Myopathy in Childhood Muscle-Specific Kinase Myasthenia Gravis

BackgroundAdult and pediatric patients suffering from MuSK (muscle-specific kinase) -antibody positive myasthenia gravis exhibit similar features to individuals with acetylcholine receptor (AChR) antibodies, but they differ in several characteristics such as a predominant bulbar, respiratory and neck weakness, a generally worse disease severity and a tendency to develop muscle atrophy. Muscle atrophy is a rare phenomenon that is usually restricted to the facial muscles.ResultsWe describe a girl with MuSK-antibody positive myasthenia gravis who developed a myopathy with severe generalized muscular weakness, muscle atrophy, and myopathic changes on electromyography.ConclusionThis is the first published example of a generalized myopathic syndrome in myasthenia gravis. We review the relevant literature and discuss the hypothesis of a mitochondrial myopathy as a pathogenic mechanism in MuSK-antibody positive myasthenia gravis.     

重症肌无力治疗研究的工具和方法

重症肌无力(MG)病程长,且临床表现存在多样性,这些因素使对某一疗法的疗效客观评价的难度较大。规范化的临床评估对疗效判断具有重要意义。以严重性评价作为基础,有多种量表可用于MG疗效评价的各个方面。本文介绍这些量表并探讨相关的方法学问题。     

Myasthenia gravis in children: a longitudinal study

BACKGROUND: Juvenile myasthenia gravis (JMG) is an uncommon disease. Unlike adults, clinical characteristics and outcomes of myasthenia gravis (MG) are not well studied in children. PATIENTS AND METHODS: Case records of 77 patients with MG who were 15 years of age or less at disease onset, evaluated over a period of 34 years at the National Institute of Mental Health and Neurosciences, Bangalore, India, were reviewed. Their clinical characteristics and response to therapy was compared with 290 patients with MG onset after 15 years of age. RESULTS: Median age at onset was 8 years and mean period of follow-up was 6.2 years (range 6 months to 25 years). At presentation, 30% of patients had ocular myasthenia and the rest had generalized disease. Twenty-one patients (27%) had disease confined to ocular muscles throughout the course and three had limb girdle myasthenia. Familial myasthenia was more common than adult onset disease, 10 patients had positive family history. Unlike adults, none of the patients had associated autoimmune disease. Fifty-two patients (67%) received corticosteroids, and azathioprine was added in five patients. Thymectomy was performed in 11 patients, six below the age of 15 years. Thymic histology was normal in one and showed hyperplasia in eight and thymoma in one. Four patients had crisis. At the end of follow-up, 25 patients were asymptomatic, 28 had partial improvement, and nine remained unchanged or worsened and two died. Ten patients achieved complete stable remission. CONCLUSIONS: This study shows some distinctive characteristics of JMG, such as higher frequency of ocular myasthenia, benign course, better long-term outcome and lack of association of thymoma and other autoimmune disorders.     

Giant cell polymyositis and myocarditis associated with myasthenia gravis and thymoma

We describe an unusual case of myasthenia gravis. Our patient had been diagnosed as having myasthenia gravis with thymoma at the age of 64 years, and died of acute respiratory failure at the age of 80 years. Post mortem examination revealed CD8‐positive lymphocytic infiltration with numerous giant cells in the skeletal muscles and myocardium. Immunohistochemical and ultrastructural studies revealed that there were two types of giant cells: histiocytic and myocytic in origin. Furthermore, both types of giant cells were immunopositive for proteins implicated in the late endosome and lysosome‐protease systems, suggesting that endocytosis may be the key mechanism in the formation of giant cells. The present case, together with a few similar cases reported previously, may represent a particular subset of polymyositis, that is, giant cell polymyositis and myocarditis associated with myasthenia gravis and thymoma.     

硫唑嘌呤合用皮质类固醇治疗重症肌无力危象的疗效观察

目的:硫唑嘌呤合用皮质类固醇治疗重症肌无力危象的疗效观察。材料和方法:男女各3例。年龄26～48岁。其中5例重症肌无力眼肌型,1例重症肌无力延髓型。病程1.5～8年。都经胸腺瘤切除,术后2～5月出现重症肌无力危象。当皮质类固醇激素治疗效果不佳时,加用硫唑嘌呤100～150mg/天治疗。结果:在3～4周内完全脱离人工呼吸机,除轻度眼睑下垂,2例肢体肌力Ⅴ度、4例肢体肌力Ⅳ度。结论:硫唑嘌呤合用皮质类固醇治疗重症肌无力危象是有效的。     

T‐cell lymphoproliferative disorder following mycophenolate treatment for myasthenia gravis

Immunosuppressive therapies are critical in the management of numerous conditions including myasthenia gravis. Mycophenolate mofetil is a widely used, oral immunosuppressive agent that is considered to have few adverse effects compared with similar drugs. We report the case of a patient who developed T‐cell lymphoproliferative lesions following long‐term treatment with mycophenolate mofetil and prednisone for myasthenia gravis. The lesions resolved following cessation of the treatment. This case highlights a serious complication of a commonly used drug. Muscle Nerve, 2009     

Management of Juvenile Myasthenia Gravis

Juvenile myasthenia gravis is an uncommon autoimmune disorder. Its management is not standardized. Juvenile myasthenia gravis is pathophysiologically similar to myasthenia gravis in adults. However, a number of significant particularities related to race, age at onset, severity, and antibody status complicate the management. We summarize the unique clinical features of juvenile myasthenia gravis and review the therapeutic options.     

Variable effect of calcium channel blockers on the decremental response in experimental autoimmune myasthenia gravis

We tested the effect of intravenous administration of verapamil and nimodipine on the decremental response in rabbits with experimental autoimmune myasthenia. Nimodipine produced an immediate augmentation of the decremental response to 3-Hz nerve stimulation, which lasted about 30 min. In contrast, verapamil caused marked amelioration of the decrement beginning 30 min after injection. Our findings are consistent with previous reports suggesting that verapamil has a presynaptic effect of enhanced acetylcholine release at the neuromuscular junction. Since evaluation of a drug effect in vivo in animals with experimental autoimmune myasthenia gravis may be more pertinent to its effect on patients with myasthenia gravis (MG), verapamil might prove to be safer in MG than nimodipine. However, due to the additional effects of calcium channel blockers, the safety of their use in myasthenia gravis cannot be inferred from the experimental results. © 1994 John & Sons, Inc.     

Tongue force in patients with myasthenia gravis

OBJECTIVES: The aim was to study tongue force in patients with bulbar myasthenia gravis and compare it with that of patients with ocular myasthenia gravis, patients in clinical remission who previously suffered from bulbar myasthenia gravis, and healthy subjects. MATERIAL AND METHODS: Tongue force was measured with a tongue force transducer in cranial and lateral directions, which coincide with the directions in which the tongue exerts force during swallowing, speech, and mastication. RESULTS: Tongue force in lateral direction was significantly decreased in patients with bulbar myasthenia gravis. In addition, our findings suggest an incomplete recovery of lateral tongue force in the patients of the remission group. CONCLUSION: Our tongue force measurements may be useful for longitudinal evaluation of therapy in individual patients and also in studies of therapy efficacy in matched groups of patients if the influence of factors such as age, dental state, and sex is taken into account.     

Increased incidence of thymoma in Chinese myasthenia gravis: possible relationship with Epstein-Barr virus

Thymectomy was carried out for treatment of myasthenia gravis in 27 unselected Chinese patients and thymoma was found in 13 of them. This 48% incidence of thymomas is two to three times greater than in Japanese and European patients, respectively. The reason for the higher incidence of thymomas observed in Chinese patients may be related to the presence of the Epstein-Barr virus genome in thymoma. Furthermore, all of the thymomas in our patients were lymphoepithelial and histologically resemble nasopharyngeal carcinoma and undifferentiated carcinoma of the salivary gland. Both these tumours are closely linked to the Epstein-Barr virus and in Hong Kong, nasopharyngeal carcinoma is the third commonest cause of death from malignancy. We recommend early thymectomy for patients with myasthenia gravis particularly in geographical areas where there is a high incidence of nasopharyngeal carcinoma and undifferentiated carcinoma of the salivary gland.     

Thymolipoma in patients with myasthenia gravis: report of two cases and review

Two cases of simultaneous occurrence of myasthenia gravis (MG) and thymolipoma are described and 4 previously reported cases are reviewed. In all 6 cases, thymectomy was performed. Pre- and postoperatively, the clinical status of the patients was similar to that of late-onset MG without thymolipoma. It is possible that simultaneous occurrence of MG and thymolipoma may be coincidental.     

Seronegative myasthenia gravis

Six to 20 p.cent of patients with generalized myasthenia gravis and 30 to 50 p.cent of those with ocular myasthenia gravis do not have anti AchR antibodies. Strict clinical, pharmacological and electrophysiological criteria are needed for the diagnosis of sero-negative myasthenia gravis. Sero-negative myasthenia gravis is an autoimmune disorder. But thymic hyperplasia is generally absent. Antibodies directed against the muscle receptor of tyrosine kinase (anti MuSK antibodies) were recently demonstrated in 40 to 70 p.cent of patients with sero-negative myasthenia gravis. Sero-negative and sero-positive myasthenia gravis may be clinically very similar. But sero-negative myasthenia gravis may express predominantly severe oculobulbar weakness or mainly neck, shoulder and respiratory muscle weakness. Sero-negative myasthenia gravis is never associated with thymoma. Sero-negative myasthenia gravis responds to immunodulation but perhaps less well than sero-positive myasthenia gravis.     

Myasthenia gravis: clinical, immunological, and therapeutic advances

We give an update on clinical, immunological, and therapeutic advances in the field of myasthenia gravis, including a summary of suggested therapeutic recommendations.     

Diagnostic difficulties in myasthenia gravis

Four patients with myasthenia gravis presented with severe, largely isolated, bulbar and respiratory muscles weakness. Tensilon tests were positive and antiacetylcholine receptor (anti-AChR) antibody titers were negative in all patients. Only 1 patient had a greater than 10% decremental response during the period of respiratory failure. Although routine nerve conduction studies were normal, all had very low-amplitude diaphragmatic compound muscle action potentials. Three patients had abundant fibrillation potentials and positive sharp waves largely restricted to respiratory muscles. Clinical and electrophysiological findings improved with corticosteroids, and surprisingly, decremental responses became positive in all patients. The assessment of patients with largely isolated bulbar and respiratory muscle weakness due to myasthenia gravis may be difficult and misleading, as anti-AChR antibody titers may be negative, decremental responses may be absent, and electrophysiological assessment atypical. Due consideration of clinical symptomatology, a Tensilon test, and a trial of immunosuppression may be necessary to establish the diagnosis. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:577–583, 1998.     

Passive transfer of seronegative myasthenia gravis to mice

Muscle weakness in myasthenia gravis is due to autoantibody-induced loss of functional acetylcholine receptors (AChR). About 15% of myasthenia gravis patients, however, do not have detectable anti-AChR antibodies. To investigate the effect of their plasma immunoglobulins on neuromuscular transmission, mice were injected with plasma (and in some cases purified immunoglobulin G (IgG)) from 7 “seronegative” myasthenia gravis (SMG) patients, and neuromuscular transmission parameters were examined. When injected for 15 days, all patients' plasma caused reductions in miniature endplate potential amplitudes, while endplate potential quantal content was significantly reduced by plasma from 4 of the 7 patients. There were no changes in ACh-induced depolarization or single channel properties, and ₁₂₅l-α-bungarotoxin binding studies showed no effect on AChR number, except in 1 case. Purified IgG injected for 3 days had similar effects to plasma injected for 15 days. Our findings confirm that SMG is autoantibody mediated and that there are pathogenic IgG antibodies. SMG appears to be a heterogeneous disorder and the target(s) for the antibodies may be diverse. © 1994 John Wiley & Sons, Inc.     

重症肌无力患者汉密尔顿抑郁量表评分分析

目的探讨重症肌无力(myasthenia gravis,MG)患者汉密尔顿抑郁量表(Hamilton depression rating scale,HDRS)评分情况及其影响因素分析。方法横断面研究2013-07—2015-03作者医院就诊的188例MG患者的临床资料和HDRS评分情况,并根据HDRS评分将其分为抑郁组和非抑郁组,分析两组MG患者的临床特点及其与HDRS评分间的关系。结果所纳入MG患者男女比例为1.02∶1,眼肌型重症肌无力(ocular myasthenia gravis,OMG)和全身型重症肌无力(generalized myasthenia gravis,GMG)的比例为1.2∶1,以OMG起病和以GMG起病患者的比例为6.2∶1,病程中位数为2年,四分位数间距为1.8年,平均量化重症肌无力评分(quantitative myasthenia gravis,QMG)为(6.7±2.3)分,平均HDRS评分为(8.7±3.4)分,并发抑郁者65例,未并发抑郁者123例。影响HDRS评分和抑郁发生的相关因素包括性别(P0.01)、MG类型(P0.01)、QMG得分(P0.01)和美国重症肌无力协会(myasthenia gravis foundation of America,MGFA)分型(P0.01)、有无甲状腺功能亢进(P0.05)。结论影响MG患者HDRS评分和抑郁发生的相关因素包括性别、MG类型、QMG评分和MGFA分型、有无甲状腺功能亢进,充分认识其抑郁发生情况有利于更好地治疗MG。     

Association between musk antibody concentrations and the myasthenia gravis composite score in 3 patients: A marker of relapse?

Introduction: Muscle-specific tyrosine kinase (MuSK) autoantibody related myasthenia gravis is characterized by bulbar and respiratory manifestations, a poor response to anticholinergics, and a generally good response to plasma exchange and rituximab. It is not known if MuSK-antibody (Ab) levels could be used to predict the clinical course Methods: Three patients for whom frequent long-term monitoring of MuSK-Ab levels and the Myasthenia Gravis Composite (MGC) scores were performed are described. Results: A close relationship existed between the MuSK-Ab concentrations and the MGC score. Furthermore, a rise in Ab concentration preceded a more serious clinical relapse in all patients Conclusions: These findings suggest that MuSK-Ab concentrations may be a useful biomarker for the long-term monitoring of MuSK myasthenia gravis, particularly while in clinical remission. This may allow preemptive escalation of therapy to prevent clinical relapse, and conversely permitting greater weaning of unnecessary immunosuppression. Muscle Nerve, 2019     

Eosinophilia, myositis, and myasthenia gravis associated with a thymoma

Hypereosinophilia has been associated with a wide variety of systemic disorders, including myositis. Myositis develops in a minority of patients with myasthenia gravis associated with a thymoma. We present a patient who developed a life-threatening myopathy in which testing demonstrated the concurrence of hypereosinophilia, myositis, and myasthenia gravis associated with thymoma. Thymoma-associated T-cell abnormalities may well have contributed to this rare association. This case underscores the need to reevaluate constantly the presumed cause of clinical complaints, as more than one cause may be present.     

CA-antibody: an immunological marker of thymic neoplasia in myasthenia gravis?

We have examined sera from 141 patients with myasthenia gravis and 11 non-myasthenia gravis patients with thymoma for antibodies to a citric acid extract of skeletal muscle (CA-antibodies). Sera were obtained from 5 different centers. The thymus histology was defined in each case. Sera from 56/66 patients (85%) with thymoma contained CA-antibodies, while such antibodies were only detected in 6/75 (8%) of the non-thymoma patients. None of the patients with thymus hyperplasia had CA-antibodies. One MG patient who developed MG after a bone-marrow transplantation, also developed CA-antibodies. The remaining 5 CA positive non-thymoma MG patients were all greater than 65 years and had thymic atrophy. Two of them had myasthenia gravis and polymyalgia rheumatica. In 2 thymoma patients with non-detectable levels of CA-antibodies before thymectomy, such antibodies were demonstrated in high titres after the operation. In 2 other sera from thymoma patients, the titres of CA-antibodies fell to less than 32 after thymectomy. There were 3 sera with CA-antibodies among 11 sera from non-MG patients with thymic tumours.     

Fiberoptic endoscopic evaluation of swallowing with simultaneous tensilon application in diagnosis and therapy of myasthenia gravis

Background Dysphagia is a common symptom in myasthenia gravis (MG). Clinical examination alone fails to detect and grade myasthenic dysphagia sufficiently. For a more precise examination of swallowing function in myasthenia gravis additional technical tools are necessary. Objective To investigate the diagnostic and therapeutic impact of fiberoptic endoscopic evaluation of swallowing with simultaneous Tensilon application (FEES-Tensilon Test) in myasthenia gravis. Methods FEES-Tensilon Test was performed following a standardized protocol. Four severely affected patients with dysphagia as their leading symptom were examined. Dysphagia was characterized by five salient endoscopic findings: leakage, delayed swallowing reflex, penetration, aspiration and residues. If a normalisation or at least an improvement of swallowing function occurred shortly after Tensilon administration the FEES-Tensilon Test was rated as being positive. Results In three patients the FEES-Tensilon Test successfully detected MG-related dysphagia. In one patient with dysphagia caused by oculopharyngeal muscular dystrophy the FEES-Tensilon Test was truly negative. Beside an early diagnosis of MG-related dysphagia, the FEES-Tensilon Test was useful in the differentiation between myasthenic and cholinergic crisis and in guiding treatment decisions. In all patients the FEES-Tensilon Test was superior to clinical evaluation of dysphagia. No severe side effect occurred while performing the FEES-Tensilon Test. Conclusion The FEES-Tensilon Test is a suitable tool in the diagnosis and therapy of myasthenia gravis with pharyngeal muscles weakness.