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.     

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.     

Double filtration plasmapheresis benefits myasthenia gravis patients through an immunomodulatory action

Double filtration plasmapheresis (DFPP) is used to treat myasthenia gravis (MG). However, the definite mechanism is unclear. This study investigated whether DFPP improves MG through an immunomodulatory action. Thirty-five MG patients were randomly divided into two treatment groups: Group A (DFPP combined with oral methylprednisolone) and Group B (oral methylprednisolone alone). Their antibody levels, clinical scores, cytokine levels, and CD4⁺CD25^highFoxp3⁺ (regulatory T cell [Treg]) levels were then determined. Anti-titin antibody levels were significantly lower in Group A compared with Group B after treatment. The clinical remission rate in Group A was significantly higher than in Group B. The changes in cytokine levels (interleukin [IL]-2, IL-4, IL-10, and interferon-γ) in sera and the peripheral blood mononuclear cell culture supernatants did not significantly differ before and after the treatments in both groups (p < 0.05). The soluble intercellular adhesion molecule-1 (sICAM-1) levels were lower in Group A than in Group B (p < 0.05). MG patients exhibited a lower percentage of Treg cells than normal patients. DFPP combined with methylprednisolone treatment increased the Treg cell percentage more than treatment with methylprednisolone alone (p < 0.05). DFPP treatment more effectively lowers sICAM-1 and increases Treg cell expression, consequently benefiting MG patients.     

Plasmapheresis in myasthenia gravis. A comparative study of daily versus alternately daily schedule

OBJECTIVES: The aim of this study was to compare the efficacy of different protocols of plasmapheresis in the treatment of myasthenia gravis (MG). MATERIALS AND METHODS: We treated 30 MG patients with plasmapheresis on either a daily or alternately daily schedule for 5 consecutive sessions. Acetylcholine receptor antibody (AchRAb), serum proteins including albumin, globulin, immunoglobulin G (IgG), IgA, and IgM, and MG score were measured before and after the course of plasmapheresis in each group of patients. RESULTS: The mean percent reductions of serum proteins including IgA (81.5% vs 69.7%), IgM (95.6% vs 87.1%), and globulin (63.2% vs 50.1%) were significantly higher in the daily group. There were no significant differences in AchRAb and IgG levels after treatment between these 2 groups. However, the reduction of MG score was greater in the daily group. All the patients tolerated plasmapheresis well except for 2.7% of them who experienced hypotension. CONCLUSION: Our results suggest that daily plasmapheresis may be more effective in the treatment of patients with advanced MG.     

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     

Psychosocial aspects in myasthenic patients treated by plasmapheresis

Knowledge about the postintervention psychosocial status of myasthenia gravis (MG) is limited and based on questionnaire studies. In this study, the effects of improvement in muscle strength with plasmapheresis treatment on both quality of life (QoL) and psychological status of MG patients were studied. Between January 2008 and December 2009, 29 MG patients were enrolled to receive one course of plasmapheresis treatment. Differences in baseline and posttherapy clinical, laboratory, and psychosocial measures were determined. The mean MG score decreased from 7.8 points at baseline to 4.2 after plasmapheresis, accompanied by the mean antibody clearance of 56%. Psychosocial tests showed significant pre- and posttherapy differences in illness identity (mean scores 23.62 and 20.79 points, respectively) and disability (mean scores 11.28 and 7.63 points, respectively) (p < 0.01). No significant differences were found for the other indices. Although both anxiety and depression scores did not differ significantly, there was a clear change in patients, as evidenced by their decreases in severity after treatment. The mean mental components scores of QoL were still less than 40 after treatment, indicating that myasthenic patients need assistance in adapting to their disease. Thus, although plasmapheresis treatment achieved immediate improvement of myasthenic symptoms, reduced disability, and better illness identity, both emotional status and QoL did not differ significantly after intervention. Systematical evaluation for patients’ illness perceptions and emotional problems are warranted and related strategies should be taken for long-term stabilization of psychosocial function.     

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.     

Predictors of response to immunomodulation in patients with myasthenia gravis

Introduction: Factors determining response to intravenous immunoglobulin (IVIg) and plasmapheresis in myasthenia gravis (MG) have not been evaluated systematically. Methods: This study included patients treated with IVIg (n = 63) or plasmapheresis (n = 42) from two trials evaluating IVIg vs. placebo or plasmapheresis in MG. Response was defined as improvement in the quantitative myasthenia gravis score (QMGS) of ≥3.5 points at day 14. Baseline clinical, electrophysiological, and immunological factors were analyzed as predictors. Results: Baseline QMGS, acetylcholine receptor antibody (AChRAb) positivity, single‐fiber electromyography (SFEMG) jitter, and percent abnormal pairs and percent blocking pairs were higher in responders than in non‐responders. Using multivariate logistic regression, the odds ratio for response was 13.0 (1.01–381.5) in QMGS 11–17 and 15.3 (1.34–414.3) in QMGS >17 compared with QMGS <11. Conclusions: Baseline QMGS, AChRAb positivity, and SFEMG parameters were more abnormal in patients who responded to treatment. Using multivariate regression, baseline QMGS remained as the only significant independent predictor of response. Muscle Nerve, 2012     

Burden of illness in patients with treatment refractory myasthenia gravis

Introduction: This study assessed the clinical burden of refractory myasthenia gravis (MG), relative to nonrefractory MG. Methods: Rates of myasthenic crises, exacerbations, inpatient hospitalizations, and emergency room (ER) visits over a 1‐year period were measured for 403 refractory, 3,811 nonrefractory, and 403 non‐MG control patients from two administrative health plan databases. Results: Compared with nonrefractory patients, a significantly greater percentage of refractory patients had at least one myasthenic crisis (21.3% vs. 6.1%; P < 0.001) and at least one exacerbation (71.2% vs. 32.4%; P < 0.001) over a 1‐year period. Refractory patients were also significantly more likely to be hospitalized and/or have an ER visit than nonrefractory patients and non‐MG controls (P < 0.001 for all). Discussion: Refractory MG patients have significantly greater clinical burden and are more likely to utilize intensive healthcare resources than nonrefractory patients. Furthermore, refractory patients may be at greater risk of crises throughout the disease course than previous studies have suggested. Muscle Nerve 58 : 99–105, 2018     

Prevalence and clinical aspects of immigrants with myasthenia gravis in northern Europe

Introduction: Multiethnic studies can provide etiological clues toward the genetic and environmental influence of a disease. The aim of this study was to determine prevalence and clinical features of myasthenia gravis (MG) in immigrants compared with native patients in 2 population‐based cohorts. Methods: This cross‐sectional study included 843 MG patients (375 from Norway and 468 from the Netherlands). Ethnic background was defined by questionnaires. Results: Among the participating MG patients, 163 of 843 (19.3%) were first or second generation immigrants, mainly from Europe, Asia, and South America. No marked prevalence differences were found between immigrants and native ethnic groups. MG with muscle specific kinase antibodies and MG with thymoma were more frequent in Asian MG immigrants compared with other ethnic groups (8% vs. 0–4%; P < 0.001 and 21% vs. 6–10%; P < 0.001), respectively. Conclusions: Our findings indicate that Asian immigrant MG patients carry genetic factors or environmental/lifestyle factors which contribute to their specific phenotype, even after migration. Muscle Nerve 55 : 819–827, 2017     

Double filtration plasmapheresis in the treatment of myasthenic crisis--analysis of prognostic factors and efficacy

OBJECTIVES: To examine the prognostic factors and outcome of myasthenia gravis (MG) patients in crisis with double filtration plasmapheresis (DFP) treatment. MATERIAL AND METHODS: A total of 15 patients experienced 20 episodes of crisis during the study period. Plasmapheresis was carried out using a double filtration METHOD: Demographic information, clinical features of crisis, and associated complications were analyzed. RESULTS: The median duration of crisis was 9 days. Chest infection was the most common precipitant of crisis. Twelve out of the 20 episodes (60%) responded well to DFP and mechanical ventilation was discontinued after the third session of DFP in 8 of them. Three significant predictors for prolonged crisis were shorter intervals between the onset of MG and the first crisis (P=0.04), higher serum bicarbonate levels at baseline (P=0.03) and the thymic pathology of thymoma (P=0.03). CONCLUSION: DFP can ameliorate the profound weakness in crisis and seems to be a rational therapy for patients with myasthenic crisis.     

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.     

Single fiber EMG as a prognostic tool in myasthenia gravis

Introduction: Single fiber electromyography (SFEMG) is the most sensitive diagnostic tool for diagnosis of myasthenia gravis (MG). Its prognostic value is not known. Methods: We retrospectively analyzed the clinical course of 232 MG patients who presented with only mild symptoms and had SFEMG of the orbicularis oculi muscle. We correlated their SFEMG results with the severity of their later clinical course. Results: During the observation period 39 patients (17%) developed severe disease exacerbations, and 193 (83%) remained stable. Patients with severe disease exacerbation had a significantly higher mean jitter value (P < 0.0001), a greater percentage of fibers with increased jitter (P < 0.0001), and/or impulse blocking (P < 0.0001) on SFEMG. Conclusions: The extent of the SFEMG abnormalities in this study correlated with the later clinical course of MG. Muscle Nerve 54 : 1034–1040, 2016     

Correlating extent of neuromuscular instability with acetylcholine receptor antibodies

In a retrospective study of 86 patients with myasthenia gravis (MG), we correlated the acetylcholine receptor (AChR) antibody titers with single‐fiber EMG studies to explore whether a relationship exists between these parameters. We found that the AChR antibody titers correlated significantly with the mean of the mean consecutive difference of orbicularis oculi (OO, P < 0.0001) and extensor digitorum communis (EDC, P < 0.0001). The correlation was found to be stronger in OO. The antibody titers also correlated with the percentage of potential pairs with increased jitter in both muscles and, again, the correlation was more significant in OO (P < 0.0001) than in EDC (P = 0.001). We speculate that this relationship is stronger in OO than in the limb muscles, because the architectural and immunological differences in the motor unit render OO more vulnerable and sensitive to disturbances in neuromuscular transmission. Muscle Nerve, 2009     

免疫吸附与双重血浆置换治疗急性Guillain-Barre综合征疗效及安全性的研究

目的比较免疫吸附(IA)与双重血浆置换(DFPP)治疗急性Gu illain-Barre综合征(GBS)的疗效及安全性。方法60例急性GBS患者随机分为IA组及DFPP组,分别采用IA及DFPP方法治疗;观察治疗后神经功能改善状况;检测治疗前后血液中免疫系列、补体系列及总蛋白水平。结果IA组与DFPP组神经功能缺损程度均随时间变化而改善;两组间Hughes评分差异无显著性;半年后IA组MRC病情评分显著优于DFPP组(P<0.05)。两组血液中的补体C3及免疫球蛋白IgG、IgA水平与治疗前相比显著降低(P<0.05~0.01);两组间清除免疫球蛋白及补体量差异无显著性。DFPP组并发症的发生率高于IA组,但差异无显著性。结论IA及DFPP均是治疗急性GBS有效的方法,IA疗效及安全性优于DFPP。     

MuSK antibody clearance during serial sessions of plasmapheresis for myasthenia gravis

To evaluate the relationship of antibody clearance and clinical improvement for myasthenia gravis (MG) patients with MuSK antibody (MuSKAb) receiving one course of double-filtration plasmapheresis (DFP) treatment, we prospectively recorded their MG scores and measured MuSKAb concentrations before and after each DFP treatment session in two MuSKAb-positive patients. The clinical improvement trends roughly paralleled the reductions of MG score, except for the late rebound of MuSKAb in the 6th DFP treatment session, without concomitant clinical worsening in one patient. Longitudinal analysis on the serological changes during the serial sessions revealed that the levels of MuSKAb fell by 44%, 59%, 79%, 82%, 92%, and 71% in patient 1 and 52%, 70%, 78%, 87%, and 90% in patient 2. The titers of MuSKAb decreased constantly during the first 5 DFP treatment sessions. MuSKAb clearance per session for the 11 sessions ranged from 19% to 56%, with a mean of 45%. In conclusion, DFP was effective for MuSKAb removal and amelioration of clinical weakness for our two patients with MuSKAb. A 5-session protocol cleared 90% of serum MuSKAb.     

Rituximab treatment of myasthenia gravis: A systematic review

Rituximab is a chimeric mouse/human anti‐CD20 monoclonal immunoglobulin. We reviewed the efficacy and safety of rituximab in 169 myasthenia gravis (MG) patients from case reports and series. Antibodies to the acetylcholine receptor (AChR) were present in 59% and muscle‐specific tyrosine kinase (MuSK) in 34%. Modified Myasthenia Gravis Foundation of America postintervention scale of minimal manifestations (MM) or better occurred in 44%, and combined pharmacologic and chronic stable remission in 27% overall; MM or better was achieved in 72% of MuSK MG and 30% of AChR MG (P < 0.001). Posttreatment relapses decreased more in MuSK MG (P = 0.05). Response predictors were MuSK MG, less severe disease, and younger age at treatment. Among a responder subset, 26% of AChR and 82% of MuSK MG patients showed decreased posttreatment antibody titers. Rituximab was generally well tolerated. Detectable serum rituximab and depleted CD20⁺ B‐cells were observed up to 20 and 16 weeks, respectively, after 4 weekly infusions. Muscle Nerve 56 : 185–196, 2017     

Electrophysiological profile of the patients with MuSK positive myasthenia gravis

Abstract

Objectives:

To determine the electrophysiological profile of our cohort of patients with muscle-specific tyrosine kinase (MuSK) positive myasthenia gravis (MG).

Methods:

Repetitive nerve stimulation test (RNS) and jitter analysis using concentric needle electrode were performed in 31 MuSK and in 28 acetylcholine receptor (AChR) positive MG patients.

Results:

Pathological RNS was verified in 16 (51·6%) MuSK and 26 (92·9%) AChR MG patients (P < 0·01). Pathological jitter analysis was registered in 28 (90·3%) MuSK and 26 (92·9%) AChR MG patients (P > 0·05). Increased jitter was present in extensor digitorum communis (EDC) in 23 (74·2%) MuSK and in 25 (89·3%) AChR MG patients (P > 0·05) as well as in orbicularis oculi (OO) muscle in 24 (85·7%) MuSK and 22 (81·5%) AChR MG patients (P > 0·05). Lower mean value of mean consecutive difference (MCD) and fewer potential pairs with increased jitter were registered in MuSK MG compared to AChR MG patients only in EDC muscle (P < 0·05). In MuSK MG patients, increased jitter was observed to be more frequent in patients with longer disease duration (P < 0·05) and also in those patients exhibiting more severe disease forms (P < 0·01) only in EDC muscle.

Discussion:

Repetitive nerve stimulation test has low sensitivity in MuSK MG patients, while jitter analysis shows high sensitivity, especially in facial muscles. The EDC muscle in MuSK MG patients usually shows increased jitter in more severe disease forms and later in the course of the disease.     

Oral corticosteroid therapy and present disease status in myasthenia gravis

Introduction: The aim of this study was to elucidate the effectiveness of oral prednisolone (PSL) according to dosing regimen in 472 patients with myasthenia gravis (MG). Methods: We compared the clinical characteristics and PSL treatment between 226 patients who achieved minimal manifestations (MM) or better and 246 patients who remained improved (I) or worsened, according to the MG Foundation of America postintervention status. Results: Achievement of MM or better at peak PSL dose (odds ratio 12.25, P < 0.0001) and combined use of plasma exchange/plasmapheresis (PE/PP) and/or intravenous immunoglobulin (IVIg) (odds ratio 1.92, P = 0.04) were associated positively, and total PSL dose during the past year (odds ratio 0.17, P = 0.03) was associated negatively with present MM or better status. Conclusions: Higher PSL dose and longer PSL treatment do not ensure better outcome. In the absence of a good response, the PSL dose should be decreased by combining with modalities such as PE/PP or IVIg. Muscle Nerve 51 :692–696, 2015