The Clinical Course of New-Onset Ocular Myasthenia Gravis Caused by Pfizer-BioNTech COVID-19 Vaccine.

PURPOSE: Myasthenia gravis (MG) caused by COVID-19 vaccine had been reported, but the clinical course of new-onset ocular MG had never been described. We would like to document the clinical course of a patient with new-onset ocular MG which was caused by Pfizer-BioNTech COVID-19 vaccine. CASE REPORT: A 39-year-old woman noticed diplopia one week after she accepted the first dose of Pfizer- BioNTech COVID-19 vaccine. Diagnosis of ocular MG was made after investigation. Despite intravenous immunoglobulins, pyridostigmine and prednisolone therapy, she had no improvement until 10 days after treatment. She then rapidly improved, and almost fully recovered in the following 10 days. We had observed this patient for 8 months. After tapering off steroid, she remained stable to date, though she still suffered from transient diplopia on awakening. CONCLUSION: No matter the symptoms at onset, the clinical course or the response to steroid therapy was identical to ocular MG that we had ever known. Ocular MG caused by COVID-19 vaccine could probably be an iatrogenic life-long disease.

The short and long-term effects of open vs minimally invasive thymectomy in myasthenia gravis patients: a systematic review and meta-analysis.

OBJECTIVE: Thymectomy has been utilized as a treatment for Myasthenia Gravis (MG) for many decades, with both open and minimally invasive surgical (MIS) techniques currently used. Although MIS has shown improved short-term results, long-term effects remain uncertain. This systematic review and meta-analysis aim to compare the post-operative and long-term outcomes of MIS versus open thymectomy in MG patients. METHODS: MEDLINE, EMBASE and CENTRAL databases were searched from inception till January 2022 for keywords related to MG and open or MIS thymectomy. Primary outcome was complete stable remission (CSR), and secondary outcomes were clinical improvement, complications, length of stay, operation time, and blood loss. Grading of recommendations, assessment, development, and evaluation was used to assess the certainty of evidence. RESULTS: 26 studies with 3588 patients were included in the analysis. At 1, 3 and 5 years, there was no statistical difference noted in CSR between open versus MIS thymectomy. However, CSR was improved at 1 year for MIS thymectomy in non-thymomatous MG (P = 0.03). There was no significant difference in rates of partial clinical improvement between techniques at 1-year. Although analyses on length of hospital stay and blood loss showed improvement following MIS thymectomy, operative time was shorter for open thymectomy. CONCLUSION: This is the first systematic review and meta-analysis assessing long-term effects of MIS versus open thymectomy in MG patients. Given the lack of significant differences noted, either MIS or open thymectomy can be performed, based on surgeon preference. Further high-level, long-term research should be conducted to determine the benefit of each technique.

Smoking and younger age at onset in anti-acetylcholine receptor antibody-positive myasthenia gravis.

Smoking is a known risk factor for the development and progression of several autoimmune diseases. Previous studies have pointed out the association of smoking with the development and worsening of symptoms in myasthenia gravis (MG), but further investigation is necessary to confirm this association. Smoking history was investigated in a cross-sectional study of 139 patients with anti-acetylcholine receptor antibody-positive MG, and the association of smoking history with the age at the onset of MG was analyzed. Patients who had been smoking at the onset of MG were significantly younger compared with those who had never smoked or had quit before the onset of MG. A linear regression analysis adjusting for sex and the presence/absence of thymoma showed a significant association between smoking at onset and younger age at onset (regression coefficient -9.05; 95% confidence interval, -17.6, -0.51; p = 0.039). Among patients with smoking exposure within 10 years prior to or at the onset of MG, women were significantly younger at the onset of MG compared with men. Our results suggest that smoking is an independent risk factor for the earlier development of anti-acetylcholine receptor antibody-positive MG and further support the putative link between smoking and MG.

Pembrolizumab-induced Myasthenia Gravis: Literature Review of Ocular Manifestations and a Refractory Case.

Immune checkpoint inhibition is a new and promising therapy approved for the treatment of various malignancies. Pembrolizumab is a potent tumor suppressor that acts by upregulating the immune system to recognize cancer cells which may result in disrupted self-tolerance. We describe a case and perform a literature review of myasthenia gravis with ocular manifestations after treatment with pembrolizumab. Our case had bilateral ptosis refractory to conventional treatment, and she remained functionally blind as a result. The literature review included 28 cases of immune-related myasthenia gravis, and a 30% mortality rate excluding deaths from primary cancer progression was shown. Under half had full symptom resolution (n=13, 46%), and there was no clear correlation between specific management strategies and prognosis. Patients with isolated ocular myasthenia gravis (n=9, 32%) were twice as likely to be symptom-free after treatment compared with generalized myasthenia gravis (75% vs. 39%). Respiratory involvement was associated with twice the mortality rate (60% vs. 33%) and triple the risk of noncomplete symptom resolution (20% vs. 61%). The majority of cases had their pembrolizumab discontinued (n=20, 71%), but 3 were successfully rechallenged by utilizing prophylactic low-dose steroids. Patients with immune-related myasthenia gravis experience increased mortality and morbidity but if steroid-responsive, may benefit from the reintroduction of anti-programmed cell death protein 1 therapy for end-stage malignancy with close monitoring. A high index of clinical suspicion for immune-related adverse effects are critical in an era of rising immunotherapy use.

Early-Onset Myasthenia Gravis Following COVID-19 Vaccination.

As coronavirus disease 2019 (COVID-19) has spread worldwide, the rate of COVID-19 vaccination uptake is encouraging. Neurological complications associated with COVID-19 vaccines such as stroke, Guillain-Barré syndrome, and Bell's palsy have been reported. Recently, late-onset myasthenia gravis (MG) following COVID-19 vaccination has been reported. To date, however, there has been no evidence of increased risk of early-onset MG following COVID-19. Here, we report a case of a patient with new-onset MG that arose after receiving a COVID-19 vaccine. A 33-year-old woman suddenly experienced generalized weakness and diplopia on the evening she had received the second dose of the Pfizer-BioNTech COVID-19 vaccine. The temporal relationship suggests that this new-onset MG is related to the vaccination. It also implies that COVID-19 vaccination could trigger early-onset MG symptoms in patients at risk of MG.

Perioperative Outcomes of Thymectomy in Myasthenia Gravis: A Thoracic Surgery Database Analysis.

BACKGROUND: There is clinical equipoise regarding the perioperative and long-term outcomes of autoimmune myasthenia gravis (MG) patients undergoing open vs minimally invasive thymectomy, particularly for nonthymomatous MG. This analysis utilizes multicenter, real-world clinical evidence to assess perioperative complications of open and minimally invasive thymectomy techniques in MG patients. METHODS: Thymectomy cases from 2009 to 2019 in MG patients were identified in The Society of Thoracic Surgeons General Thoracic Surgery Database. Thymectomies were grouped by surgical technique: transthoracic (TT), transcervical (TC), video-assisted thoracoscopic surgery (VATS), or robotic VATS (RVATS). Multivariable logistic regression models assessed the association between surgical technique and perioperative complications. RESULTS: Analysis of nonthymomatous cases (n = 1725) revealed VATS (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.83), RVATS (OR, 0.73; 95% CI, 0.48-1.26), and TC (OR, 0.19; 95% CI, 0.06-0.62) thymectomies had lower odds of perioperative complications than TT thymectomies. VATS (OR, 2.29; 95% CI, 0.63-8.30) and RVATS (OR, 4.08; 95% CI,1.21-3.78) thymectomies had higher odds of perioperative complications than TC thymectomies. Analysis of thymomatous cases (n = 311) found no significant difference in the odds of perioperative complications in TT vs minimally invasive (VATS/RVATS) procedures. The proportion of RVATS procedures increased from 6.43% to 44.27%, while TT (56.43% to 34.35%) and TC (19.29% to 6.87%) thymectomies decreased. CONCLUSIONS: Minimally invasive and TC thymectomies have fewer perioperative complications than TT thymectomies when performed for nonthymomatous MG. Minimally invasive procedures are increasingly performed for both nonthymomatous and thymomatous disease. There is a nationwide shift toward minimally invasive procedures, even for thymoma resections. Long-term neurological outcome data are needed to determine whether a reduced perioperative risk for minimally invasive thymectomies translates to improved MG outcomes.

Robotic Thymectomy for Thymomas: A Retrospective Follow-up Study in the Netherlands.

BACKGROUND: The Maastricht University Medical Center+ is a Dutch center of expertise appointed by the Netherlands Federation of University Medical Centers for the treatment of thymomas. The aim of this study was to investigate the long-term oncologic, surgical, and neurologic outcomes of all patients who underwent a robotic thymectomy for a thymoma at Maastricht University Medical Center+. METHODS: We retrospectively analyzed the clinical-pathologic data of all consecutive patients with a thymoma who underwent robotic thymectomy using the DaVinci robotic system at Maastricht University Medical Center+ between April 2004 and December 2018. Follow-up data were collected from 60 referring Dutch hospitals. RESULTS: In total, 398 robotic thymectomies were performed, and 130 thymomas (32.7%) were found. Median follow-up time was 46 months; median procedure time, 116 minutes; and median hospitalization time, 3 days. In 8.4% of patients, a conversion was performed, and in 20.8%, a complication was registered. The majority of myasthenic patients with a thymoma went into remission, mostly within 12 to 24 months after thymectomy (81%). No statistical difference was found in the number of complications, conversions, incomplete resections, or deaths between patients with myasthenia gravis and nonmyasthenic patients. Thirty-six patients (27.7%) underwent postoperative radiotherapy. The recurrence rate was 9.1%, and the 5-year thymoma-related survival rate was 96.6%. CONCLUSIONS: Robotic thymectomy was found to be safe and feasible for early stage thymomas, most advanced-stage thymomas, and thymomatous myasthenia gravis. A national guideline could contribute to the improvement of the oncologic follow-up of thymic epithelial tumors in the Netherlands.

Post-thymectomy myasthenia gravis: a case report and systematic review of literature.

Myasthenia gravis (MG) is an autoimmune condition affecting the neuromuscular junction characterised by weakness and fatiguability, carrying a high morbidity if treatment is delayed. A clear association with thymoma has led to management with thymectomy as a common practice, but MG presenting post-thymectomy has rarely been reported. We present a case of an 82- year-old woman developing fatigue, ptosis and dysarthria 3 months after thymectomy. After a clinical diagnosis of MG was made, she responded well to prompt treatment with prednisolone and pyridostigmine. Her anti-acetylcholine receptor antibody (anti-AChR) subsequently came back positive. Our systematic review reveals that post-thymectomy MG can be categorised as early-onset or late-onset form with differing aetiology, and demonstrated correlation between preoperative anti-AChR titres and post-thymectomy MG. The postulated mechanisms for post-thymectomy MG centre around long-lasting peripheral autoantibodies. Clinicians should actively look for MG symptoms in thymoma patients and measure anti-AChR preoperatively to aid prognostication.

Antibodies to Full-Length Agrin Protein in Chinese Patients With Myasthenia Gravis.

This study aimed to establish a cell-based assay (CBA) for the detection of agrin antibodies (Agrin-Ab) to explore the clinical features of agrin antibody-positive Chinese patients with myasthenia gravis (Agrin-MG). We developed a CBA based on the human full-length agrin protein expressed in HEK293T cells for the reliable and efficient detection of Agrin-Ab. Clinical data and serum samples were collected from 1948 MG patients in 26 provinces in China. The demographic and clinical features of Agrin-MG patients were compared with those of other MG patient subsets. Eighteen Agrin-MG cases were identified from 1948 MG patients. Nine patients were Agrin-Ab positive, and nine were AChR-Ab and Agrin-Ab double-positive (Agrin/AChR-MG). Eleven (61.11%) patients were males older than 40 years of age. The initial symptom in 13 (81.25%) cases was ocular weakness. Occasionally, the initial symptom was limb-girdle weakness (two cases) or bulbar muscle weakness (one case). Agrin-MG patients demonstrated slight improvement following treatment with either acetylcholinesterase inhibitor or prednisone; however, the combination of the two drugs could effectively relieve MG symptoms. In China, Agrin-MG demonstrated seropositivity rates of 0.92%. These patients were commonly middle-aged or elderly men. The patients usually presented weakness in the ocular, bulbar, and limb muscles, which may be combined with thymoma. These patients have more severe diseases, although the combination of pyridostigmine and prednisone was usually effective in relieving symptoms.

Clinical Efficacy and Safety of Eculizumab for Treating Myasthenia Gravis.

Myasthenia gravis (MG) is an autoimmune disease primarily mediated by acetylcholine receptor antibodies (AChR-Ab), cellular immune dependence, and complement system involvement. Since the AChR on the postsynaptic membrane is destroyed by an immune attack, sufficient endplate potential cannot be generated, resulting in the development of a synaptic transmission disorder at the neuromuscular junction and in muscle weakness. The role of the complement system in MG has been demonstrated in animal models and clinical tests, and it has been determined that complement inhibition in patients with MG can prevent disease induction and reverse its progression. Eculizumab is a humanized monoclonal antibody that inhibits the cleavage of complement protein C5 and prevents autoimmune damage; additionally, it has received subsequent approval by the Federal Drug Administration of the United States for MG treatment. However, various concerns regarding the use of eculizumab persist. In this review, we have discussed the treatment time, cost effectiveness, long-term efficacy, and tolerability of eculizumab for MG treatment. We have also summarized historical information and have presented perspectives on this new therapeutic modality.

Cemiplimab- and nivolumab-induced myasthenia gravis: two clinical cases.

Immune-related myasthenia gravis is a rare, disabling, and potentially fatal adverse event of immune checkpoint inhibitor treatment. It is important to identify and manage it promptly. We present two cases of immune-related de novo myasthenia gravis observed at the Modena Cancer Center in two elderly patients treated with two anti-PD-1 monoclonal antibodies: cemiplimab and nivolumab.

COVID-19 and Myositis: What We Know So Far.

PURPOSE: Myositis as a rare manifestation of COVID-19 is only recently being reported. This review examines the current literature on COVID-19-induced myositis focusing on etiopathogenesis, clinical presentations, diagnostic practices, and therapeutic challenges with immunosuppression, and the difficulties experienced by rheumatologists in established myositis in the COVID-19 era. RECENT FINDINGS: COVID-19 is associated with a viral myositis attributable to direct myocyte invasion or induction of autoimmunity. COVID-19-induced myositis may be varied in presentation, from typical dermatomyositis to rhabdomyolysis, and a paraspinal affliction with back pain. It may or may not present with acute exponential elevations of enzyme markers such as creatine kinase (CK). Virus-mediated muscle inflammation is attributed to ACE2 (angiotensin-converting enzyme) receptor-mediated direct entry and affliction of muscle fibers, leading on to innate and adaptive immune activation. A greater recognition of the stark similarity between anti-MDA5-positive myositis with COVID-19 has thrown researchers into the alley of exploration - finding common etiopathogenic basis as well as therapeutic strategies. For patients with established myositis, chronic care was disrupted during the pandemic with several logistic challenges and treatment dilemmas leading to high flare rates. Teleconsultation bridged the gap while ushering in an era of patient-led care with the digital transition to tools of remote disease assessment. COVID-19 has brought along greater insight into unique manifestations of COVID-19-related myositis, ranging from direct virus-induced muscle disease to triggered autoimmunity and other etiopathogenic links to explore. A remarkable shift in the means of delivering chronic care has led patients and caregivers worldwide to embrace a virtual shift with teleconsultation and opened doorways to a new era of patient-led care.

Concurrent thyrolipomatosis and thymolipoma in a patient with myasthenia gravis: a case report and review of the literature.

We present a case of a man with a background of myasthenia gravis who presented with a neck lump, which was diagnosed as thyrolipomatosis in continuity with a very large thymolipoma. Following removal of these lesions, the patient's myaesthenic symptoms improved. While thymolipomas are often seen in the context of myasthenia gravis, thyrolipomatosis is a rare entity and to our knowledge the concurrent finding of both lesions with myasthenia gravis has never been reported. We highlight the important imaging features of both entities and the clinical importance of recognising them.

Downregulation of DNMT3a expression by RNAi and its effect on NF-κBs expression of thymic epithelial cells.

OBJECTIVE: To understand the characteristics of DNA methyltransferase 3a (DNMT3a) in thymoma associated Myasthenia Gravis reveal its transcriptional regulator network as while as analyze the effect of DNMT3a on Rel/ nuclear factor-kappaB family (RelA/RelB) and its downstream autoimmune regulatory factor (Aire). METHODS: Tissues of 30 patients with thymoma, with or without myasthenia gravis (MG), were collected and the DNMT3a protein expression were evaluated through immunohistochemistry. We performed mRNA expression profiling microarray detection and analysis, and integrated the analysis by constructing protein-protein interaction networks and the integration with other database. We identified molecular difference between low and high DNMT3a in the thymoma by heatmap. We also performed PCR validation in thymoma tissues. The DNMT3a-shRNA plasmid was transfected into TEC cells, and these cells were treated with 5-aza-2-deoxycytidine, a blocker of DNMT3a. After the down-regulation of DNMT3a in TEC cells, the transcript and protein levels of RelA, RelB, Aire, and CHRNA3 were evaluated by western blotting. In addition, changes in gene expression profiles were screened through microarray technology. We performed differential gene analysis in the thymoma cohort by heatmap with R (v.4.3.0) software. RESULTS: In 30 matched tissue specimens, the expression of DNMT3a protein in thymoma with MG was lower than that in thymoma. Through mRNA expression profiling analysis, we constructed a co-expression network of DNMT3a and found direct interaction between IKZF1 and DNMT3a, and this co-expression relationship was overlappted with Cistrome DB database. We found up-regulation of 149 mRNAs and repression of 177 mRNAs in thymoma with MG compared with thymoma. Gene ontology and pathway analysis show the involvement of a multitude of genes in the mis-regulation of MG-related pathways. RNA interference significantly reduced the level of mRNA of DNMT3a, which proved that plasmid DNMT3a was effective. In comparison to the control group, the levels of DNMT3a, Aire, and CHRNA3 mRNA and protein in TEC cells transfected with DNMT3a-shRNA interference plasmid were significantly decreased, while the expression level of RelA and RelA/RelB was significantly increased. CONCLUSIONS: Our study reveals the DNMT3a-NF-κB pathway has a major effect on MG, and can be used as a marker for diagnosis as well as a target for MG treatment.

The Association Between Asthma and Risk of Myasthenia Gravis: A Systematic Review and Meta-analysis.

PURPOSE: This study aimed to investigate the association between asthma and risk of myasthenia gravis (MG) using the method of systematic review and meta-analysis. METHODS: Potentially eligible studies were identified from Medline and EMBASE databases from inception to July 2020 using search strategy that comprised terms for "Asthma" and "Myasthenia Gravis". Eligible cohort study must consist of one cohort of individuals with asthma and another cohort of individuals without asthma. Then, the study must report relative risk (RR) with 95% confidence intervals (95% CIs) of incident MG between the groups. Eligible case-control studies must include cases with MG and controls without MG. Then, the study must explore their history of asthma. Odds ratio (OR) with 95% CIs of the association between asthma status and MG must be reported. Point estimates with standard errors were retrieved from each study and were combined together using the generic inverse variance method. RESULTS: A total of 6,835 articles were identified. After two rounds of independent review by five investigators, two cohort studies and three case-control studies met the eligibility criteria and were included into the meta-analysis. Pooled analysis showed that asthma was significantly associated with risk of MG with the pooled risk ratio of 1.38 (95% CI 1.02-1.86). Funnel plot was symmetric, which was not suggestive of publication bias. CONCLUSION: The current study found a significant association between asthma and increased risk of MG.

Thymoma pathology and myasthenia gravis outcomes.

INTRODUCTION: There is limited evidence regarding the impact of World Health Organization (WHO) subtype of thymoma on post-thymectomy outcome of thymoma-associated myasthenia gravis (TAMG). The objective was to determine if the pathological subtypes of thymoma were associated with post-thymectomy outcomes of myasthenia gravis (MG), in patients with TAMG. METHODS: We performed a retrospective study of consecutive patients with TAMG who attended the neuromuscular clinic between January 2018 and December 2019 with a minimum follow-up of 1 y after thymectomy. Outcome measures were MG Impairment Index (MGII), single-simple question (SSQ), Myasthenia Gravis Foundation of America post-intervention status (MGFA PIS) and non-responder MG status at last assessment. RESULTS: Ninety-five patients were included; mean age at onset was 48.1 ± 12.1 y; 54(56.8%) were females. Thirteen patients developed MG post-thymectomy. The most common thymoma was WHO type B2 in 39 (41.1%). Most patients (40, 42.1%) had Masaoka stage II thymoma. There was no association of thymoma subtypes or Masaoka stage of disease with age, gender, MG phenotype, serology, post-thymectomy onset, interval from onset to thymectomy, MGII, SSQ, MGFA PIS, or non-responder status. Associations were found between positive serology and lower MGII (11.1 ± 14.2 vs 23 ± 12.9, P = .050), thymic follicular hyperplasia (TFH) and higher SSQ (89.3 ± 11.7 vs 80.1 ± 20.2, P-.043), and lack of recurrence and higher SSQ (84.1 ± 18 vs 72.5 ± 20, P = .037). DISCUSSION: The WHO pathological subtype of thymoma did not correlate with MG outcomes. However, positive acetylcholine antibody serology, presence of TFH, and non-recurrence of thymoma predict a favorable outcome.

Noninfectious neurologic complications of hematopoietic cell transplantation: A systematic review.

OBJECTIVE/BACKGROUND: Neurological complications occur at a high frequency after hematopoietic cell transplantation (HCT). However, an absence is noted in the published literature as regards the quantification of the exact burden and the outcomes thereof. In this systematic review, we endeavored to detail if the recipients of HCT developed any noninfectious neurological events/complications. METHODS: According to the PICO criteria, medical literature was searched. Complications that were evaluated included: stroke, peripheral neuropathy, myasthenia gravis, seizures, and posterior reversible encephalopathy syndrome. After strictly defining relevant variables and parameters, data from 173 eligible articles were then extracted accordingly, from the full text for each, for quantitative analysis; additionally, two American Society of Hematology conference abstracts were also subject to data extraction. RESULTS: As is evident from the results of the data analysis, an increased frequency of these complications was seen in the HCT recipient population in comparison to the general population. The relative risk ranged from 1.33× to 142× depending on the complication studied. CONCLUSION: These findings demonstrate that the recipients of HCT had a significantly higher risk of neurological complications and that their early recognition can enhance the monitoring of HCT survivors for the early developmental signs of neurological toxicity. This would facilitate timely interventions, thus ensuring a better quality of life.

The case of a 30-year-old man with subacute gait instability, weakness, and muscle spasms.

A 30-year-old healthy man presents after a fall with diffuse weakness and pain and recent onset left eye ptosis in the setting of three weeks of progressive bilateral leg weakness, gait instability, and difficulty washing his hair due to upper extremity weakness. He had also developed stiffness in his neck and shoulders and uncontrollable muscle spasms. Exam was notable for ptosis, fatiguing weakness in extremities, increased tone, hyperreflexia with clonus, and spastic gait. A mediastinal mass was found on chest CT (Fig. 1), and biopsy confirmed an invasive thymoma with positive nodes. Serum testing was positive for antibodies to acetylcholine receptors as well as glutamic acid decarboxylase.

Thymus-derived B cell clones persist in the circulation after thymectomy in myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular, autoimmune disease caused by autoantibodies that target postsynaptic proteins, primarily the acetylcholine receptor (AChR) and inhibit signaling at the neuromuscular junction. The majority of patients under 50 y with AChR autoantibody MG have thymic lymphofollicular hyperplasia. The MG thymus is a reservoir of plasma cells that secrete disease-causing AChR autoantibodies and although thymectomy improves clinical scores, many patients fail to achieve complete stable remission without additional immunosuppressive treatments. We speculate that thymus-associated B cells and plasma cells persist in the circulation after thymectomy and that their persistence could explain incomplete responses to resection. We studied patients enrolled in a randomized clinical trial and used complementary modalities of B cell repertoire sequencing to characterize the thymus B cell repertoire and identify B cell clones that resided in the thymus and circulation before and 12 mo after thymectomy. Thymus-associated B cell clones were detected in the circulation by both mRNA-based and genomic DNA-based sequencing. These antigen-experienced B cells persisted in the circulation after thymectomy. Many circulating thymus-associated B cell clones were inferred to have originated and initially matured in the thymus before emigration from the thymus to the circulation. The persistence of thymus-associated B cells correlated with less favorable changes in clinical symptom measures, steroid dose required to manage symptoms, and marginal changes in AChR autoantibody titer. This investigation indicates that the diminished clinical response to thymectomy is related to persistent circulating thymus-associated B cell clones.