Generalized myasthenia gravis with acetylcholine receptor antibodies: A guidance for treatment.

BACKGROUND: Generalized myasthenia gravis (MG) with antibodies against the acetylcholine receptor is a chronic disease causing muscle weakness. Access to novel treatments warrants authoritative treatment recommendations. The Nordic countries have similar, comprehensive health systems, mandatory health registers, and extensive MG research. METHODS: MG experts and patient representatives from the five Nordic countries formed a working group to prepare treatment guidance for MG based on a systematic literature search and consensus meetings. RESULTS: Pyridostigmine represents the first-line symptomatic treatment, while ambenonium and beta adrenergic agonists are second-line options. Early thymectomy should be undertaken if a thymoma, and in non-thymoma patients up to the age of 50-65 years if not obtaining remission on symptomatic treatment. Most patients need immunosuppressive drug treatment. Combining corticosteroids at the lowest possible dose with azathioprine is recommended, rituximab being an alternative first-line option. Mycophenolate, methotrexate, and tacrolimus represent second-line immunosuppression. Plasma exchange and intravenous immunoglobulin are used for myasthenic crises and acute exacerbations. Novel complement inhibitors and FcRn blockers are effective and fast-acting treatments with promising safety profiles. Their use depends on local availability, refunding policies, and cost-benefit analyses. Adapted physical training is recommended. Planning of pregnancies with optimal treatment, information, and awareness of neonatal MG is necessary. Social support and adaptation of work and daily life activities are recommended. CONCLUSIONS: Successful treatment of MG rests on timely combination of different interventions. Due to spontaneous disease fluctuations, comorbidities, and changes in life conditions, regular long-term specialized follow-up is needed. Most patients do reasonably well but there is room for further improvement. Novel treatments are promising, though subject to restricted access due to costs.

The epidemiology and societal costs of myasthenia gravis in Norway: A non-interventional study using national registry data.

BACKGROUND AND PURPOSE: With the emergence of new treatment options for myasthenia gravis (MG), there is a need for information regarding epidemiology, healthcare utilization, and societal costs to support economic evaluation and identify eligible patients. We aimed to enhance the understanding of these factors using nationwide systematic registry data in Norway. METHODS: We received comprehensive national registry data from five Norwegian health- and work-related registries. The annual incidence and prevalence were estimated for the period 2013-2021 using nationwide hospital and prescription data. The direct, indirect (productivity losses) and intangible costs (value of lost life-years [LLY] and health-related quality of life [HRQoL]) related to MG were estimated over a period of 1 year. RESULTS: In 2021, the incidence of MG ranged from 15 to 16 cases per year per million population depending on the registry used, while the prevalence varied between 208.9 and 210.3 per million population. The total annual societal costs of MG amounted to EUR 24,743 per patient, of which EUR 3592 (14.5%) were direct costs, EUR 8666 (35.0%) were productivity loss, and EUR 12,485 (50.5%) were lost value from LLY and reduced HRQoL. CONCLUSION: The incidence and prevalence of MG are higher than previously estimated, and the total societal costs of MG are substantial. Our findings demonstrate that productivity losses, and the value of LLY and HRQoL constitute a considerable proportion of the total societal costs.

Adverse Childhood Experiences and the Risk of Multiple Sclerosis Development: A Review of Potential Mechanisms.

Adverse childhood experiences (ACEs), such as abuse, neglect, and household dysfunction, contribute to long-term systemic toxic stress and inflammation that may last well into adulthood. Such early-life stressors have been associated with increased susceptibility to multiple sclerosis (MS) in observational studies and with the development of experimental autoimmune encephalomyelitis in animal models. In this review, we summarize the evidence for an ACE-mediated increase in MS risk, as well as the potential mechanisms for this association. ACEs dysregulate neurodevelopment, stress responses, and immune reactivity; they also alter the interplay between the immune system and neural networks. All of this may be relevant for MS risk. We further discuss how ACEs induce epigenetic changes and how the toxic stress caused by ACEs may reactivate the Epstein-Barr Virus (EBV), a key risk factor for MS. We conclude by suggesting new initiatives to obtain further insights into this topic.

Case report: Seropositive myasthenia gravis complicated by limbic encephalitis positive for antibodies to AMPAR and Lgi1.

Objectives: Autoantibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and leucine-rich glioma-inactivated 1 (Lgi1) are associated with autoimmune encephalitis. We described an acetylcholine receptor (AChR)-positive patient with myasthenia gravis who developed limbic encephalitis with antibodies to AMPAR and Lgi1. Methods: A single-case report with detailed, prospective clinical and biomarker data including serial laboratory testing and histopathology. Results: A 49-year-old woman was diagnosed with anti-AChR antibody-positive generalized myasthenia gravis in 1983. After 9 months of the removal of thymoma in 1984, she developed influenza-like symptoms and then symptoms of limbic encephalitis. Retrospective analysis of serum showed high concentrations of anti-AMPAR and lower concentrations of anti-Lgi1 antibodies. Cerebral CT was normal, EEG showed bifrontal dysrhythmia, and CSF showed mild pleocytosis. Immuno-histochemical examination of the thymoma confirmed staining for Glur2, a subunit of AMPAR. The patient recovered with mild sequelae, but low levels of anti-AMPAR and anti-Lgi1 antibodies were detectable for over 25 years subsequently. Discussion: This case confirms earlier reports of AMPAR-associated autoimmune encephalitis co-occurring with thymoma and myasthenia gravis and is unique in its observational length. It shows, moreover, that antibodies to AMPAR and Lgi1 can persist despite clinical recovery.

Myasthenia gravis and congenital myasthenic syndromes.

Myasthenia gravis is an autoimmune disorder caused by antibodies against elements in the postsynaptic membrane at the neuromuscular junction, which leads to muscle weakness. Congenital myasthenic syndromes are rare and caused by mutations affecting pre- or postsynaptic function at the neuromuscular synapse and resulting in muscle weakness. MG has a prevalence of 150-250 and an annual incidence of 8-10 individuals per million. The majority has disease onset after age 50 years. Juvenile MG with onset in early childhood is more common in East Asia. MG is subgrouped according to type of pathogenic autoantibodies, age of onset, thymus pathology, and generalization of muscle weakness. More than 80% have antibodies against the acetylcholine receptor. The remaining have antibodies against MuSK, LRP4, or postsynaptic membrane antigens not yet identified. A thymoma is present in 10% of MG patients, and more than one-third of thymoma patients develop MG as a paraneoplastic condition. Immunosuppressive drug therapy, thymectomy, and symptomatic drug therapy with acetylcholine esterase inhibitors represent cornerstones in the treatment. The prognosis is good, with the majority of patients having mild or moderate symptoms only. Most congenital myasthenic syndromes are due to dysfunction in the postsynaptic membrane. Symptom debut is in early life. Symptomatic drug treatment has sometimes a positive effect.

High-dose folic acid and cancer risk; unjustified concerns by von Wrede and colleagues regarding our paper.

Women using antiseizure medication in pregnancy are often advised to use high doses of folic acid supplements (1mg to 5 mg) to reduce the risk of teratogenicity. Recently, we published a report showing an association between maternal prescription fill of high dose folic acid in relation to pregnancy and childhood cancer in the offspring. The report has sparked a debate about which dose of folic acid that should be recommended in pregnancy in women in need of antiseizure medication. In this Commentary, we explain our findings and the method used in our report, and answer recent questions that have emerged.

Occurrence and severity of myasthenic crisis in an unselected Turkish cohort of patients with myasthenia gravis.

Myasthenia gravis (MG) is a disorder of the neuromuscular junction that can deteriorate into myasthenic crisis, involving weakness of bulbar and respiratory muscles. In this study, we describe the clinical manifestations of myasthenic crisis, identify risk factors, and examine treatments and outcomes. All 95 patients with generalized MG treated at our center during the last 10 years were included in this retrospective study. We collected data from the patients' records, including clinical follow-ups, muscle antibodies, thymic status, and treatments. The characteristics of patients who did and did not experience myasthenic crisis were compared. Features of all myasthenic crises were also assessed. Twelve patients (13%) developed myasthenic crisis during the observation period. Men were more often affected at older ages. Seven patients experienced multiple myasthenic crises. Thymoma increased the risk of a crisis, whereas thymic hyperplasia decreased the risk. Myasthenic crises were more common in the summer months. No patients died during a myasthenic crisis. Risk factors for myasthenic crisis were thymoma, older age, MuSK antibodies, and previous crises. Individualized and active immunosuppressive treatment and optimal intensive care during crises provide a good outcome for patients with generalized MG.

Myasthenia gravis, respiratory function, and respiratory tract disease.

Myasthenia gravis (MG) is characterized by muscle weakness caused by autoantibodies that bind to the postsynaptic membrane at the neuromuscular junction and impair acetylcholine receptor function. Weakness of respiratory muscles represents the most severe MG manifestation, and 10-15% of all patients experience an MG crisis with the need of mechanical ventilatory support at least once in their life. MG patients with respiratory muscle weakness need active immunosuppressive drug treatment long term, and they need regular specialist follow-up. Comorbidities affecting respiratory function need attention and optimal treatment. Respiratory tract infections can lead to MG exacerbations and precipitate an MG crisis. Intravenous immunoglobulin and plasma exchange are the core treatments for severe MG exacerbations. High-dose corticosteroids, complement inhibitors, and FcRn blockers represent fast-acting treatments that are effective in most MG patients. Neonatal myasthenia is a transient condition with muscle weakness in the newborn caused by mother's muscle antibodies. In rare cases, treatment of respiratory muscle weakness in the baby is required.

Treatment considerations in myasthenia gravis for the pregnant patient.

INTRODUCTION: Myasthenia gravis (MG) is an autoimmune disease where muscle antibodies form against the acetylcholine receptor (AChR), MuSK, or LRP4 at the neuromuscular junction leading to weakness. Patients worry about consequences for pregnancy, giving birth, nursing, and child outcome. AREAS COVERED: This review lists the pharmacological treatments for MG in the reproductive age and gives recommendations. Consequences for pregnancy, giving birth, breastfeeding, and child outcome are discussed. EXPERT OPINION: Pyridostigmine, corticosteroids in low doses, and azathioprine are regarded as safe during pregnancy and should be continued. Mycophenolate mofetil, methotrexate, and cyclophosphamide should not be used in reproductive age. Rituximab should not be given during pregnancy. Other monoclonal IgG antibodies such as eculizumab and efgartigimod should be given only when regarded strictly necessary to avoid long-term and severe incapacity. Intravenous and subcutaneous immunoglobulin and plasma exchange are safe treatments during pregnancy and are recommended for exacerbations with moderate or severe generalized weakness. Most MG women have spontaneous vaginal deliveries. Indications for Cesarean section are obstetrical and similar to non-MG women. Neonatal myasthenia manifests as a transient weakness caused by the mother's IgG muscle antibodies and affects 10% of the babies. MG women should be supported in their wish to have children.

Cancer Risk in Children of Mothers With Epilepsy and High-Dose Folic Acid Use During Pregnancy.

Importance: Women with epilepsy are recommended high doses of folic acid before and during pregnancy owing to risk of congenital anomalies associated with antiseizure medications. Whether prenatal exposure to high-dose folic acid is associated with increases in the risk of childhood cancer is unknown. Objective: To assess whether high-dose folic acid supplementation in mothers with epilepsy is associated with childhood cancer. Design, Setting, and Participants: Observational cohort study conducted with nationwide registers in Denmark, Norway, and Sweden from 1997 to 2017. Analyses were performed during January 10, 2022, to January 31, 2022. Mother-child pairs were identified in medical birth registers and linked with information from patient, prescription, and cancer registers, as well as with sociodemographic information from statistical agencies, and were categorized by maternal diagnosis of epilepsy. The study population consisted of 3 379 171 children after exclusion of 126 711 children because of stillbirth or missing or erroneous values on important covariates. Exposures: Maternal prescription fills for high-dose folic acid tablets (≥1 mg daily) between 90 days before pregnancy start and birth. Main Outcomes and Measures: First onset of childhood cancer at younger than 20 years. Cox proportional hazards models were used to calculate adjusted hazard ratios with corresponding 95% CIs, adjusted for potential confounders. Cumulative incidence at aged 20 years was used as a measure of absolute risk. Results: The median age at the end of follow-up in the study population of 3 379 171 children was 7.3 years (IQR, 3.5-10.9 years). Among the 27 784 children (51.4% male) born to mothers with epilepsy, 5934 (21.4%) were exposed to high-dose folic acid (mean dose, 4.3 mg), with 18 exposed cancer cases compared with 29 unexposed, producing an adjusted hazard ratio of 2.7 (95% CI, 1.2-6.3), absolute risk if exposed of 1.4% (95% CI, 0.5%-3.6%), and absolute risk if unexposed of 0.6% (95% CI, 0.3%-1.1%). In children of mothers without epilepsy, 46 646 (1.4%) were exposed to high-dose folic acid (mean dose, 2.9 mg), with 69 exposed and 4927 unexposed cancer cases and an adjusted hazard ratio of 1.1 (95% CI, 0.9-1.4; absolute risk, 0.4% [95% CI, 0.3%-0.5%]). There was no association between children born to mothers with epilepsy who were prenatally exposed to antiseizure medications, but not high-dose folic acid, and an increased risk of cancer (absolute risk, 0.6%; 95% CI, 0.2%-1.3%). Conclusions and Relevance: Prenatal exposure to high-dose folic acid was associated with increased risk of cancer in children of mothers with epilepsy.

Physical training and exercise in myasthenia gravis.

Myasthenia gravis is characterized by muscle weakness and fatigue. As sustained muscle use increases the weakness, the value of physical training programs has previously been questioned. This is a review to clarify the safety and usefulness of systematic training in myasthenia gravis, based on a systematic search in available databases using the relevant key words. Ten intervention studies including 159 patients with generalized disease have been published regarding the effect of systematic physical training, three of them on respiratory muscles. Muscle strength improved, and in the majority of the studies also daily function and quality of life. The feeling of fatigue not directly related to actual muscle weakness was less influenced by physical training. Continuous training was necessary to maintain the improved function. Physical training and exercise are safe in myasthenia gravis. This can improve both muscle strength and daily function. Type and intensity of systematic training should be adapted in the individual patient. A minimum of 150 min of exercise per week is recommended for myasthenia gravis patients with mild and moderate disease.

International Consensus Guidance for Management of Myasthenia Gravis: 2020 Update.

OBJECTIVE: To update the 2016 formal consensus-based guidance for the management of myasthenia gravis (MG) based on the latest evidence in the literature. METHODS: In October 2013, the Myasthenia Gravis Foundation of America appointed a Task Force to develop treatment guidance for MG, and a panel of 15 international experts was convened. The RAND/UCLA appropriateness method was used to develop consensus recommendations pertaining to 7 treatment topics. In February 2019, the international panel was reconvened with the addition of one member to represent South America. All previous recommendations were reviewed for currency, and new consensus recommendations were developed on topics that required inclusion or updates based on the recent literature. Up to 3 rounds of anonymous e-mail votes were used to reach consensus, with modifications to recommendations between rounds based on the panel input. A simple majority vote (80% of panel members voting "yes") was used to approve minor changes in grammar and syntax to improve clarity. RESULTS: The previous recommendations for thymectomy were updated. New recommendations were developed for the use of rituximab, eculizumab, and methotrexate as well as for the following topics: early immunosuppression in ocular MG and MG associated with immune checkpoint inhibitor treatment. CONCLUSION: This updated formal consensus guidance of international MG experts, based on new evidence, provides recommendations to clinicians caring for patients with MG worldwide.

AChR antibodies show a complex interaction with human skeletal muscle cells in a transcriptomic study.

Acetylcholine receptor (AChR) antibodies are the most important pathogenic marker in patients with myasthenia gravis (MG). The antibodies bind to AChRs on the postsynaptic membrane, and this leads to receptor degradation, destruction, or functional blocking with impaired signal at the neuromuscular junction. In this study, we have explored the effects of AChR antibodies binding to mature human myotubes with agrin-induced AChR clusters and pathways relevant for AChR degradation using bulk RNA sequencing. Protein-coding RNAs and lncRNAs were examined by RNA sequencing analysis. AChR antibodies induced marked changes of the transcriptomic profiles, with over 400 genes differentially expressed. Cholesterol metabolic processes and extracellular matrix organization gene sets were influenced and represent AChR-trafficking related pathways. Muscle contraction and cellular homeostasis gene sets were also affected, and independently of AChR trafficking. Furthermore, we found changes in a protein-coding RNA and lncRNA network, where expression of lncRNA MEG3 correlated closely with protein-coding genes for cellular homeostasis. We conclude that AChR antibodies induce an active response in human skeletal muscle cells which affects key intra- and extracellular pathways.

Maternal complications in pregnancy and childbirth for women with epilepsy: Time trends in a nationwide cohort.

OBJECTIVE: Obstetric trends show changes in complication rates and maternal characteristics such as caesarean section, induced labour, and maternal age. To what degree such general time trends and changing patterns of antiepileptic drug use influence pregnancies of women with epilepsy (WWE) is unknown. Our aim was to describe changes in maternal characteristics and obstetric complications in WWE over time, and to assess changes in complication risks in WWE relative to women without epilepsy. METHODS: This was a nationwide cohort study of all first births in the Medical Birth Registry of Norway, 1999-2016. We estimated maternal characteristics, complication rates, and risks for WWE compared to women without epilepsy. Main maternal outcome measures were hypertensive disorders, bleeding in pregnancy, induction of labour, caesarean section, postpartum hemorrhage, preterm birth, small for gestational age, and epidural analgesia. Time trends were analyzed by logistic regression and comparisons made with interaction analyses. RESULTS: 426 347 first births were analyzed, and 3077 (0.7%) women had epilepsy. In WWE there was an increase in proportions of induced labour (p<0.005) and use of epidural analgesia (p<0.005), and a reduction in mild preeclampsia (p = 0.006). However, the risk of these outcomes did not change over time. Only the risk of severe preeclampsia increased significantly over time relative to women without epilepsy (p = 0.006). In WWE, folic acid supplementation increased significantly over time (p<0.005), and there was a decrease in smoking during pregnancy (p<0.005), but these changes were less pronounced than for women without epilepsy (p<0.005). CONCLUSIONS: During 1999-2016 there were important changes in maternal characteristics and complication rates among WWE. However, outcome risks for WWE relative to women without epilepsy did not change despite changes in antiepileptic drug use patterns. The relative risk of severe preeclampsia increased in women with epilepsy.

Myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.

Antiepileptic and psychiatric medication in a nationwide cohort of patients with glioma WHO grade II-IV.

INTRODUCTION: Glioma is the most common intracranial primary brain tumor. Patients with glioma often suffer from epilepsy, anxiety and depression. Aims of this study were to identify risk factors for drug-treated anxiety and depression, and to determine the use of psychiatric medication in a national glioma cohort. METHODS: Data from the Cancer Registry of Norway on all persons diagnosed with glioma WHO grade II-IV 2004-2010 were linked with data from the Norwegian Prescription Database. Cox regression analysis was used to assess risk factors for drug-treated anxiety and depression. Standardized incidence ratios were calculated for psychiatric medication dispensed to glioma patients and compared to the general population. RESULTS: The glioma cohort consisted of 1056 males and 772 females. Of the 1828 patients, 565 had glioma grade II-III, and 1263 had grade IV. The patients with glioma grade II-III who were treated with levetiracetam had an increased risk for drug-treated anxiety compared to patients without levetiracetam; hazard ratio 2.8 (95% confidence interval 1.7-4.9). Female gender increased the risk for drug-treated anxiety compared to males in patients with glioma grade IV; hazard ratio 1.5 (95% confidence interval 1.2-2.0). Antidepressants were less frequently dispensed to patients with glioma grade II-III and epilepsy than to the general population. CONCLUSIONS: Patients with glioma grade II-III on levetiracetam had an increased risk for drug-treated anxiety. The subgroup of patients with glioma grade II-III and epilepsy received less antidepressants than the general population.

Myasthenia gravis and infectious disease.

BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is an autoimmune disease with muscular weakness as the only symptom, and often with immunosuppressive treatment. All these aspects could have relevance for the risk of infections as well as their prophylactic and curative treatment. METHODS: This is a review article, where Web of Science has been searched for relevant key words and key word combinations. Full papers were selected first by title and then by abstract. RESULTS AND CONCLUSIONS: MG can be triggered and worsened by infections. No virus or other pathogen has been proven to have a specific link to MG. Treatment with immunosuppressive drugs and thymectomy implies a slightly increased risk for infections. Infections should be actively treated, but a few antibiotics are avoided due to potential interference with neuromuscular transmission. Hospitalization and intensive care may be necessary during infections because of MG deterioration and risk of insufficient respiration. Vaccinations are generally recommended in MG, but live microorganisms should be avoided if possible in immunosuppressed patients.