Spontaneous development of myasthenia gravis and myositis following treatment with pembrolizumab: a case report.

BACKGROUND: Immune checkpoint inhibitors are a relatively new advancement in the world of cancer therapy. As such, their adverse effects have yet to be fully understood, with only recent literature documenting autoimmune phenomena secondary to their utilization. Specific immune checkpoint inhibitors have recently been linked with the development of myasthenia gravis, which is classically known to manifest spontaneously in patients. Given the relative rarity of this presentation, the risk of misdiagnosis and subsequent mortality and morbidity is concerning. CASE PRESENTATION: We discuss the case of a 73-year-old male who presented with clinical symptoms of myasthenia gravis and myositis shortly after beginning treatment with Pembrolizumab. The diagnosis of myasthenia gravis was initially missed at an outside hospital, which delayed initiation of proper treatment. CONCLUSION: While the incidence of "de-novo" diseases secondary to immune checkpoint inhibitors might be increasing, guidelines regarding best treatment options do not yet exist, leaving many providers at a loss when faced with making clinical decisions surrounding patients with De novo myasthenia gravis. Thus, our goal is to underscore the importance of early recognition of this disease, and emphasize the need for a standard of care as immune checkpoint inhibitors usage becomes more prevalent.

Ectopic cervical thymoma in myasthenia gravis: a case report.

BACKGROUND: Ectopic cervical thymoma (ECT) is an extremely rare tumor, especially in association with myasthenia gravis (MG). CASE PRESENTATION: We report a case of myasthenia gravis with an ectopic thymoma in the neck, whose myasthenic symptoms significantly improved after complete removal of the mass. A 55-year-old woman with generalized myasthenia gravis (MG) experienced worsening neuromuscular weakness after abruptly discontinuing pyridostigmine. Testing revealed acetylcholine receptor-antibody (AChR-Ab) positivity and a cervical mass initially thought to be thyroid or parathyroid was identified as a thymoma, type A. Post-surgery and radiation therapy, her myasthenic symptoms improved significantly with less prednisone and pyridostigmine requirements over time and no need for additional immunotherapies. CONCLUSIONS: Diagnosing ECTs is challenging due to rarity, atypical locations, and inconclusive fine needle aspiration cytology (FNAC) results, often misinterpreted as thyroid or parathyroid lesions. As proper management of patients with MG, including thymectomy, offers favorable clinical outcomes such as significant improvement in myasthenic complaints and reduced immunosuppressive medication requirements, clinicians should be vigilant of the ectopic locations of thymomas to ensure timely diagnosis and intervention.

A predictive nomogram for short-term outcomes of myasthenia gravis patients treated with low-dose rituximab.

BACKGROUND: This study aims to establish and validate a predictive nomogram for the short-term clinical outcomes of myasthenia gravis (MG) patients treated with low-dose rituximab. METHODS: We retrospectively reviewed 108 patients who received rituximab of 600 mg every 6 months in Huashan Hospital and Tangdu Hospital. Of them, 76 patients from Huashan Hospital were included in the derivation cohort to develop the predictive nomogram, which was externally validated using 32 patients from Tangdu Hospital. The clinical response is defined as a ≥ 3 points decrease in QMG score within 6 months. Both clinical and genetic characteristics were included to screen predictors via multivariate logistic regression. Discrimination and calibration were measured by the area under the receiver operating characteristic curve (AUC-ROC) and Hosmer-Lemeshow test, respectively. RESULTS: Disease duration (OR = 0.987, p = 0.032), positive anti-muscle-specific tyrosine kinase antibodies (OR = 19.8, p = 0.007), and genotypes in FCGR2A rs1801274 (AG: OR = 0.131, p = 0.024;GG:OR = 0.037, p = 0.010) were independently associated with clinical response of post-rituximab patients. The nomogram identified MG patients with clinical response with an AUC-ROC (95% CI) of 0.875 (0.798-0.952) in the derivation cohort and 0.741(0.501-0.982) in the validation cohort. Hosmer-Lemeshow test showed a good calibration (derivation: Chi-square = 3.181, p = 0.923; validation: Chi-square = 8.098, p = 0.424). CONCLUSIONS: The nomogram achieved an optimal prediction of short-term outcomes in patients treated with low-dose rituximab.

[AChR Antibody-Positive Myasthenia Gravis].

Herein, we describe the mechanisms, diagnostic procedures, and treatment options for acetylcholine receptor (AChR) antibody-positive myasthenia gravis (MG). The upstream pathomechanism of this condition involves AChR-sensitized T cell-dependent B cell proliferation and the subsequent production of pathogenic autoantibodies. Downstream molecules include AChR antibodies that activate complement pathways, resulting in the destruction of motor endplates. We further introduce newly-developed molecular targeted drugs for the treatment of MG that aims to secure patients' health-related quality of life.

[Muscle-Specific Receptor Tyrosine Kinase Antibody Positive Myasthenia Gravis].

Reportedly, patients with muscle-specific kinase (MuSK) antibody-positive myasthenia gravis (MG) account for approximately 3.0% of all patients with MG in Japan. Compared with patients who have acetylcholine receptor antibody-positive MG, those with MuSK antibody-positive MG show young-onset disease with female predominance, a low rate of ocular involvement (5.9%), and greater severity of dysphagia. The aforementioned types of MG are indistinguishable based on clinical symptoms and electrophysiological tests, and measurement of MuSK antibodies is essential for diagnosis. Thymectomy and complement inhibitors are not indicated for treatment, and acetylcholinesterase inhibitors, steroids, immunosuppressants, plasma exchange, intravenous immunoglobulin therapy, and neonatal Fc receptor inhibitors are used.

Case report: A highly active refractory myasthenia gravis with treatment of telitacicept combined with efgartigimod.

There is always a lack of effective treatment for highly active refractory generalized myasthenia gravis (GMG). Recently, telitacicept combined with efgartigimod significantly reduces circulating B cells, plasma cells, and immunoglobulin G, which brings promising therapeutic strategies. We report a case of a 37-year-old female patient with refractory GMG, whose condition got significant improvement and control with this latest treatment after multiple unsuccessful therapies of immunosuppressants. The new combination deserves further attention in the therapeutic application of myasthenia gravis.

Increased serum interleukin-41 correlates with disease severity in myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease mediated by pathogenic antibodies produced by abnormally activated B cells, resulting in neuromuscular junction transmission dysfunction. Interleukin-41 (IL-41) is a novel immunomodulatory cytokine that has been implicated in various metabolic, inflammatory, and autoimmune diseases. The role of IL-41 in MG is still unclear up to now, our study aimed to investigate the level of IL-41 in MG patients and its correlation with clinical features and inflammatory indicators. METHODS: Totally, 60 MG patients and 30 healthy controls (HC) were recruited. Baseline data and laboratory parameters were routinely recorded through electronic medical systems. IL-41 levels were measured by enzyme-linked immunosorbent assay. Proportions of T-cell and B-cell subsets and natural killer cells were analyzed by flow cytometry. The correlation between serum IL-41 and MG related parameters was investigated, and the clinical value of IL-41 in the diagnosis of MG was evaluated by receiver operator characteristic curve (ROC) analysis. RESULTS: Serum IL-41 levels in MG patients were higher than in HC, and were higher in Myasthenia Gravis Foundation of America (MGFA) III + IV group than that in MGFA I + II group. Serum IL-41 was positively correlated with MG-specific activities of daily living scale (MG-ADL), MGFA classification, platelet to lymphocyte ratio (PLR), and proportion of CD19+ B cells, while it was negatively correlated with high-sensitive C-reactive protein (hs-CRP) and circulatory plasma cells in MG patients. Serum IL-41 levels increased in patients who were treated with efgartigimod during the first cycle of therapy. However, compared to disease initiation, serum IL-41 levels decreased when clinical features steadily improved. ROC analysis showed that IL-41 had a diagnostic value for MG. CONCLUSION: The present findings suggested that serum IL-41 was increased in MG patients and was positively associated with the severity of the disease. IL-41 may be essential to the immunopathological mechanism of MG and a potential biomarker for MG.

A retrospective multicenter study on clinical and serological parameters in patients with MuSK myasthenia gravis with and without general immunosuppression.

Introduction: Muscle-specific kinase (MuSK)- myasthenia gravis (MG) is caused by pathogenic autoantibodies against MuSK that correlate with disease severity and are predominantly of the IgG4 subclass. The first-line treatment for MuSK-MG is general immunosuppression with corticosteroids, but the effect of treatment on IgG4 and MuSK IgG4 levels has not been studied. Methods: We analyzed the clinical data and sera from 52 MuSK-MG patients (45 female, 7 male, median age 49 (range 17-79) years) from Italy, the Netherlands, Greece and Belgium, and 43 AChR-MG patients (22 female, 21 male, median age 63 (range 2-82) years) from Italy, receiving different types of immunosuppression, and sera from 46 age- and sex-matched non-disease controls (with no diagnosed diseases, 38 female, 8 male, median age 51.5 (range 20-68) years) from the Netherlands. We analyzed the disease severity (assessed by MGFA or QMG score), and measured concentrations of MuSK IgG4, MuSK IgG, total IgG4 and total IgG in the sera by ELISA, RIA and nephelometry. Results: We observed that MuSK-MG patients showed a robust clinical improvement and reduction of MuSK IgG after therapy, and that MuSK IgG4 concentrations, but not total IgG4 concentrations, correlated with clinical severity. MuSK IgG and MuSK IgG4 concentrations were reduced after immunosuppression in 4/5 individuals with before-after data, but data from non-linked patient samples showed no difference. Total serum IgG4 levels were within the normal range, with IgG4 levels above threshold (1.35g/L) in 1/52 MuSK-MG, 2/43 AChR-MG patients and 1/45 non-disease controls. MuSK-MG patients improved within the first four years after disease onset, but no further clinical improvement or reduction of MuSK IgG4 were observed four years later, and only 14/52 (26.92%) patients in total, of which 13 (93.3%) received general immunosuppression, reached clinical remission. Discussion: We conclude that MuSK-MG patients improve clinically with general immunosuppression but may require further treatment to reach remission. Longitudinal testing of individual patients may be clinically more useful than single measurements of MuSK IgG4. No significant differences in the serum IgG4 concentrations and IgG4/IgG ratio between AChR- and MuSK-MG patients were found during follow-up. Further studies with larger patient and control cohorts are necessary to validate the findings.

Juvenile ocular myasthenia gravis: a report of two cases.

We report 2 cases of pediatric ocular myasthenia gravis. The first case was a 7-year-old girl who presented with bilateral ophthalmoplegia and ptosis that correlated with the onset of upper respiratory symptoms. Neuroimaging and acetylcholine receptor antibody testing were unremarkable. The ice pack test was positive. Symptoms greatly improved with pyridostigmine, with full resolution of ophthalmoplegia achieved by 8-month follow-up. The second case was a 4-year-old girl who presented emergently with ptosis and bilateral ophthalmoplegia. Acetylcholine receptor antibodies testing was positive. The patient was started on pyridostigmine and intravenous immunoglobulin and is scheduled to follow-up with pediatric ophthalmology in the outpatient setting.

Markedly upregulated serum semaphorin 4A as a novel activity marker of myasthenia gravis.

Myasthenia gravis (MG) is an autoantibody-mediated disease of the neuromuscular junction. Semaphorin 4A (Sema4A) is involved in the activation of T cells in various inflammatory disorders. In this study, we aimed to investigate whether Sema4A is involved in the pathogenesis of MG. We measured serum Sema4A concentrations in 30 treatment-naïve MG patients with acetylcholine receptor (AChR) antibodies, 7 with muscle-specific tyrosine kinase (MuSK) antibodies and 21 normal controls. As a result, serum Sema4A levels were significantly higher in patients with AChR antibody-positive MG and MuSK antibody-positive MG than in controls (p ≤ 0.0001 for both MG groups). Serum Sema4A levels were correlated with AChR antibody levels (Spearman's ρ = 0.39, p = 0.03) and MG Foundation of America clinical classification classes (Spearman's ρ = 0.38, p = 0.04) in patients with AChR antibody-positive MG. In conclusion, high serum Sema4A levels may reflect T-cell activation, and this molecule could be a potential marker of disease activity in MG.

Uraemic brainstem encephalopathy mimicking ocular myasthenia: a case report.

BACKGROUND: Uraemia causes a generalised encephalopathy as its most common neurological complication. Isolated brainstem uraemic encephalopathy is rare. We report a case of fatigable ptosis and complex ophthalmoplegia in brainstem uraemic encephalopathy. CASE PRESENTATION: A 22-year-old Sri Lankan man with end stage renal failure presented with acute onset diplopia and drooping of eyelids progressively worsening over one week. The patient had not complied with the prescribed renal replacement therapy which was planned to be initiated 5 months previously. On examination, his Glasgow coma scale score was 15/15, He had a fatigable asymmetrical bilateral ptosis. The ice-pack test was negative. There was a complex ophthalmoplegia with bilateral abduction failure and elevation failure of the right eye. The diplopia did not worsen with prolonged stare. The rest of the neurological examination was normal. Serum creatinine on admission was 21.81 mg/dl. The repetitive nerve stimulation did not show a decremental pattern. Magnetic resonance imaging (MRI) of the brain demonstrated diffuse midbrain and pontine oedema with T2 weighted/FLAIR hyperintensities. The patient was haemodialyzed on alternate days and his neurological deficits completely resolved by the end of the second week of dialysis. The follow up brain MRI done two weeks later demonstrated marked improvement of the brainstem oedema with residual T2 weighted/FLAIR hyperintensities in the midbrain. CONCLUSIONS: Uraemia may rarely cause an isolated brainstem encephalopathy mimicking ocular myasthenia, which resolves with correction of the uraemia.

[Myasthenia Gravis - Update]. / Myasthenia gravis ­ Update.

Myasthenia gravis - still a challenge for sufferers and doctors in 2023. But which therapy is best suited? Our clinically experienced experts have summarized the current guidelines for diagnosis and treatment in order to provide optimal support for those affected. Find out how you can carry out a quick and targeted diagnosis and which treatment options are available to alleviate the course of the disease.

Taste disorders and alopecia in myasthenia gravis.

BACKGROUND: Non-motor symptoms in myasthenia gravis (MG) are rarely confirmed. Although there are some small cohort studies, a large-systemic survey has not yet been performed. METHODS: We investigated the incidence and clinical characteristics of patients with MG who had taste disorders and alopecia using data of 1710 patients with MG enrolled in the Japan MG Registry 2021. RESULTS: Among them, 104 (6.1%) out of 1692 patients and 138 (8.2%) out of 1688 patients had histories of taste disorders and alopecia, respectively. Among the patients with MG, taste disorders were significantly more common in women, those with severe symptoms, refractory MG, or thymoma-associated MG, and were less common in those with ocular MG. The taste disorders often occurred after the onset of MG and often responded to MG treatments. Alopecia was more common in MG patients with a history of bulbar palsy and thymoma, and it often occurred before the onset of MG and sometimes responded to MG treatments. Multivariate logistic regression analysis revealed taste disturbance was associated with worst quantitative MG score and thymoma-associated MG; and alopecia was associated with thymoma-associated MG. CONCLUSION: Clinicians should be aware of the non-motor symptoms in MG, especially in patients with severe myasthenic symptoms and thymoma-associated MG.

Accuracy of Repetitive Ocular Vestibular-Evoked Myogenic Potentials to Diagnose Myasthenia Gravis in Patients With Ptosis or Diplopia.

BACKGROUND AND OBJECTIVES: We developed repetitive ocular vestibular-evoked myogenic potentials (roVEMP) as an electrophysiologic test that allows us to elicit the characteristic decrement of extraocular muscles in patients with ocular myasthenia gravis (OMG). Case-control studies demonstrated that roVEMP reliably differentiates patients with OMG from healthy controls. We now aimed to evaluate the diagnostic accuracy of roVEMP for OMG diagnosis in patients with ptosis and/or diplopia. METHODS: In this blinded prospective diagnostic accuracy trial, we compared roVEMP in 89 consecutive patients presenting with ptosis and/or diplopia suspicious of OMG with a multimodal diagnostic approach, including clinical examination, antibodies, edrophonium testing, repetitive nerve stimulation of accessory and facial nerves, and single-fiber EMG (SFEMG). We calculated the roVEMP decrement as the ratio between the mean of the first 2 responses compared with the mean of the sixth-ninth responses in the train and used cutoff of >9% (unilateral decrement) in a 30 Hz stimulation paradigm. RESULTS: Following a complete diagnostic work-up, 39 patients (44%) were diagnosed with ocular MG, while 50 patients (56%) had various other neuro-ophthalmologic conditions, but not MG (non-MG). roVEMP yielded 88.2% sensitivity, 30.2% specificity, 50% positive predictive value (PPV), and 76.5% negative predictive value (NPV). For comparison, SFEMG resulted in 75% sensitivity, 56% specificity, 55.1% PPV, and 75.7% NPV. All other diagnostic tests (except for the ice pack test) also yielded significantly higher positive results in patients with MG compared with non-MG. DISCUSSION: The study revealed a high sensitivity of 88.2% for roVEMP in OMG, but specificity and PPV were too low to allow for the OMG diagnosis as a single test. Thus, differentiating ocular MG from other neuro-ophthalmologic conditions remains challenging, and the highest diagnostic accuracy is still obtained by a multimodal approach. In this study, roVEMP can complement the diagnostic armamentarium for the diagnosis of MG. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with diplopia and ptosis, roVEMP alone does not accurately distinguish MG from non-MG disorders. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov: NCT03049956.

Ten-year fracture risk in Japanese patients with myasthenia gravis: A comprehensive assessment using the fracture risk assessment tool.

BACKGROUND: Myasthenia gravis (MG) is an immune disorder that causes muscle weakness with an increasing prevalence, particularly among the elderly in Japan. Glucocorticoid treatment for MG is problematic for bone health because of reduced bone density and increased fracture risk. The fracture risk assessment tool (FRAX®) can estimate fracture risk, but its applicability in patients with MG remains uncertain. METHODS: A prospective cohort study was conducted on 54 patients with MG between April and July 2012. Bone mineral density (BMD) was measured, and FRAX® scores were calculated with and without BMD. We also adjusted FRAX® scores based on glucocorticoid dosage. Patients were monitored for major osteoporotic fractures (MOF) until June 2022. Statistical analyses included Kaplan-Meier curves and Cox proportional hazards models. RESULTS: The study group included 12 men and 42 women with a mean age of 62 years. Higher FRAX® scores correlated with increased fracture risk, particularly in the hip and lumbar regions. The 10-year fracture-free rate was significantly lower in the high-FRAX® score group. The FRAX® score using BMD is a significant predictor of MOF risk. The hazard ratio for FRAX® scores was 1.17 (95% CI 1.10-1.26). CONCLUSION: We demonstrated the effectiveness of the FRAX® tool in assessing fracture risk among patients with MG. High FRAX® scores correlated with increased fracture risk, emphasizing its importance. These findings support the incorporation of FRAX® assessment into clinical management to enhance patient care and outcomes. However, the small sample size and observational nature suggest a need for further research.

Serum globulin in children with myasthenia gravis: predicting relapse and prognosis.

OBJECTIVE: Serum globulin is associated with inflammatory or immune disorders. However, it has not been established whether it is associated with myasthenia gravis (MG). We investigated the association between globulin with relapse and prognosis in children with MG. METHODS: A cohort of 148 MG cases and 150 healthy children were retrospectively enrolled from January 2015 to December 2021. Multivariate logistic and Cox regression models were used to analyze the treatment outcomes and recurrence of case group, exploring the influence of globulin. RESULTS: Compared with the control group, globulin levels in the MG group were slightly increased (t = 7.244, p < 0.001). After a mean follow-up of 2.25 ± 1.05 years, 35 cases relapsed, with a relapse rate of 23.65%. Logistic regression analysis showed that globulin levels at admission [adjusted odds ratio (OR) = 1.233, 95% confidence interval (CI) 1.028-1.472, p = 0.018] were independent risk factors for relapse. Cox regression analysis confirmed that globulin levels at admission affects relapse-free time [adjusted hazard ratio (HR) = 0.552, 95% CI 0.357-0.852, p = 0.007]. Receiver operating characteristic curve determined 25.10 as the optimal cutoff value for globulin. Cox regression showed that high globulin levels (>25.10) at admission (adjusted HR = 0.607, 95% CI 0.383-0.961, p = 0.033) were independent risk factors for poor therapeutic outcomes at follow-up. Ordinal logistic regression showed that globulin affects the treatment plan (OR = 1.445, 95% CI 1.223-1.847, p = 0.014). CONCLUSIONS: Elevated globulin levels in children with MG on admission predicts a high relapse rate and poor long-term therapeutic efficacies.

Serum globulin in children with myasthenia gravis: predicting relapse and prognosisFirst, the globulin in the MG children was higher than in the healthy controls, and there was some correlation between the globulin and the level of systemic inflammation.Second, globulin has been associated with relapse of MG in children. The higher the globulin, the higher the relapse rate and the shorter the time to prevent a relapse.Third, both initial and final globulin were related to the effect of MG in children, and the higher the long-term effect, the worse the long-term effect. It also influenced the change in treatment plan.

Detection of Autoantibodies Against the Acetylcholine Receptor, Evaluation of Commercially Available Methodologies: Fixed Cell-Based Assay, Radioimmunoprecipitation Assay and Enzyme-Linked Immunosorbent Assay1.

Background/Objective: Myasthenia Gravis (MG) is an autoimmune disorder characterized by pathogenic autoantibodies (AAbs) targeting nicotinic acetylcholine receptors (AChR), disrupting neuromuscular communication. RadioImmunoPrecipitation Assay (RIPA) is recommended to detect AChR AAbs, but its complexity and radioactive requirements limit widespread use. We compare non-RIPA anti-AChR immunoassays, including Cell-Based Assay (CBA) and two ELISA kits, against the gold standard RIPA. Methods/Results: 145 samples were included with medical indication for anti-AChR testing. By the RIPA method, 63 were negative (RIPA-Neg < 0.02 nmol/L), 18 were classified as Borderline (≥0.02 -1 nmol/L), and 64 were positive (RIPA-Pos > 1 nmol/L). The competitive ELISA showed poor agreement with RIPA (Kappa = 0.216). The indirect ELISA demonstrated substantial agreement with RIPA (Kappa = 0.652), with ∼76% sensitivity and ∼94% specificity for MG diagnostic. The CBA, where fixed cells expressing clustered AChR were used as substrate, exhibited almost perfect agreement with RIPA (Kappa = 0.984), yielding ∼98% sensitivity and 96% specificity for MG. In addition, a semiquantitative analysis showed a strong correlation between CBA titration, indirect ELISA, and RIPA levels (r = 0.793 and r = 0.789, respectively). Conclusions: The CBA displayed excellent analytical performance for MG diagnostic when compared to RIPA, making it a potential replacement for RIPA in clinical laboratories. Some solid-phase assays (such as the indirect ELISA applied here), as well as CBA titration, offer reliable options to estimate anti-AChR AAb levels after confirming positivity by the CBA.∥.