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ObjectiveTo evaluate whether eculizumab helps patients with anti–acetylcholine receptor–positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension.MethodsPatients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study.ResultsA total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1–4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected.ConclusionEculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population.ClinicalTrials.gov IdentifierREGAIN, NCT01997229; REGAIN open-label extension, NCT02301624.Classification of EvidenceThis study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo.

Summary Myasthenia gravis (MG) is characterized by muscle weakness and fatigue caused by the presence of autoantibodies against the acetylcholine receptor (AChR) or the muscle-specific tyrosine kinase (MuSK). Activated T, B and plasma cells, as well as cytokines, play important roles in the production of pathogenic autoantibodies and the induction of inflammation at the neuromuscular junction in MG. Many studies have focused on the role of cytokines and lymphocytes in anti-AChR antibody-positive MG. Chronic inflammation mediated by T helper type 17 (Th17) cells, the promotion of autoantibody production from B cells and plasma cells by follicular Th (Tfh) cells and the activation of the immune response by dysfunction of regulatory T (Treg) cells may contribute to the exacerbation of the MG pathogenesis. In fact, an increased number of Th17 cells and Tfh cells and dysfunction of Treg cells have been reported in patients with anti-AChR antibody-positive MG; moreover, the number of these cells was correlated with clinical parameters in patients with MG. Regarding cytokines, interleukin (IL)-17; a Th17-related cytokine, IL-21 (a Tfh-related cytokine), the B-cell-activating factor (BAFF; a B cell-related cytokine) and a proliferation-inducing ligand (APRIL; a B cell-related cytokine) have been reported to be up-regulated and associated with clinical parameters of MG. This review focuses on the current understanding of the involvement of cytokines and lymphocytes in the immunological pathogenesis of MG, which may lead to the development of novel therapies for this disease in the near future.

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II-IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56·6 [SEM 4·5] vs 68·3 [4·5]; rank-based treatment difference -11·7, 95% CI -24·3 to 0·96; p=0·0698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals.

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (-2.4 [1.34] and - 3.3 [0.65]); Quantitative Myasthenia Gravis (-2.9 [1.98] and - 4.3 [0.79]); Myasthenia Gravis Composite (-4.5 [2.63] and - 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (-8.6 [5.68] and - 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population. ispartof: JOURNAL OF THE NEUROLOGICAL SCIENCES vol:407 ispartof: location:Netherlands status: published

According to the 2014 Japanese clinical guidelines for myasthenia gravis, the most important priority in treatment is maintaining patients' health-related quality of life. Therefore, the initial treatment goal is defined as maintaining a postintervention status of minimal manifestations or better (according to the Myasthenia Gravis Foundation of America classification) with an oral prednisolone dose of 5 mg/day or less. Every effort should be made to attain this level as rapidly as possible. To achieve this goal, the guidelines recommend minimizing the oral prednisolone dose, starting calcineurin inhibitors early in the course of treatment, using intravenous methylprednisolone infusion judiciously (often combined with plasma exchange/plasmapheresis or intravenous immunoglobulin), and effectively treating patients with an early, fast-acting treatment strategy. The early, fast-acting treatment strategy enables more frequent and earlier attainment of the initial goal than other strategies. Thymectomy is considered an option for treating nonthymomatous early-onset myasthenia gravis in patients with antiacetylcholine receptor antibodies and thymic hyperplasia in the early stages of the disease.

ObjectiveWe examined the correlation between the dosing regimen of oral prednisolone (PSL) and the achievement of minimal manifestation status or better on PSL ≤5 mg/day lasting >6 months (the treatment target) in patients with generalised myasthenia gravis (MG).MethodsWe classified 590 patients with generalised MG into high-dose (n=237), intermediate-dose (n=187) and low-dose (n=166) groups based on the oral PSL dosing regimen, and compared the clinical characteristics, previous treatments other than PSL and prognosis between three groups. The effect of oral PSL dosing regimen on the achievement of the treatment target was followed for 3 years of treatment.ResultsTo achieve the treatment target, ORs for low-dose versus high-dose regimen were 10.4 (PConclusionA low-dose PSL regimen with early combination of other treatment options may ensure earlier achievement of the treatment target in generalised MG.

Objectives To clarify the social disadvantages associated with myasthenia gravis (MG) and examine associations with its disease and treatment. Design Cross-sectional study. Setting and participants We evaluated 917 consecutive cases of established MG seen at 13 neurological centres in Japan over a short duration. Outcome measures All patients completed a questionnaire on social disadvantages resulting from MG and its treatment and a 15-item MG-specific quality of life scale at study entry. Clinical severity at the worst condition was graded according to the MG Foundation of America classification, and that at the current condition was determined according to the quantitative MG score and MG composite. Maximum dose and duration of dose ≥20 mg/day of oral prednisolone during the disease course were obtained from the patients9 medical records. Achievement of the treatment target (minimal manifestation status with prednisolone at ≤5 mg/day) was determined at 1, 2 and 4 years after starting treatment and at study entry. Results We found that 27.2% of the patients had experienced unemployment, 4.1% had been unwillingly transferred and 35.9% had experienced a decrease in income, 47.1% of whom reported that the decrease was ≥50% of their previous total income. In addition, 49.0% of the patients reported feeling reduced social positivity. Factors promoting social disadvantages were severity of illness, dose and duration of prednisolone, long-term treatment, and a depressive state and change in appearance after treatment with oral steroids. Early achievement of the treatment target was a major inhibiting factor. Conclusions Patients with MG often experience unemployment, unwilling job transfers and a decrease in income. In addition, many patients report feeling reduced social positivity. To inhibit the social disadvantages associated with MG and its treatment, greater focus needs to be placed on helping patients with MG resume a normal lifestyle as soon as possible by achieving the treatment target.

The majority of patients with myasthenia gravis (MG), an organ-specific autoimmune disease, harbor autoantibodies that attack the nicotinic acetylcholine receptor (nAChR-Abs) at the neuromuscular junction of skeletal muscles, resulting in muscle weakness. Single cell manipulation technologies coupled with genetic engineering are very powerful tools to examine T cell and B cell repertoires and the dynamics of adaptive immunity. These tools have been utilized to develop mAbs in parallel with hybridomas, phage display technologies and B-cell immortalization. By applying a single cell technology and novel high-throughput cell-based binding assays, we identified peripheral B cells that produce pathogenic nAChR-Abs in patients with MG. Although anti-nAChR antibodies produced by individual peripheral B cells generally exhibited low binding affinity for the α-subunit of the nAChR and great sequence diversity, a small fraction of these antibodies bound with high affinity to native-structured nAChRs on cell surfaces. B12L, one such Ab isolated here, competed with a rat Ab (mAb35) for binding to the human nAChR and thus considered to recognize the main immunogenic region (MIR). By evaluating the Ab in in vitro cell-based assays and an in vivo rat passive transfer model, B12L was found to act as a pathogenic Ab in rodents and presumably in humans.These findings suggest that B cells in peripheral blood may impact MG pathogenicity. Our methodology can be applied not only to validate pathogenic Abs as molecular target of MG treatment, but also to discover and analyze Ab production systems in other human diseases.

Background The incidence of concurrent myasthenia gravis (MG) and neuromyelitis optica spectrum disorder (NMOSD) is higher than what chance predicts, yet it remains unclear why MG and NMOSD appear concurrently. Objective The purpose of the present study was to examine the clinical features of the concurrence of these diseases. Methods Clinical details were analyzed retrospectively. Results Three (0.5%) out of 631 MG patients had confirmed ( n =2) or suspected ( n =1) NMOSD. Two of these patients were women. All showed early-onset MG (EOMG) that preceded NMOSD and were positive for acetylcholine receptor antibody (AChR-Ab). Two patients were tested for aquaporin 4 antibody (AQP4-Ab) and were positive. Two patients were treated with a thymectomy that preceded NMOSD. Two patients had decreased frequency of regulatory T (Treg) cells. We identified in the literature 46 patients with both MG and NMOSD. Our results of female predominance, EOMG, MG preceding NMOSD, and positive AChR-Ab are consistent with previous descriptions. Conclusions This is the first report to examine the frequency of NMOSD in Japanese patients with MG. The reduction and/or dysfunction of Treg cells may be one cause of NMOSD development in MG.

Background and purpose There is no general consensus as to whether autoimmune myasthenia gravis (MG) is associated with heart diseases, despite the fact that myocarditis, a serious cardiac involvement treatable by immunotherapy, is a complication of MG. It has been observed previously that MG patients with clinically suspected myocarditis had anti-Kv1.4 antibodies. The purpose of this study was to disclose the association between anti-Kv1.4 antibodies and cardiac involvements in MG patients. Methods Anti-Kv1.4 antibody was detected by an immunoprecipitation assay using 35S-labeled rhabdomyosarcome cellular extract as the antigen source. Cardiac findings including electrocardiography (ECG) and clinical features of clinically suspected myocarditis in MG patients with anti-Kv1.4 antibodies were investigated. Ultrasound echocardiography (UCG) of ex vivo chick embryos was performed to determine the suppressive effects of sera with or without anti-Kv1.4 antibodies on heart muscle functions. Results Seventy (10.8%) of 650 MG patients had anti-Kv1.4 antibodies and 60% of them had abnormal ECG findings with high frequencies of T-wave abnormality and QT prolongation. Clinically suspected myocarditis was found in eight MG patients with anti-Kv1.4 antibodies but in none of the MG patients without anti-Kv1.4 antibodies. Most patients showed rapid deterioration with lethal arrhythmias such as ventricular tachycardia, sick sinus syndrome, or complete atrial ventricular block and severe heart failure. It was concluded using UCG of ex vivo chick embryos that MG serum with anti-Kv1.4 antibodies suppressed heart muscle functions. Conclusion It has been demonstrated that anti-Kv1.4 antibodies are possible markers for cardiac involvements in MG patients.

There are no immunological markers to predict the prognosis of thymoma-associated myasthenia gravis (MG). Clinical and immunological factors associated with thymoma recurrence or MG relapse were examined by logistic analyses in 56 Japanese patients with thymoma-associated MG. Patients with anti-Kv1.4 antibodies showed higher frequencies of thymoma recurrence and MG relapse compared to those without. Anti-Kv1.4 antibody, Masaoka stage 4, World Health Organization type B3, and adjuvant radiotherapy were associated with thymoma recurrence. Multivariate analyses showed that anti-Kv1.4 antibody was the only independent factor associated with MG relapse. Anti-Kv1.4 antibody is a useful predictor of the prognosis of thymoma-associated MG.

Background We have previously reported using two-step cluster analysis to classify myasthenia gravis (MG) patients into the following five subtypes: ocular MG; thymoma-associated MG; MG with thymic hyperplasia; anti-acetylcholine receptor antibody (AChR-Ab)-negative MG; and AChR-Ab-positive MG without thymic abnormalities. The objectives of the present study were to examine the reproducibility of this five-subtype classification using a new data set of MG patients and to identify additional characteristics of these subtypes, particularly in regard to response to treatment. Methods A total of 923 consecutive MG patients underwent two-step cluster analysis for the classification of subtypes. The variables used for classification were sex, age of onset, disease duration, presence of thymoma or thymic hyperplasia, positivity for AChR-Ab or anti–muscle-specific tyrosine kinase antibody, positivity for other concurrent autoantibodies, and disease condition at worst and current. The period from the start of treatment until the achievement of minimal manifestation status (early-stage response) was determined and then compared between subtypes using Kaplan-Meier analysis and the log-rank test. In addition, between subtypes, the rate of the number of patients who maintained minimal manifestations during the study period/that of patients who only achieved the status once (stability of improved status) was compared. Results As a result of two-step cluster analysis, 923 MG patients were classified into five subtypes as follows: ocular MG (AChR-Ab-positivity, 77%; histogram of onset age, skewed to older age); thymoma-associated MG (100%; normal distribution); MG with thymic hyperplasia (89%; skewed to younger age); AChR-Ab-negative MG (0%; normal distribution); and AChR-Ab-positive MG without thymic abnormalities (100%, skewed to older age). Furthermore, patients classified as ocular MG showed the best early-stage response to treatment and stability of improved status, followed by those classified as thymoma-associated MG and AChR-Ab-positive MG without thymic abnormalities; by contrast, those classified as AChR-Ab-negative MG showed the worst early-stage response to treatment and stability of improved status. Conclusions Differences were seen between the five subtypes in demographic characteristics, clinical severity, and therapeutic response. Our five-subtype classification approach would be beneficial not only to elucidate disease subtypes, but also to plan treatment strategies for individual MG patients.

Introduction In this study we sought to clarify the effects of early fast-acting treatment (EFT) strategies on the time course for achieving the treatment target in generalized myasthenia gravis (MG). Methods This retrospective study of 923 consecutive MG patients analyzed 688 generalized MG patients who had received immunotherapy during the disease course. The time to first achieve minimal manifestations (MM) or better while receiving prednisolone at ≤5 mg/day for ≥6 months (MM-or-better-5mg) up to 120 months after starting immunotherapy was compared between EFT and non-EFT patients. Results Achievement of MM-or-better-5mg was more frequent and earlier in the EFT group (P = 0.0004, Wilcoxon test; P = 0.0001, log-rank test). Multivariate Cox regression analysis calculated a hazard ratio of 1.98 (P < 0.0001) for utilization of EFT. Dosing regimens of oral steroids in EFT produced no differences in the time course. Conclusions EFT strategies are advantageous for early achievement of MM-or-better-5mg. Muscle Nerve 55: 794–801, 2017

The MG-QOL15 is a validated, health-related quality of life (HRQOL) measure for myasthenia gravis (MG). Widespread use of the scale gave us the opportunity to further analyze its clinimetric properties.We first performed Rasch analysis on1,300 15-item Myasthenia Gravis Quality of Life scale (MG-QOL15) completed surveys. Results were discussed during a conference call with specialists and biostatisticians. We decided to revise 3 items and prospectively evaluate the revised scale (MG-QOL15r) using either 3, 4, or 5 responses. Rasch analysis was then performed on1,300 MG-QOL15r scales.The MGQOL15r performed slightly better than the MG-QOL15. The 3-response option MG-QOL15r demonstrated better clinimetric properties than the 4- or 5-option scales. Relative distributions of item and person location estimates showed good coverage of disease severity.The MG-QOL15r is now the preferred HRQOL instrument for MG because of improved clinimetrics and ease of use. This revision does not negate previous studies or interpretations of results using the MG-QOL15. Muscle Nerve 54: 1015-1022, 2016.

Objective: We developed an assay that detects autoantibodies against the main immunogenic region (MIR) located at the extracellular end of the nicotinic acetylcholine receptor (AChR) a subunit, and investigated its clinical relevance in myasthenia gravis (MG). Methods: In this retrospective cohort study, we measured MIR antibody (Ab) titres in sera obtained before treatment and analysed their associations with clinical parameters in 102 MG patients from two neurological centres. MIR Ab titres were determined using a modified competition immunoprecipitation assay in the presence or absence of monoclonal antibody 35. Results: 11 of 23 (47.8%) ocular type and 66 of 72 (91.7%) generalised type MG patients were positive for the presence of MIR Abs, defined as a titre >16.8% (3 SDs above the mean for 70 healthy controls). A significantly higher MIR Ab titre (p, Journal of Neurology, Neurosurgery & Psychiatry, 83(9), pp.935-940; 2012

Immune responses to ER stress have been closely related to the pathogenesis of autoimmune diseases. Using an immunoprecipitation assay, 24 (7.1%) of 336 MG serum samples immunoprecipitated a 90-kDa protein from the muscle cellular extracts, but none of the disease or healthy control sera. The 90-kDa protein was affinity-purified and found to match to ER chaperon GRP94 by matrix-assisted laser desorption/ionization-time of flight mass spectroscopy analysis. The frequency of associated autoimmune diseases was much higher in the anti-GRP94-positive than the -negative patients (71% versus 11%, p0.001). Autoimmunity to ER chaperone GRP94 is associated with a subset of MG patients who have additional autoimmune diseases.

Introduction. When treating ocular myasthenia gravis (MG), the risk/benefit profile of corticosteroids is unclear, and acetylcholinesterase inhibitors are not very effective. We examined the efficacy of topical naphazoline in the treatment of myasthenic blepharoptosis. Methods. Sixty MG patients with blepharoptosis (32 with ocular symptoms only and 28 with mild generalized symptoms) were enrolled in a multicenter open trial of topical naphazoline. The effects were reported by patients via a questionnaire and were also confirmed for each patient at the clinic. Results. Among 70 eyes of 60 patients, 20 eyes (28.6%) of 17 patients (28.3%) exhibited a marked response (full eye opening), and 24 eyes (34.3%) of 20 patients (33.3%) showed a good response (adequate but incomplete eye opening). Topical naphazoline was evaluated as useful in the treatment of myasthenic blepharoptosis by >70% of the patients. Conclusions. Topical naphazoline was found to be an effective supplementary symptomatic treatment for myasthenic blepharoptosis. Muscle Nerve 44: 41–44, 2011.

neurological centers constituting the Japan MG Registry Study Group. All of the patients were interviewed about the clinical features of their MG and whether they had undergone blepharoptosis surgery. A total of 19 patients (2.8%; 7 men, 12 women; mean age: 65.7 years) had undergone blepharoptosis surgery, and were further evaluated by using a questionnaire. Questions regarding the timing of the surgery (relative to MG onset), the ease of eyelid opening [over both the short term ( ≤ 1 year) and long term (>1 year), postoperatively], aesthetic outcome (scarring), overall satisfaction with the surgery, and any noted complications. Three-point Likert scales were used to assess the ease of eyelid opening (much easier, easier, worse), scarring (very minimal, minimal, visible), and overall satisfaction with the surgery (very satisfied, satisfied, dissatisfied). To evaluate scarring, the patients answered the questionnaires with their attending neurologists in the out-patient clinics. The actual surgeons were not present to help in obtaining unbiased opinions from the patients. All clinical information was collected after the patients had provided written Dear Sir, Myasthenia gravis (MG) is an antibodymediated, neuromuscular transmission disorder. Its clinical manifestations range from ocular myasthenia, which can be visually disabling, to myasthenic crisis, with patients experiencing life-threatening respiratory insufficiencies [1] . Several effective medical treatments are available for the ocular symptoms of MG [2–6] ; however, physicians often struggle to treat patients with longstanding blepharoptosis [7–9] . Moreover, although blepharoptosis surgery is occasionally applied in such cases [10, 11] , the indications and clinical effectiveness of blepharoptosis surgery for MG patients remains unclear. In the present study, we retrospectively investigated the clinical features of blepharoptosis surgery by interviewing 19 Japanese patients with MG.

Background/Aims: In treating myasthenia gravis (MG), our aims were to achieve early minimal manifestations (MM) by performing early aggressive therapy (EAT) using plasmapheresis and high-dose intravenous methylprednisolone, and then to maintain the status with low-dose oral corticosteroids (EAT strategy). We examined the merits of the EAT strategy. Methods: We retrospectively analyzed long-term effects of the EAT strategy (duration of therapy: 4.1 years) for 49 de novo MG patients and compared the effects to those of high-dose oral prednisolone therapy for 22 patients. Results: The EAT group achieved marked early improve- ment with much lower doses of oral prednisolone compared to the high-dose prednisolone group. The patients who achieved MM with prednisolone ≤5 mg/day were more frequent in the EAT group at both 1 year (57.1 vs. 4.5%) and final observation (77.6 vs. 27.3%). Both new-onset diabetes and patients who had complained of moon face were less frequent in the EAT group. However, in the EAT group, due to a temporary inability to maintain MM, additional short-term hospitalizations to return to MM by EAT were required. Conclusions: The EAT strategy has advantages of early improvement with less frequent steroid-related complications. The labor and cost required are evident disadvantages.

Background: Cyclosporine (CsA) microemulsion pre-concentrate (MEPC) is a potential steroid-sparing agent for myasthenia gravis (MG) patients; however, there is a paucity of information on the long-term use of CsA MEPC in these patients. Objectives: We examined the efficacy and safety of CsA MEPC therapy administered to MG patients in a 2-year prospective open trial. Methods: From Hanamaki General Hospital and Keio University Hospital, 28 patients provided informed consent. They were enrolled in a prospective open study of CsA MEPC for the initial 6-month observation period; after this 9 were defined as poor responders and excluded from the long-term analysis. Results: The proportion of patients with minimal manifestations or pharmacologic remission status increased significantly. Among 18 patients taking oral prednisolone, 16 (88.9%) achieved a ≧50% reduction in prednisolone dose. Time to attain the minimal quantitative MG (QMG) score (4.2 ± 2.6) was 4.2 ± 4.2 months. Time to attain the minimal dose of prednisolone (2.9 ± 3.1 mg/day) was 9.3 ± 6.9 months. The dose of CsA MEPC was reduced to 2.6 mg/kg/day 2 years after starting the drug. Both total and ocular QMG scores were significantly decreased at 6 months and were generally maintained thereafter. The dose of prednisolone was significantly reduced at 1 year, and further reduced at 2 years. BMI decreased significantly, and 9 of 12 (75%) patients complaining of moon face reported that this had resolved on exit. All patients tolerated CsA MEPC without significant side effects. Conclusion: CsA MEPC therapy in responder MG patients suppressed disease severity, reduced steroid requirements, and alleviated steroid-related side effects. These findings should be confirmed by prospective controlled double-blind trials.

Purpose To investigate the association between glucocorticoid-induced osteoporosis and myasthenia gravis (MG) using a cross-sectional survey in Japan. Methods We studied 363 patients with MG (female 68%; mean age, 57 ± 16 years) who were followed at six Japanese centers between April and July 2012. We evaluated the clinical information of MG and fractures, bone markers, and radiological assessment. Quality of life was measured using an MG-specific battery, MG-QOL15. Results Glucocorticoids were administered in 283 (78%) of 363 MG patients. Eighteen (6%) of 283 MG patients treated with prednisolone had a history of osteoporotic fractures. The duration of glucocorticoid therapy, but not the dose of prednisolone, was associated with the osteoporotic fractures in MG patients. Bone mineral density was significantly decreased in the MG patients with fractures. The multivariate analyses showed that the total quantitative MG score was the only independent factor associated with osteoporotic fractures (OR = 1.30, 95% CI 1.02–1.67, p = 0.03). MG patients who had experienced fractures reported more severe difficulties in activities of daily living. Conclusion Glucocorticoid-induced osteoporosis aggravates quality of life in patients with MG.

SummaryIn order to define the role of angiotensin II (AngII) receptor subtypes, AT1 and AT2, in platelet activation, we examined the effects of AngII and receptor antagonists on both aggregability and phosphorylation status of protein kinase C (PKC) isoforms in human platelets obtained from 56 healthy volunteers. AngII promoted both spontaneous and agonist (collagen and ADP) stimulated platelet aggregation at concentrations of 10 nM or less, but the promotion effects were lost at 100 nM. Antagonism of AT1 receptor inhibited the promotion effects of AngII at 10 nM or less. On the other hand, antagonism of AT2 receptor enhanced platelet aggregability modestly with AngII at 10 nM or less, and markedly with 100 nM AngII. Furthermore, with 10 nM AngII, phospho-PKCα/βII expression in platelets was increased after collagen stimulation and was inhibited by antagonism of AT1 receptor. With 100 nM AngII, expression levels of phospho-PKCα/ βII remained low even after collagen stimulation but were markedly enhanced by antagonism of AT2 receptor. These findings suggest that at 10 nM or below, AngII promotes aggregability and PKC phosphorylation in human platelets through the AT1 receptor, which can be inhibited by AT1 receptor antagonists, but at higher concentrations, the promotion effects were lost through the opposing action of the AT2 receptor. The present study may provide an additional mechanism for AT1 receptor antagonism, which would provide clinical benefit to patients with stroke or cardiovascular disease accompanied by hypertension.

We examined interleukin-2 (IL-2) production by phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMs) from 75 untreated myasthenia gravis (MG) patients and 48 control patients. Patients with MG consisted of those with elevated PBM IL-2 production (>1,250 pg/ml; mean + 2SD of the controls) (n = 29, 39%) and those with normal PBM IL-2 production (

Over-expression of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) in PC12 cells, independent of agonistic stimulation, induces marked neurite outgrowth and high capacity for migration and adherence (differentiation-like transformation), and increases tolerance against cell damage. In the present study, we investigated the effects of alpha7nAChR over-expression and nicotine on ERK phosphorylation and N-cadherin expression by comparing 3 groups of cells: PC12 cells transfected with alpha7 subunit cDNA (alpha7pCMV cells); untransfected PC12 cells exposed to 50 microM nicotine (PC12 cells+nicotine); and PC12 cells transfected with vector only (pCMV cells). alpha7 subunit protein was detected in alpha7pCMV cells at 24 to 72 h after transfection. alpha7pCMV cells exhibited sustained expression of phospho-ERKs (p42 and p44) at 24 to 72 h after transfection, and differentiation-like transformation at 72 h after transfection. PC12 cells+nicotine exhibited transient expression of phospho-ERKs at 48 h after addition of nicotine, but did not exhibit differentiation-like transformation. Neither ERK phosphorylation nor differentiation-like transformation was observed in pCMV cells. Expression of surface N-cadherin increased at 72 h after transfection on alpha7pCMV cells, but did not increase on PC12 cells+nicotine or pCMV cells. These findings suggest that, in PC12 cells, over-expression of alpha7nAChR induces sustained activation of ERK, which probably promotes N-cadherin expression and differentiation-like transformation.

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).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.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.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.

Background and Purpose Myasthenia gravis (MG) is often categorized into thymoma-associated MG, early-onset MG with onset age

Immunohistochemical expression of natural killer T (NKT) cell-associated markers (Valpha24 and CD56) and perforin in relation to CD44-highly positive (CD44(high)) cells was studied in hyperplastic thymuses from patients with myasthenia gravis (MG) whose symptoms dramatically improved after thymectomy and compared with non-MG control thymuses. In the control thymuses, Valpha24-positive (Valpha24(+)) and CD56-positive (CD56(+)) cells were sparsely distributed in the medullary area only. In contrast, in hyperplastic MG thymus, Valpha24(+) and CD56(+) cells were more frequent in connective tissue, appeared to have penetrated the thymic parenchyma, and most coexpressed CD44(high). Perforin-positive cells were not present in the control thymus, but were in the connective tissue and perilobular cortical areas in the hyperplastic MG thymus. Most of these perforin-positive cells were CD44(high) and were located near blood vessels. They appeared to have migrated directly from the vascular system and penetrated the thymic parenchyma. Some perforin-positive cells coexpressed Valpha24, CD56, or both. These findings suggest that in this particular type of MG thymus, NKT-like cells may have increased via a CD44- and perforin-mediated mechanism, leading to an imbalance in the immune system that favored an antibody-mediated autoimmunity against the acetylcholine receptor.

Changes with age in the methylation status of cytosines in a promoter region of the τ gene were investigated in autopsy human cerebral cortex, using the bisulfite method, polymerase chain reaction (PCR) and direct sequencing of PCR products. While the total number of methylcytosines decreased with age, the changes in methylation status differed among transcription factor binding sites. Cytosines in the AP2-binding sites were never methylated in any of the cases studied at any age. Methylcytosines in the binding sites for Sp1, a transcriptional activator, significantly increased with age, whereas those in the binding sites for GCF, a repressor of GC-rich promoters, significantly decreased with age. These findings suggest that the methylation status of cytosines in the promoter region of the τ gene alters with age to decrease its transcriptional activity in the human cerebral cortex.

Age-related changes in nicotinic acetylcholine receptor (nAChR) subunit alpha7 messenger RNA (mRNA) expression in postmortem human frontal cortex and putamen of controls and status lacunaris patients were investigated using nonradioactive reverse transcription(RT)-PCR. In the frontal cortex of control brains, alpha7 subunit mRNA significantly decreased with age (P0.05). In the putamen, alpha7 subunit mRNA expression was significantly lower than that in the frontal cortex (P0.0001), and showed no significant correlation with age. However, in cases with status lacunaris in the putamen, alpha7 subunit mRNA expression was significantly higher compared with controls (P0.001). The reduction in alpha7 nAChR in the frontal cortex with age may decrease functional cholinergic synapses and cortical activity, and play a role in the cognitive impairments associated with normal aging. The functional significance of the upregulation of alpha7 nAChR mRNA in ischemic conditions remains to be determined.

Methylation status of cytosines and its changes with age in the promoter region (-226 approximately -101) of the amyloid precursor protein (APP) was analyzed using bisulfite genomic sequencing in the cerebral cortex of human autopsy brain. Cytosines at 13 locations were methylated in at least one of the cases studied. Methylcytosines at these locations was more frequent in cases/=70 years old (26%) than in cases70 years old (8%) (p0.05). Cytosines at -207, -204, -200, and -182 are frequently methylated, and the frequency of methylcytosine in these locations was significantly higher in cases/=70 years old (55%) than cases70 years old (5%) (p0.01). These cytosines constituted one of the 9-bp-long GC-rich elements (GGGCGC G/A GG) or an 11-bp inverted repeat (GGCCGT CGGCC). The present findings indicate that some cytosines, particularly those at -207 approximately -182, in the promoter region of the APP gene are frequently methylated and suggest that their demethylation with age may have some significance in the development of Abeta deposition in the aged brain. The relative importance of these elements in the total promoter activity of the APP gene remains to be definitively established.

We present a simple and rapid procedure for quantifying mRNA in the brain after RT-PCR, in which the intensity of the ethidium bromide luminescence of PCR products is measured directly from electrophoretic gels by a highly sensitive CCD camera combined with an image analyzing computer system (Gel Doc 1000 system). The CCD camera allows the mRNA in the ethidium bromide-stained PCR-amplified bands to be quantified in a broad exponential range of PCR cycles. The proposed protocol enables standard curves to be constructed to examine the relationship between the number of reaction cycles and amplified log intensity and between the amount of sample RNA for RT-PCR and amplified intensity. The method was applied to nicotinic acetylcholine receptor (nAChR) subunits α4 and β2 mRNA in postmortem human putamen in the present study, but is also applicable to mRNAs of other receptors and neurotransmitter precursor peptides. Themes: Neurotransmitters, modulators, transporters, and receptors Topics: Acetylcholine receptors: nicotinic

Cerebral blood flow and oxygen metabolism were examined in two patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) using positron emission tomography (PET). Regional cerebral blood flow (rCBF), regional cerebral oxygen metabolic rate (rCMRO2) and regional oxygen extraction fraction (rOEF) were determined with the steady-state technique using oxygen-15-labeled tracers (15O2, C15O2 and C15O). Case 1, a 45-year-old woman, presented with abrupt onset of fluent aphasia. T2-weighted magnetic resonance imaging (MRI) showed a high signal intensity lesion in the left temporoparietal region. The first PET study on day 16 showed increased rCBF and decreased rCMRO2 in the temporal region. In the second PET study, on day 35, rCBF in the temporal region had decreased. Case 2 was a 19-year-old male; the second son of Case 1. He complained of transient blurring of vision, and then generalized tonic-clonic convulsion occurred. A PET study six days before this stroke-like episode demonstrated increased rCBF in both frontal lobes and putamen, where MRI showed lesions after the episode. Focal hyperemia of the lesion antedated and lasted for at least sixteen days after the stroke-like episode in these MELAS patients. These stroke-like episodes appear to be the result of metabolic dysfunction in neural tissue, although the role of an ischemic vascular event cannot be ruled out.

Age-related changes in nicotinic acetylcholine receptor (nAChR) subunit alpha4 and beta2 messenger RNA (mRNA) expression in the postmortem human frontal cortex and hippocampus was investigated using the reverse transcription-polymerase chain reaction (RT-PCR). In the frontal cortex, both alpha4 and beta2 subunit mRNA expression decreased with age. In the hippocampus, alpha4 subunit mRNA expression was unaltered, while beta2 subunit mRNA expression significantly decreased with age. These findings suggest that nAChR transcription decreases during aging with differing vulnerability between subunits and brain regions, which could in part contribute to the reduction in cognitive functions seen in the elderly.

Expression of messenger RNAs (mRNAs) encoding the D1 and D2 dopamine receptors as a function of age was determined in the human putamen using the reverse transcription-polymerase chain reaction (RT-PCR). In cases without multiple small infarcts (status lacunaris) in the putamen, D1 mRNA expression was unaltered, while D2 mRNA expression significantly decreased with age. Both D1 and D2 mRNA expression was lower in cases with status lacunaris. The reduction in D1 receptors primarily located on striatonigral neurons or D2 receptors primarily located on striatopallidal neurons may inhibit thalamocortical neurons. The decreased transcription of D1 and D2 receptor genes may in part account for increased susceptibility to hypokinetic disorders in the elderly.

Gamma-aminobutyric acid (GABA)/substance P (SP) neurons and GABA/enkephalin (Enk) neurons in the striatum exert opposing influence on the regulation of movement. The loss of GABA/SP neurons results in hypokinetic disorders (parkinsonism), whereas the loss of GABA/Enk neurons results in hyperkinetic disorders (e.g. chorea). The present study determined age-related changes in the beta-preprotachykinin (the precursor of SP) and preproenkaphalin (the precursor of Enk) messenger RNA (mRNA) ratio in the postmortem human putamen using the reverse transcription-polymerase chain reaction (RT-PCR). The ratio of beta-preprotachykinin to preproenkephalin mRNA expression decreased with age. The reduction in the beta-preprotachykinin/preproenkephalin mRNA ratio was more marked in cases with multiple small infarcts (status lacunaris) in the putamen. These findings may in part explain the susceptibility of the elderly, particularly of those with ischemic changes in the striatum to hypokinetic disorders.

In thymomas associated with myasthenia gravis (MG), the authors found that perivascular infiltrates of memory lymphocytes and mature dendritic cells (DCs) were more frequent in patients with early improvement after thymectomy than in patients without response to thymectomy. Although these findings may be limited to particular types of thymoma, thymectomy may interrupt the recruitment of mature DCs in thymus and export of activated T cells to extra-thymic tissues, thereby improving the disease.

Presently, myasthenia gravis (MG) is seldom lethal. However, full remission without immune treatment is not common, and many patients still find it difficult to maintain daily activities. To both determine factors affecting health-related quality of life (QOL) and propose an appropriate treatment target for patients with MG, we evaluated 640 consecutive patients with MG seen at 11 neurological centers. Two-year follow-up data were obtained for 282 patients. Correlations between detailed clinical facotrs and the Japanese version of the 15-item MG-specific QOL scale were analyzed.In the cross-sectional analysis of 640 MG patients, multivariate regression revealed that disease severity as evaluated by MG Composite (p < 0.0001), but not quantitative MG score, total dose of oral prednisolone (p = 0.002), but not current dose, and Cushingoid appearance index (p = 0.0004) showed significant negative effects on QOL. Achieving status of Minimal Manifestations or better with prednisolone ≤ 5 mg/day was found to exert a major positive impact on QOL in both the cross-sectional and 2-year follow-up patient samples and can be recommended as a treatment target.

The aim of this study was to determine factors affecting health-related quality of life (HRQOL) and to propose appropriate treatment targets for patients with myasthenia gravis (MG).We evaluated 640 consecutive patients with MG seen at 11 neurological centers. Two-year follow-up data were obtained for 282 patients. Correlations between detailed clinical factors and the Japanese version of the 15-item MG-specific QOL scale score were analyzed.In a cross-sectional analysis of 640 MG patients, multivariate regression revealed that disease severity, as evaluated by the MG Composite (P0.0001), total dose of oral prednisolone during the last year (P=0.002), and Cushingoid appearance index (P=0.0004), showed significant negative effects on HRQOL, but the quantitative MG score and current prednisolone dose did not.Achieving minimal manifestations (MM) status or better with prednisolone ≤ 5 mg/day was found to exert a major positive impact on HRQOL in both the cross-sectional and 2-year follow-up patient samples and can be recommended as a treatment target.

Many patients with myasthenia gravis (MG) still find it difficult to maintain daily activities due to chronic residual fatigability and long-term side effects of oral corticosteroids, since full remission is not common. Our analysis demonstrated that disease severity, oral corticosteroids, and depressive state are the major factors negatively associated with QOL, and that QOL of MM status patients takingor = 5 mg prednisolne/day is identically good as that seen in CSR and is a target of treatment. In order to achieve early MM or better status with prednisolneor = 5 mg/day, we advocate the early aggressive treatment strategy that can achieve early improvement by performing an aggressive therapy using combined treatment with plasmapheresis and high-dose intravenous methylprednisolone and then maintain an improved status using low-dose oral corticosteroids and calcineurin inhibitors.

We produced a Japanese translation of the 15-item myasthenia gravis (MG)-specific quality of life (QOL) scale (MG-QOL15), assessed its reliability and validity, and examined clinical factors affecting the self-perceived QOL in MG. Consecutive 327 patients with MG seen at six neurological centers were evaluated. All patients completed an MG-QOL15 Japanese version (MG-QOL15-J), the Beck Depression Inventory-Second Edition (BDI-II), and a generic health-related QOL questionnaire, the SF-36. Disease severity was determined according to the MG Foundation of America (MGFA) quantitative MG score and the MG composite. The MG-QOL15-J exhibited adequate internal reliability, test-retest repeatability, and concurrent validity with SF-36, disease severity, and known-patient groups categorized by MGFA postintervention status. Multivariate analysis revealed severity, dose of oral corticosteroids, and BDI-II as independent factors negatively affecting QOL. The MG-QOL15-J is anticipated to be a valuable clinical measure of QOL in Japanese patients with MG.

The advent of effective immune treatment has meant that myasthenia gravis (MG) is most often not lethal. However, many MG patients still find it difficult to maintain daily activities due to chronic residual fatigability and long-term side effects of medication, since full remission without immune treatment is not common. Our analysis demonstrated that disease severity, dose of oral corticosteroids, and depressive state are the major independent factors negatively associated with self-reported QOL (MG-QOL15-J score). It is noteworthy that oral corticosteroid, the first-line agent for MG, is negatively associated with patients' QOL. When the analysis took into account MGFA postintervention status and dose of oral prednisolne (PSL), the MG-QOL15-J score of MM status patients taking ≤ 5 mg PSL per day is identically low (i.e., just as good QOL) as that seen in CSR and is a target of treatment. In order to veer away from high-dose oral corticosteroids and to achieve early MM or better status with PSL ≤ 5 mg/day, we advocate the early aggressive treatment strategy that can achieve early improvement by performing an aggressive therapy using combined treatment with plasmapheresis and high-dose intravenous methylprednisolone and then maintain an improved clinical status using low-dose oral corticosteroids and calcineurin inhibitors (cyclosporine microemulsion and tacrolimus). The early stages of MG are susceptible to treatment with calcineurin inhibitors. When using cyclosporine microemulsion for MG, blood concentrations 2 h after administration (C2) correlate with clinical improvement and immediately before administration (C0) with side effects (increased serum creatinine and/or hypertension). Monitoring of C2 and C0 levels is useful to estimate efficacy and safety of the drug.

Introduction: Our study aim was to produce a Japanese translation of the 15-item Myasthenia Gravis Quality-of-Life Scale (MG-QOL15), assess its reliability and validity, and examine clinical factors affecting self-perceived QOL in MG. Methods: We evaluated 327 consecutive patients with MG seen at six neurological centers. All patients completed the Japanese version of the MG-QOL15 (MG-QOL15-J), the Beck Depression Inventory—second edition (BDI-II), and a generic health-related QOL questionnaire, the SF-36. Disease severity was determined according to the Myasthenia Gravis Foundation of America (MGFA) quantitative MG score and the MG composite. Results: The MG-QOL15-J exhibited adequate internal reliability, test–retest repeatability, and concurrent validity with SF-36, disease severity, and known-patient groups categorized by MGFA post-intervention status. Multivariate analysis revealed severity, dose of oral corticosteroids, and BDI-II as independent factors negatively affecting QOL. Conclusion: The MG-QOL15-J is anticipated to be a valuable clinical measure of QOL in Japanese patients with MG. Muscle Nerve 46: 166–173, 2012

Thymic abnormalities were first noticed at autopsies of patients with myasthenia gravis (MG) more than 100 years ago. The thymus is believed to play an important role in the pathogenesis of MG, an autoimmune disease mediated by antibodies against the acetylcholine receptor (AChR) of skeletal muscles. Production of these antibodies in B cells is T cell dependent. T cells potentially specific for AChR are probably generated in the thymus via nontolerogenic thymopoiesis by an aberrant function of thymic epithelial cells. However, generation of these AChR-specific T cells is not the cause of MG, because these cells are also found in healthy individuals. The pathogenetic step in MG involves the activation of these potentially AChR-specific T cells; this activation is the trigger to develop the disease and a therapeutic target. The intra-thymic activation of AChR-specific T cells is probably limited to particular types of MG patients: those with early-onset MG in whom the thymus exhibits lymphofollicular hyperplasia (TLFH) and a few patients in whom MG is associated with a thymoma. The majority of thymomas and atrophic thymuses of patients with late-onset MG, an increasingly common condition, do not exhibit this T cell-activation process. In this paper, we review the available literature on thymic changes (TLFH, thymoma, and atrophic thymus) and the relationship of these changes to the pathogenesis of MG.

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.

The objective was to assess which clinical factors of patients with myasthenia gravis (MG) are associated with responsiveness to calcineurin inhibitors (CNIs, cyclosporine and tacrolimus). We retrospectively analyzed the 6-month effects of CNIs in 62 MG patients. We excluded the influence of other immune treatments and determined factors associated with response to CNIs. The frequency of patients who achieved neither aor =3-point reduction in quantitative MG score nor aor =25% reduction in daily dose of prednisolone (poor responders) reached 35.5% (22/62) and 64.5% (40/62), respectively, compared with patients who achieved at least one of these improvements (responders). Neither dose nor blood concentration of CNIs differed between groups. Multivariate logistic regression analysis revealed time since onset of disease [odds ratio (OR) = 0.85, P = 0.005] and presence of thymoma (OR = 5.56, P = 0.05) as clinical factors that predict response to CNIs. As for MG-related autoantibody status, an autoantibody against a voltage-gated potassium channel, Kv1.4, was associated with response (OR = 9.01, P = 0.04) and showed a correlation with the presence of thymoma (P0.01). In MG, the early stages of disease and thymoma-associated MG are responsive to treatment with CNIs.

Objective To investigate the clinical, histological, and immunological features of patients with myasthenia gravis (MG) who also developed myocarditis and/or myositis. Design Observational and retrospective case series. Setting Keio University, Hanamaki General Hospital, Kanazawa University, Nagasaki University, and Juntendo University. Patients A cohort of 8 patients with MG with clinically defined inflammatory myopathies. Interventions Clinical and histological features were described. Serological analyses included MG-related antistriational autoantibodies (those to titin, ryanodine receptor, muscular voltage-gated potassium channel Kv1.4) and myositis-specific autoantibodies. Results Of 924 patients with MG, 8 (0.9%) had inflammatory myopathies. The mean (SD) onset age of MG was 55.3 (10.3) years. All patients showed severe symptoms with bulbar involvement; 5 patients had myasthenic crisis and 4 had invasive thymoma. Myocarditis was found in 3 patients and myositis in 6. Myocarditis, developing 13 to 211 months after the MG onset, was characterized by heart failure and arrhythmias. Myositis, developing before or at the same time as MG, affected limb and paraspinal muscles. Histological findings of skeletal muscles showed CD8 + lymphocyte infiltration. Seven patients had 1 of these antistriational autoantibodies but not myositis-specific autoantibodies. Immunomodulatory therapy was required for all patients and was effective for both MG and inflammatory myopathies, although 1 patient died. Conclusions Heart and skeletal muscles are autoimmune targets in some patients with MG. This autoimmunity has a broad clinical spectrum with antistriational autoantibodies. Published online September 14, 2009 (doi:10.1001/archneurol.2009.229).

Purpose: To examine whether the monitoring of cyclosporine (CsA) blood concentrations is of benefit in CsA microemulsion pre-concentrate (MEPC) therapy for myasthenia gravis (MG). Methods: We measured CsA blood concentrations both 2 h after administration (C2) and immediately before administration (C0) and examined associations with changes to clinical parameters in 20 MG patients treated with CsA MEPC in an unblinded, 6-month prospective open trial. Results: Initial dose of CsA MEPC (4.7 ± 0.5 mg/kg/day) provided both high C2 levels and safe C0 levels. Disease severity, daily dose of prednisolone, acetylcholine receptor–antibody titre levels and levels of interleukin-2 production by peripheral blood mononuclear cells were significantly reduced following treatment with CsA MEPC. A significant correlation existed between C2 levels following the initial dose and clinical improvement in responder MG patients. C0 levels were significantly higher in patients who exhibited increased serum creatinine or hypertension compared with patients free from side effects. Body mass index of individual patients was significantly correlated with C0 level, and may thus offer a useful marker to predict C0 levels. Discussion: CsA MEPC was effective at suppressing symptoms and T-cell-dependent pathogenesis of MG, and monitoring of C2 and C0 levels can be useful to estimate efficacy and safety of the drug.