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.     

血浆置换治疗在重症肌无力患者中的应用--附57例临床疗效分析

目的确定血浆置换（ＰＰ）治疗重症肌无力（ＭＧ）的起效时间、疗效,评价其疗效是否与降低血中乙酰胆碱受体抗体（ＡＣｈＲＡｂ）有关。方法ＰＰ第１周隔日１次,共３次,以后每周１次。用健康人血浆及血浆代用品进行ＰＰ,一般每次２０００ｍＬ（即７０６代血浆５００ｍＬ,血浆１５００ｍＬ）,置换当日及置换后每日于固定时间根据临床绝对记分法进行评分,同时每日晨取血查ＡＣｈＲＡｂ。结果痊愈、基本痊愈、显效、好转和无效分别为１、４、２３、２２和６例,总有效率８９．４７％。共有３５人、５２次在置换中出现不同程度副作用,包括口周麻木、四肢麻木、荨麻疹、寒战、发热和低血压等,经对症处理后好转。结论ＰＰ起效迅速,在肌无力危象抢救中有重要价值,但单独使用疗效不持久,应用得当可减少副作用。     

Plasma exchange in myasthenia gravis: effect on anti-AChR antibodies and other autoantibodies

Plasma exchange (PE) was performed in 6 patients with myasthenia gravis (MG). Acetylcholine receptor (AChR) antibodies and other MG-correlated antibodies were quantified each day before, during and after PE. The antibody concentrations decreased during PE with a consisting increase between two exchanges. Repeated PE induced a transient decline in the AChR antibody concentration. The clinical improvement was maximal during the week after PE and correlated in time with increasing concentrations of AChR antibodies.     

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.     

Intravenous immunoglobulin in the preparation of thymectomy for myasthenia gravis

OBJECTIVES: A clinical trial including six patients was conducted to assess the effect of intravenous immunoglobulin (IVIg) in the preparation of thymectomy for patients with myasthenia gravis (MG). MATERIAL AND METHODS: Six consecutive patients of type IIB MG treated with IVIg at a dose 0.4 g/kg daily for 5 days before thymectomy were enrolled in this study. RESULTS: All patients responded positively to this treatment. Improvement began to occur 1-9 days after starting the injection (mean 3.33 days), and reached a maximum in 3-19 days (mean 6.50 days). Thymectomy was performed 9-13 days (mean 11.20 days) after starting the injection in five of the six patients with uneventful post-operative courses. CONCLUSION: IVIg might be an alternative to plasmapheresis (PE) in the prethymectomy preparation of MG patients, and thymectomy should be performed within 2 weeks after IVIg treatment to minimize the perioperative complications. Controlled trial vs PE enrolling more patients is needed to assess the significance of the IVIg in the preparation of thymectomy for patients of MG.     

Plasmapheresis combined with lymphocytapheresis and cytotoxic drugs as a therapeutic modality in neuroimmunological diseases

Rebound after plasmapheresis is thought to be due to enhanced antibody and/or immune complex production. To prevent rebound a combination of steroids and immunosuppressive drugs has been used: lymphocytapheresis was employed in most patients, for not more than 10 sessions. 50 patients with myasthenia gravis, inflammatory myopathy, chronic dysimmune polyneuropathy and immune complex polyneuropathy have been treated and longlasting benefits obtained in 35 patients. Rebound effects were observed only when cytotoxic drugs were not given or discontinued too soon. 8 patients who had been treated by plasmapheresis combined with steroids alone, after some recurrences of their disease, were switched to cytotoxic drugs, steroids and lymphocytapheresis combined with plasma exchange: in this group 7 patients eventually gained long lasting remissions. Our clinical experience strongly supports the hypothesis of a synergy between plasmapheresis and immunosuppressive measures.

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Sommario Si ritiene che il possibile effetto rebound che consegue alla plasmaferesi sia dovuto all'incremento di anticorpi e/o di immuno-complessi. Per prevenire tale effetto si utilizzano farmaci steroidei e immunosopressori; la linfocitoaferesi è stata applicata in diversi pazienti, ma per non più di 10 sedute. Gli AA. hanno trattato 50 pazienti affetti da miastenia, polimiosite, polineuropatie croniche disimmuni e polineuropatie da immuno-complessi con buoni risultati a distanza in 35 casi; un effetto rebound è stato osservato soltanto nei casi in cui non era stato instaurato o era stato interrotto inopportunamente un trattamento immunosoppressivo. In 8 pazienti che erano stati trattati con plasmaferesi associata a soli farmaci steroidei, dopo alcune recidive sintomatologiche della malattia, è stato instaurato uno schema terapeutico che prevedeva cortisonici, immunosopressori e linfocitoaferesi associati alla plasmaferesi: in 7 casi sono state così ottenute delle remissioni di lunga durata. Sulla scorta di tale esperienza clinica si ritiene fondata l'ipotesi di un sinergismo tra plasmaferesi e trattamento immunosoppressivo.

     

Plasma exchange in myasthenia gravis: clinical effect

Seventeen patients suffering from myasthenia gravis were treated with plasma exchange. Serious complications were not encountered. The effect usually appeared on the second or the third day of treatment. In 12 patients with a total of 31 plasma exchange courses, the treatment resulted in a shift in Osserman group. Six of these had long-standing remissions. Three patients responded moderately and two patients did not respond to plasma exchange.     

Plasma exchange in myasthenia gravis: changes in serum complement and immunoglobulins

Serum concentrations of C4, IgG, IgA, and IgM were followed in 8 selected patients with myasthenia gravis (MG) during a 5-day course of plasma exchange (PE), using donor plasma as a replacement solution. C3 activation products (C3b, iC3b and C3c) and the terminal SC5b-9 complement complex were measured in 4 of the patients. All patients improved during the treatment, including 2 patients without detectable antibodies to AChR in serum. The main findings of the study were marked complement activation and an approximately 50% fall in the serum concentrations of IgM and C4 during PE, independent of the concentrations in the donor plasma. The concentrations of IgG and IgA did not change significantly. The fall in C4 during PE is presumably caused by C4 consumption. We postulate that the fall in IgM is an effect of a complement-induced vasodilatation and that PE-induced complement consumption may influence the effect of PE in patients with MG.     

静脉注射免疫球蛋白与血浆置换治疗重症肌无力的meta分析

目的系统评价静脉注射免疫球蛋白(IVIg)与血浆置换(PLEX)治疗重症肌无力(MG)的有效性和安全性。方法计算机检索Cochrane图书馆、Pubmed、Embase、CNKI及万方数据库,系统收集国内外有关这两种方式治疗MG的相关文献。按系统评价的方法,由2名研究员独立对文献进行质量评价和资料提取后,采用Rev Man 5.2软件进行Meta分析。结果共纳入9篇文献,合计2132例MG患者。Meta分析结果显示,IVIG与PLEX治疗MG的有效性无明显差异[OR=0.94,95%CI(0.57,1.32),P=0.79];IVIg与PLEX的治疗相关不良反应发生率也无明显差异[OR=0.91,95%CI(-0.37,2.21),P=0.83]。结论 IVIG与PLEX对MG的治疗效果以及治疗相关的不良反应发生率均无明显差异,因此,临床上可根据具体情况选择合适的治疗方式。     

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.     

Clinical profile and outcome of myasthenic crisis in a tertiary care hospital: A prospective study

Background:

The present understanding of the clinical course, complications, and outcome of myasthenic crisis (MC) is based chiefly on observational studies and retrospective case series.

Aim:

To study the baseline demographic and clinical variables, risk factors, complications, outcome, and mortality in patients of MC.

Materials and Methods:

All patients of myasthenia gravis (MG) who presented with myasthenic crisis between July 2009 and December 2010 were included.

Results:

Ten patients of MC were included in this study. The median age of the patients was 40.5 years (range 14-71 years). Seven were females and three were males. Nine had generalized MG and one patient had oculobulbar involvement only. Median duration of disease was 3 years (range 1 month to17 years). Two patients had thymoma. Two patients had history of thymectomy in the past. Infection was the most common triggering factor accounting for five cases (50%) followed by inadequate treatment/drug withdrawal in three (30%) and steroid initiation and hypokalemia in the remaining two patients (20%). Median duration of MC was 12 days (range 3-28 days). Mortality was in 3 out of 10 (30%) during MC. Management in the intensive care unit (ICU) and treatment with plasma exchange/intravenous immunoglobulins were associated with good outcome.

Conclusions:

Ventilator support and management in intensive care unit are the most important components in the management of MC. The high mortality rate seen in present study may be more reflective of the actual ground reality in resource constrained developing countries, however, larger prospective studies are needed to confirm these findings.     

Epidemiological and clinical characteristics of myasthenia gravis in Belgrade, Yugoslavia (1983–1992)

This is the first epidemiological study of myasthenia gravis (MG) in the area of Belgrade. During the survey period (1983 1992), 124 incidental cases of MG were observed, producing an average annual incidence rate of 7.1 per million population (women, 8.3; men, 5.8). Age and sex specific incidence rates for females demonstrated a bimodal pattern, with the first peak in the age group between 20 and 40, and the second peak in the age group 70-80. The age-specific rates for males showed unimodal pattern, reaching a maximum in the age group between 60 and 80. There was a tendency of more frequent disease appearance in the urban as opposed to the suburban districts. On the prevalence day, December 31, 1992, the point prevalence rate was 121.5 per million (women, 142.5; men, 98.8). Only for incidental cases, the point prevalence rate was 77.1 (women, 83.2; men, 70.4). The average annual mortality rate was 0.47 per million (females, 0.52; males, 0.42), while cumulative lethality was 5.6 (women, 5.6; men, 5.7). Most frequently initial symptoms were ocular, occurring in 58% patients. Through the period of investigation ocular symptoms were generalized in 68%, most frequently in the first 2 years (62.5%). Thymoma was confirmed in 11.3% of patients. In this group there was equal presence of both sexes, older median age at onset, and more severe clinical course of MG. Associated autoimmune disease was found in 17 out of 124 incidental cases (13.7%). The most common were thyroid diseases (7.3%). Family history of MG was recorded in 2 cases belonging to 1 family (1.6%).     

Predicting the course of myasthenic weakness following double filtration plasmapheresis

OBJECTIVE: To evaluate the clinical course of patients with myasthenia gravis (MG) up to 3 months after double filtration plasmapheresis (DFP). MATERIAL AND METHODS: We recorded the MG score and measured the level of acetylcholine receptor antibody (AchRAb) at baseline and day 1 (D1), week 1 (W1), 1 month (M1), 2 (M2) and 3 months (M3) after DFP in 16 MG patients. Based on the difference in score during follow-up, we divided our patients into clinical improvement (CI) and clinical worsening (CW) groups. RESULTS: The MG score decreased in all courses from a mean of 8.1 at baseline to 5.6 at D1, and to 4.7, 4.0, 3.8, and 3.7 at W1, M1, M2, and M3, respectively. In the CW group, AchRAb levels were significantly higher at M1 (P = 0.022). The AchRAb level at W1 correlated significantly with the MG score at M3 (P = 0.027) and the changes of MG score from W1 to M1 (P = 0.029). The ratio of AchRAb levels of M1 to W1 correlated well with MG score at W1 (P = 0.032), at M3 (P = 0.001), and the changes of MG score from W1 to M1 (P = 0.004). CONCLUSION: Excessive rebounds of AchRAb level at W1 may suggest clinical worsening and further increases in AchRAb level at M1 predict poorer outcome after DFP.     

Recovery from global amnesia during plasma exchange in myasthenia gravis: report of a case

A 47-year old thymectomized woman with myasthenia gravis, receiving prednisone therapy, developed amnesia for recent events during a benign acute febrile illness. Plasma exchange was performed 9 months later, and was followed by a dramatic improvement of the mnemonic dysfunction.     

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.     

非胸腺瘤性眼外肌麻痹起病重症肌无力胸腺切除时机探讨

目的比较非胸腺瘤性眼外肌麻痹起病重症肌无力(ocular onset myasthenia gravis,OMG-O)患者于不同病程行胸腺切除后病情缓解与向全身型重症肌无力(GMG)转化的差异,以期对手术时机进行探讨。方法采用双向队列研究方法,对作者医院2005年1月至2017年9月因药物治疗效果不佳而行胸腺切除的86例OMG-O患者,按起病至手术时间间隔分为早手术组(≤1年)、晚手术组(>1年),比较两组患者不同随访时间理想状态(干预后状态达到轻微异常及更好)率、GMG转化率的差异。结果 (1)与早手术组比较,晚手术组少年MG(<18岁)比例较高,起病至手术时间间隔、起病至使用激素时间间隔、激素用药时间较长(均P <0.05)。(2)与晚手术组比较,早手术组术后第3年理想状态率高(P=0.029),而第2、4~8年理想状态率有升高趋势,但差异无统计学意义(P>0.05)。(3)9例术后发生GMG转化,起病至发生GMG转化时间中位数17.8个月,其中6例(66.7%)在3年内发生GMG转化。早手术组与晚手术组间GMG转化率比较,差异无统计学意义(12.5%比8.7%;χ~2=0.049,P=0.825)。结论对于药物治疗无效或不耐受的OMG-O患者,早期行胸腺切除手术疗效较好;但即使手术,仍有可能发生GMG转化,约1/2患者于起病后1.5年内发生,约2/3于起病后3年内发生。