Comparison between double-filtration plasmapheresis and immunoadsorption plasmapheresis in the treatment of patients with myasthenia gravis

Two techniques for plasmapheresis are used in the treatment of myasthenia gravis (MG): immunoadsorption (IA) and double filtration (DR). This controlled study evaluated the differences between these techniques in clinical effects and serological changes. Five patients with generalized MG (clinical states IIb and III) were enrolled; each patient received IA and DF plasmapheresis on separate occasions. Immunosorba TR-350 with an affinity to acetylcholine receptor antibodies (AchRAb) was used for IA, while Evaflux 4A was used as the plasma fractionator for DF. Each course of treatment consisted of five sessions of apheresis. MG score, titers of AchRAb, immunoglobulins (IG), and plasma biochemistry were assessed by blinded examiners before and immediately after the entire course of treatment. Both treatments effectively ameliorated symptoms of MG. There were no significant changes in MG score between the two groups (IA vs. DF: 2.2 vs. 2.6, P>0.5). IA had a higher clearance rate of AchRAb than DF (66 % vs. 54 %, P<0.05), while DF removed more IgA (72 % vs. 21 %, P< 0.05) and IgM (89 % vs. 57 %, P<0.01) than did IA. Although IA removed AchRAb more effectively than DF, the clinical effects between these two treatments were similar. The titers of AchRAb cannot reflect the clinical severity. Some circulating factors other than AchRAb may contribute to the pathogenesis of MG. Received: 10 September 1999, Received in revised form: 7 February 2000, Accepted: 24 February 2000     

Double filtration plasmapheresis in myasthenia gravis - analysis of clinical efficacy and prognostic parameters

OBJECTIVES: The aim of this study was to evaluate the efficacy of double filtration plasmapheresis (DFP) in the treatment of patients with myasthenia gravis (MG) and to analyze the possible prognostic factors related to responsiveness to DFP. MATERIALS AND METHODS: We treated 45 MG patients, 26 women and 19 men aged 21-72 years, with DFP for 5 consecutive sessions. All were affected by severe generalized or respiratory weakness with an Osserman's classification of group 2 or 3 and had not responded to previous treatments. RESULTS: Thirty-eight out of 45 patients (84%) achieved significant improvements after DFP. The baseline MG score and removal rate for immunoglobulin G (IgG) were significantly higher in the patients with good response than in the other response groups. Poor responders were more likely to have thymoma and a longer interval among sessions of DFP. Better response in patients with age at onset of less than 40 years was associated with higher MG score. Serum concentration of all proteins tested fell as follows (mean +/- SD): IgM, 88+/-7%; IgA, 71+/-11%; IgG, 59+/-14%; globulin, 52+/-11%; AchRAb, 47+/-14%; and albumin, 27+/-10%. All the patients tolerated plasmapheresis well except for 2.2% who experienced hypotension. CONCLUSION: In this study, DFP was effective and safe in the treatment of patients with severe generalized MG. The factors correlating with the better clinical response were high MG score, a thymic pathology of non-thymoma, daily apheresis, young age at onset, and high removal rate for IgG.     

Changes in serum cytokine levels during plasmapheresis in patients with myasthenia gravis

Background: The effect of plasmapheresis on cytokine levels in patients with myasthenia gravis (MG) has not been well established. Methods: Cytokine levels were measured in 19 patients with MG before and after treatment with one course of double‐filtration plasmapheresis (DFP). The control group comprised 6 age‐ and sex‐matched healthy volunteers. Results: At baseline, patients with MG had higher levels of IL‐10 than normal controls. The levels of IL‐2, IL‐4, IL‐5, and tumor necrosis factor‐α were almost undetectable in MG patients. After a single session of DFP treatment, IL‐10 levels were significantly increased. After three sessions, IL‐10 levels were still higher than those at baseline. Elevated IL‐10 level was significantly associated with use of immunosuppressant drugs, thymectomy, and good response to DFP treatment. Conclusions: Interleukin‐10 might play a crucial role in the pathogenesis and perpetuation of MG.     

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。     

CD4CD25 regulatory T cell in childhood ocular myasthenia gravis

Dysfunction of CD4⁺CD25⁺ regulatory T cell (Treg) has been demonstrated to play an important role in the development of autoimmune myasthenia gravis. This T cell subset, which has potent regulatory properties against immune response, has been reported to have a numerical or functional defect in patients with myasthenia gravis. We examined various T cell subsets, including CD4⁺CD25⁺Treg in peripheral blood mononuclear cells using flow cytometry in a pediatric patient suffering from ocular myasthenia gravis. Contrary to previous reports, the percentage of CD4⁺CD25⁺Treg in peripheral blood decreased significantly after successful treatment with prednisolone. This discrepancy could result from diversity within the immunopathogenesis of myasthenia gravis and may underpin a particular subgroup of myasthenia gravis seen in the East-Asian pediatric population.     

免疫抑制剂对重症肌无力病人T淋巴细胞亚型的影响

目的观察重症肌无力(MG)病人细胞免疫的异常改变和免疫抑制剂对重症肌无力(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60例MG病人的病情严重程度和免疫抑制治疗2个月后的临床疗效;采用直接免疫荧光染色和流式细胞仪技术测定60例病人和60名志愿健康者周围血中T淋巴细胞亚型的百分率,并测定糖皮质激素或环磷酰胺免疫抑制治疗前及治疗后2个月T淋巴细胞亚型的变化。结果未治疗MG组外周血中CD8 T淋巴细胞的百分率较正常对照组显著下降(P<0.01);CD4 T淋巴细胞的百分率和CD4 /CD8 T细胞的比例较正常对照组均显著升高(P<0.01)。经激素或环磷酰胺治疗2个月后MG组随着临床症状的改善,外周血中总T细胞(CD3 )和CD8的百分率较治疗前均显著升高(P<0.01;P<0.05);CD4 T淋巴细胞的百分率和CD4 /CD8 T细胞的比例较治疗前均显著下降(P<0.01)。结论MG病人有T淋巴细胞亚型的变化,免疫抑制治疗对T淋巴细胞亚群有明显影响,提示T淋巴细胞亚型的测定可为激素、环磷酰胺等免疫疗法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。     

Double seronegative myasthenia gravis with anti-LRP 4 antibodies

About 10% of patients with generalized myasthenia gravis do not have detectable antibodies to acetylcholine receptor or muscle specific kinase (double seronegative myasthenia). The presence of anti-low density lipoprotein receptor-related protein 4 antibodies (LRP4 Abs) has recently been reported in variable proportion of double seronegative cases. We report the presenting characteristics of two double seronegative myasthenic patients from Greece with anti-LRP4 antibodies shortly after disease onset. The first patient, a 52-year-old male, presented with a one month history of isolated neck extensor weakness; the second patient is a 52-year-old female with three months history of ocular–bulbar-cervical myasthenic weakness. Both patients presented with mild severity and responded promptly and adequately to pyridostigmine. In the female patient thymic residual tissue was detected on CT of the mediastinum. She underwent thymectomy, and histological examination revealed follicular hyperplasia. This is the first clinical report of the presenting features of newly diagnosed myasthenia with anti-LRP4 antibodies. The clinical and therapeutic implications of the anti-LRP4 antibody positivity remain to be clarified.     

女性重症肌无力1316例临床特点分析

目的　研究女性重症肌无力 (MG)的临床特点及某些实验室指标。方法　回顾性分析1984～ 2 0 0 2年我院诊治的 1316例女性MG患者的临床资料 ,检测乙酰胆碱受体抗体和血清性激素水平 ,并与同期诊治的男性MG患者进行对比分析。结果　MG患者男女比例基本相同 (1∶1 0 1) ,但不同年龄段男女患者比例差异有显著意义 ;延髓肌型MG虽少见 ,但女性 (6 0例 )患者明显多于男性 (35例 ,P <0 0 5 ) ;女性MG患者病情加重或者发生危象存在特殊诱因 ;女性MG患者伴胸腺瘤者较男性低 ;女性MG患者合并其他自身免疫性疾病者更多 ;MG患者存在性激素水平异常 ,女性较男性为甚。结论　我国女性MG的临床特点与男性MG相比有其独特之处 ,充分认识这些特点将有利于指导临床的诊断和治疗。     

插指状细胞在重症肌无力患者非瘤性胸腺内的变化

探讨胸腺内插指状细胞（ＩＤＣ）在重症肌无力（ＭＧ）发病中的作用。方法采用Ｓ－１００蛋白抗体用免疫组织化学方法对３０例ＭＧ患者非瘤性胸腺内Ｓ－１００蛋白阳性ＩＤＣ的分布和数量观察研究。同时取１０例不同年龄的正常胸腺作对照。结果ＭＧ非瘤性胸腺内ＩＤＣ数目明显增多（Ｐ＜０．０５），且ＩＤＣ数目的多少和胸腺髓质上皮细胞的增生程度呈正相关。结论ＩＤＣ可能参与ＭＧ的发病，胸腺髓质内增生的上皮细胞在ＭＧ自身免疫过程中起一定作用。     

Inhibition of peripheral blood natural killer cell cytotoxicity in patients with myasthenia gravis treated with plasmapheresis

Background and purpose: Myasthenia gravis (MG) is an autoimmune disorder that may involve natural killer (NK) cells. Although NK cells are part of the innate immune system, they also influence adaptive immune responses. Double‐filtration plasmapheresis (DFP) is an effective therapy for MG crisis. Thus, we examined the effects of DFP on the cytotoxicity of NK cells. Methods: A total of 20 patients with MG and 16 healthy controls were recruited for the study. Ficoll‐Paque‐isolated peripheral blood mononuclear cells (PBMCs) and K562 cells were used as the effector and target cells, respectively. NK cell cytotoxicity was analyzed using flow cytometry immediately before and after DFP and upon course completion. Results: Double‐filtration plasmapheresis treatment decreased significantly the NK cell cytotoxicity in patients with MG, especially in good responders, those who were positive for acetylcholine receptor (AChR) antibodies, and those receiving immunosuppressants. Conclusions: The decrease in NK cell cytotoxicity after DFP and the decline of AChR antibody titer were observed in good responders indicating that this could benefit patients with MG.     

重症肌无力患者胸腺肥大细胞的形态数量和超微结构研究

为探讨研究重症肌无力（ＭＧ）患者胸腺内肥大细胞的形态数量和其超微结构变化与ＭＧ发病的关系。方法对２８例ＭＧ患者作胸腺肥大细胞的形态半定量分析和光镜观察，其中１６例的胸腺进行电镜检查。结果ＭＧ胸腺不仅表现组织学异常，且肥大细胞数量明显增多，尤其是在非增生胸腺内出现大量肥大细胞，而在增生的髓质和生发中心区几乎见不到。电镜观察提示肥大细胞与上皮细胞、Ｔ淋巴细胞和毛细血管关系密切，且含多种形态的分泌颗粒。结论肥大细胞对胸腺细胞的分化成熟、胸腺屏障和胸腺功能，以及ＭＧ发病均起到一定的重要作用。     

Outcome of plasmapheresis in myasthenia gravis: delayed therapy is not favorable

Introduction: The purpose of this study was to compare the in‐hospital mortality and complication rates after early and delayed initiation of plasma exchange (PLEX) in patients with myasthenia gravis (MG). Methods: Our cohort was identified from the Nationwide Inpatient Sample database for the years 2000 through 2005. Early treatment was defined as therapy with PLEX administered within the first 2 days from hospital admission. Univariate and multivariate analyses were employed. Results: One thousand fifty‐three patients were treated and included in the analysis. A delay in receiving PLEX was associated with higher mortality (6.56% vs. 1.15%, P < 0.001) and increased complications (29.51% vs. 15.29%, P < 0.001). Adjusted analysis showed increased mortality [odds ratio (OR) 2.812; 95% confidence interval (CI) 1.119–7.069] and complications (OR 1.672; 95% CI 1.118–2.501) with delayed PLEX therapy. Conclusions: Delaying PLEX therapy for MG by more than 2 days after admission may lead to higher mortality and complication rates, and thus prompt therapy is warranted. Muscle Nerve 43: 578–584, 2011     

重症肌无力T细胞受体基因重排的检测及其临床意义

目的胸腺病变情况与重症肌无力患者的治疗及预后密切相关，为了能早期诊断胸腺瘤。方法用Ｓｏｕｔｈｅｒｎ杂交，分别以ＴＣＲ－α、β及γ为探针检测了一组重症肌力无力患者Ｔ细胞受体（ＴＣＲ）基因重排。结果６例患者ＤＮＡ经ＥｃｏＲＩ酶切，与ＴＣＲ－α、β探针杂交时有一条异常的重排带。这６例患者已４例经手术证实为胸腺肿瘤。结论ＴＣＲ基因重排可能为早期诊断胸腺瘤提供帮助。     

重症肌无力患者外周血T淋巴细胞亚群凋亡的研究

目的探讨外周血T淋巴细胞亚群凋亡在重症肌无力(MG)免疫发病机制中的作用及临床意义。方法采用流式细胞术结合免疫荧光抗体法测定了45例MG患者和40例正常对照组外周血CD4~ T淋巴细胞、CD8~ T淋巴细胞百分数及其凋亡状况,并对24例MG患者在应用糖皮质激素治疗后外周血T淋巴细胞亚群凋亡状况进行了观察。结果MG患者组外周血CD8~ T淋巴细胞百分率较正常对照组明显降低,CD4~ /CD8~ 比值较正常对照组明显升高：MG患者组外周血CD4~ T淋巴细胞凋亡程度较正常对照组明显降低；MG患者外周血CD4~ T淋巴细胞凋亡程度与MG类型、预后密切相关：应用糖皮质激素治疗后MG患者外周血CD4~ T淋巴细胞凋亡程度明显增强。结论MG患者存在T淋巴细胞亚群的分布异常及CD4~ T淋巴细胞凋亡功能障碍,其凋亡程度可能与MG类型、预后密切相关,糖皮质激素对MG患者外周血CD4~ T淋巴细胞凋亡缺陷具有纠正作用。     

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.     

儿童重症肌无力伴甲状腺功能亢进88例临床分析

目的研究儿童重症肌无力(MG)伴甲状腺功能亢进症(甲亢)的临床特点及治疗.方法对88例儿童MG伴甲亢患者的临床资料和治疗方法进行回顾性研究,并与同时期成人MG伴甲亢患者进行比较.结果男性35例,女性53例;就诊时MG患者Ⅰ型72例,ⅡA型8例,ⅡB型6例,Ⅳ型2例;先有甲亢后有MG18例,先有MG后有甲亢34例,MG和甲亢同时发生36例;合并癫痫6例,伴胸腺增生16例;经过治疗60.23%的患者痊愈,7.95%的患者无效.结论儿童与成年人MG合并甲亢患者在性别上发病无统计学差异,而临床类型分布不同,儿童组以Ⅰ型多见;两种疾病的发生顺序不同,儿童先发生甲亢者较少,成人组先发生甲亢者多见.儿童MG伴甲亢患者的临床表现复杂,诊断较难,容易误诊和漏诊,提高对本病的认识是改善预后的关键.     

The thymus in seronegative myasthenia gravis patients

Summary In 5–10% of all patients with typical generalised myasthenia gravis (MG), serum antibody to the acetylcholine receptor (AChR) is undetectable. To determine whether these represent a distinct subgroup, we have compared the thymuses of 14 seronegatives, 70 seropositives and 12 non-myasthenic controls. By quantitative immunohistology on coded sections, the 7 seronegative samples were clearly distinguishable from the controls by the pronounced lymph node-type T-cell areas in the medulla. While these closely resembled those in the seropositive cases, germinal centres were significantly sparser, and total in vitro IgG production was disproportionately low (per B cell) in the 12 cases tested. Furthermore, specific anti-AChR production was never detected in any of these cultures. The data support the view that the medullary T-cell areas are the most consistent abnormalitiy in the MG thymus (though it may not be primary), and they strongly imply that seronegative and seropositive MG are distinct entities.     

伴其他自身免疫性疾病的重症肌无力临床特点分析

目的分析伴其他自身免疫性疾病的重症肌无力患者之临床特点、药物疗效、预后和转归。方法共83例重症肌无力患者,分为伴其他自身免疫性疾病重症肌无力(AIDMG)组(24例)和不伴其他自身免疫性疾病重症肌无力(NAIDMG)组(59例),比较两组患者性别、发病年龄、首发症状、胸腺异常等临床特点、不同治疗措施之疗效和预后。结果两组患者性别(χ2=8.467,P=0.004)、眼睑下垂侧别(χ2=9.830,P=0.007)、发病2年内病程情况(χ2=15.255,P=0.001)差异具有统计学意义,而发病年龄(χ2=1.728,P=0.228)、首发症状(χ2=0.252,P=0.791)、胸腺异常(χ2=3.200,P=0.202)组间差异无统计学意义。两组患者溴吡斯的明(χ2=0.411,P=0.395)、糖皮质激素(χ2=0.156,P=0.513)、静脉注射免疫球蛋白(χ2=0.359,P=0.462)、免疫抑制剂(χ2=0.081,P=0.526)、胸腺切除术(χ2=0.337,P=0.391)等治疗措施之疗效,以及眼肌型重症肌无力进展为全身型重症肌无力比例(χ2=1.826,P=0.148)、进展时间(Fisher确切概率法:P=0.639)、首发症状(Fisher确切概率法:P=0.196)和复发时间(Fisher确切概率法:P=1.000)差异均无统计学意义。结论 AIDMG患者多见于女性,首发症状为眼睑下垂,以双侧同时受累为主;发病2年内较NAIDMG患者更易复发。     

重症肌无力患者血清Titin抗体的研究

目的探讨重症肌无力患者血清titin抗体检测的临床意义,并了解其对预后判断的价值。方法应用酶联免疫吸附法检测80例MG患者、30例其他神经系统疾病患者及30例健康对照者血清titin抗体水平,并对比胸腺手术前后变化。结果 MG组、MG伴胸腺瘤(MGT)组、晚发型MG患者、其他神经系统疾病组titin-Ab阳性率分别为42.5%、77.3%、77.8%、3.3%,健康对照者titin-Ab均为阴性;对其中54例进行胸腺手术的MG患者手术前后titin-Ab滴度下降,差异具有显著性(P0.05)。结论 titin-Ab阳性多见于晚发型MG、MGT,特别是B型胸腺瘤患者,血清titin-Ab检测可作为MG诊断的参考指标,尤其对MG伴胸腺瘤患者可能更具有临床意义,对胸腺手术预后判断有一定帮助。     

Dropped head as an unusual presenting sign of myasthenia gravis

Abstract Prominent or isolated weakness of cervical extensor muscles is a relatively rare clinical sign. Commonly, this is known as “dropped-head syndrome”. This abnormal flexion of the head may occur in a variety of neuromuscular diseases and in a few non-neurological disorders as well. The case we describe concerns a 61-year-old woman with dropped-head syndrome as the unique complaint of myasthenia gravis.