重症肌无力患者血清Titin抗体和AchR抗体检测的意义

目的 探讨重症肌无力(MG)患者血清Titin抗体及乙酰胆碱受体(AchR)抗体的检测意义.方法 采用酶联免疫吸附试验(ELISA)对81例MG患者和80例对照组成员进行Titin和AchR抗体的检测.结果 Titin抗体对MG具有特异性,它在合并胸腺瘤的MG(MGT)、晚发型MG患者中有较高的阳性率(分别为80%、69.4%)和抗体水平,明显高于早发型MG患者的阳性率(25%)和抗体水平,差异均有统计学意义(P<0.05).而早发型MG患者中AchR抗体阳性率比晚发型MG患者明显增高.并且早发型MG患者的AchR抗体水平也明显高于晚发型MG和MGT患者,差异均有统计学意义(P<0.05).结论 两种抗体检测为MG诊断和病因学研究提供了重要证据,联合检测可以提高MG诊断的灵敏度.     

晚发型重症肌无力临床研究

目的探讨晚发型重症肌无力(Myasthenia gravis,MG)患者的临床特点。方法回顾性研究40例晚发型MG的临床特点并与早发型MG比较。结果晚发型MG患者男/女比例高于早发型MG,为1.22:1。晚发型MG的症状由眼肌受累演变至全身症状(占67.5%)显著高于早发型MG(占38.7%)。晚发型MG的肌无力程度较早发型MG肌无力程度严重,而且血清乙酰胆碱受体(acetylcholine receptor,AchR)抗体阳性率及抗体水平均显著低于早发型MG低,但Titin抗体阳性率及抗体水平却显著高于早发型MG。胆碱酯酶抑制剂对晚发型MG的疗效不如早发型MG。结论晚发型MG是一个免疫异质性的MG亚群,它的临床表现以及血清免疫学特点不同于早发型MG。     

Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence?

BACKGROUND: Patients with MG often have other autoantibodies in addition to those against the acetylcholine receptor (AChR). It has been suggested that antibodies to the muscle protein titin may be diagnostic of a thymoma, but they have also been found in patients with late-onset MG. Antibodies to certain cytokines have also been detected in patients with MG and thymoma, and it is not clear whether these antibodies could be more useful clinically. The authors measured antibodies against titin and the cytokines interferon alpha (IFNalpha) and interleukin 12 (IL12) in patients with MG and thymoma or thymoma recurrence, and in patients with MG but without thymoma presenting before (early-onset MG) or after (late-onset MG) 40 years of age. METHOD: Levels of titin, IFNalpha, and IL12 antibodies were determined by radioimmunoassay in 191 patients with MG and 82 controls. RESULTS: As previously reported, titin antibodies were uncommon in patients with early-onset MG. However, in patients with late-onset MG, titin antibodies had similar prevalence and levels to those in patients with MG and thymoma, although the antibodies were uncommon in patients between 40 and 60 years of age presenting without a tumor. By contrast, cytokine antibodies were more common in patients with thymoma than in patients without thymoma, and cytokine antibodies typically increased substantially if the thymoma recurred. CONCLUSIONS: Measurement of titin antibodies has limited use in predicting the presence of a tumor, unless the patient is less than 60 years of age, but measurement of IFNalpha and IL12 antibodies may be helpful in identifying patients with a thymoma recurrence, particularly when mediastinal imaging is equivocal.     

Characteristics of late-onset myasthenia gravis

An increasing incidence of myasthenia gravis (MG) has been reported in the elderly, but the full clinical ramifications of late-onset myasthenia gravis (LOMG) remain unclear. We describe the clinical features of our cohort of patients with MG with an emphasis on an onset after the age of 50. This was a retrospective analysis of medical records of a cohort of patients followed in two tertiary neuromuscular clinics and comparison of early onset MG (EOMG) versus LOMG. There were 174 patients with a mean age of onset of 55.2?±?19.1?years, and 44 % were women. Late onset of myasthenia gravis after age 50 was reported in 114 patients (66 %). Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p?=?0.003), and frequency of elevated titers of anti-MuSK antibodies was similar in both groups (present in 38 % of all tested seronegative patients). Myasthenic crisis was equally common in generalized EOMG and LOMG (13 %). Ocular MG was more common in LOMG compared to EOMG (40 vs. 18 %, p?=?0.021). Diabetes was more prevalent with LOMG (27 vs. 5 %; p?=?0.0002). Overlapping clinical features of EOMG and LOMG are consistent with a continuous clinical spectrum of a single condition, with more frequent occurrence of seropositive and ocular MG with a late onset. A higher burden of comorbidities, such as diabetes mellitus, may warrant a modified approach to treatment of myasthenia in LOMG. However, overall disease severity may not be higher with aging. These observations have implications for design of MG clinical trials and outcomes studies.     

Nonthymoma early-onset- and late-onset-generalized myasthenia gravis--a retrospective hospital-based study

OBJECTIVE: Acquired myasthenia gravis (MG) is predominantly due to nicotinic acetylcholine receptor (AChR) autoantibodies (Ab). Differences between nonthymoma early-onset and late-onset MG were reported. We studied the clinical and serological characteristics of nonthymoma AChR Ab-positive-generalized MG patients. PATIENTS AND METHODS: Chinese AChR Ab-positive-generalized MG patients who had generalized disease for 3 years or longer were studied. RESULTS: Among 41 such patients, 25 (61%) were female. The mean onset age was 43.5 years (range 9-78 years) and the mean follow-up duration was 7.8 years (range 3-20 years). Sixteen (39%) patients had late-onset disease (onset age >or=50 years). Compared to early-onset patients (onset age <50 years), late-onset patients were characterized by male predominance (p=0.002), absence of thymic lymphofollicular hyperplasia (p=0.036), and a higher striated muscle Ab seropositivity rate (94% versus 4%, p<0.001). Although there was no statistically significant difference in clinical severity and outcome or response to treatment between late-onset and early-onset patients, 50% and 75% of late-onset patients had moderate or severe disease at onset and worst status, respectively, compared to 28% and 52% for early-onset patients at onset and worst status, respectively. Also 63% of late-onset patients had disease progressed within first 3 years compared to only 40% of early-onset patients did. CONCLUSION: Nonthymoma late-onset-generalized MG patients were common among Hong Kong Chinese, with a statistically non-significant trend that it was clinically more severe than early-onset MG but with similar clinical outcome or response to treatment; >90% of these patients were seropositive for striated muscle Ab.     

重症肌无力患者血清抗Titin抗体检测的临床意义

目的探讨重症肌无力(myasthenia gravis,MG)患者血清抗Titin抗体检测的临床意义。方法用重组体MGT-30(提纯的Titin片断)作为抗原,应用ELISA对77例MG患者(包括25例胸腺瘤患者)、58例其他神经系统疾病患者及46例健康对照者进行血清抗Titin抗体检测。结果MG、MG合并胸腺瘤和年龄超过40岁而无胸腺瘤的晚发型MG患者组中抗Titin抗体的阳性率分别为63.6%、80%和70.6%,而其他神经系统疾病组和健康对照者中抗Titin抗体阳性者较少,分别为15.5%、6.5%。MG患者组的阳性率明显高于对照组。结论血清抗Titin抗体检测可作为MG诊断的参考指标,尤其对合并胸腺瘤患者可能更具有临床意义。     

Studying the relationship between clinical features and mental health among late-onset myasthenia gravis patients

BACKGROUNDMental disorders are common comorbidities among individuals with neurological diseases, and the prevalence of depressive and anxiety-related symptoms in newly referred patients at neurology outpatient clinics is high. There have been few studies on the mental health of patients with late-onset myasthenia gravis (MG).AIMTo examine the relationship between clinical features and the mental health symptoms within late-onset MG patients.METHODSA total of 105 patients diagnosed with MG were recruited consecutively from a neuromuscular outpatient clinic between December 2020 and February 2021. Patients were classified into two groups: early-onset MG (age at onset < 50 years, n = 63) and late-onset MG (age at onset ≥ 50 years, n = 42). Social demographic data and information about marital status, education level, clinical symptoms, serum antibody levels, and therapies used were collected for all participants. Participants were also evaluated using the Myasthenia Gravis Composite scale, the Myasthenia Gravis Activities of Daily Living scale, the Myasthenia Gravis Quality of Life 15 (MG-QOL-15) questionnaire, the 17-item version of the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). The relationship between clinical features and mental health in late-onset MG patients was examined using multivariate logistic regression analyses. RESULTSLate-onset MG patients were more prone to dyspnea, had higher levels of serum anti-acetylcholine receptor antibodies, and higher total scores on the MG-QOL-15, HAM-D, and HAM-A questionnaires, than early-onset MG patients had (P < 0.05). Among those with late-onset MG, female patients had higher total HAM-D and HAM-A scores than male patients had (P < 0.05). High scores on the QOL-15 questionnaire were associated with higher incidences of anxiety and depression, and the association was found to be independent after adjusting for confounding risk factors. In the late-onset subgroup, the areas under the receiver operating characteristic curves for the MG-QOL-15 score-based diagnostic accuracy for anxiety and depression state were 0.816 (P = 0.001) and 0.983 (P < 0.001), respectively.CONCLUSIONHigher MG-QOL-15 scores were a risk factor for anxiety and depression in late-onset MG, and women with late-onset MG were more likely to have anxiety and depression than men were.     

The severity of myasthenia gravis correlates with the serum concentration of titin and ryanodine receptor antibodies

BACKGROUND: Myasthenia gravis (MG) is caused by autoantibodies to the acetylcholine receptor (AChR). Non-AChR muscle autoantibodies are present in many MG serum samples, mainly from patients with thymoma or late-onset MG. The exact relationship between MG severity and several non-AChR muscle antibodies is unknown. OBJECTIVE: To study the correlation between the severity of MG and the concentration of antibodies against striated muscle tissue sections, titin, citric acid antigen, ryanodine receptor, and AChR. SETTING: The severity of MG was graded in 146 consecutive patients with MG, and their serum samples were tested for the presence of autoantibodies. Ten patients who were titin antibody positive were observed in longitudinal follow-up. RESULTS: No significant difference was found in MG severity between late-onset and thymoma MG. Titin, citric acid antigen, and ryanodine receptor antibodies occurred significantly more often among patients with severe MG than among patients with less severe disease. Changes in MG severity correlated with changes in titin antibody titer in the individual patient. Titin antibodies showed a better longitudinal correlation with disease severity than the AChR antibodies. CONCLUSIONS: Non-AChR muscle autoantibodies occurred more frequently in severe MG regardless of MG subgroup. Thymoma per se does not generate a more severe MG. It may well be the presence of a humoral immune response to non-AChR muscle antigens such as titin, citric acid antigen, and ryanodine receptor that leads to a severe disease, not the presence of thymoma or a late age of onset. These antibodies can serve as important prognostic markers in MG regardless of the presence of thymoma.     

Clinical and immunological differences between early and late-onset myasthenia gravis in Japan

Immunological characteristics of myasthenia gravis (MG) with late-onset have not been fully elucidated. We examined several autoantibodies and HLA-DRB1 genotyping in 260 Japanese MG patients. Sixty-two MG patients had thymoma. The others were divided into early-onset and late-onset groups separated by an age of 50 years. The ocular form was more frequent in late-onset compared to early-onset group. Seropositivity of anti-muscle-specific tyrosine kinase antibody was 2-3% in acetylcholine receptor-seronegative patients. HLA-DRB1 genotyping failed to detect statistical differences in specific alleles between each group and healthy controls. The immunological profiles in late-onset MG were different from early-onset in Japan.     

Clinical characteristics and prognosis of very late-onset myasthenia gravis in China

Alteration in onset-age distribution in myasthenia gravis (MG) and its increasing prevalence among the elderly underscores the need for a better understanding of the clinical course of MG and the establishment of personalized treatment. In this study we reviewed the demographics, clinical profile, and treatment of MG. Based on onset age, eligible patients were classified as early-onset MG (onset age ≥18 and <50 years), late-onset MG (onset age ≥50 and <65 years), and very late-onset MG (onset age ≥65 years). Overall, 1160 eligible patients were enrolled. Patients with late- and very late-onset MG showed a male predominance (P=0.02), ocular MG subtype (P=0.001), and seropositivity for acetylcholine receptors and titin antibodies (P<0.001). In very late-onset MG, a lower proportion of patients retained minimal manifestations status or better, a higher proportion of patients had MG-related deaths (P<0.001), and a shorter maintenance time of minimal manifestation status or better was seen at the last follow-up (P=0.007) than that in patients with early- and late-onset MG. Non-immunotherapy may associated with a poor prognosis in patients in the very late-onset group. Further studies on very late-onset MG patients should be performed to evaluate the relationship between immunotherapy and prognosis.     

重症肌无力患者血清Ryanodine受体抗体检测及意义

目的探讨Ryanodine受体（RyR）抗体在重症肌无力（myasthenia gravis，MG）诊断中的临床意义。方法采用ELISA法检测89例MG患者、66例其他神经系统疾病患者和66名正常对照者血清RyR抗体水平。结果MG组血清RyR抗体阳性率显著高于其他神经系统疾病组和正常对照组（P〈0．05），其敏感性和特异性分别为55．0％和91．7％。晚发型MG患者血清RyR抗体阳性率（74．4％）明显高于早发型MG（37．0％，P〈0．05）。MG合并胸腺瘤（MGT）和未合并胸腺瘤（nMGT）患者血清RyR抗体阳性率差异无统计学意义（P〉0．05）。将MG患者根据Osserman评分进行分型，各型血清RyR抗体阳性率及其吸光度值大小与病情严重程度无相关性（P〉0．05）。结论RyR抗体多见于晚发型MG，对诊断MG具有较高的敏感性和特异性。     

Clinical Significance of Repetitive Compound Muscle Action Potentials in Patients with Myasthenia Gravis: A Predictor for Cholinergic Side Effects of Acetylcholinesterase Inhibitors

MethodsWe retrospectively reviewed the clinical records and electrodiagnostic findings of MG patients who underwent electrodiagnostic studies and diagnostic neostigmine testing (NT).ResultsAmong 71 MG patients, 9 could not tolerate oral pyridostigmine bromide (PB) and 17 experienced side effects of PB. R-CMAPs developed in 24 patients after NT. The highest daily dose of PB was lower in the patients with R-CMAPs (240 mg/day vs. 480 mg/day, p<0.001). The frequencies of PB intolerance and side effects were higher in the patients with R-CMAPs than in those without R-CMAPs [37.5% vs. 0% (p<0.001) and 45.8% vs. 12.8% (p=0.002), respectively]. The MG Foundation of America postintervention status did not differ significantly between MG patients with and without R-CMAPs, and the response to immunotherapy was also good in both groups.ConclusionsSide effects of and intolerance to AChEIs are more common in MG patients with R-CMAPs than in those without R-CMAPs. AChEIs should be used carefully in MG patients with R-CMAPs. The presence of R-CMAPs after NT may be a good indicator of the risks of PB side effects and intolerance.     

Myasthenia gravis: disease severity and prognosis

Objectives –  To examine myesthenia gravis (MG) severity and long-term prognosis in seronegative, seropositive, and thymoma MG.
Materials and Methods –  Four series of patients were studied retrospectively. Severity and treatment were assessed each year, and muscle antibodies were assayed.
Results –  Seropositive MG patients had a more severe course than seronegative MG patients. MG severity was higher in non-thymectomized compared to thymectomized early-onset MG patients. MG severity did not differ between thymectomized and non-thymectomized late-onset patients. There was no significant difference in MG severity between thymoma and non-thymoma MG patients.
Conclusions –  MG is more severe in seropositive MG patients. With proper treatment, especially early thymectomy, the long-term prognosis is good in seropositive MG patients. The present studies indicate a benefit of thymectomy in early-onset MG, but no dramatic benefit in late-onset MG. Similar MG severity and outcome was seen in thymoma and non-thymoma MG.     

Frequency of autoimmune diseases in myasthenia gravis: a systematic review

The course of myasthenia gravis (MG) may get complicated by the development of other autoimmune diseases. Estimates of the frequency of autoimmune diseases will help inform patients and physicians, direct health policy discussion, provide etiologic clues, and optimize the management of MG. However, the frequency of autoimmune diseases in people with MG is still uncertain. A systematic search for English language studies was conducted by MEDLINE and EMBASE from 1960 through 2010. Incidence studies and case series of all MG subtypes with information about autoimmune diseases were included; 25 studies met the inclusion criteria. Although there was considerable heterogeneity, the pooled estimate of the coexisting autoimmune diseases in MG was 13% (95% confidence interval, 12%-14%). Autoimmune thyroid disease seems to occur more frequently than other autoimmune conditions in MG patients. Heterogeneity in study estimates could be explained by ascertainment bias and case mix. Furthermore, autoimmune diseases occurred significantly more often in females and anti-acetylcholine receptor seropositive MG patients. Patients with MG have an increased frequency of coexisting autoimmune diseases. Autoimmune diseases seem to occur more often in female and seropositive MG patients. Further research is needed to expand our understanding of these associations.     

Polyneuropathy associated with IgM vs IgG monoclonal gammopathy: comparison between clinical and electrophysiological findings

Vrethem M, Reiser N, Lauermann C, Svanborg E. Polyneuropathy associated with IgM vs IgG monoclonal gammopathy: comparison between clinical and electrophysiological findings.
Acta Neurol Scand: 2010: 122: 52–57.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – The neuropathy associated with IgM monoclonal gammopathy (IgM‐MG) is regarded as a sensorimotor, mainly demyelinating neuropathy. It is not fully known whether the neuropathy in IgG‐MG is caused by the same mechanisms and shows the same electrophysiological characteristics. We aimed at making a comparison between clinical and neurophysiological findings in these two conditions. Patients and methods – Twenty‐seven patients with IgM‐associated neuropathy [18 with anti‐myelin‐associated glycoprotein (anti‐MAG) antibodies] were compared with 15 age‐matched patients with IgG‐associated neuropathy. Results – Patients with IgM‐associated neuropathy (especially those with anti‐MAG antibodies) had significantly clinically more severe disabilities with involvement of both motor and sensory functions compared with patients with IgG‐associated neuropathy in whom clinical sensory disturbances were more prominent than motor dysfunction. Motor and sensory conduction velocities were significantly lower and distal latencies significantly longer in the IgM group than in the IgG group concerning the median, ulnar and peroneal nerves. Fifty‐four per cent of the patients in the IgM group did not present a sensory response of the median nerve vs 13% in the IgG group. There was also a significant difference concerning absent responses from the peroneal and sural nerves in the IgM vs IgG group (peroneal: 48% vs 13%, sural: 88% vs 27%). Conclusion – Polyneuropathy associated with IgM‐MG, especially when associated with anti‐MAG antibodies, appears to have more of a demyelinating involvement that meets the criteria for demyelination. This was not as clear in those associated with IgG. The IgG neuropathy showed less and milder deficit in the electrophysiological studies.     

晚发型糖原累积病II型的临床和病理研究

目的：总结晚发型糖原累积病II型（CSDII型）的临床及病理学特点。方法：回顾性分析11例GSDII型患者的临床和病理资料,并对部分患者进行随访。结果：临床表现为对称性四肢肌无力,以近端受累为主,可伴有呼吸肌无力,肌酸激酶（cK）可有不同程度升高,肌电图检查均呈肌源性损害肌电表现,可伴肌强直电位。外周血α-1,4-葡萄糖苷酶活性明显减低,肌肉活组织检查均以肌纤维空泡样变为主要病理特征,过碘酸希夫反应可见空泡内大量糖原沉积,酸性磷酸酶染色阳性。结论：晚发型GSDII型多表现为慢性肌病,易累及四肢肌和呼吸肌,血清CK轻度至中度升高,肌肉病理见明显空泡样变。α-葡萄糖苷酶活性明显减低,有助于确诊。     

Clinical evaluation and management of myasthenia gravis

Myasthenia gravis (MG) is a syndrome of fluctuating skeletal muscle weakness that worsens with use and improves with rest. Eye, facial, oropharyngeal, axial, and limb muscles may be involved in varying combinations and degrees of severity. Its etiology is heterogeneous, divided initially between those rare congenital myasthenic syndromes, which are genetic, and the bulk of MG, which is acquired and autoimmune. The autoimmune conditions are divided in turn between those that possess measurable serum acetylcholine receptor (AChR) antibodies and a smaller group that does not. The latter group includes those MG patients who have serum antibodies to muscle-specific tyrosine kinase (MuSK). Therapeutic considerations differ for early-onset MG, late-onset MG, and MG associated with the presence of a thymoma. Most MG patients can be treated effectively, but there is still a need for more specific immunological approaches.     

Late-onset major depression: clinical and treatment-response variability

OBJECTIVE: To explore clinical and treatment-response variability in late-onset vs early-onset non-bipolar, non-psychotic major depression. METHODS: We grouped patients from a late-life depression treatment study according to illness-course characteristics: those with early-onset, recurrent depression (n = 59), late-onset, recurrent depression (n = 27), and late-onset, single-episode depression (n = 95). Early-onset was defined as having a first lifetime episode of major depression at age 59 or earlier; late-onset was defined as having a first episode of major depression at age 60 or later. We characterized the three groups of patients with respect to baseline demographic, neuropsychological, and clinical characteristics, use of augmentation pharmacotherapy to achieve response, and treatment outcomes. RESULTS: Rates of response, remission, relapse, and termination were similar in all three groups; however, patients with late-onset, recurrent major depression took longer to respond to treatment than those with late-onset, single-episode depression (12 weeks vs 8 weeks) and had more cognitive and functional impairment. Additionally, patients with recurrent depression (whether early or late) were more likely to require pharmacotherapy augmentation to achieve response than patients with a single lifetime episode. CONCLUSION: Late-onset, recurrent depression takes longer to respond to treatment than late-onset single-episode depression and is more strongly associated with cognitive and functional impairment. Further study of biological, neuropsychologic, and psychosocial correlates of late-onset, recurrent depression is needed.     

Autoantibodies in thymoma-associated myasthenia gravis and their clinical significance

Myasthenia gravis (MG) is characterized by the development of antibodies that act against the acetylcholine receptor (AChR) present at the postsynaptic site of neuromuscular junctions. Some MG patients have antibodies that bind in a cross-striational pattern to skeletal and heart muscle tissue sections (striational antibodies). These antibodies react with the epitopes on the muscle protein titin, ryanodine receptor (RyR), and voltage-gated K channel α subunit, Kv1.4. Since these 3 molecules are expressed in the thymoma tissue of MG patients, striational antibodies are frequently detected in thymoma-associated MG. More severe MG symptoms in thymoma-associated MG may be due to the presence of striational autoantibodies. The anti-titin antibody, usually detected by enzyme-linked immunosorbent assay (ELISA), is found in 20-40% of all MG patients, and is more common in late-onset MG patients. The anti-RyR antibody, detected by Western blotting or ELISA, is found in 13-38% of all MG patients, and is known to inhibit Ca2+ release from sarcoplasmic reticulum and excitation-contraction coupling of the muscle. The anti-Kv1.4 antibody, detected by the immunoprecipitation assay with 35S-labeled extract from rhabdomyosarcoma cells, is found in 12-15% of all MG patients. Autoimmune myocarditis may develop in MG patients who have the anti-Kv1.4 antibody. In addition, the anti-Kv1.4 antibody is a useful marker to check the response to calcineurin inhibitors. In summary, the detection of striational antibodies provides more specific clinical information in MG patients.     

Increased binding of anti-acetylcholine receptor antibodies to thymic antigen in patients with myasthenia gravis and other autoimmune diseases, as compared to those with myasthenia gravis alone

We compared the binding activity against acetylcholine receptors solubilized from human muscle (AChRM) and human thymus (AChRT), of sera from patients with myasthenia gravis (MG) alone, to those of sera from patients with myasthenia gravis and associated autoimmune diseases (MG AD). The sera of the MG AD group bound relatively better to thymic antigen (86% vs. 62%). This group was found to contain a higher proportion of women over 40 years of age (more than 50% of the group). The expression of a particular AChR antigen in normal human thymus may be one of the factors involved in the pathogenesis of MG, especially when this disease is associated with other autoimmune disorders.