经脊髓炎-IgG抗体阳性与阴性共存的视神经脊髓炎疾病谱一家系

视神经脊髓炎(neuromyelitis optica,NMO)早期被认为是多发性硬化(multiple sclerosis,MS)的特殊亚型.2004年发现水通道蛋白4( AQP4) IgG抗体后[1],大多数学者认为,NMO与MS发病机制不同,是一种独立的疾病,并且将NMO扩大为视神经脊髓炎疾病谱(NMO spectrum disorders,NMOSD),后者包括NMO、NMO限定型(单次或复发性长节段脊髓炎、复发性或双侧同时发生的视神经炎)、亚洲视神经脊髓型多发性硬化、伴有系统性自身免疫性疾病的视神经炎或长节段脊髓炎以及伴有NMO特征性脑部病灶(下丘脑、胼胝体、脑室旁或脑干)的视神经炎或脊髓炎[2].     

What proportion of AQP4-IgG-negative NMO spectrum disorder patients are MOG-IgG positive? A cross sectional study of 132 patients

Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been described in patients with neuromyelitis optica spectrum disorders (NMOSD) without aquaporin-4 antibodies (AQP4-IgG). We aimed to identify the proportion of AQP4-IgG-negative NMOSD patients who are seropositive for MOG-IgG. In a cross sectional study, we reviewed all patients seen in the National NMO clinic over the last 4 years (after the availability of MOG-IgG testing), including clinical information, MRI, and antibody tests. 261 unique patients were identified. 132 cases satisfied the 2015 NMOSD diagnostic criteria. Of these, 96 (73%) were AQP4-IgG positive and 36 (27%) were AQP4-IgG negative. These 36 patients were tested for MOG-IgG and 15/36 (42%) tested positive. 20% (25/125) of the patients who did not satisfy NMOSD criteria had MOG-IgG. Approximately half of seronegative NMOSD is MOG-Ig seropositive and one in five of non-NMOSD/non-MS demyelination is MOG-IgG positive. Since MOG-associated demyelinating disease is likely different from AQP4-IgG disease in terms of underlying disease mechanisms, relapse risk and possibly treatment, testing for MOG-IgG in patients with AQP4-IgG-negative NMOSD and other non-MS demyelination may have significant implications to management and clinical trials.     

光相干连续断层成像术在视神经脊髓炎谱系病的临床应用

目的探讨光相干连续断层成像术(OCT)在视神经脊髓炎谱系病(NMOSD)的临床应用。方法利用OCT对49例NMOSD患者(NMOSD组)和1 5例健康对照志愿者(对照组)视乳头周围视网膜神经纤维层(RNFL)厚度进行比较;NMOSD组再根据是否伴视神经炎、水通道蛋白抗体状态(AQP4-IgG)等对NMOSD组分为伴视神经炎(NMOSD-ON)亚组(34例);不伴视神经炎(NMOSD-NON)亚组(15例)。比较各亚组的RNFL厚度差异;采用扩展病残状态评分(EDSS)评价神经功能缺损程度,分析EDSS与RNFL是否存在相关性。结果 NMOSD患者受累眼的RNFL各象限厚度与未受累眼和对照组比较显著变薄(P0.01);NMOSD未受累眼与对照组比较,RNFL厚度差异无显著性(P0.05)。AQP4-IgG阳性或阴性NMOSD-ON亚组的RNFL厚度比较差异无显著性(P0.05);RNFL厚度变化与NMOSD残障的严重程度无相关性(P0.05)。结论 RNFL变薄仅在NMOSD受累眼表现,厚度变化与AQP4-IgG无关,OCT可能有助于临床对NMOSD诊疗提供参考指标。     

Paraneoplastic neuromyelitis optica spectrum disorders: three new cases and a review of the literature

Neuromyelitis optica spectrum disorders (NMOSD) occasionally develop in patients with tumor in relation to aquaporin-4 IgG (AQP4-IgG), representing a new paraneoplastic phenomenon. We reported three patients with paraneoplastic NMOSD and provided a comprehensive review of the literature. A total of 34 cases with paraneoplastic NMOSD were identified from our own case database (n = 3) and the previous literature (n = 31). The median age at NMOSD-related symptom onset was 50.5 years, and 91% of the cases were female. 11 (32%) cases had breast carcinoma. In 15 (44%) cases, NMOSD-related symptoms preceded tumor detection [median, 4 (range 1–180) months], and in 19 (56%) cases, symptoms followed tumor detection [median, 12 (range 3–180) months]. 5/14 (36%) cases had hiccups and vomiting as the initial symptoms, with the involvement of medulla oblongata. In 10/14 (71%) cases, cervical spinal cord was involved. In contrast to idiopathic NMO, NMOSD is more likely to be paraneoplastic than in patients aged over 50 years at the onset of symptoms, especially for female patients. Breast carcinoma is the most common tumor associated with paraneoplastic NMOSD, accounting for nearly a third of all types of tumors. Paraneoplastic NMOSD usually involves medulla oblongata and cervical spinal cord. We recommend adding AQP4-IgG as an onconeural antibody, but its clinical utility warrants further investigations.     

Temporal dynamics of cerebrospinal fluid anti-aquaporin-4 antibodies in patients with neuromyelitis optica spectrum disorders

Neuromyelitis optica spectrum disorders (NMOSD) are associated with anti-aquaporin-4 autoantibodies (AQP4-IgG). Limited data is available on longitudinal cerebrospinal fluid (CSF) AQP4-IgG and their relation to disease activity and inflammatory parameters. AQP4-IgG titers were measured in matched longitudinal serum and CSF samples of 12 patients with NMOSD by an immunofluorescence assay and correlated with clinical parameters. CSF AQP4-IgG were present in patients with high serum titers and correlated with spinal MRI lesion length and CSF parameters. Clinical improvement was associated with a decrease in CSF, but not serum, AQP4-IgG titers. Thus, CSF AQP4-IgG were associated with clinical activity and neuroinflammation.     

Lesions of the posterior limb of the internal capsule in neuromyelitis optica spectrum disorder

Posterior limb of the internal capsule lesions (PLICL) are one of the MRI features of neuromyelitis optica spectrum disorder (NMOSD). However, there is no evidence that such lesions are pathogenically related to NMOSD. We retrospectively analyzed features of PLICL in NMOSD, and other central nervous system inflammatory disorders, in 561 patients. We also examined the pathological samples of six patients. Of the 561 patients investigated, PLICL were found in 65 patients (11.6%). Lesions were bilateral in 26 cases (40%) and unilateral in 39 cases (60%). Unilateral lesions were mainly located on the left side (74.3%, 29/39). Of the 65 patients with PLICL, 46 patients had NMOSD (70.8%) and were positive for anti-aquaporin (AQP4-IgG), four had NMOSD (6.2%) and were AQP4-IgG negative, 10 patients had multiple sclerosis (MS), three patients had NMDAR encephalitis, and two had autoimmune meningoencephalitis. Of the six patients whose pathological samples were evaluated, all had PLICL and were negative for AQP4-IgG, and none had pathological NMOSD lesion features. These cases included three patients with multiple sclerosis, one with anti-N-methyl-D-aspartate receptor encephalitis, and two with autoimmune meningoencephalitis. In conclusion, PLICL are found not only in patients with NMOSD, but also in MS and other disorders.     

Pruritus in neuromyelitis optica spectrum disorders and multiple sclerosis

PurposeDifferential diagnosis between neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) at early stage remains challenging at present. Pruritus is reported as a common or specific feature in NMOSD with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). We aim to verify whether pruritus can help in distinguishing NMOSD from MS.MethodsWe retrospectively reviewed the medical records of consecutive cases of NMOSD and MS patients, demographic data, clinical features, whether or not had pruritus, serum AQP4-IgG status and magnetic resonance imaging (MRI) results.Results21.0% (22/105) of NMOSD patients and 2.1% (2/96) of MS patients reported pruritus during disease course (p < 0.01). 20.5% (18/88) of AQP4-IgG positive and 23.5% (4/17) of AQP4-IgG negative NMOSD patients reported pruritus during disease course (p = 0.775). 12.4% (13/105) of NMOSD and 1.0% (1/96) of MS patients reported pruritus at the first attack episode of disease (p < 0.01). 20.0% (21/105) of NMOSD and 1.0% (1/96) of MS patients reported pruritus at the first and second attack episodes of disease (p < 0.01).ConclusionPruritus is a common and relatively specific feature in either AQP4-IgG positive or negative NMOSD. Pruritus occurs more frequently in NMOSD than MS, which may help in distinguishing NMOSD from MS, especially at early stage.     

Diagnostic utility of NMO/AQP4-IgG in evaluating CNS inflammatory disease in Thai patients

Epidemiological studies in Thailand have reported that inflammatory demyelinating diseases (IDDs) commonly affect the optic nerve and spinal cord. We investigated the diagnostic utility of aquaporin (AQP)-4-IgG testing in 31 consecutive patients evaluated for CNS IDDs in 3 academic Thai hospital neurology clinics between February 2008 and January 2009. Patients were classified into 3 clinical diagnostic groups: Neuromyelitis optica (NMO, n=10) multiple sclerosis (MS, n=5) and unclassified IDD (n=16). All sera were tested blindly by cell binding (Euroimmun) assay (CBA). Sera were also tested by indirect immunofluorescence assay (IFA) and ELISA (RSR/Kronus). After initial screening by CBA, AQP4-IgG was detected in 6 NMO patients (60%); 3 of the 4 seronegative cases were receiving immunosuppressants. AQP4-IgG was detected in 13 unclassified IDD cases (81%), but in no MS cases. Cell binding assay and ELISA were more sensitive than IFA (p=0.0004). The 81% seropositivity rate in "unclassified" patients suggests that AQP4 autoimmunity accounts for a significant proportion of Thai CNS inflammatory demyelinating disease, especially those with optic neuritis or transverse myelitis, with or without abnormal brain MRI, in whom a specific diagnosis or clear-cut treatment approach is unclear.     

An update on epidemiology,diagnosis & management of NMO-SD in the tertiary neurology department of Marrakech (Morocco)

IntroductionNeuromyelitis optica (NMO) and NMO spectrum disorders (NMO-SD) are inflammatory demyelinating diseases of the central nervous system. There are few epidemiological studies devoted to NMO, especially in Africa and the Middle East, but individual cases and series have been reported from many countries across the African continent.ObjectivesTo describe the epidemiology, diagnosis, and management of NMO patients followed at the Mohammed VI University Hospital of Marrakech.Patients and methodsThis was a hospital-based retrospective study of 52 patients with NMO diagnosed and followed at the Neurology department of the University Hospital of Marrakech from 2004 to July 2019. The 2006 diagnostic criteria of NMOSD were used for patients admitted before 2015 for inflammatory disease of the central nervous system and the 2015 diagnostic criteria of NMO-SD for all patients thereafter. Collected data were analysed using SPSS software.ResultsThe study concerned 52 patients, 18 males and 34 females. Median age at disease onset was 32.5 years (range 7–55). Mean time between symptom onset and diagnosis of NMO was nine months 18 days (range 7 days to 4 years). In most patients, manifestations included visual acuity, tetraparesis, and sensorial disorders. Refractory vomiting and hiccup were noted in the first attack in 19% of patients. Two patients had hypersomnia and polyphagia, and one had been treated for depression ten months before the development of severe tetraplegia. Magnetic resonance imaging did not show any brain lesions in 29% of patients. Cervical myelitis extending to more than three vertebrae was found in 60% of patients. AQP4-antibody assay was performed only in 57.7% of patients, and was positive in 38.4%; anti-MOG was positive in four anti-AQP4 seronegative patients. Management strategies for NMO-SD included methylprednisolone pulses (70% of patients), plasmapheresis (25%), and rituximab (since 2017) for 46%. Outcome was favourable in 40% of patients and has remained stable in 50% of them.ConclusionAnti-NMO assays, made available during the last five years with the help of The Guthy-Jackson Charitable Foundation, have led to a clear jump in the number of cases diagnosed. Major advances in the field of epidemiology, imaging, and pathophysiology of NMO-SD have led to improved patient care and outcome.     

Neuromyelitis Optica Spectrum Disorders

Since the discovery of aquaporin 4-IgG, a sensitive and highly specific biomarker of neuromyelitis optica (NMO), a wide range of syndromes have been recognized as being associated with this condition. This observation has led to new proposed terminology for the entire disorder, NMO spectrum disorders (NMOSD). The discovery of a pathogenic autoantibody and its target antigen has also facilitated basic research into the immunopathogenesis of the disease. Key advances include establishment of passive transfer animal models demonstrating the pathogenic potential of the autoantibody and confirming an important role of complement suggested by immunopathology of NMO brain lesions and of B-cell subsets, plasmablasts in particular. These discoveries have led to phase 1 clinical trials of targeted immunotherapy with potential for improved efficacy and less toxicity than current empiric immunosuppressant medications used to treat NMOSD. Randomized clinical trials are beginning to assess the efficacy and safety of a variety of immunotherapies in NMOSD. Therapeutic options are likely to increase, and improved outcomes in NMOSD patients are anticipated.