Acetylcholine receptor expression in human extraocular muscles and their susceptibility to myasthenia gravis

In myasthenia gravis (MG), extraocular muscle (EOM) weakness is often an initial and persisting symptom. It has been proposed that acetylcholine receptor (AChR) from EOM is antigenically different from AChR of other innervated muscles and that the presence of antibodies to fetal AChR expressed in EOM causes their weakness. We have (1) studied mRNA expression for each of the AChR subunits (α, β, γ, δ, and ?) in human muscle, including EOM, and (2) compared the binding of sera from ocular myasthenia gravis (OMG) patients with fetal (α₂βγδ) and adult (α₂β?δ) human AChRs. RNase protection assays showed that expression of the AChR γ-subunit (fetal-type) mRNA in EOM was comparable with that in other innervated muscle types. By contrast, ?-subunit (adult-type) mRNA was expressed at much higher levels in EOM than in other muscles studied. Moreover, some OMG sera bound specifically to adult AChR. These results do not support the contention that susceptibility of EOM in MG results from expression of fetal AChR and indicate that the inclusion of antigen from a source rich in adult AChR in the MG diagnostic assay will increase the yield of positive results in OMG patients.     

重症肌无力被动转移大鼠模型眼外肌的易感机制研究

目的探讨眼外肌在重症肌无力发病过程中的易感机制。方法给予SD大鼠腹腔注射mAb35建立重症肌无力被动转移(PTMG)大鼠模型,对照组大鼠注射等量生理盐水。选取PTMG组和对照组大鼠眼外肌、膈肌、胫前肌3种骨骼肌组织。采用乙酰胆碱酯酶(AChE)染色法观察神经肌肉接头(NMJ)并检测NMJ面积和灰度;采用银环蛇毒免疫组化法检测乙酰胆碱受体(AChR)数量;采用电镜观察NMJ超微结构和其AChR情况,并分析比较神经末端面积和突触后膜面积的比值以及突触前后膜长度的比值。结果 AChE染色结果显示,对照组眼外肌NMJ面积相对其他两种骨骼肌更小(P<0.01),PTMG组眼外肌与其他两种骨骼肌NMJ面积比较无统计学差异(P>0.05)。银环蛇毒免疫组化结果显示,PTMG组和对照组眼外肌与其它两种骨骼肌间AChR灰度值比较均有统计学差异(P<0.01)。电镜观察结果显示,PTMG组3种骨骼肌突触前后膜长度比值均较对照组下降(P<0.01),神经末端面积与突触后膜面积比值较对照组增加(P<0.01),其中眼外肌的变化较其他骨骼肌更为显著。结论 PTMG大鼠模型眼外肌易感机制可能与眼外肌和其他骨骼肌间NMJ面积、AChR数量差异造成眼外肌NMJ安全系数较低有关。     

Single fiber electromyography of extraocular muscles: A sensitive method for the diagnosis of ocular myasthenia gravis

We performed single fiber electromyography (SFEMG) in the superior rectus and levator palpebralis (SR-LP) muscles of 17 patients with pure ocular myasthenia gravis (MG) and 9 controls. Thirteen patients were also assessed with SFEMG in the orbicularis oculi (OO) muscle. All the MG patients but none of the control subjects showed abnormal SFEMG jitter in the SR-LP muscles. On the other hand, only 62% of the MG patients had abnormal SFEMG jitter in the OO muscle. The procedure was well tolerated by the patients, and complications were minor. We conclude that SFEMG of the SR–LP muscles is a safe and highly sensitive technique for the diagnosis of ocular MG. © 1995 John Wiley & Sons, Inc.     

重症肌无力发病机制的研究进展

重症肌无力 (myastheniagravis,MG)是一种神经肌肉接头 (neuromuscularjunction,NMJ)传递功能障碍的自身免疫性疾病,其发病机制尚未完全阐明。传统观点认为MG的发病与乙酰胆碱受体自身抗体(AChR Ab)介导的体液免疫密切相关,但最近发现NMJ处其他抗体、抗原特异性T细胞、细胞因子、调节性T细胞、遗传因素等在MG的发病中也扮演了重要的角色。一、体液免疫临床上发现大约 80%的MG患者血清中能检测到AChR Ab,称为血清阳性重症肌无力 (seropositivemyastheniagravis,SPMG),而另外 20%的MG患者体内不能检测到AChR Ab,即所谓血清…     

Neurogenic muscle involvement in myasthenia gravis: A clinical and histopathological study

An investigation was made into the occurrence of muscular atrophy and muscular pathology in a series of 170 patients with myasthenia gravis. The results can be summarized as follows: (1) Of the 148 patients with generalized myasthenia gravis, 14 showed local muscular atrophies. Of 10 biopsies from atrophic muscles, eight showed neurogenic changes, with or without lymphocytic infiltrations. One biopsy showed lymphocytic infiltrations only, and one showed type II-fibre atrophy (Table 1). No relationship was demonstrable between the presence of clilnical muscular atrophy and age, sex, duration of the disease, severity of the disease, presence of a thymoma, or drug resistant ophthalmoplegia. (2) In this group of patients 61 biopsies were examined from 46 individuals; 40 of these biopsies were taken from the quadriceps muscle. A thymoma was present in 17 patients. Examination disclosed neurogenic changes in 17 biopsies, lymphocytic infiltrates in 21, and myositis in one biopsy (Table 2). A distinct correlation was established between the presence of a thymoma and lymphocytic infiltrates, but none was demonstrable between thymoma and neurogenic changes (Table 3). (3) An enzyme-histochemical study was carried out in 35 cases, including 12 with neurogenic changes. A normal differentiation of type I- and type II-fibres was observed in eight instances, type grouping of type II-fibres in three, and type II-fibre atrophy in two cases. (4) In 21 patients and 19 controls, the smallest mean diameter was determined in the quadriceps muscle. Both type I- and type II-fibres proved to have a smaller mean diameter in the female patients than in the controls. In the male patients this could not be proven. (5) Of the eight patients who had died without disorders of ventilation, 90 muscle specimens were examined postmortem. Four of these patients had a thymoma. Lymphocytic infiltrations, found in 32 biopsy specimens, were mostly observed in the presence of a thymoma. Neurogenic changes were apparently unrelated to the presence of a thymoma (Tables 5 and 6). The post mortem examination included the spinal cord in five, and peripheral nerves in three cases. No abnormalities were found. (6) The muscular atrophy found in patients with myasthenia is not a myopathy but an affection of the lower motor neurone. Neurogenic changes were regularly found in the muscles of patients with myasthenia, even without muscular atrophy. The finding of these changes is no reason to reject the diagnosis. It is postulated that denervation occurs at the neuromuscular junction as a result of permanent absence of acetylcholine.     

Cytokines and the pathogenesis of myasthenia gravis

Myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG) are caused by autoantibodies against nicotinic acetylcholine receptor (AChR) in skeletal muscle. The production of anti-AChR antibodies is mediated by cytokines produced by CD4⁺ and CD8⁺ T helper (Th) cells. Emerging investigations of the roles of cytokines in MG and EAMG have revealed that the Th2 cell related cytokine interleukin 4 (IL-4), an efficient growth promoter for B-cell proliferation and differentiation, is important for anti-AChR antibody production. IL-6 and IL-10 have similar effects. The Th1 cytokine IFN-γ is important in inducing B-cell maturation and in helping anti-AChR antibody production and, thereby, for induction of clinical signs and symptoms. Results from studies of time kinetics of cytokines imply that IFN-γ is more agile at the onset of EAMG, probably being one of the initiating factors in the induction of the disease, and IL-4 may be mainly responsible for disease progression and persistance. Even though other Th1 cytokines like IL-2, tumor necrosis factor α (TNF-α), and TNF-β as well as the cytolytic compound perforin do not directly play a role in T-cell-mediated help for anti-AChR antibody production, they are actually involved in the development of both EAMG and MG, probably by acting in concert with other cytokines within the cytokine network. In contrast, transforming growth factor β (TGF-β) exerts immunosuppressive effects which include the down-regulation of both Th1 and Th2 cytokines in MG as well as EAMG. Suppressive effects are also exerted by interferon α (IFN-α). Based on elucidation of the role of cytokines in EAMG and MG, treatments that up-modulate TGF-β or IFN-α and/or suppress cytokines that help B-cell proliferation could be useful to improve the clinical outcome. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 543–551, 1997     

Reduction of miniature end-plate potential amplitude in extraocular and limb muscles in an animal model of myasthenia gravis

Miniature end-plate potential (MEPP) amplitudes of the superior oblique extraocular muscle (EOM) and forelimb flexor digitorum longus muscle (FDL) of rats with experimental autoimmune myasthenia gravis (EAMG) were expressed as reductions from mean MEPP amplitudes of the respective muscles of pair-matched control animals. Postjunctional blockade of neuromuscular transmission at EOM end-plates was no greater than at limb muscle end-plates. In contrast, the amount of reduction measured in EAMG-affected FDLs (52.3%) was marginally, but significantly, greater than that in EOMs (38.3%). A weak correlation was present between the MEPP reduction observed in an animal's FDL and that recorded in its EOM.     

Rituximab treatment of myasthenia gravis: A systematic review

Rituximab is a chimeric mouse/human anti‐CD20 monoclonal immunoglobulin. We reviewed the efficacy and safety of rituximab in 169 myasthenia gravis (MG) patients from case reports and series. Antibodies to the acetylcholine receptor (AChR) were present in 59% and muscle‐specific tyrosine kinase (MuSK) in 34%. Modified Myasthenia Gravis Foundation of America postintervention scale of minimal manifestations (MM) or better occurred in 44%, and combined pharmacologic and chronic stable remission in 27% overall; MM or better was achieved in 72% of MuSK MG and 30% of AChR MG (P < 0.001). Posttreatment relapses decreased more in MuSK MG (P = 0.05). Response predictors were MuSK MG, less severe disease, and younger age at treatment. Among a responder subset, 26% of AChR and 82% of MuSK MG patients showed decreased posttreatment antibody titers. Rituximab was generally well tolerated. Detectable serum rituximab and depleted CD20⁺ B‐cells were observed up to 20 and 16 weeks, respectively, after 4 weekly infusions. Muscle Nerve 56 : 185–196, 2017     

A case of myasthenia gravis appearing after thymomectomy: with histopathological investigation]

We report a 64-years old man who had myasthenia gravis (MG) appearing after surgical removal of thymoma. His thymoma was not removed completely due to adhesion with other organs. Histopathologicaly, the thymoma was an invasive and predominantly epithelial type. CD45RO positive cells increased in the thymus. After five months of thymectomy, he received radiation therapy because the remaining tumor grew up slightly. The radiation was effective, and the recurrence of tumor has never been detected after that. However, nine months after the surgery, he noticed ptosis and double vision, and he was diagnosed as MG because of positive serum anti-AchR antibody and positive Tensilon test. He received oral prednisolone, and he has kept a good condition. Previous reports have shown that an extensive thymectomy tends to reduce the incidence of post-operative MG. In our case, the remaining thymoma might increase the risk of MG. And the removed thymus might contain an unknown regulatory factor that could inhibit a development of MG. The risk factor for development of post-operative MG should be investigated in future.     

Thymectomy in myasthenia gravis a review

The role of thymectomy in the management of myasthenia gravis is reviewed in the light of the published data and of a personal series. The patients in whom the operation is most successful are non thymomatous patients aged between 10 and 40 years with an MG history of less than 3 years. There is no sex prevalence. Lasting improvement may be expected. There are no proven correlations between biological indices like the germinal centers in the thymus and/or AChR antibody titers and the postoperative course of the disease. Complete removal of the thymus seems to be crucial and hence the transsternal approach is preferred. The operation, less effective in patients with thymona than in those with an active thymus, is nonetheless necessary to in these patients prevent putative damage to surrounding organs from thymona infiltration. Why thymectomy should be effective in patients with an active thymus and not in those with a thymona may be revealed by in vitro studies of the interactions between thymic cells and peripheral B cells, now in progress.

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Sommario Viene rivisto alla luce dei dati della letteratura e della casistica personale il ruolo della timectomia nella terapia della miastenia. Dei pazienti non portatori di timoma i migliori risultati si ottengono in quelli di età fra i 10 e i 40 anni con una durata della malattia minore di tre anni. Non vi è prevalenza di sesso. Ci si può attendere un miglioramento duraturo. Non vi sono prove di una correlazione tra gli indici biologici germinativi quali i centri germinali nel timo e o il titolo degli anticorpi contro i ricettori acetilcolinici e il decorso post-operatorio della malattia. É fondamentale la completa asportazione del timo e perciò è preferibile la scelta della tecnica di approccio transternale. Nei pazienti con timoma la timectomia è meno efficace ma l'intervento è necessario per evitare danni derivanti dall'infiltrazione del timoma sugli organi circostanti. Il perché della efficacia della timectomia nei pazienti con un timo attivo ma non in quelli con timoma potrà essere chiarito dagli studi in vitro sulle interazioni tra cellule timiche e quelle periferiche B, studi che sono ormai in stadio avanzato.

     

A systematic review of diagnostic studies in myasthenia gravis

We performed a systematic review to identify studies that reported the accuracy of tests for the diagnosis of myasthenia gravis. We identified 20 studies of reasonable, although variable, methodological quality upon which to base estimates of the accuracy of the ice test, rest test, Tensilon test, acetylcholine receptor antibodies, repetitive nerve stimulation and single fiber electromyography for the diagnosis of myasthenia gravis. After examining inter-study heterogeneity for each diagnostic modality, we calculated pooled estimates of sensitivity and specificity as well as positive and negative likelihood ratios. Results are reported separately for ocular and generalized myasthenia. Studies that have examined the performance of anti-acetylcholine receptor antibody testing and single fiber electromyography were generally of better quality than those that examined other diagnostic modalities. We suggest that caution should be exercised in the interpretation of the diagnostic performance of these tests given the methodological limitations of the studies upon which test performance is based.     

Decremental response of the nasalis and hypothenar muscles in myasthenia gravis

Repetitive nerve stimulation (RNS) is a standard diagnostic procedure in myasthenia gravis (MG). Although RNS sensitivity is highest in weak muscles, RNS is easier to perform in distal muscles that are often not affected. Twenty-five patients with MG were assessed to compare the sensitivity of RNS of the nasalis muscle to that of the hypothenar muscles. Abnormal decrement was found in hypothenar muscles in 9 patients (36%) and in the nasalis muscle in 13 patients (52%). RNS of the nasalis muscle appeared more useful to detect abnormal neuromuscular transmission in patients with oculobulbar MG (5 of 5) than hypothenar RNS (1 of 5). In patients with generalized MG, hypothenar muscles had a similar yield of abnormal RNS tests.     

重症肌无力患者胸腺病变的CT和病理对照研究

目的　探讨胸部 CT对胸腺病变的诊断价值。方法　对 2 2例重症肌无力患者胸部 CT和胸腺病理检查结果进行对照研究。结果　胸部 CT对胸腺异常诊断的敏感性达 88.8% ,特异性为 81.8%。其中对正常胸腺、胸腺增生和胸腺瘤诊断的特异性分别为 6 6 .7%、5 0 .0 %和 91.7%。结论　胸部 CT是诊断胸腺病变的较好方法 ,其诊断的敏感性和特异性高低与胸腺病变的性质相关 ,对胸腺瘤的诊断价值最高 ,能为提示或除外胸腺瘤的诊断提供帮助 ,为临床治疗提供指导     

干扰素-γ在重症肌无力发病机制中的作用

重症肌无力(myasthenia gravis,MG)是由乙酰胆碱受体抗体(acetylcholine receptor antibody,AChRAb)介导、细胞免疫依赖性补体参与的自身免疫性疾病,主要累及神经肌肉接头处突触后膜上的     

Immunosuppressive treatment of rippling muscles in patients with myasthenia gravis

Rippling muscle disease is a rare autosomal dominant disorder that may occur sporadically. In this report two patients presenting with rippling muscles followed by myasthenia gravis are described. Our first patient developed rippling muscles about 1 month after infection with Yersinia enterocolitica. Two years later myasthenia gravis appeared. Our second patient had a 2-year history of asthma prior to the onset of rippling muscles which preceded the myasthenic symptoms by 4–8 weeks. Acetylcholine receptor and anti-skeletal muscle antibody titers were positive in both patients. In both patients the rippling phenomena worsened with pyridostigmine treatment but markedly improved after immunosuppression with azathioprine.     

AChR myasthenia gravis switching to MuSK or double antibody positive myasthenia gravis in two children and literature review

Muscle–specific tyrosine kinase antibody (MuSK–Ab) and acetylcholine receptor antibody (AChR–Ab) coexistence in myasthenia gravis (MG) is very rare. In this report, two children with AChR–Ab switching to double antibody positive MG (DP–MG) or MuSK–Ab positive MG (MuSK–MG) are described. Six similar cases were found in the literature via online database search. Therefore, this study describes eight patients in total, six female and two male. The average age of onset was 7.25 ± 5.95 years. Four AChR–MG patients switched to DP–MG with no known precipitating factor and four switched after thymectomy (two to MuSK–MG and two to DP–MG). After the serological switch, the patients transitioned to the phenotype of MuSK–MG and responded poorly to cholinesterase inhibitors and well to corticosteroids and plasma exchange.