AChR及MuSK双抗体阳性重症肌无力三例并文献复习

目的报道3例乙酰胆碱受体(AChR)抗体和肌肉特异性酪氨酸激酶(MuSK)抗体双抗体阳性重症肌无力(myasthenia gravis,MG)患者的临床特点、诊疗和预后,并复习既往相关文献,以提高对这一特殊MG类型的认识。方法对作者医院3例AChR及MuSK双抗体阳性的确诊MG病例进行报道,并检索近20年Medline和万方中文数据库,选择国内外报道的上述双抗体阳性的确诊MG病例中包含临床特点、实验室检查及诊疗结果的文章,结合作者医院病例分析和总结AChR及MuSK双抗体阳性MG的临床特点及诊治情况。结果8篇文献中的7例MG,包括作者医院的3例,共10例AChR及MuSK双抗体阳性MG纳入分析,男4例、女6例,平均起病年龄(45.5±24.1)岁,起病症状包括眼睑下垂到呼吸困难轻重不等,受累肌群可包括眼外肌(9/10)、球部肌肉(9/10)、颈肌(7/10)、四肢肌(8/10)和呼吸肌(6/10),肌无力危象发生率高(5/10)。9例行肌电图检查,8例重复电刺激(RNS)阳性,4例行单纤维肌电图(SFEMG)检测者均为阳性。双抗体阳性可在发病之初即为双阳性,也可在AChR抗体阳性基础上随着病情进展而发展形成,多在病情加重时出现,病情好转后亦可出现抗体转阴。溴吡斯的明+免疫抑制剂治疗对多数患者有效(8例中4例有效、4例部分有效);4例患者肌无力危象时使用血浆置换(PE)、2例重症患者使用利妥昔单抗治疗均有效,2例患者使用环孢素治疗,其中1例有效,2例患者硫唑嘌呤治疗均无改善。结论双抗体阳性MG患者任何年龄均可发病,女性居多,总体受累范围广,病情重,免疫抑制剂治疗个体差异大,PE对于危象效果好,双抗体表达情况随病情动态波动。     

激素冲击对血浆置换治疗吉兰-巴雷综合征疗效的影响:临床疗效对比观察

目的观察合并应用激素冲击治疗对血浆置换(PE)治疗吉兰-巴雷综合征(GBS)患者疗效的影响。方法对发病后2周内入院的GBS患者采用分组对照观察,其中甲基强地松龙(MP)冲击组7例,PE治疗组12例,PE合并MP冲击组11例。治疗4周后比较不同治疗方案对GBS的疗效。结果入院时MP冲击组、PE治疗组和PE合并MP冲击组Hughes评分分别为(3.1±0.7)、(3.4±0.8)和(3.5±1.1),差异无统计学意义(P>0.05)。治疗4周后比较各组评分改善情况结果表明,PE治疗组及PE合并MP冲击组均较MP冲击组病情改善明显(均P<0.05);而PE治疗组和PE合并MP冲击组的病情改善差异均无统计学意义(P>0.05)。另外,PE治疗组和PE合并MP冲击组在治疗4周时Hughes评分进步1分以上的比例分别为91.7%和81.8%,治疗4周后两组患者可独立步行5 m以上的比例分别为9/12例(75%)和9/11例(81.8%),均无统计学意义(P>0.05)。结论PE治疗和PE合并MP冲击对GBS疗效均明显优于单纯MP冲击治疗。至于MP冲击治疗对PE治疗GBS的短期疗效影响,尚有待于扩大样本进一步观察。     

重症肌无力患者外周血单个核细胞IFN-γ及IL-4的研究

目的　探讨重症肌无力 ( MG)患者乙酰胆碱受体 ( ACh R)特异性 T细胞免疫应答及其与乙酰胆碱受体抗体 ( ACh RAb)间的关系。方法　应用体外细胞培养和 ELISA方法检测 MG患者外周血单个核细胞 ( PBMNC)经 ACh R刺激后产生 IFN-γ和 IL-4的水平。结果　 MG患者 IFN-γ和 IL-4的诱生水平均比对照组明显升高( P<0 .0 1 ) ;ACh RAb阳性组 MG患者 IFN-γ和 IL-4的诱生水平明显高于 ACh RAb阴性组 ( P<0 .0 1和 P<0 .0 5 )。结论　MG患者无论为 ACh RAb阳性或阴性 ,均存在 ACh R特异性 T细胞激活 ,IFN-γ和 IL-4均与自身抗体的产生有关。     

肌肉特异性受体酪氨酸激酶抗体阳性重症肌无力

目的 探讨不同血清抗体重症肌无力(MG)的临床特征.方法 用荧光免疫沉淀法(FIPA)和荧光免疫细胞染色法(CBA)检测119例MG患者血清乙酰胆碱受体抗体(AChR-Ab)和肌肉特异性受体酪氨酸激酶抗体(MuSK-Ab)水平.比较AChR-Ab阳性、MuSK-Ab阳性、血清抗体阴性MG的临床特征.结果 纳入119例患者中,90例AChR-Ab阳性(75.6%),29例阴性:其中5例MuSK-Ab阳性(17.2%),24例血清抗体阴性(82.8%).AChR-Ab阳性、MuSK-Ab阳性和血清抗体阴性MG 3组比较,男女比例和平均发病年龄差异均无统计学意义.3例MuSK-Ab阳性的患者主要表现为延髓肌受累;79.2%(19/24)的血清抗体阴性MG患者表现为美国MG协会(MGFA)Ⅰ型;2例MuSK-Ab阳性的患者MGFA≥Ⅲ型;MuSK-Ab滴度水平与患者病情严重程度相关(r=0.941,P=0.014);MuSK-Ab阳性的患者均未发现有胸腺的异常.结论 MuSK-Ab仅出现在AChR-Ab阴性患者的血清中.MuSK-Ab阳性的患者主要表现为延髓肌受累,病情较重且不伴有胸腺的病变.MuSK-Ab阳性的MG可能是不同于血清AChR-Ab阳性的MG的又一亚型.     

斜方肌肌电图运动单位动作电位成人正常参考值的建立

目的 探讨不同血清抗体重症肌无力(MG)的临床特征.方法 用荧光免疫沉淀法(FIPA)和荧光免疫细胞染色法(CBA)检测119例MG患者血清乙酰胆碱受体抗体(AChR-Ab)和肌肉特异性受体酪氨酸激酶抗体(MuSK-Ab)水平.比较AChR-Ab阳性、MuSK-Ab阳性、血清抗体阴性MG的临床特征.结果 纳入119例患者中,90例AChR-Ab阳性(75.6%),29例阴性:其中5例MuSK-Ab阳性(17.2%),24例血清抗体阴性(82.8%).AChR-Ab阳性、MuSK-Ab阳性和血清抗体阴性MG 3组比较,男女比例和平均发病年龄差异均无统计学意义.3例MuSK-Ab阳性的患者主要表现为延髓肌受累;79.2%(19/24)的血清抗体阴性MG患者表现为美国MG协会(MGFA)Ⅰ型;2例MuSK-Ab阳性的患者MGFA≥Ⅲ型;MuSK-Ab滴度水平与患者病情严重程度相关(r=0.941,P=0.014);MuSK-Ab阳性的患者均未发现有胸腺的异常.结论 MuSK-Ab仅出现在AChR-Ab阴性患者的血清中.MuSK-Ab阳性的患者主要表现为延髓肌受累,病情较重且不伴有胸腺的病变.MuSK-Ab阳性的MG可能是不同于血清AChR-Ab阳性的MG的又一亚型.     

重症肌无力患者甲状腺功能和甲状腺抗体情况的临床分析

目的　了解重症肌无力 ( MG)患者甲状腺功能及甲状腺抗体的情况。方法　回顾性分析了 2 67例临床确诊 MG患者的甲状腺素水平 ,对其中 2 64例患者检测了甲状腺球蛋白抗体 ( TGAb)和甲状腺过氧化物酶抗体( TPOAb)或甲状腺微粒体抗体 ( TMAb)。结果　 5 5例 ( 2 0 .6% )患者有甲状腺功能异常 ,48例 ( 1 8.2 % )至少有 1项上述抗体阳性。甲状腺功能异常的 MG患者中 , 、 、 型抗体阳性者较多 ( P <0 .0 1 )。甲状腺抗体阳性者较抗体阴性者 MG发病晚 ( P <0 .0 5 ) ;甲状腺抗体阴性 MG患者有甲状腺功能障碍者 MG发病早于功能正常组 ( P <0 .0 5 )。甲状腺功能异常、抗体阳性的 MG患者病程较抗体阴性者长 ( P <0 .0 5 ) ;甲状腺抗体阳性者伴发胸腺增生或胸腺瘤的几率明显增高 ( P <0 .0 5 )。结论　MG合并甲状腺功能异常并不少见 ,甲状腺抗体阳性、功能异常的 MG患者病程长 ,伴发胸腺增生或胸腺瘤的几率高 ,临床应予以重视。     

重症肌无力病人血清非免疫球蛋白成分中的14KD蛋白

在21例抗体阳性、20例抗体阴性重症肌无力(MG),18例其他神经科疾病(OND)患者和19例正常对照血清中制备非免疫球蛋白(Ig)成分。并予以聚丙烯酰胺凝胶电泳(SDS-PAGE)和等电聚焦(IEF)电泳分析。结果显示,大多数MG病人的非Ig成分电泳图谱中有一分子量为14KD的特异蛋白区带,其出现频度以抗体阴性MG(85％)最高,与抗体阳性MG(52.38％)比较差异有显著性(P<0.05)。14KD蛋白可能参与了MG的发病,尤其在抗体阴性MG中的作用可能更为重要。     

血液净化治疗吉兰-巴雷综合征新进展

血液净化(plasmpheresis)指通过非肾脏途径将体内的毒素、抗体、免疫复合物以及其他有害物质从血液中排出，实现机体向健康状态转变。目前临床应用主要有三种：(1)单纯血浆置换(plasma exchange，PE)，即将血浆分离器分离出的血浆全部去除，代以置换同等量的新鲜冰冻血浆或白蛋白溶液；(2)双重血浆置换(double filtration plasmapheresis,DFPP)     

甲状腺抗体异常与MG的相关性分析

目的对甲状腺抗体血清浓度与MG之间的相关性进行研究。方法选取我院收治的MG患者100例,检测其甲状腺抗体(TRAb、TPOAb、TGAb),分析其相关性。结果100例MG中,甲状腺抗体阳性65例(65%),阴性35例(35%)。甲状腺抗体阳性组与阴性组中Ⅰ型(40;20)均较其他分型多,且抗体阳性组Ⅰ型高于阴性组,差异有统计学意义(χ~2=4.57,P0.05)。2组Ⅱ型、Ⅲ型、Ⅳ型、Ⅴ型比较差异均无统计学意义(χ~2=2.34,P0.05;χ~2=3.09,P0.05;χ~2=2.91,P0.05;χ~2=2.78,P0.05)。抗体阳性组的MG较抗体阴性组的MG平均发病年龄大,差异有统计学意义(t=3.79,P0.05)。结论 MG甲状腺抗体异常明显升高,可能与两者存在共同的抗原决定簇、存在免疫交叉反应有关。     

血浆置换、丙种球蛋白、甲基强的松龙治疗重症肌无力的疗效观察与护理

目的　探讨依次采用少量血浆置换、大剂量丙种球蛋白与大剂量甲基强的松龙治疗重症肌无力 (MG)Ⅱb或Ⅲ型的临床疗效及安全性。方法　对符合Osserman分型的Ⅱb或Ⅲ型的 3 7例MG患者 ,按住院先后顺序随机分为观察组 18例 ,依次采用少量血浆置换、大剂量丙种球蛋白、大剂量甲基强的松龙治疗。对照组 19例 ,大剂量地塞米松静滴。结果　观察组症状缓解快 ,激素治疗过程中发生呼吸肌瘫痪与使用呼吸机现象少 ,住院时间短、死亡率低 (均P <0 0 5 )。结论　依次采用少量血浆置换、大剂量丙种球蛋白与大剂量甲基强的松龙治疗Ⅱb或Ⅲ型MG疗效显著 ,安全性高。     

Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis

We have conducted a trial to randomly assess the efficacy and tolerance of intravenous immunoglobulin (IVIg) or plasma exchage (PE) in myasthenia gravis (MG) exacerbation and to compare two doses of IVIg. Eighty-seven patients with MG exacerbation were randomized to receive either three PE (n = 41), or IVIg (n = 46) 0.4 gm/kg daily further allocated to 3 (n = 23) or 5 days (n = 23). The main end point was the variation of a myasthenic muscular score (MSS) between randomization and day 15. The MSS variation was similar in both groups (median value, +18 in the PE group and +15.5 in the IVIg group; p = 0.65). Similar efficacy, although slightly reduced in the 5-day group was observed with both IVIg schedules. The tolerance of IVIg was better than that of PE with a total of 14 side effects observed in 9 patients, 8 in the PE group and 1 in the IVIg group (p = 0.01). Although our trial failed to show a pronounced difference in the efficacy of both treatments, it exhibited a very limited risk for IVIg. IVIg is an alternative for the treatment of myasthenic crisis. The small sample sizes in our trial, however, could explain why a difference in efficacy was not observed. Further studies are needed to compare PE with IVIg and to determine the optimal dosage of IVIg.     

Seronegative myasthenia gravis: clinical features, response to therapy and synthesis of acetylcholine receptor antibodies in vitro

Circulating autoantibodies against the acetylcholine receptor (AChR-Ab) are an important diagnostic tool in myasthenia gravis (MG). Lack of antibodies may cast doubt upon the diagnosis, the immune-mediated mechanism and the nature of the antigen. We examined clinical and laboratory features, response to immunotherapy and production of AChR-Ab in vitro, in 12 seronegative MG patients who were followed up for 2-30 years. It was possible to divide those patients into 2 groups: 7 patients with systemic muscle weakness, with a severe disease and with response to immunosuppressive therapies. The other group of 5 patients was characterized by oculobulbar symptomatology, a relatively benign course and immunotherapy was ineffective in 3 treated patients. Five patients underwent thymectomy and gland histology was normal in all of them. In none of 9 patients examined, were AChR-Ab synthesized in vitro (compared to 65% of seropositive myasthenic patients). Thus seronegative generalized MG is probably an autoimmune disease though the autoantigen is presently unknown and is responsive to immunosuppressive treatment. Seronegative oculobulbar MG might represent a separate disease entity in which immunological mechanisms play no significant role.     

Myasthenia in SCID mice grafted with myasthenic patient lymphocytes: role of CD4+ and CD8+ cells

OBJECTIVES: Acetylcholine receptor (AChR)-specific CD4+ cells are present in MG patients, and synthesis of the high-affinity immunoglobulin G (IgG) autoantibodies (autoAb) against the muscle AChR that causes MG symptoms requires intervention of CD4+ cells. The role of CD4+ cells in MG pathogenesis has been postulated but never proven. MG patients do not have anti-AChR cytotoxic phenomena, and it has been assumed that CD8+ cells do not have a pathogenic role in MG. However, CD8+ cells may facilitate rodent experimental MG, raising the possibility that CD8+ cells might be necessary also in MG. In this study we examined whether CD4+ and CD8+ cells play a role in the pathogenesis of MG and whether CD4+ cells specific for AChR epitope sequences recognized by most MG patients ("universal" epitopes) drive the synthesis of pathogenic antibodies. METHODS: First we characterized a chimeric human-mouse model of MG in severe combined immunodeficiency (SCID) mice engrafted with blood lymphocytes (BL) from MG patients. We used that model to determine whether CD4+ and CD8+ cells are necessary for transfer of MG symptoms. We engrafted SCID mice intraperitoneum with BL from 19 MG patients and 5 healthy controls. We engrafted some mice with either BL, BL depleted in CD4+ or CD8+ cells from the same patient, or CD4+ depleted BL reconstituted with CD4+ T cells from the same patient, specific for "universal" AChR epitopes or for two unrelated antigens, tetanus and diphtheria toxoids. We tested the mice for myasthenic symptoms for 7 to 18 weeks. RESULTS: Mice transplanted with BL, or CD8+ depleted BL, or CD4+-depleted BL reconstituted with anti-AChR CD4+ cells from MG patients frequently developed myasthenic weakness. The mice had human anti-AChR Ab in the serum and bound to muscle AChR. Mice transplanted with BL from controls, or CD4+-depleted BL from MG patients, or CD4+-depleted BL from an MG patient reconstituted with CD4+ cells specific for tetanus or diphtheria toxoids did not develop myasthenic weakness or anti-AChR Ab. CONCLUSIONS: CD4+ cells are necessary for MG pathogenesis; CD8+ cells may not be. CD4+ cells specific for "universal" AChR epitopes help the synthesis of pathogenic Ab.     

Seronegative myasthenia gravis

Some myasthenia gravis (MG) patients do not have detectable acetylcholine receptor (AChR) antibodies and have been termed "seronegative" (SNMG) in many previous studies. A high proportion of patients with purely ocular symptoms, ocular MG, are seronegative; this may be because the sensitivity of the assay is insufficient to detect low levels of circulating AChR antibodies and because of intrinsic differences in the ocular muscles that make them more susceptible to circulating factors. Seronegative generalized myasthenia is proving to be heterogeneous both clinically and immunologically. Plasma from SNMG patients often contains a factor, probably an immunoglobulin M antibody, that alters AChR function in in vitro assays, but its target is not yet clear. A variable proportion of SNMG patients have antibodies to the muscle-specific tyrosine kinase (MuSK). These antibodies are directed against the extracellular domain of MuSK and inhibit agrin-induced AChR clustering in muscle myotubes. Although the role of these antibodies in causing myasthenic symptoms in vivo has not been elucidated, MuSK antibodies appear to define a group of patients who are often female with bulbar weakness, contrasting with MuSK antibody-negative SNMG patients who are more likely to have generalized weakness. MuSK antibody-positive patients may also differ in the distribution of their electrophysiological abnormalities and their responses to treatments.     

重症肌无力被动转移动物模型的研究

目的 :探讨血清阳性 (SPMG)和阴性重症肌无力 (SNMG)被动转移动物模型 (P EAMG)的异同。方法 :用ELISA法将重症肌无力 (MG)患者分为SNMG和SPMG两组 ,然后分别用两组患者血清制作P EAMG ,观察两组小鼠的临床表现、电生理及神经肌接头(NMJ)的改变。结果 :SPMG和SNMG组小鼠均表现出明显的肌无力症状 ,低频重复电刺激出现明显衰减反应 ,但SNMG组小鼠肌无力症状较SPMG组明显为轻 ,SPMG和SNMG组小鼠NMJ处棕黄色沉积物明显减少、变细短。结论 :SNMG和SPMG均是自身抗体介导的自身免疫性疾病 ,但两者不完全相同     

Patterns and severity of neuromuscular transmission failure in seronegative myasthenia gravis

OBJECTIVES: To compare the clinical and electrophysiological features of myasthenia gravis (MG) patients with (seropositive) or without (seronegative) antibodies to acetylcholine receptor. To investigate whether antibodies to muscle specific kinase (MuSK) and ryanodine receptor (RyR) are associated with particular features. METHODS: Clinical profiles and single fibre electromyography (SFEMG) in the extensor digitorum communis (EDC) were reviewed in consecutive 57 seropositive and 13 seronegative patients. Antibodies to MuSK and RyR were measured by immunoassays. RESULTS: Of the 13 seronegative patients, four (31%) were positive for MuSK antibodies and seven (54%) were positive for RyR antibodies, including all four MuSK positive patients. Clinical features were similar at presentation for seropositive and seronegative patients, but MuSK positive patients frequently developed myasthenic crises. Despite the similar clinical severities at the time of examination, the proportion with positive jitter (93% of seropositive patients, 50% of MuSK positive patients, and 44% of MuSK negative patients) and the extent of jitter (mean consecutive difference: 76 micros in seropositive patients, 36 micros in MuSK positive patients, and 30 micros in MuSK negative patients) were less in seronegative MG patients compared with seropositive MG patients. CONCLUSIONS: Seronegative MG is heterogeneous with respect to the presence of antibodies to MuSK. Impairment of neuromuscular synaptic transmission in EDC is less marked in seronegative than seropositive MG despite the similar clinical severity. This discrepancy may partly reflect the distribution of affected muscles in seronegative patients, but it is possible that other factors, such as impaired excitation-contraction coupling resulting from RyR antibodies, contribute to the clinical phenotype.     

Myasthenia gravis and myasthenic syndromes

More than a decade ago myasthenic symptoms were observed in rabbits immunized with acetylcholine receptor (AChR) [119] and AChR deficiency was found at the neuromuscular junction in human myasthenia gravis (MG) [36]. By 1977 the autoimmune character of MG and the pathogenic role of AChR antibodies had been established by several measures. These included the demonstration of circulating AChR antibodies in nearly 90% of patients with MG [87], passive transfer with IgG of several features of the disease from human to mouse [149], localization of immune complexes (IgG and complement) on the postsynaptic membrane [30], and the beneficial effects of plasmapheresis [20, 123]. Substantial subsequent progress has occurred in understanding the structure and function of AChR and its interaction with AChR antibodies. The relationships of the concentration, specificities, and functional properties of the antibodies to the clinical state in MG have been carefully analyzed, and the mechanisms by which AChR antibodies impair neuromuscular transmission have been further investigated. The clinical classification of MG has been refined, the role of the thymus gland in the disease has been further clarified, and new information has become available on transient neonatal MG. The prognosis for generalized MG is improving, but there is still no consensus on its optimal management. Novel therapeutic approaches to MG are now being explored in animal models. Recognition of the autoimmune origin of acquired MG also implied that myasthenic disorders occurring in a genetic or congenital setting had a different cause. As a result, a number of congenital myasthenic syndromes have come to be recognized and investigated. Finally, an acquired disorder of neuromuscular transmission different from MG, the Lambert-Eaton myasthenic syndrome, has also been shown to have an autoimmune basis. In this syndrome, active zone particles of the presynaptic membrane are direct or indirect targets of the pathogenic autoantibodies.     

Myasthenia Gravis Appearing After Thymectomy: a Case Report and Review of the Literature

A small proportion of thymoma patients without myasthenia gravis (MG) have been observed to develop MG after total removal of the thymoma. However, the underlying cause is not yet known due to the rarity of postoperative MG patients. We report a 39-year-old man in whom MG appeared after surgical removal of a thymoma. Computed tomography and magnetic resonance imaging showed no signs of recurrent or metastatic thymoma. Administration of pyridostigmine bromide resulted in the prompt improvement of myasthenic symptoms. Our observations indicate that postoperative follow-up care with monitoring of possible postoperative MG is necessary after resecting a thymoma.     

A short plasma exchange protocol is effective in severe myasthenia gravis

Summary Plasma exchange has been reported to be a successful therapeutic procedure for the treatment of severely compromised myasthenic patients, but the optimal regimen in terms of costs or clinical benefit has not so far been determined. We have investigated the efficacy of a short plasmapheresis protocol of two exchanges 1 day apart in a series of 70 patients with severe forms of myasthenia gravis. Patients were evaluated before and 7 days after the first exchange. A positive outcome was observed in 70% of the plasma exchange cycles performed. Disease severity did not seem to be a negative prognostic factor for the efficacy of this short protocol, which was well tolerated by patients. In only 1 case were major side-effects observed. In spite of its short duration, the exchange treatment plus concomitant immunosuppressive drug therapy was not followed by early clinical deterioration.