Deterioration Of Myasthenia Gravis Research Articles

Severe worsening of myasthenic symptoms after the eculizumab discontinuation

Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction. The neuromuscular junction damage associated with MG is caused by anti-acetylcholine receptor (AChR) antibody and complements. Recently, eculizumab (an anti-C5 monoclonal antibody) was approved for patients with anti-AChR antibody-positive generalized refractory MG. Here, we report a Japanese man with MG who well responded to eculizumab, but experienced acute severe worsening of myasthenic symptoms 2months after its discontinuation. Plasmapheresis did not improve his symptoms; hence, eculizumab was re-administered, resulting in a dramatic response within a week. This is an informative case because eculizumab discontinuation in patients with MG has been very rarely reported. If eculizumab treatment is clinically well effective and AChR antibody titer does not decrease, clinicians should be aware that acute and critical deterioration of MG may occur after the eculizumab discontinuation.

Myasthenia gravis and pregnancy: retrospective evaluation of 27 pregnancies in a tertiary center and comparison with previous studies.

To share our experience with the management of pregnancies in women with myasthenia gravis (MG) in a tertiary center. The study retrospectively evaluated 27 pregnancies in 12 patients. The pregnancies were divided into 3 groups on the basis of the clinical course of MG during pregnancy: improvement (n = 7), disease-stable (n = 9), and deterioration (n = 11). The groups were compared with respect to patient characteristics, clinical features, and obstetric outcomes. There were 4 miscarriages (14.8%), 3 preterm births (11.1%), and 4 cases of preterm premature rupture of the membranes (PPROM) (14.8%). Exacerbation was observed in 25.9% of the cases; the remission rate during the postpartum period and after miscarriage was 37%. The cesarean section (CS) rate was 78.3%. Pregnancies with deterioration of MG were statistically more likely to have higher miscarriage, preterm birth, PPROM, CS, and transient neonatal MG rates, in addition to a lower gestational age at birth, birth weight, and 5-min Apgar score than pregnancies with improved or stable disease (p values < 0.001, 0.04, 0.03, 0.009, 0.02, < 0.001, 0.002, and 0.043, respectively). Physicians who manage pregnant women with MG must be familiar with the clinical features of the condition; a multidisciplinary approach is necessary for a better prognosis.

Statins and Myotoxic Effects Associated With Anti-3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Autoantibodies

Statins have a variety of myotoxic effects and can trigger the development of inflammatory myopathies or myasthenia gravis (MG) mediated by immunomodulatory properties. Autoantibodies to 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) have been identified in patients with statin-associated myopathy. The purpose of the present study is to develop an enzyme-linked immunosorbent assay (ELISA) of anti-HMGCR antibodies and to elucidate the clinical significance of anti-HMGCR antibodies in Japanese patients with inflammatory myopathies or MG.We enrolled 75 patients with inflammatory myopathies, who were all negative for anti-signal recognition particle and anti-aminoacyl transfer RNA synthetase antibodies. They were referred to Keio University and National Center of Neurology and Psychiatry between October 2010 and September 2012. We also studied 251 patients with MG who were followed at the MG Clinic at Keio University Hospital. Anti-HMGCR antibodies were detected by ELISA. We investigated demographic, clinical, radiological, and histological findings associated with anti-HMGCR antibodies.We established the anti-HMGCR ELISA with the recombinant protein. Protein immunoprecipitation detected autoantigens corresponding to HMGCR. Immunohistochemistry using muscle biopsy specimens revealed regenerating muscle fibers clearly stained by polyclonal anti-HMGCR antibodies and patients’ serum. Anti-HMGCR autoantibodies were specifically detected in 8 patients with necrotizing myopathy. The seropositivity rate in the necrotizing myopathy patients was significantly higher than those in the patients with other histological diagnoses of inflammatory myopathies (31% vs 2%, P = 0.001). Statins were administered in only 3 of the 8 anti-HMGCR-positive patients. Myopathy associated with anti-HMGCR antibodies showed mild limb weakness and favorable response to immunotherapy. All 8 patients exhibited increased signal intensities on short T1 inversion recovery of muscle MRI. Of the 251 patients with MG, 23 were administered statins at the onset of MG. One late-onset MG patient experienced MG worsening after 4-wk treatment with atorvastatin. However, anti-HMGCR antibodies were not detected in the 251 MG patients except for one early-onset MG patient with no history of statin therapy.Anti-HMGCR antibodies are a relevant clinical marker of necrotizing myopathy with or without statin exposure, but they are not associated with the onset or deterioration of MG.

Pathomechanisms of paraneoplastic myasthenia gravis.

Thymic T cell development is characterized by sequential selection processes to ensure generation of a self-tolerant, immuncompetent mature T cell repertoire. Malfunction of any of these selection processes may potentially result in either immunodeficiency or autoimmunity. Myasthenia gravis (MG) is a typical autoimmune manifestation of thymic epithelial tumors (thymomas) and is related to the capacity of these tumors to generate and export mature T cells. Analysis of the factors that lead to autoimmunization in thymomas will help to understand the mechanisms that prevent MG under physiological conditions in humans. In a comparison of MG(+) and MG(-) thymomas, we could show that only thymomas capable of generating mature CD45RA+CD4+ T cells are associated with MG (p< 0.0001), while terminal thymopoiesis was abrogated in MG(-) thymomas. In particular, acquisition of the CD27+CD45RA+ phenotype appears to be a critical checkpoint of late T cell development in the human thymus and may play an important role in the prevention of autoimmunity. Moreover, MG(-) thymomas were virtually depleted of regulatory (CD4+CD25+) T cells (regT), while regT were readily detectable in MG(+) thymomas, albeit at significantly reduced numbers compared to control thymuses. Thus, in MG(+) thymoma patients, thymectomy apparently also results in removal of a regulatory T cell pool and may explain the frequent temporary postoperative deterioration of MG in these patients.

A CASE OF THYMOMATOUS MYASTHENIA GRAVIS WITH LUNG CANCER

A case of myasthenia gravis with thymoma and lung cancer is reported. A 68-year-old woman was hospitalized with myasthenia gravis and complaints of ptosis, diplopia and neck fatigability. Chest roentogenograms revealed a tumor shadow in the right middle lung field after admission. Brushing smear cytology by bronchoscopy indicated primary epidermoid carcinoma of the lung. The patient received prednisolone on alternate days. The dose was increased stepwisel from 30mg per day to 100mg to prevent acute deterioration of myasthenia gravis after thymectomy. Extended thymectomy reverling a thymoma, which was not clear by chest roentogenogram, tomogram, or CT scanning, and right upper lobectomy with lymph node dissection was performed. The postoperative course was uneventful, and the patient was discharged 47 days after surgery. Clinicopathological correlations of thymoma and lung cancer as well as of myasthenia gravis and lung cancer are discussed.

Invasive thymoma with myasthenia gravis.

In 261 surgically treated patients with myasthenia gravis (MG), 26 had an invasive thymoma and 49 had a noninvasive thymoma. Invasive thymoma was seen in 41% of thymomatous MG patients older than 40 years of age, and 28% in patients younger than 40 years of age. Of 19 patients who underwent total or subtotal thymothymomectomy accompanied by irradiation (4000 rad), 17 were still alive on an average 6.5 years after surgery. The deterioration of MG by the irradiation was observed in 7 of 20 irradiated cases. Thus, postoperative irradiation is effective but should be done with attention to the deterioration of MG. The prognosis of MG in patients with an invasive thymoma was poorer than that in patients with a noninvasive thymoma.