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Clinical features and treatment status of adult myasthenia gravis in Japan
Abstract
Objective
Myasthenia gravis (MG) is classified as early-onset MG (EOMG; age at onset ≤49 years), late-onset MG (LOMG; age at onset ≥50 years) or thymoma-associated MG (TAMG) (E-L-T classification). To clarify the characteristics of each group in the E-L-T classification in Japan, we carried out multicenter analyses of MG. MethodsA total of 640 adult patients from 11 MG centers participated in the study. Age at onset, sex, clinical symptoms, frequency of crisis, thymic pathology, positivity of autoantibodies against acetylcholine receptor (AChR) and muscle-specific receptor tyrosine kinase (MuSK), selected treatment, Cushingoid appearance and post-intervention status were evaluated in each group. ResultsEOMG, LOMG and TAMG accounted for 44%, 33%, and 23% of the patients, respectively. Females predominated in the EOMG group (77%), whereas there was no sex difference in the LOMG group. The frequency of ocular MG was the highest in the LOMG group (EOMG 15%, LOMG 38%, TAMG 12%). Bulbar symptoms and crisis were most frequent in the TAMG group. Anti-AChR antibody was always positive in patients with TAMG (EOMG 70%, LOMG 78%, TAMG 99%), whereas anti-MuSK antibody was never positive in TAMG patients, and more frequently detected in EOMG patients than in LOMG patients. Thymectomy was carried out in 51% of EOMG patients, 26% of LOMG patients and 97% of TAMG patients. Immunotherapy was carried out most aggressively in TAMG patients, and least aggressively in LOMG patients. Minimal manifestations or better with prednisolone ≤5 mg were achieved only in one-third of EOMG and TAMG patients. Conclusion
Thymoma-associated MG required the most aggressive immunotherapy, followed by early-onset MG.
... Based on age of onset, the distribution of early onset MG is more dominating with a percentage of 66,7% dan the proportion of woman is higher than man with a percentage of 72,7%. This results align with research by Murai where among the subjects of 640 MG patient, it was found that the proportion of early onset MG is higher than late onset MG with the ratio of 43,85 versus 33,6% and is dominated by woman with percentage of 77% [9]. Research by Belimezi on 1526 positive AChR MG patients in Greek also shows a proportion of woman (929) is higher than man (597) [6]. ...
... This also differs with research done by Bubuioc et al. that says the age of onset of MG in man is usually around 50-70 years old, backed by research by Tandon K that also says that LOMG is more common in man and is related with thymic athropy [12]. On the contrary, research by [9]. Also founds man and woman percentage is almost similar in LOMG. ...
... Myasthenia gravis is divided in two based on age of onset, Early Onset Myasthenia Gravis (EOMG) that happens before 50 years old and Late Onset Myasthenia Gravis (LMOG) that happens after 50 years old [4], [16]. Age of onset is one of many important factors because EOMG has different characteristic with LOMG [9]. There are several things that influenced the difference between both age of onset group. ...
Myasthenia Gravis (MG) is a neuromuscular disease in which autoantibodies against the acetylcholine receptor (AChR) cause muscle weakness. AChR antibodies are very specific in MG because they are found in about 85% of cases. There are two MG subtypes based on age of onset, namely MG Early Onset (<50 years old), dominated by women, and MG Late Onset (≥50 years old), dominated by men. Several studies have shown different results regarding AChR antibody levels in both ages of onset and gender. The present study is observational analytic research that used a cross-sectional design. The subjects were 33 MG patients selected based on inclusion and exclusion criteria using consecutive sampling. The research data used from secondary data. The researcher used the Spearman and Eta Test to analyze the data. The majority of MG patients were dominated by women (72,7%) and had age of onset <50 years old (67%). The median of AChR antibody level in MG patients was 30.7 pmol/L. The results of the correlation statistical test between the age of onset and AChR antibody levels showed p=0.808 and r=0.044. The correlation test between gender on AChR antibody levels showed p=0.759 and r=0.056. There is no significant correlation between age of onset and gender with acetylcholine receptor antibody levels. This work is licensed under a Creative Commons Attribution Non-Commercial 4.0 International License.
... Furthermore, the characteristic temporal relationship between onset of MG and NMOSD cannot result from random chance, given that age of onset is similar between these diseases (MG: 31.9-56.3 years; NMOSD: 32.6-45.7 years) [6][7][8][9][10][11][12]. Notably, NMOSD develops after thymectomy in 64.1% of all the cases, which is in clear contrast to cases with MS (0%). ...
... MS [2,[63][64][65][66][67][68][69][70] Morvan syndrome [4,[71][72][73][74][75][76][77][78][79][80][81] CIS [3,46,82] Recurrent myelitis [3,83] ADEM [3] Anti-NMDAR encephalitis [39] General clinical characteristics of MG [8][9][10][11][12]84] is not necessarily true. NMOSD could develop soon after resolution of the last exacerbation of MG, as in our cases 1 and 2. ...
... MS [2,[63][64][65][66][67][68][69][70] Morvan syndrome [4,[71][72][73][74][75][76][77][78][79][80][81] CIS [3,46,82] Recurrent myelitis [3,83] ADEM [3] Anti-NMDAR encephalitis [39] General clinical characteristics of MG [8][9][10][11][12]84] p value CNS disorders preceding MG 6 (9.5%) (n = 63) differences between MG cases comorbid with NMOSD and MS were still apparent (Table 1). Notably, MG and thymectomy preceded onset of NMOSD in most cases, whereas MS did not follow thymectomy. ...
Myasthenia gravis (MG) is occasionally associated with autoimmune diseases in the central nervous system (CNS), such as neuromyelitis optica spectrum disorder (NMOSD), multiple sclerosis (MS), Morvan syndrome, and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Here, we report five original cases associated with autoimmune disorders in the CNS among 42 patients with MG in a single tertiary hospital in Japan (11.9%). In four of these five cases, the second disease developed when the preceding disease was unstable. Accurate diagnosis of the newly developing disease may be difficult in such cases, because some neurological symptoms can be seen in both disorders. This implies the great importance of recognizing the possible co-occurrence of MG and disorders in the CNS. In addition, a comprehensive review of the literature revealed distinct clinical characteristics depending on the associated disease in the CNS, including thymic pathology and temporal relationship between MG and associated CNS disorders. Notably, NMOSD usually develops after the onset of MG and thymectomy, in clear contrast to MS. Thymoma is highly prevalent among patients with Morvan syndrome, in contract to cases with NMOSD and MS. The analysis of clinical characteristics, representing the first such investigation to the best of our knowledge, suggests different pathogeneses of these autoimmune diseases in the CNS, and provides significant implications for clinical practice.
... In this study, LOMG is defined as age at onset C50 years and non-thymomatous MG, as previously reported [7]. The diagnosis of MG was made based on clinical features and positivity for one or more of the following tests: edrophonium test, electrophysiological tests (repetitive nerve stimulation test and/or single-fiber electromyography), and presence of antibodies against the AChR or muscle-specific tyrosine kinase. ...
... Our results show that thymectomy in generalized LOMG patients with thymic hyperplasia could have beneficial effects compared to those with involuted thymus. Two years after thymectomy, remission (complete stable remission or pharmacologic remission in MGFA PIS) was achieved in 60 % of patients with thymic hyperplasia and 26 % of patients with involuted thymus, respectively, which were much higher compared with the data of a recent Japanese large retrospective study (the remission rate in LOMG patients was 14.8 %) [7]. Moreover, we identified that the proportion of patients with MM or better status with B5 mg prednisolone at 2 years post-thymectomy was 100 and 62 %, respectively. ...
... Moreover, we identified that the proportion of patients with MM or better status with B5 mg prednisolone at 2 years post-thymectomy was 100 and 62 %, respectively. Murai et al. [7] have shown that the proportion of Japanese LOMG patients with MM or better status with B5 mg/day prednisolone was 53.9 %. Achieving MM or better status with prednisolone B5 mg/day was found to exert a major positive impact on health-related quality of life and is recommended as a treatment target [9]. ...
Thymectomy is an effective treatment for myasthenia gravis (MG). However, there is limited data on its effectiveness in non-thymomatous late-onset MG (LOMG). The aim of this study was to analyze the effects of thymectomy in LOMG. We retrospectively reviewed the 2-year post-thymectomy prognosis in 39 consecutive patients with non-thymomatous, anti-acetylcholine receptor antibody positive, and generalized LOMG (age at onset ≥50 years). The MG foundation of America (MGFA) classification, MGFA post-intervention status, dosage of prednisolone and pyridostigmine, and anti-acetylcholine receptor antibody titers were evaluated. Among the 39 LOMG patients, thymic hyperplasia was seen in 5 (12.8 %). MGFA classification and prednisolone dosage before thymectomy were similar between the LOMG with thymic hyperplasia group (n = 5) and the LOMG with involuted thymus group (n = 34). Two years after thymectomy, the LOMG patients with thymic hyperplasia showed higher proportion of remission (60 vs. 26 %) and received lower prednisolone dosage compared to patients with involuted thymus (0.8 vs. 4.0 mg/day). Notably, the proportion of patients with minimal manifestation or better status with receiving ≤5 mg/day prednisolone was much higher in the thymic hyperplasia group than in the involuted thymus group (100 vs. 62 %). In conclusion, thymectomy could have beneficial effects in generalized LOMG, particularly in patients with thymic hyperplasia.
... Other concurrent striational autoantibodies also affect clinical features [2]. MG is often classified as follows based on the thymic abnormalities present and age at onset: thymoma-associated MG (TAMG); early-onset MG with age at onset ,50 years; and late-onset MG with age at onset $50 years [3][4][5]. However, the use of 50 years as the boundary for age at onset remains controversial. ...
... ''MG with thymic hyperplasia'' (THMG), ''sero-negative'' (without AChR-Ab) and ''doubleseronegative'' (with neither AChR-Ab nor MuSK-Ab) MG are also employed as subtypes in clinical settings. Furthermore, ocular MG represents a unique category distinguished from the generalized form [4]. The present study attempted to clarify subtypes of MG from a statistical perspective using two-step cluster analysis and discrimination analysis. ...
... Among 676 consecutive MG patients surveyed in the Japan MG registry study of 2012 [4,6], 640 adult patients for whom all the information required for the present analysis was available provided written informed consent [6] and participated in the present statistical study. ...
Background and Purpose
Myasthenia gravis (MG) is often categorized into thymoma-associated MG, early-onset MG with onset age <50 years, and late-onset MG with onset age ≥50 years. However, the boundary age of 50 years old between early- and late-onset MG remains controversial, and each category contains further subtypes. We attempted to classify MG from a statistical perspective.
Methods
We analyzed 640 consecutive MG patients using two-step cluster analysis with clinical variables and discrimination analysis, using onset age as a variable.
Results
Two-step cluster analyses categorized MG patients into the following five subtypes: ocular MG; MG with thymic hyperplasia (THMG); generalized anti-acetylcholine receptor antibody (AChR-Ab)-negative MG; thymoma-associated MG; and generalized AChR-Ab-positive (SP) MG without thymic abnormalities. Among these 5 subtypes, THMG showed a distribution of onset age skewed toward a younger age (p<0.01), whereas ocular MG and SPMG without thymic abnormalities showed onset age skewed toward an older age (p<0.001 and p<0.0001, respectively). The other 2 subtypes showed normal distributions. THMG appeared as the main component of early-onset MG, and ocular MG and SPMG without thymic abnormalities as the main components of late-onset MG. Discrimination analyses between THMG and ocular MG and/or SPMG without thymic abnormalities demonstrated a boundary age of 45 years old.
Conclusions
From a statistical perspective, the boundary age between early- and late-onset MG is about 45 years old.
... 4,19 Sebaliknya, Murai dkk menunjukkan proporsi early onset MG lebih banyak dibandingkan late onset MG dengan dominasi perempuan. 20 Early onset MG dikatakan banyak ditemukan terutama pada populasi Asia dan kemungkinan berhubungan dengan genetik HLA-DR3,HLA-B8. 21 Suatu penelitian menunjukkan terdapat hubungan kuat antara Genome Wide Association (GWAS) pada subgrup early onset MG dengan TNFAIP3-interacting protein-1 (TNIP-1) dan lokus B-HLA. ...
... Hal serupa dikemukakan pada penelitian lain yang mendapatkan gejala awal MG terbanyak adalah gejala okular. 3,17,20 Gejala okular terjadi saat awitan disebabkan karena neuron motor yang menginervasi otot ekstraokular memiliki frekuensi firin yang tinggi sehingga mudah terjadi kelelahan miastenik. Selain itu, otot ekstraokular terdiri dari serabut tonik yang jika terjadi kehilangan AChR maka akan menghasilkan penurunan potensial pada akhir saraf (endplate) dan terjadilah penurunan kekuatan signifikan pada serabut tersebut. ...
Pendahuluan: Antibodi reseptor asetilkolin (anti-AChR) merupakan antibodi utama dalam patogenesis penyakit miastenia gravis (MG). Pemeriksaan antibodi ini merupakan salah satu pemeriksaan penting dalam menegakkan diagnosa. Gambaran klinis MG dapat terbagi menjadi MG okular, MG generalisata dan MG bulbar. Tiap individu dapat memiliki derajat keparahan yang berbeda yang dinilai berdasarkan MG composite score (MG-cs). Tujuan: Untuk mengetahui adanya hubungan kadar anti-AChR dengan derajat keparahan penyakit MG berdasarkan MG-cs di RS Cipto Mangunkusumo (RSCM). Metode: Penelitian ini merupakan studi potong lintang yang melibatkan pasien MG di RSCM pada bulan Januari 2017- November 2017. Kriteria inklusi subjek ialah pasien yang telah didiagnosa MG berusia 18-75 tahun. Pemeriksaan kadar anti-AChR dengan metode ELISA. Penilaian MG-cs dilakukan bersamaan dengan pengambilan sampel darah. Hasil: Didapatkan 72 subjek yang sesuai kriteria inklusi. Rerata usia subjek adalah 43 tahun (SD 12,56) dengan jenis kelamin perempuan lebih banyak (2,5:1). Gejala okular merupakan gejala terbanyak saat awitan (79,2%) dan early onset MG lebih banyak ditemukan (77,8%). Sebanyak 59,7% subjek memiliki seropositif anti-AChR. Tidak ada perbedaan bermakna seropositifitas anti-AChR pada kelompok berdasarkan jenis kelamin, usia awitan, tipe MG, dan pemberian terapi imunosupresan. Tidak didapatkan hubungan bermakna antara kadar anti-AChR dengan MG-cs (p=0,727). Diskusi: Kadar anti-AChR tidak berhubungan dengan derajat keparahan penyakit MG. Kata kunci: Antibodi reseptor asetilkolin, derajat keparahan MG, MG-cs
... 2.2.2. Following data was obtained from the clinical records: gender, age at onset of symptoms, duration of disease prior to initiation of therapy, thymus status (normal or abnormal thymus), MGFA classification at the time of initiation of treatment, AchR-Ab status (positive/negative/ not known), time to achieve off PyD status (TOPs) and follow up duration (21)(22)(23) . 2.2.3. ...
Purpose:
Myasthenia gravis (MG) is treated with many disease modifying therapies, namely corticosteroids, thymectomy and immunosuppressants, alone or in various combinations. But still, till today no consensus over the optimum therapy for MG has been made.
Methods:
Out of total 101 patients with MG, 37 patients fulfilled the inclusion criteria and in them we ambispectively studied factors affecting the outcome in MG treated, to induce leukopenia, with prednisolone (PSL) plus azathioprine(AZA), from January 1993 through July 2014. Patients were grouped according to the outcome: pharmacological remission (PR), complete stable remission (CSR), non-remitter and remitters with or without relapse. Their demographic characteristics, MGFA Class, dose of PSL and AZA, time to achieve remission, duration of remission, leukocyte counts, thymus status, follow-up duration, results of repetitive nerve stimulation, and side effects profile were compared.
Results:
Total 81% patients remitted; PR (83%) was commoner than CSR (p=0.003). Factors favoring remission were early onset disease, therapeutic leukopenia (p=0.003) and longer follow-up (OR5, p=0.08); those associated with relapse were abnormal thymus (CI-1.1-3.4; p=0.09), MGFA class IIb (CI 0.9-3; p=0.09) and male gender. Side effects occurred in 48%.
Conclusion:
Aggressive therapy with prednisolone plus azathioprine induces remission in a high percentage of patients with generalized MG.
... V ďalšom priebehu sa u 28 pa cientov pridružili iné myastenické príznaky. Lokalizovanú okulárnu formu MGAT sme zaznamenali u 11 pa cientov (8,9 %), čo koreluje s literárnymi údajmi [22,23]. U každého pa cienta s potvrdenou MG, vrátane okulárnej formy, je nutné realizovať CT mediastina s kontrastnou látkou na vylúčenie tymómu. ...
Introduction: Thymoma-associated myasthenia gravis (TAMG) differs from other forms of MG mainly by combined presence of intrathymic (thymus, thymoma) and extrathymic autoimmune mechanisms in their immunopathogenesis. Aims: We present a retrospective longitudinal study of 123 patients with TAMG registered in the Slovak Centre for Neuromuscular Diseases between 1978 and 2015. The aim of the study was to analyse epidemiological and clinical data, laboratory findings and factors affecting prognosis of TAMG. Material and methods: We analysed data from medical records of patients with TAMG. We examined the age at disease onset, gender, presence of autoantibodies against AChRs and MuSK and type of clinical symptomatology. We evaluated therapies used, clinical status at the last examination and prognosis of TAMG patients. Results: Out of 2, 074 MG patients, we found TAMG in 123 patients (5.9%), 46 men and 77 women. Median age at disease onset was 51 years. All patients, except one, had AChR seropositive MG. In 78 patients (63.4%) remission or significant improvement by immunotherapy and surgical treatment was achieved. The best results were obtained in patients with early TAMG diagnosis. MG has not been the primary cause of death in any patient for the last 20 years. 91 patients had benign and 32 malignant thymoma. Six patients with malignant thymoma died following thymoma dissemination, four of these had MG in remission. Conclusion: TAMG was found in 5.9 % of 2, 074 patients. TAMG is AChR-seropositive. Both, MG severity and biological characteristics of thymoma, determine TAMG prognosis. Early diagnosis and optimal treatment of TAMG are crucial for favourable prognosis.
... Myasthenia gravis (MG) is caused by autoantibodies against the acetylcholine receptor (AChR) in approximately 80% of patients and against the muscle-specific receptor tyrosine kinase (MuSK) in 10% of anti-AChR antibody-negative patients in a Japanese cohort [1]. The heterogeneous nature of the disease subgroups according to age of disease onset, thymus pathology, and presence of antibody has been studied in relation to genetic susceptibility, particularly with regards to human leukocyte antigen (HLA) type, in different ethnic populations. ...
... Forty-three Japanese patients with anti-AChR antibody positive MG and 25 healthy participants of similar age and sex (men, 9; women, 16; mean age, 52.4 years; range, 33-72 years) were included in the present study. We reviewed patient data regarding sex, age, disease duration, anti-AChR antibody titer, E-L-T classification (early-onset MG [EOMG], age at onset ≤ 49 years; late-onset MG [LOMG], age at onset ≥ 50 years; thymoma-associated MG [TAMG]) 8 , MG Foundation of America (MGFA) classification 9 and quantitative MG (QMG) scores 9 at the time of serum sampling. No patients with MG received immunosuppressive therapy then. ...
Myasthenia gravis (MG) is an autoimmunological inflammatory disorder of the neuromuscular junction. Inflammation could be a key player for understanding the pathogenesis of MG. We measured the serum levels of 24 inflammatory cytokines in 43 patients with anti-acetylcholine receptor antibody-positive MG and 25 healthy controls. In patients with MG, serum levels of a proliferation-inducing ligand (APRIL), IL-19, IL-20, IL-28A and IL-35 were significantly increased as compared with controls (p < 0.05). Among them, IL-20, IL-28A and IL-35 were significantly decreased after treatment (p < 0.05). In clinical subtype analyses, APRIL and IL-20 were increased in patients with late-onset MG and IL-28A levels were increased in patients with thymoma-associated MG compared with healthy controls (p < 0.01). The results of the present study demonstrate both anti-inflammatory and inflammatory cytokines are upregulated in MG, reflecting the importance of cytokine-mediated inflammation and its regulation in MG pathophysiology.
... Anti-MuSK antibodies were negative in 229 ocular MG in seven reports. 4,6,12,[17][18][19][20] The ocular type of MG with anti-MuSK antibodies (MuSK-OMG) is very rare. Here, we present two cases of Japanese ocular MG patients who were seropositive for anti-MuSK antibodies. ...
Objective
Many myasthenia gravis ( MG ) patients with anti‐muscle‐specific tyrosine kinase (Mu SK ) antibodies have prominent oculobulbar symptoms or weaknesses of the neck and respiratory muscles. An ocular form of MG having anti‐Mu SK antibodies (Mu SK ‐ OMG ) is very rare. We review the clinical features of two such cases.
Methods
We reviewed cases of patients with an ocular form of MG having anti‐Mu SK antibodies, including two new cases.
Results
We found seven published cases, plus two cases described in this report. The mean age at onset of these nine patients was 37.0 ± 17.7 years, and the mean disease duration (from ocular MG onset to report) was 47.0 ± 43.1 months. The clinical courses appeared benign, but heterogeneous. Five of the patients responded to pyridstigmine. Four patients received immunotherapy, which resulted in improvement. Our two patients had mild ocular symptoms. One patient was stable with no immunosuppressive treatment, and the other patient was treated with prednisolone and tacrolimus.
Conclusions
Cases of an ocular form of MG having anti‐Mu SK antibodies do exist. The benign clinical courses and pharmacological responses to cholinesterase inhibitors imply that the antibodies might have different pathogenicities and specificities from those of Mu SK ‐generalized MG . The presence of anti‐Mu SK antibodies should therefore be determined in ocular MG patients negative for anti‐acetylcholine receptor antibodies.
... Myasthenia gravis (MG) is caused by autoantibodies against the acetylcholine receptor (AChR) in approximately 80% of patients and against the muscle-specific receptor tyrosine kinase (MuSK) in 10% of anti-AChR antibody-negative patients in a Japanese cohort [1]. The heterogeneous nature of the disease subgroups according to age of disease onset, thymus pathology, and presence of antibody has been studied in relation to genetic susceptibility, particularly with regards to human leukocyte antigen (HLA) type, in different ethnic populations. ...
Background:
Myasthenia gravis (MG) is an autoimmune disorder presumed to be associated with genetic susceptibility. This study aims to determine whether HLA is associated with MG in Japanese patients.
Methods:
We included 58 MG patients with anti-acetylcholine receptor antibody (AChR+MG) and 14 MG patients with muscle-specific receptor tyrosine kinase (MuSK+MG) and determined HLA-A, B, DRB1 and -DQB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide and primers. AChR+MG was classified into the three subgroups: early-onset MG (EOMG; n=11), late-onset MG (LOMG; n=20), and thymoma-associated MG (n=27). Healthy volunteers (n=100) served as controls.
Results:
A significant positive association was observed between MuSK+MG with the DRB1*14 [57.1%, MuSK+MG vs. 18.0%, healthy controls (HC); odds ratio (OR): 6.1] and DQB1*05 [78.6%, MuSK+MG vs. 30.0%, HC; odds ratio (OR): 8.5]. We found a negative association between LOMG and DQB1*04 [5.0%, LOMG vs. 37.0%, HC; OR: 0.09]. There was no association between other MG subgroups and HLA alleles.
Conclusion:
HLA-DRB1*14 and DQB1*05 were associated with MuSK+MG, therefore these alleles may play important roles in developing MuSK+MG across the races.
... In clinical research, the age of division is most often set at 50 years, based on ages at which the male-to-female ratios change and age-of-onset histogram findings. 34 Recently, the boundary between EOMG and LOMG was reported to be approximately 45 years-of-age from a statistical perspective using two-step cluster analysis. 35 Oral immunosuppressive therapy ...
Treatment of myasthenia gravis has depended largely on high-dose corticosteroids for decades. Although this procedure remarkably reduced the mortality rate of myasthenia gravis, it highlighted issues such as the adverse-effects of steroids and reduction in quality of life. With the recent discovery of novel autoantibodies, a numbers of alternative therapeutic options have become available. The new Japanese clinical guidelines for myasthenia gravis were published in 2014, and they proposed a novel treatment strategy utilizing these therapeutic options, which might replace high-dose steroids. They also proposed a draft of new diagnostic criteria. The present review introduces the essence of these guidelines and shares the fundamental philosophy of the treatments that value the patients' quality of life.
A 41-year-old woman diagnosed with seronegative myasthenia gravis struggled to maintain remission for a decade, facing crises every 3 months for several years. After repeated apheresis using a non-tunneled non-cuffed central venous dialysis catheter (NTNCC), complications such as catheter-related thrombus in the internal jugular veins and morbid obesity from steroids made the insertion of NTNCC increasingly difficult, leading to consideration of an alternative permanent vascular access (VA) approach. Thus, we created a subcutaneously superficialized brachial artery as the VA, which allowed the patient to undergo safe and uninterrupted apheresis therapy.
Background
A realistic treatment goal for myasthenia gravis (MG) is achieving minimal manifestations or better status with prednisolone at ≤5 mg/day (MM‐or‐better‐5 mg), considering a patient's health‐related quality of life. Prognosis prediction during the early phases of immunotherapies might be critical for determining subsequent treatment strategies; however, the appropriate biomarkers remain unknown.
Aim
This study aimed to clarify whether the reduction rate of anti‐acetylcholine receptor antibody (RR‐AChR Ab) titer levels is a useful biomarker for predicting MM‐or‐better‐5 mg achievement.
Methods
We retrospectively investigated patients with MG and AChR Abs who received immunotherapy for the first time. The RR‐AChR Ab titer levels were calculated in the early (within 30 days), middle (31–60 days), and late (61–100 days) periods after starting immunotherapies. A receiver operating characteristic (ROC) curve was generated to determine an appropriate cutoff value for RR‐AChR Abs to achieve an MM‐or‐better‐5 mg.
Results
Of 53 patients, 24 (45%) achieved MM‐or‐better‐5 mg after 1 year. For the early period, the RR‐AChR Ab cutoff value to predict MM‐or‐better‐5 mg was 1.68%/day with an area under the curve (AUC) of 0.75 (sensitivity, 85%; specificity, 70%). However, the middle and late posttreatment AUC values did not predict MM‐or‐better‐5 mg achievement.
Conclusion
The RR‐AChR Ab might be an appropriate prognostic biomarker during the early period of MM‐or‐better‐5 mg achievement. In the era of early fast‐acting treatment strategies, the RR‐AChR Ab trend after starting immunotherapies may guide the subsequent treatment choices.
Objective:
Myasthenia gravis (MG) is an antibody-mediated inflammatory disease affecting post-synaptic membranes of neuromuscular junctions, and objective biomarkers of MG disease activity are lacking. Pentraxin 3 (PTX3) is an acute-phase inflammatory glycoprotein in the same family as C-reactive protein that is associated with disease activity in several autoimmune disorders. Thus, we investigated whether circulating PTX3 is a useful biomarker of MG activity.
Methods:
Serum PTX3 was measured in 40 patients with MG who were positive for anti-acetylcholine receptor antibody, and in 30 healthy and disease controls, using a commercial enzyme-linked immunosorbent assay kit. In patients with MG, the correlation of serum PTX3 levels with disease severity scales at serum sampling, including MG Foundation of America (MGFA) classification, MG activity of daily living (MG-ADL) score, and quantitative MG (QMG) score, were investigated.
Results:
Although there was no significant difference in serum PTX3 between the MG and control groups (mean, 3346 pg/mL in MG group vs. 2870 pg/mL in control group, P = 0.56), serum PTX3 moderately correlated with all disease severity scores (MGFA classification: Spearman's ρ = 0.53, P = 0.0004; MG-ADL score: Spearman's ρ = 0.45, P = 0.004; QMG score: Spearman's ρ = 0.50, P = 0.004).
Conclusion:
Our results suggest that circulating PTX3 may reflect the extent of neuromuscular junction damage and might be involved in the pathogenesis of MG.
Introduction
Improving our knowledge on the cause of death and triggers of crisis in myasthenia gravis (MG) patients may have a patient be careful in the daily life.
Methods
We selected 233 MG patients with regular visits to our hospital between 1st May 2006 and 31 December 2018. We investigated the cause of death and trigger of crisis at our hospital.
Results
Eight MG patients were confirmed to die during the observation period, and the causes of death were four cases of cancer (breast cancer, pancreatic cancer, stomach cancer, and cancer of an unknown primary site) and two cases of sudden death (sudden cardiac arrest and cardiac arrest from choking), invasive thymoma, and vertebral artery dissection. Fourteen patients experienced crisis, and the most common trigger of crisis was respiratory infection, followed by cholinergic and intravenous methylprednisolone.
Conclusion
The most common cause of death was cancer, and the most common trigger of crisis was respiratory infection. Sudden death was characteristic of MG patients. Respiratory infection and malignancy should be considered in MG patients regularly to prevent crisis and death. Further research on sudden death in MG patients should be performed.
Objective:
To investigate the association between changes in anti-acetylcholine receptor antibody (AChR Ab) levels induced by immunosuppressive treatment and myasthenia gravis (MG) prognosis at 1-year post-treatment in patients with MG.
Methods:
We included 53 consecutive AChR Ab-positive patients with MG whose AChR Ab levels were remeasured within 100 days of initiating immunosuppressive treatment (median remeasuring time post-treatment: 71 (55-84) days). The AChR Ab level reduction rate (RR-AChRAb, %/day) adjusted for the time between treatment initiation, and AChR Ab level remeasurement was calculated as follows: (pretreatment-post-treatment AChR Ab level)/pretreatment AChR Ab level/days between therapy initiation and AChR Ab level remeasurement ×100. Participants were divided into two groups based on the cut-off value of RR-AChR Ab, determined using receiver operating characteristic analyses for achieving minimal manifestation (MM) or better status at 1-year postimmunosuppressive treatment. The Myasthenia Gravis Foundation of America postintervention status and MG activity of daily living (MG-ADL) score at 1-year post-treatment were compared between the two groups.
Results:
The RR-AChRAb cut-off value was 0.64%/day. The high RR-AChRAb group had a higher ratio of MM or better status (90% vs 65%, p=0.03) and lower MG-ADL score (median; 1 vs 2, p=0.04) than the low RR-AChRAb group. Kaplan-Meier analyses showed the early MM achievement in the high RR-AChRAb group (p=0.002, log-rank test).
Conclusions:
High RR-AChRAb is associated with a favourable outcome at 1-year post-treatment. AChR Ab remeasurement within 100 days of therapy may be useful for predicting AChR Ab-positive MG outcomes at 1-year post-treatment.
Introduction:
The majority of patients with myasthenia gravis (MG) initially present with ocular symptoms but it is difficult to predict which cases will remain as ocular MG (OMG) or will progress to generalized MG. Here, we evaluated the serological profile of Japanese OMG and its relationship with clinical features.
Methods:
Seventy-three patients with OMG from 5 Japanese myasthenia gravis (MG) centers were enrolled. Live cell-based assays (CBAs) were used to determine the presence of autoantibodies (Abs) to clustered adult (2α, β, δ, ε) and fetal (2α, β, δ, γ) acetylcholine receptor (AChR) isoforms, muscle-specific receptor tyrosine kinase (MuSK) and lipoprotein receptor-related protein-4 (LRP4).
Results:
Thirty-four of 73 (46.5%) serum samples were positive for Abs against both the adult-type and fetal-type AChR, as expected, but 7 (9.6%) and 2 (2.7%) were positive only for fetal or adult AChR-Abs, respectively. Four (5.4%) samples were positive for MuSK-Abs, but 2 of these also contained antibodies to fetal AChR or LRP4. Twenty-six (35.6%) samples were seronegative.
Discussion:
Abs against fetal-specific AChR, MuSK and LRP4 are found in some patients with OMG. Further studies attempting to predict conversion from ocular symptoms to generalized MG may benefit from the measurement of these antibodies.
High-dose intravenous methylprednisolone (IVMP) is often used as a treatment for generalized myasthenia gravis (MG); however, little is reported about the efficacy of IVMP in ocular MG. We evaluated the efficacy and safety of IVMP therapy and compared results with those of conventional oral prednisolone (PSL) treatment in ocular MG. We retrospectively studied 18 patients with ocular MG. Clinical course and safety during 6 months in 10 patients who were treated with IVMP were compared with those of 8 who were treated with PSL. IVMP (1000 mg/day) was administered one to three times within 6 months, whereas oral PSL was administered at the dose of 5–10 mg/day. The score for MG activities of daily living profile (MGADL) was assessed at baseline and at 1, 3, and 6 months after treatment. Patients who received IVMP showed faster improvements than those receiving PSL; the median changes in the ocular scores on the MGADL was −2 versus 0 at 1 month (p = 0.03), −3 versus −1 at 3 months (p = 0.07), and −3 versus −2 (p = 0.86) at 6 months. No patient in either group developed initial worsening of symptoms or generalized weakness. In conclusion, IVMP results in more rapid improvement than oral PSL therapy and can be a treatment option for ocular MG.
Objectives
Most patients with myasthenia gravis (MG) undergo thoracic imaging at initial diagnosis. However, the follow‐up protocol is unclear. The objective of the present study was to clarify the follow‐up status and main findings of thoracic imaging in patients with MG.
Methods
A total of 649 patients with disease duration ≥1 year were included in the study. The follow‐up rate and time from the initial scan to the latest thoracic imaging were evaluated. The rate of abnormality and details of abnormal findings in both non‐thymomatous MG and thymoma‐associated MG were investigated.
Results
The follow‐up thoracic imaging rate of 145 patients with thymoma‐associated MG was 71.7%, whereas just 46.2% of 504 patients with non‐thymomatous MG underwent follow‐up imaging. Abnormal findings were detected in 8.6% of patients with non‐thymomatous MG and 26.0% of those with thymoma‐associated MG. Abnormal findings included cancer, lung infection and lymph node swelling in the former, and relapse or increased size of thymoma in the latter.
Conclusions
Frequent follow up by thoracic imaging is necessary in patients with MG.
Objective
Damage‐associated molecular patterns (DAMP) and cytokines can play a crucial role in inflammation at neuromuscular junctions in myasthenia gravis (MG). However, the relationship between DAMP and cytokine levels in MG pathogenesis remains unknown. To clarify this, we examined the relationship between serum levels of DAMP and cytokines in MG patients.
Methods
Using serum data from 26 patients with anti‐acetylcholine receptor antibody‐positive MG, we investigated the relationship between the levels of DAMP (high‐mobility group box 1 [HMGB1] and peroxiredoxin 5) and cytokines (interleukin [IL]‐4, IL‐15, IL‐19, IL‐20, IL‐28A, IL‐35, a proliferation‐inducing ligand [APRIL] and vascular endothelial growth factor), which were reported to be significantly elevated in MG.
Results
Serum levels of APRIL (r = 0.4789, P = 0.0133), IL‐19 (r = 0.5496, P = 0.0036) and IL‐35 (r = 0.5396, P = 0.0044) were correlated with those of HMGB1, but no cytokine levels were correlated with peroxiredoxin 5 levels. When we carried out multivariate analyses, only APRIL (P = 0.0244) and IL‐19 (P = 0.0009) levels were correlated with HMGB1 levels.
Conclusions
HMGB1 might be related with upregulation of IL‐19 and APRIL levels in MG immunopathogenesis. These molecules could play a key role in controlling autoimmune inflammatory response, and represent a potent therapeutic target in MG.
Treatments for MG, which is an autoimmune disease, are based on immunotherapy by steroids and immunosuppressants. In Japan, treatments include cholinesterase inhibitors, thymectomy, steroids, immunosuppressants, plasma exchange, and intravenous immunoglobulin therapy. However, even when utilizing all of these treatments, the proportion of MG patients who enter complete stable remission is less than 10 %. The current goal of MG treatment is firstly to treat MG patients at onset to pharmacological remission as rapidly as possible using the above therapies; the second is reducing oral prednisolone to 5 mg/day or less to minimize disease manifestation and symptoms in daily life. Japanese MG clinical guidelines were revised in 2014, with proposed novel MG diagnostic criteria and new standard treatments. Currently, reviewing MG treatments which had been done previously is being done in each facility. Here, the authors describe the therapeutic protocol according to onset age, disease type, and pathogenic autoantibodies conducted in Nagasaki University Hospital. We have combined the MG clinical guidelines for 2014 with our experiences to date and are treating MG patients using this protocol.
Myasthenia gravis is a heterogeneous disease, and it presents various clinical differences according to the age of onset. Immunological backgrounds that cause these differences are not well understood. Kubota et al. investigated subsets of circulating T and B lymphocytes using various markers. They argued that a reduced percentage of memory B cells seems to be a characteristic of late-onset myasthenia gravis.
Calcineurin inhibitors are approved for the treatment of myasthenia gravis in Japan. Utsugisawa et al. described the use of calcineurin inhibitors and outcomes of myasthenia gravis in Japan using the data of a multicenter survey. According to the result, they argue that calcineurin inhibitors should be given more aggressively to late-onset myasthenia gravis patients and early-stage disease.
Myasthenia gravis (MG) was first described in 17(th) century. It was after 1960s, when it became clear that MG was an autoimmune disease targeting AChR. Recently, anti-MuSK and anti-Lrp4 antibodies were found as novel antibodies in MG. In 1980s, in addition to cholinesterase inhibitors, high-dose corticosteroid treatment was introduced. This dramatically reduced the mortality rate of MG, but now we recognized that side effects of steroid have influenced patients significantly, and that high dose of steroid correlate with poor QOL. Since we have more means to treat MG at present, and also in the future, we should shift to the strategy in which steroid dose is kept low.
Objectives
Calcineurin inhibitors (CNI) are approved for the treatment of myasthenia gravis (MG) in Japan. However, the extent to which CNI have been effective remains unclear. Here we report data regarding CNI use and outcomes of MG.Methods
We evaluated 640 consecutive MG patients by a multicenter survey. Patients not receiving any immune treatment were excluded, and cross-sectional and retrospective data of 515 patients receiving immune treatment with (n = 312) or without (n = 203) CNI were analyzed.ResultsCompared with patients treated without CNI, those treated with CNI had a higher frequency of MG Foundation of America Class III–V and higher severity disease at the worst clinical condition, and also had current higher severity, worse quality of life and higher daily doses of prednisolone, despite taking equivalent prednisolone dosages during the course of treatment. Achieving a treatment target was less frequent in the group treated with CNI. Onset age was not different between the two groups. Duration before CNI use after starting corticosteroids was 4.4 ± 6.3 years. Among those treated with CNI, late-onset MG patients achieved a more favorable current condition than did those with early-onset and thymoma-associated MG, whereas there was no such difference without CNI treatment.ConclusionsCNI were given to severely ill MG patients with no attempt to select those more likely to respond, and failed to exert a strong impact on MG therapy. CNI should be given aggressively to patients with factors known to enhance susceptibility to these drugs, such as higher age at onset and early-stage disease.
A nationwide multicenter analysis of Japanese patients with myasthenia gravis (MG) is reported in this issue by Murai et al. (Clin Exp Neuroimmunol. 2014; 5(1) 84–91. The study has revealed the characteristics of three subgroups of Japanese MG; early onset, late onset and thymoma-associated MG.
Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG.
This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥ 60 years) (OR 2.38, p(c)7.4 × 10(-5)). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, p(c) 4.71 × 10(-4)), a finding not previously described. No significant association was found to the DRB1*07:01 allele (p(nc) = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies.
The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.
抄録
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.
Myasthenia gravis (MG) is caused by antibodies that react mainly with the acetylcholine receptor on the postsynaptic site of the neuromuscular junction. A wide range of clinical presentations and associated features allow MG to be classified into subtypes based on autoantibody status. Striational antibodies, which react with epitopes on the muscle proteins titin, ryanodine receptor (RyR), and Kv1.4, are frequently found in MG patients with late-onset and thymoma. Antititin and anti-RyR antibodies are determined by enzyme-linked immunosorbent assay or immunoblot. More recently, a method for the detection of anti-Kv1.4 autoantibodies has become available, involving 12-15% of all MG patients. The presence of striational antibodies is associated with more severe disease in all MG subgroups. Anti-Kv1.4 antibody is a useful marker for the potential development of lethal autoimmune myocarditis and response to calcineurin inhibitors. Detection of striational antibodies provides more specific and useful clinical information in MG patients.
A retrospective chart review was performed on patients diagnosed as having myasthenia gravis in Ceará State, Brazil and who were followed from October 1981 to June 2009. Clinical and epidemiologic aspects were evaluated. In this work, 122 patients were studied, of whom 85 (69.7%) were females and 37 (30.3%) were males. The disease duration ranged from five months to 50 years (8.9±8.1 years). Age at the first symptoms varied from 0 to 74 years (31.9±14.4 years). The first main symptoms and signs were ptosis, diplopia and limb weakness. Generalized myasthenia was the most common clinical presentation, but 5.1% (n=6) persisted as ocular myasthenia. Thymectomy was performed in 42.6% (n=52) of myasthenic patients. A thymoma was present in 10 patients. Serum acetylcholine receptor (AChR) antibodies were present in 80% (n=20) of specimens tested. The data presented are similar to those of studies performed in other countries.
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.
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.
The EAT group achieved marked early improvement 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.
The EAT strategy has advantages of early improvement with less frequent steroid-related complications. The labor and cost required are evident disadvantages.
Myasthenia gravis is probably commoner than previously suspected, the annual incidence being nearer 9-10/million than earlier figures of 2-4/million. The current study found an annual incidence in Croyden of 9.1 per million (95% confidence limits 5.7-13.8 per million). Of the 22 patients (59%) seen in Croyden with newly diagnosed myasthenia gravis during the past 7 years, 13 were aged over 60. In a separate study of the age distribution of positive acetylcholine receptor antibody assays, 51% were 60 years or above in 1991, and 64% in 1994. The peak age in both sexes was 70-80, and numbers were greatest in men aged 60-80.
The authors have developed an MG activities of daily living (ADL) profile (MG-ADL)-a simple eight-question survey of MG symptoms. In 254 consecutive encounters with established MG patients, the authors compared scores from the MG-ADL to the quantitative MG score (QMG)-a standardized, reliable scale used in clinical trials. The mean MG-ADL score was 4.89+/-3.63. The mean QMG score was 10.80+/-5.70. Pearson's correlation coefficient was 0.583 (p < 0.001). The MG-ADL is an easy-to-administer survey of MG that correlates well with the QMG and can serve as a secondary efficacy measurement in clinical trials.
Myasthenia gravis (MG) is an antibody-mediated autoimmune disease of the neuromuscular junction. In approximately 80% of patients, auto-antibodies to the muscle nicotinic acetylcholine receptor (AChR) are present. These antibodies cause loss of AChR numbers and function, and lead to failure of neuromuscular transmission with muscle weakness. The pathogenic mechanisms acting in the 20% of patients with generalized MG who are seronegative for AChR-antibodies (AChR-Ab) have not been elucidated, but there is evidence that they also have an antibody-mediated disorder, with the antibodies directed towards another, previously unidentified muscle-surface-membrane target. Here we show that 70% of AChR-Ab-seronegative MG patients, but not AChR-Ab-seropositive MG patients, have serum auto-antibodies against the muscle-specific receptor tyrosine kinase, MuSK. MuSK mediates the agrin-induced clustering of AChRs during synapse formation, and is also expressed at the mature neuromuscular junction. The MuSK antibodies were specific for the extracellular domains of MuSK expressed in transfected COS7 cells and strongly inhibited MuSK function in cultured myotubes. Our results indicate the involvement of MuSK antibodies in the pathogenesis of AChR-Ab-seronegative MG, thus defining two immunologically distinct forms of the disease. Measurement of MuSK antibodies will substantially aid diagnosis and clinical management.
In European countries and the United States the incidence of elderly-onset myasthenia gravis (MG) has recently been increasing. To investigate whether the incidence of the elderly-onset MG has increased in Nagano Prefecture of Japan, we divided the patients into young and elderly groups, and retrospectively examined their incidence.
On the basis of two-step questionnaires sent to hospitals and the patient list of the intractable disease registration system in Nagano Prefecture we studied 213 MG patients diagnosed between 1982 and 2001. This 20-year period was divided into 4 five-year terms, and the incidence of MG in young- (younger than 65) and elderly-onset (65 or older) groups was investigated separately for each term.
The ratio of the elderly-onset group showed a significantly positive correlation with terms irrespective of associated thymoma (r=0.98, p<0.05). There was a significant difference in the mean onset age among the 4 terms (p<0.005). The standardized incidence of MG gradually increased in both young- and elderly-onset groups as well as in the whole age range. The elderly group showed a particularly high incidence in females (12.01/million/year) and in patients without thymoma (8.78/million/year) in the final five years.
We confirmed that the incidence of elderly-onset MG has recently been increasing in the Nagano Prefecture. Since the change of the age distribution in this district is almost identical to that of the whole country, the incidence of MG might have been increasing in Japan as a whole, particularly in the elderly population.
[Purpose] The onset of myasthenia gravis (MG) often occurs in childhood or at the age between 20 and 50 years. We had experienced several patients with a late onset age of MG. One of them had previously undergone a surgery for binocular blepharoptosis at another clinic. In this study, we reported the clinical characteristics of eight patients with a late onset age of MG.
[Subjects and Methods] Eight patients with MG diagnosed at the Fururoshi Eye Clinic between 2003 and 2013 were reviewed. Age, main complaint, lid fissure width, lid lag test, eye position, ocular movement, and anti-acetylcholine receptor antibody titer were retrospectively investigated.
[Results] The gender ratio of the patients was 1:1. Their ages ranged from 36 to 87 years (mean, 68.5 years) with 1 patient each in their 30s, 50s, and 60s, 3 in their 70s, and 2 in their 80s. The most common main complaint was "the droopy eyelids" in 6 patients, followed by "seeing double" in 3 patients, "having difficulty seeing" in 2 patients, and "poor depth perception" in 1 patient. Seven patients had experienced sudden onset of symptoms. Clinical manifestation included asymmetric blepharoptosis in all 8 patients, ocular motility disorder in 4 patients, affected superior rectus muscles in 3 patients, affected inferior oblique muscles in 4 patients, and affected lateral rectus muscle in 1 patient. The angle of deviation was 5-25⊿. The diagnosis was confirmed by an anti-acetylcholine receptor antibody test in 7 patients and by a doctor in neurointernal medicine in the remaining patient.
[Conclusion] At our clinic, 75% of the patients with MG experienced the onset at an age over 60 years. Ocular symptoms occurred suddenly and blepharoptosis was mild and asymmetric. Ocular motility disorder occurred in 50% of the patients with fluctuation seen in the angle of deviation. As cases of MG with a late onset age are increasing in Japan in recent years, the possibility of MG should be considered when an elderly patient presents with sudden symptoms of blepharoptosis and diplopia.
Introduction:
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).
Methods:
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.
Results:
In a cross-sectional analysis of 640 MG patients, multivariate regression revealed that disease severity, as evaluated by the MG Composite (P<0.0001), 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.
Conclusions:
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.
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.
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.
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.
The MG-QOL15-J is anticipated to be a valuable clinical measure of QOL in Japanese patients with MG.
An increasing incidence of myasthenia gravis (MG) has been reported in the elderly, but the full clinical ramifications of late-onset myasthenia gravis (LOMG) remain unclear. We describe the clinical features of our cohort of patients with MG with an emphasis on an onset after the age of 50. This was a retrospective analysis of medical records of a cohort of patients followed in two tertiary neuromuscular clinics and comparison of early onset MG (EOMG) versus LOMG. There were 174 patients with a mean age of onset of 55.2 ± 19.1 years, and 44 % were women. Late onset of myasthenia gravis after age 50 was reported in 114 patients (66 %). Anti-AChR antibody titers were elevated in 78 % of patients (65 % with EOMG vs. 85 % with LOMG; p = 0.003), and frequency of elevated titers of anti-MuSK antibodies was similar in both groups (present in 38 % of all tested seronegative patients). Myasthenic crisis was equally common in generalized EOMG and LOMG (13 %). Ocular MG was more common in LOMG compared to EOMG (40 vs. 18 %, p = 0.021). Diabetes was more prevalent with LOMG (27 vs. 5 %; p = 0.0002). Overlapping clinical features of EOMG and LOMG are consistent with a continuous clinical spectrum of a single condition, with more frequent occurrence of seropositive and ocular MG with a late onset. A higher burden of comorbidities, such as diabetes mellitus, may warrant a modified approach to treatment of myasthenia in LOMG. However, overall disease severity may not be higher with aging. These observations have implications for design of MG clinical trials and outcomes studies.
Myasthenia gravis (MG) is an autoimmune disorder mediated by antibodies against the acethylcholine receptor (AchR) of the neuromuscular junction in the majority of patients.
Here, we examined IgG antibodies against the type 1 nuclear antigen of Epstein-Barr virus (EBNA-1) in the sera of 158 patients with MG compared to 184 healthy controls.
Although serum concentration in the sera was not different, high anti-EBNA-1 IgG titers (above 90th percentile of the normal values) were more common in the patients (26.6 vs. 16.3%, P=0.024). In addition, high EBNA-1 IgG levels occurred more frequently amongst the 94 patients with early-onset myasthenia gravis (EOMG, 30.8%) as compared to the 64 patients with late-onset disease (LOMG, 14.1%) (P=0.021). Using multiple logistic regression, high serum concentration of the anti-EBNA-1 IgG antibodies was significantly associated with EOMG (OR: 3.17, P=0.027), even after adjustment for sex, presence/absence of anti-AchR antibodies and presence/absence of anti-Titin antibodies. Out of 39 patients with EOMG, who underwent thymectomy, 18 patients (46%) had thymoma, 6 had thymic hyperplasia (15%), and 15 patients had thymic atrophy (39%); there was no difference comparing EBNA-1 antibody titers in the sera. As no correlation was found between the titers of anti-AchR, anti-Titin, and EBNA-1 antibodies, a dysregulated heterogeneous B-cell response was unlikely to be responsible for the elevated levels of EBV-associated antibody in patients.
In summary, our data suggest that high levels of EBNA-1 antibodies are more common in MG compared to healthy controls and are especially associated with EOMG.
The thymus is believed to play an important role in the pathogenesis of myasthenia gravis (MG). The 80% of MG patients with anti-acetylcholine receptor autoantibodies fall into three clinical subgroups: 1) thymoma; 2) early-onset MG (<age of 40; EOMG) and 3) late-onset (LOMG; onset after 40). Thymectomy is widely used in EOMG, but its benefits have not been established in randomized controlled trials. A multicenter international trial (MGTX) currently seeks to determine whether thymectomy reduces corticosteroid requirements, and to look for correlations with thymic histology. We here describe the validated, standardized histological workup and reporting system used in this trial.
To clarify the prevalence and clinical characteristics of myasthenia gravis (MG) in Japan.
We performed a nationwide epidemiological survey of MG in Japan. The clinical features were compared among five groups of patients, divided according to onset age. A generalized additive model (GAM) was used to assess the linearity of these relationships.
A total of 8542 patients were reported, and detailed data were analyzed for 3141 patients. The estimated number of MG patients in Japan was 15,100, giving a prevalence of 11.8 per 100,000. Elderly-onset MG (≥ 65 years) accounted for 7.3% in 1987 (adjusted for population in 2005), but this had increased to 16.8% in 2006. Infantile-onset MG (0-4 years) accounted for 10.1% in 1987, and was still as high as 7.0% in 2006. The rate of ocular MG was highest (80.6%) in infantile-onset and lowest (26.4%) in early-onset disease, but the rate rose again in the late-onset group. GAM analysis of the ocular form showed a U-shaped curve, with a dip in the 20s. Anti-acetylcholine receptor antibodies were positive in only 50% of infantile-onset, but nearly 90% of elderly-onset patients. GAM analyses assessing the concurrence of thymoma and hyperplasia both showed reversed U-shapes, with peaks in the 50s and 20s-40s, respectively.
Persistent high incidence of infantile-onset disease and clinical heterogeneity according to onset age are characteristic features of MG in Japan.
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction, where acetylcholine receptor (AChR), muscle-specific kinase (MuSK), and low-density lipoprotein (LDL) receptor-related protein 4 (Lrp4) are essential. About 80% and 0% to 10% of patients with generalized MG have autoantibodies to AChR and MuSK, respectively, but pathogenic factors are elusive in others. Here we show that a proportion of AChR antibody-negative patients have autoantibodies to Lrp4. These antibodies inhibit binding of Lrp4 to its ligand and predominantly belong to the immunoglobulin G1 (IgG1) subclass, a complement activator. These findings together indicate the involvement of Lrp4 antibodies in the pathogenesis of AChR antibody-negative 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.
To study the concurrent and construct validity and test-retest reliability in the practice setting of an outcome measure for myasthenia gravis (MG).
Eleven centers participated in the validation study of the Myasthenia Gravis Composite (MGC) scale. Patients with MG were evaluated at 2 consecutive visits. Concurrent and construct validities of the MGC were assessed by evaluating MGC scores in the context of other MG-specific outcome measures. We used numerous potential indicators of clinical improvement to assess the sensitivity and specificity of the MGC for detecting clinical improvement. Test-retest reliability was performed on patients at the University of Virginia.
A total of 175 patients with MG were enrolled at 11 sites from July 1, 2008, to January 31, 2009. A total of 151 patients were seen in follow-up. Total MGC scores showed excellent concurrent validity with other MG-specific scales. Analyses of sensitivities and specificities of the MGC revealed that a 3-point improvement in total MGC score was optimal for signifying clinical improvement. A 3-point improvement in the MGC also appears to represent a meaningful improvement to most patients, as indicated by improved 15-item myasthenia gravis quality of life scale (MG-QOL15) scores. The psychometric properties were no better for an individualized subscore made up of the 2 functional domains that the patient identified as most important to treat. The test-retest reliability coefficient of the MGC was 98%, with a lower 95% confidence interval of 97%, indicating excellent test-retest reliability.
The Myasthenia Gravis Composite is a reliable and valid instrument for measuring clinical status of patients with myasthenia gravis in the practice setting and in clinical trials.
As the number of elderly patients with myasthenia gravis (MG) has recently increased in Europe and the USA, a retrospective survey of Japanese MG patients was conducted in a single neurological centre over several decades.
The study consisted of 112 consecutive MG patients with onset of the disease from 1971 to 2006 from an area of approximately 0.8 million inhabitants in Japan. Patients were classified into three subgroups according to age at onset: young onset (39 years old), middle aged onset (40-59 years old) and elderly onset (60 years old). The trends in incidence rate and clinical features were examined: disease severity, seropositivity for antiacetylcholine receptor antibody, occurrence of other autoimmune diseases, occurrence of thymoma and therapeutic response.
The onset adjusted age specific average annual incidence per 100,000 of the elderly onset MG patients increased 20-fold from 1981-1990 (0.06; 95% CI 0.00 to 0.36) to 2001-2006 (1.30; 95% CI 0.77 to 2.05). Clinical features of the elderly onset MG patients included low antiacetylcholine receptor antibody titres (mean 24.6 nmol/l), less frequent autoimmune overlaps (8.0%) and nearly no complete stable remission with or without thymectomy.
The increasing incidence of elderly onset MG in Japanese patients similar to that reported in Caucasians has been confirmed. The clinical features suggest different immunological backgrounds between young onset and elderly onset MG patients, irrespective of the ethnic background.
We conducted a study of the epidemiology of myasthenia gravis (MG) in four locations in central and western Virginia from 1970 through 1984. The population surveyed was 555,851 in 1984. A total of 73 new cases of MG occurred during the survey period, producing an overall average annual incidence rate of 9.1 per million. The point prevalence rate in 1980 was 13.4 per 100,000, and in 1984 it was 14.2. Approximately 15% of the population was black, and we found that incidence and prevalence rates for the black population were higher than the corresponding white population. When the population was subdivided into <50 and 50+ age groups, the incidence and prevalence were significantly higher in the older group. The rates we report here are higher than rates reported from any other locality. The reasons for the higher rates include optimal case identification, survey of a population with a higher incidence, and increasing aging of the population.
This study, a retrospective review of 165 patients with myasthenia gravis, compares the course of the disease for patients with onset before 50 and at or after 50. There were no significant differences between age groups for presenting symptoms, but more of the older patients had progressed to severe disease. More of the younger than the older patients were in remission or were asymptomatic on medication at the last visit. Sixty-two percent of those treated with steroids developed complications, with a larger portion of these being in the older group. Cataracts, infection, and bone changes were particularly significant for the older population. Complications of azathioprine treatment and plasmapheresis were less common. Thymoma was more common in the older population; these patients did no worse than the population as a whole. Sixty-five percent of our patients have undergone thymectomy, most by a modified transsternal approach. A much larger portion of those who underwent thymectomy were in remission at the last visit than those who did not.
Muscle weakness in myasthenia gravis is due to autoantibody-induced loss of functional acetylcholine receptors (AChR). About 15% of myasthenia gravis patients, however, do not have detectable anti-AChR antibodies. To investigate the effect of their plasma immunoglobulins on neuromuscular transmission, mice were injected with plasma (and in some cases purified immunoglobulin G (IgG)) from 7 "seronegative" myasthenia gravis (SMG) patients, and neuromuscular transmission parameters were examined. When injected for 15 days, all patients' plasma caused reductions in miniature endplate potential amplitudes, while endplate potential quantal content was significantly reduced by plasma from 4 of the 7 patients. There were no changes in ACh-induced depolarization or single channel properties, and 125I-alpha-bungarotoxin binding studies showed no effect on AChR number, except in 1 case. Purified IgG injected for 3 days had similar effects to plasma injected for 15 days. Our findings confirm that SMG is autoantibody mediated and that there are pathogenic IgG antibodies. SMG appears to be a heterogeneous disorder and the target(s) for the antibodies may be diverse.
Data from 756 myasthenic patients were analyzed for diagnostic criteria, clinical aspects, and therapeutic approaches. The patients were followed up at our institution from 1981 to 2001. Clinical evaluation was performed according to the myasthenia gravis score adopted at our clinic. Clinical features of each patient (comprising demographic, clinical, neurophysiological, immunological, radiological, and surgical data, as well as serial myasthenia gravis scores) were filed in a relational database containing more than 7000 records. Clinical efficacy and variables influencing outcome were assessed by life-table methods and Cox proportional hazards regression analysis. Complete stable remission, as defined by the Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America, was the end point for good prognosis. Four hundred and ninety-nine patients (66%) were female and 257 (34%) were male. Mean follow-up was 55.1 +/- 48.1 months. Onset of symptoms peaked in the third decade in females, whereas the male distribution was bimodal with peaks in the third and sixth decades. Modality of myasthenia gravis presentation was as follows: ocular, 39.3%; generalized, 28.5%; bulbar, 31.3%; and respiratory, 0.8%. Thymectomy was carried out on 63.7% of our patients by different approaches: (1) transcervical; (2) transsternal; (3) video-thoracoscopic mini-invasive surgery. The last approach has been preferentially used in more recent years and accounted for 62.4% of the thymectomized myasthenia gravis population. Univariate analysis and Kaplan-Meier analysis showed that variables such as sex (female), age at onset (below 40 years), thymectomy, and histological diagnosis of thymic hyperplasia were significantly associated with complete stable remission, whereas on multivariate analysis only age at onset below 40 years and thymectomy were confirmed.
Muscle-specific tyrosine kinase (MuSK) antibodies are found in some patients with "seronegative" myasthenia gravis (MG), but how they cause myasthenic symptoms is not clear. We visualized acetylcholine receptors (AChRs) and complement component 3 (C3) in muscle biopsies from 10 Japanese MG patients with MuSK antibodies, compared with 42 with AChR antibodies. The AChR density was not significantly decreased in MuSK antibody (Ab)-positive end-plates compared with AChR antibody-positive end-plates, and C3 was detected in only two of eight MuSK Ab-positive patients. MuSK antibodies do not appear to cause substantial AChR loss, complement deposition, or morphological damage. Effects on MuSK function need to be explored.
The incidence of myasthenia gravis (MG) from 1970 through 1999 was studied in an area with 2.3 million inhabitants. The mean annual incidence rate of early-onset MG was constant at 3.5 x 10(-6). In late-onset MG, the rate increased from 4.7 to 20.8 x 10(-6). The two onset types of MG may thus be distinct disorders. The author hypothesized that late-onset nonthymoma anti-acetylcholine receptor antibody-seropositive MG may be provoked by environmental factors.
Between 1940 and 2000 a total of 1976 patients with myasthenia gravis (MG) were studied. Diagnosis was made by improvement in weakness after anticholinesterase medication. The historical developments in diagnosis and treatment of MG are reviewed. We analyzed the clinical course of MG as influenced by age, gender, thymectomy, thymomectomy, and the presence of antibodies to acetylcholine receptors (AChR). The clinical course of MG was significantly influenced by age and gender, and these need special attention in managing patients. The most severe level of weakness and high mortality occurred during the first 1 to 2 years of the disease, after which many patients experienced improvement. For treating MG patients the usefulness of thymectomy remains to be proven, and novel drugs need to be developed to increase the number as well as normal functioning of the AChRs and other components of the neuromuscular system.
We have defined myasthenia gravis (MG) in the elderly as onset after the age of 50 years. MG is diagnosed more often today than previously. The increase is mainly found in patients over the age of 50 years. Neurologists therefore see more old patients with MG now than before. Prevalence of the early-onset form of MG seems to be unchanged. Recent data indicate that MG may still be substantially underdiagnosed in very old people. Ptosis, diplopia, weakness of the facial muscles, and problems of articulation are important clinical signs in MG and are easier to detect in a youthful appearance. Since ageing causes a decrease in the total eyelid area with sagging of the lower eyelids, a ptosis may be more difficult to diagnose in the elderly. In addition, diplopia may not be detected because of reduced vision due to macular degeneration or cataract formation. Ocular symptoms of MG are therefore more easily missed in the elderly. Thymomatous MG is more common among older patients than it is in younger onset. The mean age at onset of MG for thymoma cases is 50-60 years. Approximately 10-15% of all MG patients have a thymoma, and around 40% of all thymoma cases are associated with MG. During normal aging, the thymus tissue becomes atrophic and replaced with fat. Recent data on MG thymus pathology suggest that lymphocyte accumulation indicating residual thymus may also be found in the elderly, and that there is little qualitative difference between the young and the old thymus from MG patients. The mean concentration of antibodies to acetylcholine receptor (AChR) is lower in MG in the elderly than in early-onset or thymoma-associated MG. Seronegative MG is less common among older patients. Approximately 30% of patients with late-onset, nonthymoma MG have antibodies to titin, while such antibodies are extremely scarce in early-onset MG. Titin antibodies in MG patients seem to be associated with a higher frequency of DR7 antigen and a decrease of DR3 antigen. The antibody response in MG may therefore be influenced by the genetic background.
Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population
- Ah Maniaol
- A Elsais
- Ar Lorentzen
Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population
- Maniaol