[Fiber endoscopic evaluation of swallowing (FEES) - an important tool for diagnosing myasthenia gravis]. / Flexible endoskopische Evaluation des Schluckaktes (FEES) in der Geriatrie ­ auch in der Diagnose einer Myasthenia gravis im Alter richtungsweisend.

HISTORY AND ADMISSION FINDINGS: A 76-year old man was admitted with a globus sensation and weight loss for further investigations to our geriatric ward. A gastroscopic evaluation executed before had been unremarkable. INVESTIGATIONS: Physical examination was unremarkable, including a neurological examination. TREATMENT AND COURSE: All radiological findings (computer tomography of chest, abdomen and neck) were unremarkable. In a FEES investigation we found retentions and a reduction of frequency of swallowing after a while. During the investigation the patient complained about a muscular weakness in his neck. The assumed diagnosis of a myasthenia gravis was confirmed by antibodies against acetylcholine receptors and a decrement in repetitive irritation of the orbicularis and trapezius muscle. CONCLUSION: FEES can be a valid diagnosis tool for a pharyngeal type of a myasthenia gravis.

Efgartigimod-associated Kaposi's varicelliform eruption and herpetic conjunctivitis in a patient with seropositive ocular myasthenia gravis: a case report and review.

Background: Efgartigimod (Efgartigimod alpha fcab, Vyvgart™) is a pioneering neonatal Fc receptor (FcRn) antagonist for the treatment of severe autoimmune diseases mediated by pathogenic immunoglobulin G (IgG) autoantibodies, including myasthenia gravis (MG). It is a well-tolerated drug with minor side effects, such as headache and upper respiratory (lung) and urinary tract infections. Here, we present a case of Kaposi's varicelliform eruption (KVE) and herpetic conjunctivitis related to efgartigimod in a 60-year-old patient with ocular MG (OMG). Case description: A 60-year-old Chinese male suffered from acetylcholine receptor antibody positive (AChR Ab+) OMG for 8 years. During this period, he underwent first-line treatment with systemic corticosteroids, cyclosporine, cyclophosphamide, and so on, but had poor symptom improvement. On the recommendation of his attending neurologist, he received one cycle of intravenous efgartigimod (10mg/kg, once weekly for 4 weeks). The patient experienced fever, widespread painful blisters, and edema on the face on the third day after his last intravenous infusion. The patient also complained of increased secretions and a foreign body sensation in both eyes. Laboratory tests confirmed infection with herpes simplex virus (HSV). A diagnosis of efgartigimod-associated KVE and herpetic conjunctivitis was made. After intravenous administration (5mg/kg, 3 times a day, every 8 hours) for 10 days, the patient was cured without residual complications. Conclusions: This case is the first report of a patient with KVE and herpetic conjunctivitis related to efgartigimod in PubMed. This is rare and unusual. Clinicians should be alert to the rare symptoms related to efgartigimod.

Efgartigimod as a promising add-on therapy for myasthenic crisis: a prospective case series.

Introduction: Efgartigimod is effective and well-tolerated in patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (MG). However, the therapeutic potential and the safety profile of efgartigimod in myasthenic crisis (MC) remained largely unknown. Methods: This is an observational, prospective, multicenter, real-world study to follow 2 MC patients who initiated efgartigimod as a first-line rescue therapy and 8 cases who used it as an add-on therapy. Baseline demographic features and immunotherapies were collected, and the MG-activities of daily living (MG-ADL) scale was evaluated every week since efgartigimod treatment for 8 weeks. Additionally, serum IgG and anti-AChR antibody levels and the peripheral CD4+ T lymphocytes were measured before and after one cycle of treatment. Results: Ten patients with MC were enrolled in the study, including 9 anti-AChR antibody positive and 1 anti-muscle-specific kinase (MuSK) positive. All patients were successfully weaned from the ventilation after receiving efgartigimod treatment, with a length of 10.44 ± 4.30 days. After one cycle of infusions, the MG-ADL score reduced from 15.6 ± 4.4 at the baseline to 3.4 ± 2.2, while the corticosteroid dose was tapered from 55.0 ± 20.7 mg to 26.0 ± 14.1 mg. The proportions of regulatory T cells and naïve T cells (% in CD4+ T) significantly decreased post-efgartigimod treatment (5.48 ± 1.23 vs. 6.90 ± 1.80, P=0.0313, and 34.98 ± 6.47 vs. 43.68 ± 6.54, P=0.0313, respectively). Conclusion: These findings validated the rapid action of efgartigimod in facilitating the weaning process with a good safety profile in patients with MC.

[Thoracoscopic thymectomy for myasthenia gravis and non-invasive thymoma after COVID-19 pneumonia]. / Torakoskopicheskaya timektomiya pri miastenii i neinvazivnoi timome posle COVID-19 pnevmonii.

Modern guidelines have identified thoracoscopic thymectomy as a preferable option for myasthenia gravis and non-invasive thymoma. In the era of the new coronavirus infection, it is relevant to develop protocols for anesthetic and perioperative support of patients undergoing thymectomy for myasthenia gravis after COVID-associated pneumonia (CAP). We present the results of thoracoscopic thymectomies in patients after CAP. Multidisciplinary team should determine therapeutic support, the need for plasmapheresis and thymectomy. Plasmapheresis and glucocorticosteroids are effective in addition to anticholinesterase therapy at the stages of perioperative support for correction of neurological status in patients with myasthenia combined with chronic obstructive pulmonary disease and pulmonary hypertension. Outpatient direct anticoagulants are advisable considering the need for prolonged postoperative prevention of thrombotic events.

HSCT for stiff person syndrome and myasthenia gravis.

Recent advances in neuroimmunology have shed light on the pathogenic mechanisms underlying rare neuroimmunologic conditions such as myasthenia gravis (MG) and stiff person syndrome (SPS). Despite the rarity of these conditions, their complex manifestations and potential for irreversible disability necessitate effective therapeutic strategies. This chapter reviews the current understanding of the safety and efficacy of hematopoietic stem cell transplantation (HSCT) in MG and SPS. Several case reports and retrospective studies have demonstrated promising outcomes following HSCT in refractory MG and SPS, with significant clinical improvement and even discontinuation of chronic immunomodulatory therapy in some cases. Furthermore, HSCT may offer insights into the underlying pathophysiologic mechanisms of these conditions, particularly the role of cellular immunity. Although more research is needed to fully understand the impact of HSCT on disease pathology and outcomes, current evidence suggests that HSCT could be a valuable therapeutic option for patients with refractory MG and SPS.

Myasthenia gravis: the future is here.

Myasthenia gravis (MG) stands as a prototypical antibody-mediated autoimmune disease: it is dependent on T cells and characterized by the presence of autoantibodies targeting proteins located on the postsynaptic surface of skeletal muscle, known as the neuromuscular junction. Patients with MG exhibit a spectrum of weakness, ranging from limited ocular muscle involvement to life-threatening respiratory failure. Recent decades have witnessed substantial progress in understanding the underlying pathophysiology, leading to the delineation of distinct subcategories within MG, including MG linked to AChR or MuSK antibodies as well as age-based distinction, thymoma-associated, and immune checkpoint inhibitor-induced MG. This heightened understanding has paved the way for the development of more precise and targeted therapeutic interventions. Notably, the FDA has recently approved therapeutic inhibitors of complement and the IgG receptor FcRn, a testament to our improved comprehension of autoantibody effector mechanisms in MG. In this Review, we delve into the various subgroups of MG, stratified by age, autoantibody type, and histology of the thymus with neoplasms. Furthermore, we explore both current and potential emerging therapeutic strategies, shedding light on the evolving landscape of MG treatment.

FOSL1-mediated LINC01566 negatively regulates CD4+ T-cell activation in myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease characterized by pathogenic antibodies that target structures of the neuromuscular junction. The evidence suggests that the regulation of long noncoding RNAs (lncRNAs) that is mediated by transcription factors (TFs) plays a key role in the pathophysiology of MG. Nevertheless, the detailed molecular mechanisms of lncRNAs in MG remain largely undetermined. METHODS: Using microarray analysis, we analyzed the lncRNA levels in MG. By bioinformatics analysis, LINC01566 was found to potentially play an important role in MG. First, qRT‒PCR was performed to verify the LINC1566 expressions in MG patients. Then, fluorescence in situ hybridization was conducted to determine the localization of LINC01566 in CD4 + T cells. Finally, the impact of LINC01566 knockdown or overexpression on CD4 + T-cell function was also analyzed using flow cytometry and CCK-8 assay. A dual-luciferase reporter assay was used to validate the binding of the TF FOSL1 to the LINC01566 promoter. RESULTS: Based on the lncRNA microarray and differential expression analyses, we identified 563 differentially expressed (DE) lncRNAs, 450 DE mRNAs and 19 DE TFs in MG. We then constructed a lncRNA-TF-mRNA network. Through network analysis, we found that LINC01566 may play a crucial role in MG by regulating T-cell-related pathways. Further experiments indicated that LINC01566 is expressed at low levels in MG patients. Functionally, LINC01566 is primarily distributed in the nucleus and can facilitate CD4 + T-cell apoptosis and inhibit cell proliferation. Mechanistically, we hypothesized that LINC01566 may negatively regulate the expressions of DUSP3, CCR2, FADD, SIRPB1, LGALS3 and SIRPB1, which are involved in the T-cell activation pathway, to further influence the cellular proliferation and apoptosis in MG. Moreover, we found that the effect of LINC01566 on CD4 + T cells in MG was mediated by the TF FOSL1, and in vitro experiments indicated that FOSL1 can bind to the promoter region of LINC01566. CONCLUSIONS: In summary, our research revealed the protective roles of LINC01566 in clinical samples and cellular experiments, illustrating the potential roles and mechanism by which FOSL1/LINC01566 negatively regulates CD4 + T-cell activation in MG.

Decoding myasthenia gravis: advanced diagnosis with infrared spectroscopy and machine learning.

Myasthenia Gravis (MG) is a rare neurological disease. Although there are intensive efforts, the underlying mechanism of MG still has not been fully elucidated, and early diagnosis is still a question mark. Diagnostic paraclinical tests are also time-consuming, burden patients financially, and sometimes all test results can be negative. Therefore, rapid, cost-effective novel methods are essential for the early accurate diagnosis of MG. Here, we aimed to determine MG-induced spectral biomarkers from blood serum using infrared spectroscopy. Furthermore, infrared spectroscopy coupled with multivariate analysis methods e.g., principal component analysis (PCA), support vector machine (SVM), discriminant analysis and Neural Network Classifier were used for rapid MG diagnosis. The detailed spectral characterization studies revealed significant increases in lipid peroxidation; saturated lipid, protein, and DNA concentrations; protein phosphorylation; PO2-asym + sym /protein and PO2-sym/lipid ratios; as well as structural changes in protein with a significant decrease in lipid dynamics. All these spectral parameters can be used as biomarkers for MG diagnosis and also in MG therapy. Furthermore, MG was diagnosed with 100% accuracy, sensitivity and specificity values by infrared spectroscopy coupled with multivariate analysis methods. In conclusion, FTIR spectroscopy coupled with machine learning technology is advancing towards clinical translation as a rapid, low-cost, sensitive novel approach for MG diagnosis.

Management of apixaban anticoagulation in a patient requiring therapeutic plasma exchange: a case report and a literature review.

Therapeutic plasma exchange (TPE) is used as an effective treatment modality for a variety of autoimmune disorders. Apart from its desired effect of removing pathological blood components, it also can remove coagulation factors and drugs. Currently, there is an insufficient amount of information regarding the use of direct oral anticoagulants in this setting. In this article, we present a case report of a patient with myasthenia gravis and chronic anticoagulation with apixaban who underwent a series of TPE while continuing apixaban treatment. We observed that only 10% of daily dose was removed by the procedure and plasma levels of apixaban corresponded with expected range. TPE was not associated with shortened drug plasma half-life. We did not observe any significant alteration of apixaban pharmacokinetics during the period of TPE therapy, as well as no thrombotic or bleeding events. This case report supports the use of apixaban in patients treated by TPE, nevertheless, to firmly establish apixaban efficacy and safety profile in this clinical setting further research is needed.

Anti-AMPA receptor encephalitis with myasthenia gravis: A sinister combination associated with a high risk for underlying malignancy.

A rare subtype of autoimmune encephalitis consists of antibodies targetting the alpha-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid receptor in the central nervous system. We describe the clinical presentation and autoimmune profile of the first case of alpha-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid receptor encephalitis with concurrent anti-acetylcholine receptor antibodies in Pakistan. The patient was a 58-year-old male who presented with the characteristic symptoms of limbic encephalitis with memory loss, irritability, agitation, and confusion. Antibodies against the alpha-amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid receptor were detected in both serum and cerebrospinal fluid by indirect immunofluorescence. Computerised tomography of the chest showed an anterior mediastinal mass. The patient was treated with high dose Methylprednisolone and five sessions of plasma exchange. There was a short period of improvement; however, the patient now continues to exhibit irritability, aphasia, confusion, and memory loss. Video-assisted thoracoscopic surgery for mediastinal mass resection and histological testing was planned, however after review by the interventional radiologist the associated risks were deemed too high to proceed with the procedure and biopsy was not done.

Identification of disease phenotypes in acetylcholine receptor-antibody myasthenia gravis using proteomics-based consensus clustering.

BACKGROUND: The clinical heterogeneity of myasthenia gravis (MG), an autoimmune disease defined by antibodies (Ab) directed against the postsynaptic membrane, constitutes a challenge for patient stratification and treatment decision making. Novel strategies are needed to classify patients based on their biological phenotypes aiming to improve patient selection and treatment outcomes. METHODS: For this purpose, we assessed the serum proteome of a cohort of 140 patients with anti-acetylcholine receptor-Ab-positive MG and utilised consensus clustering as an unsupervised tool to assign patients to biological profiles. For in-depth analysis, we used immunogenomic sequencing to study the B cell repertoire of a subgroup of patients and an in vitro assay using primary human muscle cells to interrogate serum-induced complement formation. FINDINGS: This strategy identified four distinct patient phenotypes based on their proteomic patterns in their serum. Notably, one patient phenotype, here named PS3, was characterised by high disease severity and complement activation as defining features. Assessing a subgroup of patients, hyperexpanded antibody clones were present in the B cell repertoire of the PS3 group and effectively activated complement as compared to other patients. In line with their disease phenotype, PS3 patients were more likely to benefit from complement-inhibiting therapies. These findings were validated in a prospective cohort of 18 patients using a cell-based assay. INTERPRETATION: Collectively, this study suggests proteomics-based clustering as a gateway to assign patients to a biological signature likely to benefit from complement inhibition and provides a stratification strategy for clinical practice. FUNDING: CN and CBS were supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf. CN was supported by the Else Kröner-Fresenius-Stiftung (EKEA.38). CBS was supported by the Deutsche Forschungsgemeinschaft (DFG-German Research Foundation) with a Walter Benjamin fellowship (project 539363086). The project was supported by the Ministry of Culture and Science of North Rhine-Westphalia (MODS, "Profilbildung 2020" [grant no. PROFILNRW-2020-107-A]).

Extraocular muscle volume on time-of-flight magnetic resonance angiography in patients with myasthenia gravis.

INTRODUCTION/AIMS: Despite being a prominent feature of myasthenia gravis (MG), extraocular muscle (EOM) has received little attention in clinical research. The aim of this study was to examine EOM volume in patients with MG and controls using time-of-flight magnetic resonance angiography (TOF-MRA). METHODS: EOM volumes (overall and individual rectus muscles) were calculated using TOF-MRA images and compared between MG patients (including subgroups) and controls. The correlation between EOM volume and disease duration was examined. Predictive equations for the selected parameters were developed using multiple linear regression analysis. RESULTS: EOM volume was lower in MG patients than controls, especially in MG patients with ophthalmoparesis (MG-O). MG-O exhibited a moderate negative correlation between EOM volume and disease duration. Multiple linear regression showed that disease duration and EOM status (ophthalmoparesis or not) account for 48.4% of EOM volume. DISCUSSION: Patients with MG show atrophy of the EOMs, especially those with ophthalmoparesis and long disease duration.

A Fatal Case of Immune Checkpoint Inhibitor-Mediated Myasthenia Gravis, Myositis, and Cardiomyopathy Overlap Syndrome in Urothelial Carcinoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have led to improved outcomes for many cancer types. However, their use can also precipitate immune-related adverse events (irAEs) that can affect any organ system. While irAEs are often mild, they rarely affect multiple organ systems concurrently and can be fatal. CASE: We report a fatal case of myasthenia gravis, myositis, and cardiotoxicity overlap syndrome precipitated by the ICI pembrolizumab along with a brief review of available literature. CONCLUSION: Early recognition of high grade irAEs and prompt intervention is essential. Despite the poor prognosis of these overlap syndromes, current recommendations offer little guidance for severe cases and warrant a call for increased awareness and expansion of available therapeutics.

Sustained Response of Ibrutinib in a Patient with Waldenstrom Macroglobulinemia Presenting with Myasthenic Crisis as a Paraneoplastic Neurological Syndrome: A Case Report and Review of Literature.

Paraneoplastic syndrome is a broad spectrum of signs and symptoms due to neoplasm, attributed to substances produced by tumor cells, or in response to it. Myasthenia gravis (MG) is a well-known paraneoplastic neurological syndrome (PNS), frequently associated with thymic abnormalities, but rarely reported in patients with lymphoplasmacytic lymphoma.This study presents the case of a 52-year-old Indonesian male patient who was diagnosed with Waldenstrom macroglobulinemia (WM), a rare B-cell neoplasm, after developing a new onset of MG with myasthenic crisis. the patient's MG features improved with Ibrutinib as a treatment targeted toward cancer. This is the first case report presenting the treatment response of Ibrutinib in WM with myasthenic crisis. The literature was reviewed to explain the possibility of MG as a paraneoplastic syndrome of WM and the treatment response of Ibrutinib for this patient, as well as summarizing previous case reports of concomitant MG and WM.MG should be considered a paraneoplastic malignancy syndrome, including WM, during diagnostic workup. Ibrutinib should also be considered when available to patients, due to its adequate response in both previously treated and treatment naïve patients.

Effect of Immunosuppression in Risk of Developing Generalized Symptoms in Ocular Myasthenia Gravis: A Retrospective Cohort Study.

BACKGROUNDS AND OBJECTIVES: Early use of immunosuppression has been suggested to prevent generalization of ocular myasthenia gravis (OMG), but high-quality evidence is limited in this regard. We examined whether treatment with prednisone and other immunosuppressants reduce the risk of generalization in OMG. METHODS: This is a retrospective study of consecutive adults with pure OMG who had a minimum 6 months of follow-up. The main outcome was the time to developing generalized symptoms. We used propensity scores to create matched data sets of patients treated with prednisone or any immunosuppressant vs controls. We also used unmatched models with inverse probability of treatment weights (IPTW) and variable exposure times. We used Cox proportional hazards model to estimate hazard ratio (HR) for generalization, comparing treated patients vs controls. RESULTS: A total of 154 patients were included, with a mean follow-up of 87.4 ± 73 months since onset. Forty-three (28%) were generalized, and mean time to generalization from diagnosis was 24.2 ± 24.1 months. Patients who received prednisone had lower risk of generalization than controls, with pooled HR 0.43 (95% CI 0.19-1.06) for the matched model, HR 0.46 (95% CI 0.21-0.89) for the IPTW model, and for HR 0.44 (95% CI 0.23-0.81) for the time-dependent exposure model. Patients who received any immunosuppressant had lower risk of generalization, with HR 0.30 (95% CI 0.11-0.77), 0.32 (95% CI 0.14-0.70), and 0.35 (95% CI 0.15-0.80) for the matched, IPTW, and IPTW-varying exposure models, respectively. DISCUSSION: Our study provides evidence that steroidal and nonsteroidal immunosuppression in patients with OMG is associated with a reduced risk of developing generalized symptoms over time. This supports the early use of immunosuppression in this population. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that treatment of OMG with corticosteroids or nonsteroidal immunosuppressants reduces the risk of generalization.