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Medicina Clinica Aug 2023Myasthenia gravis is an autoimmune disease caused by the presence of specific antibodies targeting different postsynaptic components of the neuromuscular junction, and... (Review)
Review
Myasthenia gravis is an autoimmune disease caused by the presence of specific antibodies targeting different postsynaptic components of the neuromuscular junction, and is clinically characterized by the presence of fatigueable muscle weakness. In the etiopathogenesis plays a central role the thymus and the most frequently detected pathogenic autoantibodies are targeted to the acetylcholine receptor. The increase in the knowledge of the immunological components of the neuromuscular junction in the last two decades has been fundamental to identify new pathogenic antibodies, reduce the percentage of patients with seronegative myasthenia, and propose a classification of patients into subgroups with clinical-therapeutic interest. In addition, in recent years, new drugs have been developed for the treatment of patients with myasthenia gravis that are refractory to conventional immunosuppressive treatment.
Topics: Humans; Myasthenia Gravis; Neuromuscular Junction; Receptors, Cholinergic; Autoantibodies; Immunosuppressive Agents; Muscle Weakness
PubMed: 37248131
DOI: 10.1016/j.medcli.2023.04.006 -
Muscle & Nerve Jul 2023Myasthenic crisis (MC) is a life-threatening manifestation of myasthenia gravis (MG) defined by respiratory insufficiency that requires the use of invasive or... (Review)
Review
Myasthenic crisis (MC) is a life-threatening manifestation of myasthenia gravis (MG) defined by respiratory insufficiency that requires the use of invasive or non-invasive ventilation. This is often the result of respiratory muscle weakness but can also be due to bulbar weakness with upper airway collapse. MC occurs in approximately 15%-20% of patients with MG usually within the first 2 to 3 y of the disease course. Many crises have a specific trigger with respiratory infections being most common; however, no specific trigger is found in 30%-40% of patients. MG patients with a history of MC, severe disease, oropharyngeal weakness, muscle-specific kinase (MuSK) antibodies and thymoma appear to be at higher risk. Most episodes of MC do not occur suddenly, providing a window of opportunity for prevention. Immediate treatment is directed toward airway management and removing any identified triggers. Plasmapheresis is preferred over intravenous immune globulin as the treatments of choice for MC. The majority of patients are able to be weaned from mechanical ventilation within 1 mo and the outcomes of MC are generally favorable. The mortality rate in United States cohorts is less than 5% and mortality in MC seems to be driven by age and other medical co-morbidities. MC does not appear to affect long-term prognosis as many patients are able to eventually achieve good MG control.
Topics: Humans; Myasthenia Gravis; Muscle Weakness; Plasmapheresis; Respiration, Artificial; Thymus Neoplasms
PubMed: 37114503
DOI: 10.1002/mus.27832 -
Continuum (Minneapolis, Minn.) Dec 2023Progress is ongoing in understanding paraneoplastic neurologic disorders, with new syndromes and antibodies being described and more detailed evidence available to guide...
OBJECTIVE
Progress is ongoing in understanding paraneoplastic neurologic disorders, with new syndromes and antibodies being described and more detailed evidence available to guide workup for diagnosis and treatment to improve outcomes. Many excellent reviews have summarized the molecular features of different antibodies, but this article emphasizes the clinical features of each syndrome that may help guide initial diagnosis and treatment, which often should occur before an antibody or cancer is found to confirm the diagnosis.
LATEST DEVELOPMENTS
Recent findings include updated diagnostic criteria with validated sensitivity and specificity, discovery of novel antibodies, and clinical findings that increase the likelihood of an underlying paraneoplastic disorder. Suggestive syndromes that have been recently identified include faciobrachial dystonic seizures and pilomotor auras in anti-leucine-rich glioma inactivated protein 1 encephalitis, extreme delta brush on EEG in N-methyl-d-aspartate (NMDA)-receptor encephalitis, déjà vu aura in anti-glutamic acid decarboxylase 65 (GAD65) encephalitis, and sleep disturbances in several disorders. In addition, there is confirmed utility of brain positron emission tomography (PET) and CSF markers, including carcinoembryonic antigen and oligoclonal bands, as well as improved tests for the presence of leptomeningeal cancer cells in CSF. Associations of cancer immunotherapies with paraneoplastic syndromes and herpes simplex virus encephalitis (and COVID-19) with NMDA-receptor encephalitis have been described.
ESSENTIAL POINTS
All neurologists should be aware of advances regarding paraneoplastic neurologic syndromes, as patients can present with a wide variety of neurologic symptoms and earlier diagnosis and treatment can improve outcomes.
Topics: Humans; N-Methylaspartate; Paraneoplastic Syndromes, Nervous System; Encephalitis; Autoantibodies; Epilepsy; Receptors, N-Methyl-D-Aspartate
PubMed: 38085898
DOI: 10.1212/CON.0000000000001357 -
Handbook of Clinical Neurology 2024Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction of the neuromuscular junction resulting in skeletal muscle weakness. It is equally prevalent... (Review)
Review
Myasthenia gravis (MG) is an autoimmune disease characterized by dysfunction of the neuromuscular junction resulting in skeletal muscle weakness. It is equally prevalent in males and females, but debuts at a younger age in females and at an older age in males. Ptosis, diplopia, facial bulbar weakness, and limb weakness are the most common symptoms. MG can be classified based on the presence of serum autoantibodies. Acetylcholine receptor (AChR) antibodies are found in 80%-85% of patients, muscle-specific kinase (MuSK) antibodies in 5%-8%, and <1% may have low-density lipoprotein receptor-related protein 4 (Lrp4) antibodies. Approximately 10% of patients are seronegative for antibodies binding the known disease-related antigens. In patients with AChR MG, 10%-20% have a thymoma, which is usually detected at the onset of the disease. Important differences between clinical presentation, treatment responsiveness, and disease mechanisms have been observed between these different serologic MG classes. Besides the typical clinical features and serologic testing, the diagnosis can be established with additional tests, including repetitive nerve stimulation, single fiber EMG, and the ice pack test. Treatment options for MG consist of symptomatic treatment (such as pyridostigmine), immunosuppressive treatment, or thymectomy. Despite the treatment with symptomatic drugs, steroid-sparing immunosuppressants, intravenous immunoglobulins, plasmapheresis, and thymectomy, a large proportion of patients remain chronically dependent on corticosteroids (CS). In the past decade, the number of treatment options for MG has considerably increased. Advances in the understanding of the pathophysiology have led to new treatment options targeting B or T cells, the complement cascade, the neonatal Fc receptor or cytokines. In the future, these new treatments are likely to reduce the chronic use of CS, diminish side effects, and decrease the number of patients with refractory disease.
Topics: Female; Humans; Male; Autoantibodies; Electromyography; Immunosuppressive Agents; Myasthenia Gravis; Neuromuscular Junction
PubMed: 38494283
DOI: 10.1016/B978-0-12-823912-4.00026-8 -
The Lancet. Neurology Jan 2024Immune checkpoint inhibitors, a class of oncological treatments that enhance antitumour immunity, can trigger neurological adverse events closely resembling... (Review)
Review
Immune checkpoint inhibitors, a class of oncological treatments that enhance antitumour immunity, can trigger neurological adverse events closely resembling paraneoplastic neurological syndromes. Unlike other neurological adverse events caused by these drugs, post-immune checkpoint inhibitor paraneoplastic neurological syndromes predominantly affect the CNS and are associated with neural antibodies and cancer types commonly found also in spontaneous paraneoplastic neurological syndromes. Furthermore, post-immune checkpoint inhibitor paraneoplastic neurological syndromes have poorer neurological outcomes than other neurological adverse events of immune checkpoint inhibitors. Early diagnosis and initiation of immunosuppressive therapy are likely to be crucial in preventing the accumulation of neurological disability. Importantly, the neural antibodies found in patients with post-immune checkpoint inhibitor paraneoplastic neurological syndromes are sometimes detected before treatment, indicating that these antibodies might help to predict the development of neurological adverse events. Experimental and clinical evidence suggests that post-immune checkpoint inhibitor paraneoplastic neurological syndromes probably share immunological features with spontaneous paraneoplastic syndromes. Hence, the study of post-immune checkpoint inhibitor paraneoplastic neurological syndromes can help in deciphering the immunopathogenesis of paraneoplastic neurological syndromes and in identifying novel therapeutic targets.
Topics: Humans; Immune Checkpoint Inhibitors; Paraneoplastic Syndromes, Nervous System; Paraneoplastic Syndromes; Neoplasms; Autoantibodies
PubMed: 38101905
DOI: 10.1016/S1474-4422(23)00369-1 -
JAMA Dermatology Sep 2023
Topics: Humans; Dermatomyositis; Paraneoplastic Syndromes; Biopsy
PubMed: 37405743
DOI: 10.1001/jamadermatol.2023.1013 -
The Lancet. Neurology Dec 2023
Topics: Humans; T-Lymphocytes; Myasthenia Gravis
PubMed: 37977704
DOI: 10.1016/S1474-4422(23)00375-7 -
Frontiers in Immunology 2023Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck,... (Review)
Review
Muscle-specific kinase (MuSK) Myasthenia Gravis (MG) represents a prototypical antibody-mediated disease characterized by predominantly focal muscle weakness (neck, facial, and bulbar muscles) and fatigability. The pathogenic antibodies mostly belong to the immunoglobulin subclass (Ig)G4, a feature which attributes them their specific properties and pathogenic profile. On the other hand, acetylcholine receptor (AChR) MG, the most prevalent form of MG, is characterized by immunoglobulin (Ig)G1 and IgG3 antibodies to the AChR. IgG4 class autoantibodies are impotent to fix complement and only weakly bind Fc-receptors expressed on immune cells and exert their pathogenicity interfering with the interaction between their targets and binding partners (e.g. between MuSK and LRP4). Cardinal differences between AChR and MuSK-MG are the thymus involvement (not prominent in MuSK-MG), the distinct HLA alleles, and core immunopathological patterns of pathology in neuromuscular junction, structure, and function. In MuSK-MG, classical treatment options are usually less effective (e.g. IVIG) with the need for prolonged and high doses of steroids difficult to be tapered to control symptoms. Exceptional clinical response to plasmapheresis and rituximab has been particularly observed in these patients. Reduction of antibody titers follows the clinical efficacy of anti-CD20 therapies, a feature implying the role of short-lived plasma cells (SLPB) in autoantibody production. Novel therapeutic monoclonal against B cells at different stages of their maturation (like plasmablasts), or against molecules involved in B cell activation, represent promising therapeutic targets. A revolution in autoantibody-mediated diseases is pharmacological interference with the neonatal Fc receptor, leading to a rapid reduction of circulating IgGs (including autoantibodies), an approach already suitable for AChR-MG and promising for MuSK-MG. New precision medicine approaches involve Chimeric autoantibody receptor T (CAAR-T) cells that are engineered to target antigen-specific B cells in MuSK-MG and represent a milestone in the development of targeted immunotherapies. This review aims to provide a detailed update on the pathomechanisms involved in MuSK-MG (cellular and humoral aberrations), fostering the understanding of the latest indications regarding the efficacy of different treatment strategies.
Topics: Humans; Autoantibodies; Immunoglobulin G; Immunotherapy; Myasthenia Gravis; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic
PubMed: 37564637
DOI: 10.3389/fimmu.2023.1212757 -
Frontiers in Immunology 2023Multiple reports on the co-existence of autoimmune diseases and myasthenia gravis (MG) have raised considerable concern. Therefore, we reviewed autoimmune diseases in MG... (Review)
Review
Multiple reports on the co-existence of autoimmune diseases and myasthenia gravis (MG) have raised considerable concern. Therefore, we reviewed autoimmune diseases in MG to explore their clinical presentations and determine whether the presence of autoimmune diseases affects the disease severity and treatment strategies for MG. We reviewed all the major immune-mediated coexisting autoimmune conditions associated with MG. PubMed, Embase and Web of Science were searched for relevant studies from their inception to January 2023. There is a higher frequency of concomitant autoimmune diseases in patients with MG than in the general population with a marked risk in women. Most autoimmune comorbidities are linked to AChR-MG; however, there are few reports of MuSK-MG. Thyroid disorders, systemic lupus erythematosus, and vitiligo are the most common system autoimmune diseases associated with MG. In addition, MG can coexist with neurological autoimmune diseases, such as neuromyelitis optica (NMO), inflammatory myopathy (IM), multiple sclerosis (MS), and autoimmune encephalitis (AE), with NMO being the most common. Autoimmune diseases appear to develop more often in early-onset MG (EOMG). MS coexists more commonly with EOMG, while IM coexists with LOMG. In addition, MG complicated by autoimmune diseases tends to have mild clinical manifestations, and the coexistence of autoimmune diseases does not influence the clinical course of MG. The clinical course of neurological autoimmune diseases is typically severe. Autoimmune diseases occur most often after MG or as a combined abnormality; therefore, timely thymectomy followed by immunotherapy could be effective. In addition, thymoma-associated AChR MG is associated with an increased risk of AE and IM, whereas NMO and MS are associated with thymic hyperplasia. The co-occurrence of MG and autoimmune diseases could be attributed to similar immunological mechanisms with different targets and common genetic factor predisposition. This review provides evidence of the association between MG and several comorbid autoimmune diseases.
Topics: Humans; Female; Myasthenia Gravis; Thymoma; Comorbidity; Thymus Neoplasms; Neuromyelitis Optica; Multiple Sclerosis; Myositis; Disease Progression
PubMed: 37781409
DOI: 10.3389/fimmu.2023.1223322 -
Panminerva Medica Jun 2024Tumor-induced osteomalacia is one of paraneoplastic syndromes characterized by hypophosphatemia caused by excessive actions of fibroblast growth factor 23 (FGF23). Since... (Review)
Review
Tumor-induced osteomalacia is one of paraneoplastic syndromes characterized by hypophosphatemia caused by excessive actions of fibroblast growth factor 23 (FGF23). Since the cloning of FGF23 about 20 years ago, more widespread awareness of this disease has been achieved. However, there still remain several difficulties in the management of patients with this disease. In this review, these clinical problems are discussed together with the physiological and pathophysiological functions of FGF23. Personal proposals in the management of patients with suspected patients with tumor-induced osteomalacia are also presented.
Topics: Humans; Osteomalacia; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Paraneoplastic Syndromes; Hypophosphatemia; Neoplasms, Connective Tissue; Animals
PubMed: 38127062
DOI: 10.23736/S0031-0808.23.05047-4