重症肌无力中枢神经系统受损模型

目的近年研究结果表明，重症肌无力（ＭＧ）病变部位并不仅仅局限于神经肌接头（ＮＭＪ）处突触后膜烟碱型乙酰胆碱受体（ｎＡＣｈＲ），烟碱型乙酰胆碱受体抗体（ＡＣｈＲ－ａｂ）病理作用可能波及到中枢神经系统（ＣＮＳ）。因此，有必要建立模拟ＭＧ患者ＣＮＳ损害的动物模型，研究ＭＧ患者脑脊液中存在的ＡＣｈＲ－ａｂ引起ＣＮＳ损害的机制。方法从ＭＧ患者血中提取的ＡＣｈＲ－ａｂ经侧脑室穿刺注入到大鼠脑室系统，然后观察其症状和体征，以及用脑干听觉诱发电位仪（ＢＡＥＰ）检测鼠脑干听觉传导中枢功能。用免疫组化法（ＡＢＣ）研究ＡＣｈＲ－ａｂ与ＣＮＳ神经－ｎＡＣｈＲ之间免疫结合反应及其分布。结果大鼠除了出现脑干听觉传导中枢功能障碍外，还出现类似于ＭＧ动物模型表现的症状。免疫组化研究结果显示，神经－ｎＡＣｈＲ样阳性免疫反应广泛分布于ＣＮＳ许多部位。结论脑室内注入的ＡＣｈＲ－ａｂ与神经－ＡＣｈＲ结合引起ＣＮＳ功能障碍和出现ＭＧ动物模型样症状。我们首次建立的中枢受损的ＭＧ模型将有助于阐明ＡＣｈＲ－ａｂ引起中枢受损和ＣＮＳ下位运动神经元引起横纹肌收缩无力的机制。     

Myasthenia gravis,thymectomy, and antiacetylcholine receptor antibody

Summary The antiacetylcholine receptor antibody was titered in the serum of 63 patients with myasthenia gravis (MG) and 20 control healthy subjects. The titer was significantly high in 92% of MG patients in contrast with none of the controls and no correlation was found with the thymus pathology and the severity of the disease. The titer decreased after thymectomy almost steadily with the improvement of the myasthenic signs. The role of the antibody in the pathogenesis of the disease is discussed.

---

Zusammenfassung Die Antikörper gegen Acetylcholin-Rezeptoren wurden quantitativ im Serum von 63 Patienten mit Myasthenia Gravis und von 20 gesunden Kontrollpersonen bestimmt. Der Titer war bei 92% der Myasthenie Gravis-Patienten signifikant erhöht, jedoch bei keinem der Kontrollfälle. Es wurde keine Korrelation zwischen dem Titer einerseits und den pathologischanatomischen Besonderheiten beziehungsweise dem klinischen Schweregrad der Erkrankung andererseits festgestellt. Der Titer nahm nach Thymektomie ziemlich geradlinig ab, parallel zur klinischen Besserung der Myasthenie. Es wird die Rolle der Antikörper bei der Pathogenese der Erkrankung diskutiert.

     

重症肌无力患者胸腺手术后血清AchRab和CAEab的变化

目的：研究重症肌无力（MG）患者手术后血清乙酰胆碱受体抗体（AchRab）与抗骨骼肌柠檬酸提取物抗体（CAEab）的变化。方法：用固相酶联免疫吸附法测定血清AchRab和CAEab。结果：MG患者血清AchRab和CAEab的水平明显高于对照组（P＜0．01）。AchRab水平在手术后1个月开始下降（P＜0．05）,在手术后1年下降更明显（P＜0．01）;CAEab水平在手术后1个月和6个月下降不明显（P＞0．05）,在手术后1年下降有显著性差异（P＜0．05）。手术后1年患者血清中AchRab和CAEab水平仍高于对照组（P＜0．01）。结论：手术后血清AchRab和CAEab的检测有助于了解患者的病情。     

重症肌无力患者血清IgG-乙酰胆硷受体抗体亚型研究

目的 探讨重症肌无力（ＭＧ）患者血清ＩｇＧ－乙酰胆硷受体抗体（ＡＣｈＲＡｂ）亚型的分布规律及其临床意义。方法 采用ＡＢＣ－ＥＬＩＳＡ法检测４３例ＭＧ组和２５例临床对照组、２０例正常对照组血清中ＩｇＧ－ＡＣｈＲＡｂ亚型ＩｇＧ１－４。结果 ＭＧ组与两对照组相比ＩｇＧ１和ＩｇＧ４亚型抗体无显著差别,ＩｇＧ２亚型抗体显著升高（Ｐ〈０．０５）,ＩｇＧ３亚型抗体显著降低（Ｐ〈０．０５）;ＭＧ组各临床类型间各亚型抗体无显著差别。结论 ＩｇＧ－ＡＣｈＲＡｂ亚型以ＩｇＧ２活性为主,但未显示与ＭＧ临床类型有关。     

胸腺切除对重症肌无力患者T淋巴细胞亚型的影响

目的：观察胸腺切除(Tx)术对重症肌无力(MG)病人的临床疗效及对T淋巴细胞亚型的影响。方法：用许氏评分法观察30例伴胸腺增生或胸腺瘤的MG患者的病情严重程度及Tx术后2个月的临床疗效;采用直接免疫荧光染色和流式细胞仪技术测定60名志愿健康者和30例伴胸腺增生或胸腺瘤的MG患者Tx术前及术后2个月T淋巴细胞亚型的变化。结果：伴胸腺增生或胸腺瘤的MG病人Tx术前外周血中CD4＋T淋巴细胞的百分率较正常人显著增多(P＜0．01),CD8＋T淋巴细胞的百分率较正常人显著减少(P＜0．01),CD4＋/CD8＋T细胞的比例明显增高(P＜0．01)。伴胸腺增生MG病人Tx术后随着临床症状的改善,CD8＋T淋巴细胞的百分率较术前显著升高(P＜0．05),CD4＋/CD8＋T细胞的比例较术前显著下降(P＜0．05)。伴胸腺瘤MG病人Tx术后随着临床症状的改善,CD4+T淋巴细胞的百分率较术前显著下降(P＜0．05),CD4＋/CD8＋T细胞的比例较术前显著下降(P＜0．05)。结论：重症肌无力患者T淋巴细胞亚型的测定既可以为MG免疫病理学的发病机理的研究提供实验依据,也能为Tx治疗MG提供一个客观的实验室指标,为判断疾病的转归提供实验依据。     

重症肌无力病人乙酰胆碱受体抗体的测定及临床意义

用ＥＬＩＳＡ（固相酶联免疫吸附）法测定１７２例ＭＧ病人血清乙酰胆碱受体抗体（ＡｃｈＲａｂ），结果显著高于健康献血员组和非ＭＧ病人组。不同性别、病程及临床类型与ＡｃｈＲａｂ无相关性，但４１～５０岁组的显著高于其他年龄组。６７例类固醇激素治疗组、２２例大剂量两种球蛋白治疗组、１２例胸腺切除术组及３例ＭＧ危象病人２４次血浆交换疗法（ＰＥ）组，治疗后伴随肌无力症状的好转，ＡｃｈＲａｂ均显著低于治疗前。结果表明：ＡｃｈＲａｂ测定为ＭＧ诊断提供了可靠的实验依据，为类固醇激素、大剂量丙种球蛋白、胸腺切除术和ＰＥ等治疗ＭＧ提供理论依据和疗效评定的实验指标，进一步证实了ＭＧ免疫学发病机理。     

重症肌无力患者血清白细胞介素—6水平测定

目的探讨重症肌无力(MG)与白细胞介素-6(IL-6)的关系.方法采用双抗体夹心ELISA法对30例MG患者用糖皮质激素(GC)治疗前、治疗2个月后和22例正常对照血清IL-6、乙酰胆碱受体抗体(AchRab)水平进行检测.结果MG患者组血清IL-6水平显著高于对照组(P＜0.01),MG患者组血清IL-6水平在用GC治疗2个月后显著降低(P＜0.01),其血清IL-6与血清AchRab水平呈正相关(r=0.693,P＜0.01).结论IL-6与MG发病密切相关,IL-6参加了MG的免疫病理过程;检测血清IL-6水平对MG临床有重要价值;GC可抑制IL-6合成及AchRab产生.     

白细胞介素-6与重症肌无力患者临床特点的关系

目的　探讨白细胞介素 6(IL 6)与重症肌无力(MG)患者临床特点的关系。方法　采用双抗体 夹心ELISA法检测36例MG患者及20名健康对照者的血清IL 6和乙酰胆碱受体抗体(AchRAb)水平,并分 析其与MG临床特点的关系。结果　MG患者血清IL 6水平高于健康对照者(P<0.01);AchRAb阳性患者 高于阴性患者(P<0.05);全身型患者高于眼肌型患者(P<0.05);病情重者高于病情轻者(P<0.05);急性 期高于非急性期(P<0.01);预后差者高于预后好者(P<0.05);伴胸腺异常者高于胸腺正常者(P<0.05)。 结论　IL 6与MG临床特点相关,在MG发病机制中起重要作用。血清IL 6水平可间接反映体内免疫功能紊 乱的程度,对判断MG患者病情、预后和指导治疗有重要的参考价值。     

Myasthenia gravis associated with etanercept therapy

Etanercept is an antagonist of tumor necrosis factor alpha that was developed to treat rheumatoid arthritis. In this report we present a patient who developed myasthenia gravis while taking etanercept and had resolution of symptoms after stopping it. This is the first report of this potential side effect and is of additional interest, because etanercept has been proposed as a treatment for myasthenia gravis. Muscle Nerve, 2009     

重症肌无力患者外周血单个核细胞白细胞介素6活性变化

探讨白细胞介素 6(IL -6)在重症肌无力 (MG)发病机理中的作用及其临床意义。　　方法　采用3H -TdR掺入法检测 40例正常对照及 42例MG患者外周血单个核细胞IL -6分泌活性。　　结果　MG患者组IL -6活性显著高于正常对照组 ,且IL -6活性变化与乙酰胆碱受体抗体产生以及与MG临床类型、病情、预后密切相关。　　结论　IL -6在MG发病机理中起着重要作用 ,检测IL -6活性对区分MG临床类型、判断病情、推测预后、指导治疗有重要的参考价值。     

重症肌无力合并肌电图肌源性损害53例临床和电生理特点

目的研究重症肌无力（myasthenia gravis，MG）合并肌电图肌源性损害患者的临床和电生理特点。方法收集1998-2006年中国医学科学院北京协和医院神经科肌电图室收治的MG合并肌源性损害患者共53例，对其临床和电生理特点进行回顾性分析。结果在本组患者中，早发型患者占69．81％（37／53），早发型中女性患者明显多于男性（分别为26例和11例,X^2=5．281，P〈0．05）。延髓部肌肉受累者多见，占50．94％（27／53）。仅1例患者具有肌肉萎缩的临床表现。合并其他免疫相关疾病患者占15．09％（8／53）。2例患者（3．77％）重复频率电刺激正常，但肌电图示肌源性损害。15例患者进行肌酶谱检查，其中1例轻度异常。结论对于MG合并肌源性损害的患者，要结合临床特征、电生理检查等进行综合分析来区别“真性”和“假性”的肌源性损害。行甲状腺功能、自身抗体等检查有助于发现潜在的自身免疫系统疾病。     

Neonatal myasthenia gravis: Clinical and immunological study of seven mothers and their newborn infants

We studied 7 mothers with myasthenia gravis (MG) and their infants. We confirmed that the development of neonatal MG was not related to the serum titer of maternal anti-acetylcholine receptor antibody (anti-AChR ab). To investigate the possibility that specific immunization of the newborn infant had occurred, serial serum determinations of total and 'specific' anti-AChR IgG and IgM were performed. We found that: the decay in total IgG was within the normal range in all the babies; there was a shorter half-life of 'specific' IgG, compared to total IgG, in 3 of the cases, 2 of which did have neonatal MG; no difference was found between the decay of anti-AChR ab in the babies who had neonatal MG and those who did not; there was no anti-AChR IgM-associated activity. Our data suggest that neonatal MG is due to maternal anti-AChR abs and that affected infants do not produce specific antibodies.     

我国华南地区MuSK抗体阳性重症肌无力患者的临床特点

目的分析我国华南地区骨骼肌特异性酪氨酸激酶抗体(MuSK-Ab)阳性重症肌无力(myasthenia gravis,MG)的临床特点。方法回顾性收集2017年8月至2019年8月在中山大学附属第一医院确诊的住院MuSK抗体阳性MG(MuSK-MG)患者26例,并选取同期收治的乙酰胆碱受体抗体(AChR-Ab)阳性MG(AChR-MG)患者157例作为对照组,比较两组患者临床特点以及对治疗反应的差异。结果与AChR-MG患者比较,MuSK-MG患者女性构成(80.8%比58.0%,P<0.05)、平均发病年龄〔(43.12±13.02)岁比(36.04±17.97)岁,P<0.05〕高,球部肌受累(96.2%比70.1%,P<0.01)和肌无力危象(myasthenic crisis,MC;61.4%比28.7%,P<0.05)更常见。两组患者新斯的明试验阳性率(61.5%比70.7%)、低频重复神经电刺激(RNS)阳性率(78.3%比83.3%)比较差异无统计学意义(均P>0.05)。在治疗反应方面,胆碱酯酶抑制剂(AChEIs)对MuSK-MG患者的有效率低于AChR-MG患者(16.0%比58.6%,P<0.01)。两组患者发生MC期间,对血浆置换(PLEX)的反应优于静脉注射丙种球蛋白(IVIG)。结论我国华南地区MuSK-MG以40岁左右女性多见,与AChR-MG比较易累及球部肌和呼吸肌,容易发生MC。MuSK-MG对AChEIs的反应性低于AChR-MG。RNS对我国华南地区MuSK-MG诊断的敏感性与AChR-MG比较无统计学差异,但高于欧美人群。PLEX在MuSK-MG患者的危象前或危象状态中的应用可显著缓解病情。     

Prognosis of thymectomy in myasthenia gravis patients with thymus hyperplasia

Purpose: To compare the post-thymectomy prognosis in different conditions of myasthenia gravis (MG) patients with thymus hyperplasia. Materials and methods: Collecting medical record and carrying out the follow-up study of 123 myasthenia gravis patients with thymus hyperplasia who have underwent thymectomy during the period between 2003 and 2013. Dividing into different groups based on gender, age of onset, duration of disease and Myasthenia Gravis Association of America (MGFA) clinical classification to analyze different prognosis in different groups. Results: Complete stable remission (CSR) was achieved in 71 of 123 patients (59.5%). There is no gender-related difference in achieving CSR. Patients with early onset of MG (≤40 years old) or disease duration less than 12 months had significantly higher CSR rates than those with late onset of MG (>40 years old) or disease duration more than 12 months respectively, while no difference was found in remission rate between MGFA clinical classification I and MGFA II. Conclusion: Myasthenia gravis patients with thymus hyperplasia who had thymectomy are proved to possess greater chance of achieving CSR. The onset age of disease and duration are the prognostic factors.     

Myasthenia gravis with muscle‐specific tyrosine kinase antibodies: A narrative review

Growing evidence provides new insights about myasthenia gravis (MG) with antibodies against muscle‐specific tyrosine kinase (MuSK‐MG), including its pathogenesis, clinical and electrophysiological manifestations, and treatment. Data now support the presence of both presynaptic and postsynaptic dysfunction in MuSK‐MG. This is 1 of many key differences between MuSK‐MG and acetylcholine receptor antibody‐MG (AChR‐MG), especially as it pertains to potential therapeutic implications. In comparison to AChR‐MG, MuSK‐MG is generally more refractory to treatment. However, because MuSK‐MG is better understood and more readily recognized today, there are more reports of a relatively benign course. The most effective immunotherapies for MuSK‐MG are corticosteroids, plasmapheresis, and rituximab. With appropriate therapy, most patients with MuSK‐MG achieve minimal manifestation status or better on the postintervention status outlined by the Myasthenia Gravis Foundation of America. A minority of patients remain refractory to treatment, and optimal management for this group remains a considerable challenge. Muscle Nerve 58 : 344–358, 2018     

雷诺丁受体抗体阳性的重症肌无力临床特点

雷诺丁受体（ryanodine receptor, RyR）是存在于内质网/肌质网中的一种重要钙离子通道,在骨骼肌兴奋收缩偶联机制中起重要作用。RyR抗体阳性的重症肌无力（myasthenia gravis, MG）患者常合并胸腺瘤,对常规治疗不敏感,会导致延误临床早期识别及治疗。血清RyR抗体水平与患者临床症状的严重程度显著相关。该文就4例RyR抗体阳性MG患者的临床特点及治疗过程进行讨论并文献复习,旨在提高对RyR抗体阳性MG的认识及诊疗水平。     

218例重症肌无力危象的临床分析

目的总结重症肌无力危象的临床特点及急救和预防经验.方法回顾性分析1956～2004年诊治的218例患者369例次重症肌无力危象的病例资料.结果死亡51例,病死率23.39%;近十年(1994～2004年)死亡4人,病死率4.2%.结论综合利用气管切开正压辅助呼吸、激素冲击治疗、丙种球蛋白静滴及血浆交换可改善重症肌无力危象的预后,且明显降低病死率.     

Widely varying TNF-α levels in patients with myasthenia gravis

Animal studies have indicated an important role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of myasthenia gravis (MG), and trials of monoclonal antibodies that block TNF-α have shown clinical improvement. However, before a TNF-α blocking agent is proposed for treatment of MG, whether serum TNF-α level correlates with the patient’s condition should be confirmed. Therefore, we evaluated the relationship between the serum TNF-α level and clinical factors, including the quantitative MG score and the anti-acetylcholine receptor antibody level, in 33 MG patients. TNF-α levels ranged from 0.44 to 3.63 pg/mL and did not correlate with clinical factors. Overall, we found that serum TNF-α levels varied greatly among MG patients.     

Clinical outcome and predictive factors of postoperative myasthenic crisis in 173 thymomatous myasthenia gravis patients

Purpose: Thymectomy is the first-line therapy for thymomatous myasthenia gravis patients. The aim of this study is to explore the clinical outcome and predictors of postoperative myasthenic crisis (POMC) in these patients.

Method: Clinical data of 173 thymomatous myasthenia gravis patients undergoing thymectomy from January 2000 to March 2013 were, retrospectively reviewed. Variables potentially affecting the occurrence of POMC were evaluated using binary logistic regression analysis. The difference in survival was determined by the log-rank test.

Result: Fifty-one patients experienced POMC. Univariate analysis revealed that events significantly associated with increased risk of POMC include symptom duration before operation >2.75months, preoperative bulbar symptoms, incomplete resection, operation time ≥122.5 min and advanced stages (stage III or IV). Multivariate logistic regression analysis showed that preoperative bulbar symptoms (OR = 3.207 [1.413–7.278]; P = 0.005) and incomplete resection (OR = 4.182 [1.332–13.135]; P = 0.014) were independent risk factors for POMC. Twenty-eight patients (16.9%) died during the follow-up. The log-rank test revealed survival for patients with POMC was significantly worse than that for patients without POMC (P = 0.042).

Conclusion: The important risk factors for developing POMC in thymomatous myasthenia gravis patients include the preoperative bulbar symptoms and incomplete resection of thymoma. Moreover, the patients with POMC had a worse prognosis compared with patients without POMC. Our study highlights the need of appropriate preoperative management of thymomatous myasthenia gravis patients to prevent the occurrence of POMC.