Osteoporosis prevention in myasthenia gravis: a reminder

OBJECTIVES: Consensus guidelines for bone management of patients taking corticosteroids suggest two main interventions: Dual energy X-ray absorptiometry (DEXA) scanning in those taking prednisolone > or =7.5 mg daily for > or =6 months (repeated every 1-3 years as indicated). Bisphosphonate therapy for those taking prednisolone > or =15 mg daily for > or =6 months regardless of DEXA result, and also for patients with known or high risk of developing osteoporosis (including those aged >65 years). MATERIAL AND METHODS: We audited adherence to these guidelines in all adults with myasthenia gravis (MG) attending our neurology service. RESULTS: Of 80 patients with MG (47 male, mean age 63.3 years), 34 (43%) had received corticosteroids for > or =6 months. Eighteen were taking prednisolone > or =7.5 mg daily (mean dose 16.6 mg) yet only 4 of these (22%) had undergone DEXA scanning. Of the 13 patients meeting the guideline criteria to receive bisphosphonate therapy, this was prescribed to only 7 (54%). Two others were prescribed vitamin D, 2 a calcium supplement and 2 were receiving no prophylaxis. CONCLUSION: In these MG patients the guidelines were followed in only a minority. Neurologists need greater awareness of the bone health consequences of prescribing long-term corticosteroids.     

A patient of chronic graft-versus-host disease presenting simultaneously with polymyositis and myasthenia gravis]

We report a patient of polymyositis and myasthenia gravis as manifestations of chronic graft-versus-hot disease (GVHD). A 48-year-old man was diagnosed as having chronic myelogenous leukemia at the age of 42 years, and had bone marrow transplantation (BMT) two years after the onset of the disease. Since he suffered from mild liver dysfunction and cutaneous involvement manifesting chronic GVHD, he was placed on prednisolone and cyclophosphamide. As his condition improved, the prednisolone was gradually tapered. Forty-one months after the BMT, the patient developed muscle pain and muscle weakness. A diagnosis of polymyositis was made from muscle biopsy and laboratory findings. An increase in the prednisolone dose was effective but a few weeks later the patient noticed ptosis and recurrence of muscle weakness. A tensilon test and anti-acetylcholine receptor antibody produced positive results, leading to a diagnosis of myasthenia gravis. Only one case of polymyositis and myasthenia gravis as manifestations of chronic GVHD has been reported, and in our patient both symptoms appeared almost at the same time. Although neuromuscular symptoms as a manifestation of chronic GVHD are rare, all patients receiving BMT should be carefully followed up neurologically to detect neuromuscular complications.     

Prednisolone-sparing effect of cyclosporin A therapy for very elderly patients with myasthenia gravis

Three very elderly (over 80 years old) patients having generalized myasthenia gravis without thymoma were treated with cyclosporin A and followed for up to 24 months. Cyclosporin A therapy quickly improved myasthenia gravis symptoms in all cases, which allowed a rapid reduction in the prednisolone dose and improvement of prednisolone-related hyperglycemia and hypertension. Combination therapy with prednisolone and low-dose cyclosporin A not only improved the clinical symptoms of the very elderly myasthenia gravis patients but also resulted in a rapid reduction in prednisolone dosage and prednisolone-related side effects. Attention should be paid to cyclosporin A-related renal dysfunction.     

Immunoadsorption therapy for myasthenia gravis.

The results of a multicentre trial were analysed to evaluate the efficacy of immunoadsorption therapy for severe generalised myasthenia gravis. Twenty patients with myasthenia gravis who were concurrently receiving high dose prednisolone and azathioprine therapy were treated with an affinity-type adsorbent, using tryptophan-linked polyvinyl alcohol gel (IM-TR), according to a standardised treatment protocol. The 20 patients received five adsorption treatments within a period of 10 days. In 11, pronounced improvement of myasthenic weakness was seen and long-term remission was maintained. The treatment was especially effective in patients with thymic hyperplasia. Circulating acetylcholine receptor (AChR) antibodies were reduced by about 60% by treating one plasma volume. There was no difference in the rate of removal of the AChR antibodies between patients with thymic hyperplasia and patients with thymoma. No serious complications occurred during 100 procedures. It was concluded that the immunoadsorption therapy with IM-TR is useful in controlling symptoms in patients with severe myasthenia gravis who are otherwise unresponsive.     

家族性重症肌无力临床特点及其与人类白细胞抗原DQA1基因多态性的相关性研究

目的探讨家族性重症肌无力(MG)的临床特点及其与人类白细胞抗原(HLA)DQA1基因多态性的相关性。方法对15例家族性、36例散发性MG患者的临床特点进行研究,并运用聚合酶链反应序列特异性引物(PCR SSP)对HLA DQA1基因多态性进行分型。结果与散发性MG相比,家族性MG患者发病年龄较早(两者分别为18 7、34 4岁,P=0 006),病情较轻,预后较好;与散发MG组及健康对照组比较,家族性MG患者的DQA1 0301基因频率增高(三者分别为40 0%、19 4%和20 2% ),差异有统计学意义(P<0 05),这种差异在眼肌型的患者中同样存在,但未发现患者性别与DQA1相关。结论家族性MG有其独特的临床特点,DQA1 0301是家族性尤其是眼肌型MG的易患基因,提示家族性MG与散发MG可能有着不同的免疫遗传机制。     

Ocular myasthenia gravis: response to long-term immunosuppressive treatment.

OBJECTIVE: Ocular myasthenia gravis is a subtype of myasthenia gravis that causes relatively mild disability, but may convert into severe generalised muscle weakness. A universal management plan for ocular myasthenia gravis has not been established. This study was performed to determine the outcome of ocular myasthenia gravis with the currently available therapeutic options. METHODS: Retrospective analysis of 78 patients with ocular myasthenia gravis with a mean disease duration of 8.3 (range 0.5-58.3) years. RESULTS: In 54 patients (69%) symptoms and signs remained confined to the extraocular muscles during the observation period. The remaining 24 patients (31%) developed symptoms of generalised myasthenia gravis; 50% of them within two years, 75% within four years after onset. A somewhat reduced risk of generalisation was found in those with mild symptoms, normal repetitive nerve stimulation test, and low or absent antiacetylcholine receptor (AChR) antibodies at the time of diagnosis. Patients receiving immunosuppressive treatment (corticosteroids and/or azathioprine) rarely developed generalised myasthenia gravis (six of 50, 12%). Those without such treatment, usually due to uncertain diagnosis and late referral, converted into generalised myasthenia gravis significantly more often (18 of 28, 64%). CONCLUSIONS: The prognosis of ocular myasthenia gravis is good. A conventional scheme with short-term corticosteroids and long-term azathioprine seems adequate to achieve remission in most patients. The proportion of patients developing generalised myasthenia gravis was smaller in this population compared with previously published groups (usually 50%-70%). Early immunosuppressive treatment is at least partially responsible for this finding. Thymectomy (performed here in 12 patients with an abnormal chest CT) also correlated with a good outcome, but had no apparent advantage over medical treatment alone.     

Epidemiology of myasthenia gravis with anti-muscle specific kinase antibodies in The Netherlands

The epidemiology of myasthenia gravis subtypes and the frequency of antibodies to muscle-specific kinase (MuSK) was studied in patients with generalised myasthenia gravis without anti-acetylcholine receptor antibodies who had an onset of symptoms between 1990 and 2004 in a well-defined region in The Netherlands. The nationwide prevalence and incidence of myasthenia gravis with anti-MuSK antibodies were also studied. MuSK antibodies were found in 22% of patients with generalised myasthenia gravis without anti-acetylcholine receptor antibodies. Nationwide, 35 patients with MuSK myasthenia gravis were identified, yielding a prevalence of 1.9 per million (95% confidence interval (CI) 1.22 to 2.59) and an annual incidence 0.10 per million person-years (95% CI 0.06 to 0.14).     

Detection of erythrocyte immune function and circulatory immune complex in myasthenia gravis

The circulating immune complexes (CIC) and erythrocyte immune function in myasthenia gravis were studied. In order to examine CIC in the patients with myasthenia gravis the complement sensitized yeast cell agglutination (CSYCA) test and anti-C3-ELISA were used. The CIC positive rate was 92.3% in the patients tested. The CIC test was all negative in the normal control subjects. The levels of CIC were remarkable elevated in the patients with myasthenia gravis (P less than 0.01). It was found that the rosette rate of red blood cell C3b receptor was 11.27 +/- 3.27% in the CIC negative patients with myasthenia gravis and 17.60 +/- 5.10% in CIC negative patients with myasthenia gravis. The erythrocyte immune function decreased remarkably in the CIC positive patients with myasthenia gravis (P less than 0.05). The relationship between the decrease of the erythrocyte immune function and myasthenia gravis is discussed.     

Difference in distribution of muscle weakness between myasthenia gravis and the Lambert-Eaton myasthenic syndrome

BACKGROUND: Myasthenia gravis and the Lambert-Eaton myasthenic syndrome (LEMS) may have a similar distribution of muscle weakness. Deciding on a diagnosis of myasthenia gravis or LEMS on clinical grounds may therefore be difficult. OBJECTIVE: To compare the localisation of initial muscle weakness and the distribution of weakness at the time of maximum severity in patients with myasthenia gravis and LEMS. SUBJECTS: 101 patients with myasthenia gravis and 38 patients with LEMS. RESULTS: In myasthenia gravis, initial weakness involved extraocular muscles in 59%, bulbar muscles in 29%, and limb muscles in 12% of the patients. In LEMS no patient had ocular weakness, 5% had bulbar weakness, and 95% had weakness of the limbs as the first symptom (p < 0.001). At the point of maximum severity, weakness in myasthenia gravis was purely ocular in 25%, oculobulbar in 5%, restricted to the limbs in 2%, and present in both oculobulbar muscles and limbs in 68%. At this point, none of the LEMS patients had weakness restricted to extraocular or bulbar muscles (p = 0.002). The legs were affected in all LEMS patients, whereas in 12 patients with generalised myasthenia gravis limb weakness was restricted to the arms (p = 0.024). CONCLUSIONS: In a patient suspected to have a myasthenic syndrome whose first symptom is ocular weakness, LEMS is virtually excluded. Limb weakness confined to the arms is only found in generalised myasthenia gravis and not in LEMS. Muscle weakness in myasthenia gravis tends to develop in a craniocaudal direction, and in the opposite direction in LEMS.     

CD4CD25 regulatory T cell in childhood ocular myasthenia gravis

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

Ryanodine receptor antibodies related to severity of thymoma associated myasthenia gravis.

Ryanodine receptor (RyR) antibodies are detected in about 50% of patients with myasthenia gravis who have a thymoma. The RyR is a calcium release channel involved in the mechanism of excitation-contraction coupling in striated muscle. In this study the severity of myasthenia gravis assessed by a five point disability score was compared between 12 patients with myasthenia gravis, a thymoma, and RyR antibodies and 10 patients with myasthenia gravis and a thymoma but without such antibodies. Symptoms of myasthenia gravis were significantly more severe in patients with RyR antibodies. The mean (SD) disability scores were 3.7(0.5) in patients with antibodies and 2.7 (0.9) in those without at peak of illness, (p = 0.01) and 3.4(1.4) v 1.6(0.7) at the end of an average observation period of five years (p = 0.002). The number of deaths due to myasthenia gravis was five of 12 RyR antibody positive patients, and none of 10 RyR antibody negative patients (p = 0.04). RyR antibody levels correlated positively with severity of myasthenia gravis. The presence of circulating RyR antibodies seems to be associated with a severe form of thymoma associated myasthenia gravis.     

Assessment of cellular and humoral immunity of myasthenics.

A close association of autoimmune diseases or autoimmune phenomena in myasthenia gravis is well known. A comprehensive immunological study of 22 patients with myasthenia gravis showed that changes in the immune system mainly involve the thymus-derived lymphocytes (T cells). Anti-thymus antibody was present in 90% of the patients, and it paralleled the frequency of thymic abnormality in myasthenia gravis. It is postulated that in myasthenia gravis the altered T cell functions caused by anti-thymus antibody result in the formation of an array of autoantibodies including the factor which blocks the neuromuscular transmission.     

Low-dose tacrolimus for two cases of myasthenia gravis with invasive thymoma that relapsed shortly after thymectomy

Two patients with myasthenia gravis (Ossermann IIb) involving invasive thymoma who underwent extensive thymectomy manifested myasthenic crisis shortly after the procedure; however, both patients were treated with intravenous immunoglobulin and recovered from myasthenic crisis that had been deteriorating for about 1 week. Subsequently, the patients were administered a low-dose of tacrolimus (3 mg/day) in addition to prednisolone. Several months later, tacrolimus continued to control fluctuations of myasthenic symptoms and maintained remission in these patients. The serum titer of anti-Ach-receptor antibodies decreased in parallel with clinical improvement due to tacrolimus, and we accordingly reduced the dosage of prednisolone. Tacrolimus is a new immunosuppressive agent acting through the selective inhibition of helper-T-cell activation that can be reduced dosage of steroids and can maintain remission of myasthenia gravis with invasive thymoma.     

HLA class II antigens and DNA restriction fragment length polymorphism in myasthenia gravis in Japan.

Human leukocyte phenotypes and genes in the HLA class II regions were studied in 46 Japanese patients with myasthenia gravis. When the HLA phenotypes of the patients with myasthenia gravis were compared with the controls, an increased frequency of HLA-DRw53 was observed in females less than 30 years of age. The genomic DNAs of the HLA-DRw53-positive patients and DRw53-positive controls were analyzed by using four complementary DNA probes for HLA class II genes. With DQB complementary DNA as the probe, a higher incidence of the 6.5-kb or 8.2-kb BamHI fragment was observed in the patients (76.0%) compared with the controls (19.0%). In contrast, no significant difference was observed between patients and controls when complementary DNAs for DRB, DQA, and DPB were used as probes. These results indicate that the genetic background of Japanese females with early-onset myasthenia gravis is different from other patients with myasthenia gravis, and that DQB genes can greatly influence the onset of myasthenia gravis.     

Nephrotic syndrome developing in association with thymoma and myasthenia gravis

Three patients with thymoma associated myasthenia gravis complicated by the nephrotic syndrome are described. There were two male and one female patients with a mean age at presentation of 55.6 years (27–75). In all cases anti striated-muscle and acetylcholine-receptor antibodies were present. Thymectomy was performed 1.4 years (1–3) after diagnosis of myasthenia gravis; histology revealed invasive mixed lymphocytic/epithelial (1), invasive epithelial (1) and non-invasive lymphocytic/epithelial (1) cell thymoma. All patients were receiving pyridostigmine, prednisolone and azathioprine at the time nephrotic syndrome developed (a mean of 2 years after thymectomy). Renal biopsy demonstrated a minimal change nephropathy alone in all three. Remission following increased steroids occurred in two despite continuing azathioprine. Myasthenic symptoms remained stable throughout. The third patient died 3 weeks after onset of nephrotic syndrome. The cause of the nephrotic syndrome is uncertain, but an immune mechanism, possibly in genetically predisposed individuals, is perhaps most likely.     

Development of generalized disease at 2 years in patients with ocular myasthenia gravis

BACKGROUND: Generalized myasthenia gravis will develop in more than 50% of patients who present with ocular myasthenia gravis, typically within 2 years. The optimal treatment of ocular myasthenia gravis, including the use of corticosteroids, remains controversial. In addition, the prevalence of thymoma and the optimal performance of the edrophonium chloride test for ocular myasthenia remain unknown. OBJECTIVE: To assess the effect of oral corticosteroid therapy on the frequency of development of generalized myasthenia gravis within 2 years, the incidence of thymoma, and the amount of edrophonium needed for a positive test result in patients with ocular myasthenia gravis. METHODS: We reviewed an ocular myasthenia gravis database of 147 patients. Patients underwent measurement of acetylcholine receptor (AChR) antibody levels and chest computed tomography. Unless contraindicated, patients with diplopia were recommended for therapy with prednisone, up to 40 to 60 mg/d, with the dosage tapered for 5 to 6 weeks. Most continued to receive daily or alternate-day doses of 2.5 to 10 mg to prevent diplopia. Patients not given prednisone (untreated group) received pyridostigmine bromide or no medication. After the diagnosis, we documented the signs and symptoms of ocular and generalized myasthenia gravis and performed 2-year follow-up in 94 patients. RESULTS: The mean dose of edrophonium chloride to give a positive response was 3.3 mg (SD, 1.6 mg) for ptosis and 2.6 mg (SD, 1.1 mg) for ocular motor dysfunction. Thymoma occurred in 1 patient (0.7%). Generalized myasthenia gravis developed within 2 years in 4 of 58 treated and 13 of 36 untreated patients. The odds ratio (OR) for development of generalized disease in the treated group was 0.13 (95% confidence interval [CI], 0.04-0.45) compared with the untreated group. The AChR antibody level was not predictive of development of generalized myasthenia gravis at 2 years, but the risk was greater in patients with abnormal AChR antibody levels (OR, 6.33; 95% CI, 1.71-23.42). Logistic regression that included age, abnormal AChR antibody level, and prednisone therapy yielded significance only for abnormal AChR antibody level (OR, 7.03; 95% CI, 1.35-36.64) and treatment (OR, 0.06; 95% CI, 0.01-0.30). CONCLUSIONS: At 2 years, prednisone treatment appears to reduce the incidence of generalized myasthenia gravis to 7% in contrast to 36% of patients who did not receive prednisone. Thymoma, although uncommon, occurs in ocular myasthenia gravis. Only small amounts of edrophonium are needed to diagnose ocular myasthenia gravis.     

Low-dose tacrolimus for intractable myasthenia gravis

We treated two patients suffering from intractable myasthenia gravis (MG) with low-dose tacrolimus plus prednisolone. Both patients showed significant improvement of myasthenic signs, accompanied by suppressed serum anti-acetylcholine receptor antibody, waning in compound muscle action potential by repetitive nerve stimulation and IL-2 production by peripheral blood mononuclear cells. Low-dose tacrolimus plus prednisolone is a promising therapeutic regimen for intractable MG.     

Short-term effects of prednisolone on neuromuscular transmission in normal rats and those with experimental autoimmune myasthenia gravis.

Electrophysiological investigations of the effects of bath-applied prednisolone at the neuromuscular junction were performed in muscles from normal rats and rats with experimental autoimmune myasthenia gravis (EAMG). In muscles from both groups, prednisolone reversible and significantly depressed the amplitudes of minature end-plate potentials (MEPPs), end-plate potentials (EPPs) and indirectly elicited action potentials (APs) without affecting resting membrane potentials. Prednisolone also caused a significant reduction in EPP rise time to peak and half-decay time while markedly increasing MEPP frequency and AP rise time to peak and duration. These effects were shown to be dose-dependent. The percentage decrease in amplitude after prednisolone perfusion was similar for EPPs and MEPPs, indicating that the depressive effect of prednisolone at the junction is postsynaptic. In all of the parameters studied, the percentage effect of prednisolone was the same in EAMG and normal preparations. No stimulus-linked repetitive EPPs or APs were observed after prednisolone. It is concluded that prednisolone has a depressive effect on neuromuscular transmission, but that this occurs only at high concentrations of the drug which are not achieved during the treatment of myasthenia gravis.     

Relapse of ocular symptoms after remission of myasthenia gravis--a comparison of relapsed and complete remission cases

Extended thymectomy and high-dose alternate-day prednisolone administration may increase the chance of remission in myasthenia gravis (MG) patients. In cases of remission, ocular symptoms sometimes reappear after a gradual decrease or discontinuation of prednisolone administration. We compared relapsed patients with those who experienced complete remission. We found that the period from onset of MG to thymectomy and initiation of prednisolone administration was longer in the relapsed cases, which suggests that early thymectomy and administration of prednisolone can lead to a superior outcome in MG patients.     

Central acetylcholine receptor function in patients with myasthenia gravis

There are some reports on central nervous system involvements in patients with myasthenia gravis, such as abnormal EEG, and memory disturbance. Myasthenia gravis is considered to be an autoimmune disease with antibodies against the skeletal nicotinic acetylcholine receptor (n-AChR). ACh is a neurotransmitter in osmoregulation. Neuronal n-AChR plays an important role in this regulation. In order to investigate the function of neuronal n-AChR in patients with myasthenia gravis, we performed a 5% hypertonic saline infusion test on 9 patients and 9 healthy volunteers. We also carried out an orthostatic stress test (50 degree passive head-up tilt) on 6 patients with myasthenia gravis and 5 healthy controls to evaluate arginine-vasopressin (AVP) release via baroreceptors. Three of the 9 MG patients showed exaggerated plasma AVP secretion, and one revealed a blunt response to hypertonic stimulation. Both patients and controls did not differ significantly in terms of plasma AVP response to orthostatic stress. To conclude, we suggest the possibility that function of neuronal n-AChR in the central nervous system is impaired in patients with myasthenia gravis.