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PubMedDate not supplied

Management of myasthenia gravis.

Myasthenia gravis (MS) is an immune-mediated disorder characterized by fluctuating weakness and fatigue of voluntary muscles. The muscular disorder is generalized in 85% and confined to extraocular muscles in 15% of patients. Pathophysiology of MG involves generation of antiacetylcholine receptor antibodies, which leads to a reduction of the number of acetylcholine receptors at the muscular motor endplate. This in turn results in fewer acetylcholine receptors available for stimulation, lower amplitude stimulations, less muscle fiber activation, and the eventual development of weakness in the affected muscles. The diagnostic workup for MS consists of administration of anticholinesterase agents (Tensilon test), repetitive nerve stimulation, Ach-R antibody assay, and single-fiber electromyography. Management of patients with MG includes cholinesterase inhibitors, corticosteroids, thymectomy, immunosuppressants, plasma exchange, and IVIg.

Cholinesterase Inhibitors↗

PubMed1992

Factors influencing the clinical type and course of myasthenia gravis.

Myasthenia gravis is considered to be an autoimmune disease in which several factors reciprocally influence the clinical type and course. We investigated the relative importance of the following factors: anti-acetylcholine receptor antibody (AChR Ab), HLA, age at onset, autoimmunity, thymic abnormality, duration of treatment, change in AChR Ab titer and immunosuppressive therapy. The pretreatment-AChR Ab titer and HLA were shown to significantly influence the clinical type. On the other hand, the age at onset significantly influenced the clinical course. The finding that with an onset at less than 5-year-old there was a tendency for a good prognosis suggests an association between the immaturity of the muscle and immune systems, and the clinical course.

Adolescent↗

PubMed1979

A modified assay for antibody against the nicotinic acetylcholine receptor in myasthenia gravis.

Myasthenia gravis is an autoimmune disease which may be detected by the presence of serum antibodies against the nicotinic acetylcholine receptor at the neuromuscular junction. Immunoprecipitation assays have been developed to measure these immunoglobulins and calculate titres. These assays require the labelling of the receptor with 125I-alpha-bungarotoxin which binds irreversibly. However, the standard immunoprecipitation assay may significantly underestimate the titres of some myasthenic patients. We have discovered patients with antibodies specific for the alpha-bungarotoxin binding site of purified rat muscle receptor. If labelled toxin is already present on the receptor, these antibodies are unable to bind to the protein. This phenomenon may lead to underestimates of the actual antibody titre. To circumvent this problem, we have designed a modified immunoprecipitation assay to evaluate titres.

Acetylcholine↗

PubMed1988

Neuroimmunology of myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease in which the immune system attacks the nicotinic acetylcholine receptors (AChRs) of the neuromuscular junction. Anti-AChR antibodies are present in 85% of patients and bind to distinct epitopes on the surface of the AChR alpha subunits, as defined by competition with monoclonal anti-AChR antibodies. There are at least three types of the disease, defined by thymic histology, age of onset, and HLA associations, and anti-AChR antibodies show some differences in fine specificity between those with thymic hyperplasia and those with thymic tumors. Peripheral blood lymphocytes from MG patients contain T lymphocytes specifically sensitized to AChR. These are stimulated by purified Torpedo AChR and some human alpha subunit synthetic peptides. The T and B cell epitopes on the primary sequence of the alpha subunit are currently being mapped using recombinant human AChR subunit fragments.

Adult↗

PubMed2004

Clinical evaluation and management of myasthenia gravis.

Myasthenia gravis (MG) is a syndrome of fluctuating skeletal muscle weakness that worsens with use and improves with rest. Eye, facial, oropharyngeal, axial, and limb muscles may be involved in varying combinations and degrees of severity. Its etiology is heterogeneous, divided initially between those rare congenital myasthenic syndromes, which are genetic, and the bulk of MG, which is acquired and autoimmune. The autoimmune conditions are divided in turn between those that possess measurable serum acetylcholine receptor (AChR) antibodies and a smaller group that does not. The latter group includes those MG patients who have serum antibodies to muscle-specific tyrosine kinase (MuSK). Therapeutic considerations differ for early-onset MG, late-onset MG, and MG associated with the presence of a thymoma. Most MG patients can be treated effectively, but there is still a need for more specific immunological approaches.

Autoantibodies↗

PubMed2001

[Anesthesia in patients with myasthenia gravis].

Myasthenia gravis is a chronic autoimmune disease characterised by progressive weakness and easy fatigability of voluntary skeletal muscles. These symptoms are related to a decrease in the number of functional acetylcholine receptors, impaired neuromuscular transmission, and a broadened neuromuscular cleft. Symptomatic treatment is based on anticholinesterases in order to increase the synaptic dwell of acetylcholine. Immune therapy includes immune suppressive drugs, plasma exchange, immunoglobulins, and thymectomy. Anticholinesterase therapy should be continued in the current mode until anaesthesia. Regional anaesthesia should be preferred. Although sensitivity to non-depolarising neuromuscular blocking agents is increased, muscle relaxants can be administered during general anaesthesia as long as neuromuscular monitoring assesses their individual effect. Due to the individual variability in the response to muscle relaxants, accurate titration in combination with pre- and intraoperative neuromuscular monitoring is essential for myasthenic patients. Postoperatively, intensive care observation is mandatory including neuromuscular monitoring.

Anesthesia↗

PubMed2002

Etiology, mechanisms, and anesthesia implications of autoimmune myasthenia gravis.

Myasthenia gravis (MG) is the prototypical neurological autoimmune disease. It is characterized by muscle weakness that progressively worsens on repetition but improves with rest. Muscle weakness and fatigability arise from defective or decreased acetylcholine receptors at the neuromuscular junctions, where nerve signals from spinal motor neurons that innervate muscles cannot effectively induce muscle contraction. Several mechanisms of pathogenesis lead to the MG syndrome. The most prevalent cause of MG is an autoimmune disorder in which the patient produces antibodies that attack the nicotinic acetylcholine receptor at the neuromuscular junction. Anesthesia management of the patient with MG is challenging and requires specific management; however, safe and successful outcomes are achievable. This course emphasizes the autoimmune neuromuscular defect in MG, current treatments for this syndrome, contraindications of certain anesthetic drugs in this condition, and anesthetic management of a patient with MG in the operating room environment.

Anesthesia↗

PubMed2004

Pathophysiology of myasthenia gravis.

Myasthenia gravis (MG) is arguably the best understood autoimmune disease, and its study has also led to fundamental appreciation of mechanisms of neuromuscular transmission. MG is caused by antibodies against the acetylcholine receptor (AChR), which produce a compromise in the end-plate potential, reducing the safety factor for effective synaptic transmission. It is clear that AChR antibody destruction of the postsynaptic surface is dependent on complement activation. A muscle-specific kinase has been recently found to be an antigenic target in MG patients without antibodies against the AChR. Autoantibody production in MG is a T-cell-dependent process, but how a breakdown in tolerance occurs is not known. In MG there is an interesting differential involvement of muscle groups, in particular, the extraocular muscles. This article reviews normal neuromuscular transmission, mechanisms of the autoimmune process of MG, and differential susceptibility of eye muscles to MG.

Autoantibodies↗

PubMed1991

Therapeutic strategies for myasthenia gravis.

Myasthenia gravis (MG) is a complex autoimmune neurologic disorder of unknown etiology, characterized by fluctuating skeletal muscle weakness most commonly involving the muscles of the head, neck, and upper extremities. Autoantibodies directed against acetylcholine receptors on the postjunctional membrane decrease the numbers of functional acetylcholine receptors and cause membrane alterations, resulting in neuromuscular transmission failure. Diagnosis is established by history and physical examination, the "Tensilon Test," and acetylcholine receptor antibody titers. Treatment modalities include drug therapy, thymectomy, and plasmapheresis. The drugs most commonly employed are anticholinesterases, corticosteroids, and immuno-suppressive agents. Cyclosporine and intravenous immunoglobulin are promising investigational treatments. The purpose of the article is to review current concepts in the pathophysiology, immunopathology, diagnosis, and treatment of MG. Special emphasis is placed on the autoimmune form of the disease and the drugs employed in its management. Standard regimens as well as some experimental treatment modalities are reviewed.

Adrenal Cortex Hormones↗

PubMedDate not supplied

[Diagnostic problems in patients with myasthenia gravis].

Myasthenia gravis (MG) is an antigen-specific autoimmune disease in which antibodies directed against nicotinic acetylcholine receptors of the postsynaptic muscle membrane (nAChR) impair neuromuscular transmission. MG is clinically characterized by abnormal muscle fatigue and weakness. The initial symptoms and signs are often unrecognized. Therefore, we analyzed the diagnostic errors and duration of diagnostic delay in patients affected with MG (n = 444) in a ten-year period (January 1, 1983-December 31, 1992) in Yugoslavia. The initial diagnosis was correct in 44.4% of patients and erroneous in 38.4%; 17.2% of patients were admitted without an initial diagnosis. The average duration of diagnostic delay was 11 months. We present the differential diagnostic difficulties in MG and discuss the principles of diagnostic strategy which may reduce the risk of diagnostic errors in MG.

Adult↗

PubMed1997

Current and future therapies for myasthenia gravis.

Myasthenia gravis (MG) is undoubtedly the most thoroughly understood of all human autoimmune diseases. The basic defect in the disease is a decrease in the number of available acetylcholine receptors (AChR) at neuromuscular junctions caused by an antibody-mediated autoimmune attack. Current treatments aimed at restoring the available AChR, depleting the autoantibodies or suppressing the immune system have been so effective that most patients can lead normal lives. However, prolonged drug treatment is required, and this carries a potential risk of drug toxicity and, in the case of immunosuppressants, systemic immunosuppression. The ideal treatment for MG would eliminate only the abnormal autoimmune response without interfering with the immune system. During the past 20 years, impressive advances have been made in our understanding of the immunology and molecular biology of MG. Accordingly, it should be possible to design rational and immune-based therapies in the future. In this article, we briefly review the current treatment modalities for MG, and discuss the prospects for immunotherapy.

Autoantibodies↗

PubMed2004

Anesthesia issues in the perioperative management of myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction. Current anesthetic practice may require the use of neuromuscular blocking (NMB) drugs that act at this junction to facilitate control of the airway and allow procedures to be performed on a motionless MG patient. This competes with the goals of rapid emergence and recapture of preoperative muscle strength following anesthesia. In particular, avoiding prolonged periods of postoperative mechanical ventilation is a paramount concern of patients, families, and physicians. Standard anesthetic agents and, if needed, judiciously titrated NMB drugs generally allow safe emergence and immediate extubation for most low-risk MG patients. If necessary, postoperative mechanical ventilation is accomplished with the use of specialized monitoring devices that help monitor awareness and depth of sedation. Currently used intravenous sedatives allow titrated depth of sedation and rapid emergence when extubation is appropriate. Communication to the patient, family, and other caregivers of the goals of the anesthetic plan and of the patient's evolving status are also very important duties of the anesthesiologist.

Anesthesia↗

PubMed1998

T-cell interleukin-6 receptor binding in patients with myasthenia gravis.

Myasthenia gravis (MG) is a T-cell-dependent and antibody-mediated autoimmune disease of the neuromuscular junction, in which the cytokine network may be deranged. Specific receptors for interleukin (IL)-6, a cytokine with several effects on the neuroimmune system, have been found on human lymphocytes. The aim of the present study has been to assay IL-6 binding on peripheral blood T cells from MG patients. We found that T cells from MG patients have significantly more IL-6 receptors than those from controls (Bmax: 334 +/- 6 vs 251 +/- 4 (mean +/- SEM) receptors/cell). Such IL-6 binding sites are of the same type in patients and healthy subjects (Kd: 26.5 +/- 0.7 vs 25.7 +/- 0.9 (mean +/- SEM) pM). The enhanced T-cell interleukin-6 binding is due to an increased number of interleukin-6 receptors on T-helper lymphocytes. These results are discussed in terms of MG immunopathogenesis, since it has been reported that activated T cells have increased amounts of IL-6 receptors.

Adult↗

PubMed1981

[T3, T4, TSH and circulating antithyroglobulin antibodies in myasthenia gravis].

Myasthenia gravis (MG) is a rare neuromuscular disease which is known to be associated with hyperthyroidism at high frequency (3-10%). These investigations, however, are basing on studies of the basal metabolic rate, protein bound iodine (PBI) and the thyroidal radioiodine uptake. In our study (104 MG patients, 104 control subjects) we wanted to evaluate thyroid function on the basis of T3, T4, TBG and TSH radioimmunoassays and in addition we looked for the presence of circulating antithyroglobulin antibodies (Tab) and antimicrosomal antibodies (Mab). The following thyroidal states were disclosed: Thyrotoxicosis (5.8%), hypothyroidism (1.9%), preclinical hypothyroidism (3.8%) and euthyroidism (88.5%). Twenty-eight myasthenic patients were Mab-positive and twelve in addition Tab-positive. Comparing the twenty euthyroid antibody-positive MG-patients with euthyroid antibody-negatives no statistically significant differences were found in thyroid function parameters. It is discussed that part of the thyroid antibody-positive patients may have a symptomless autoimmune thyroiditis which is finally resulting in hypothyroidism via a preclinical hypothyroid status.

Adolescent↗

PubMed1996

Myasthenia gravis.

Myasthenia gravis (MG) is the classical organ specific, autoantibody mediated and T cell dependent human autoimmune disease. It is almost invariably associated with pathological alterations of the thymus. These are described here with reference to distinct models of autoimmunization against the acetylcholine receptor (AChR). In MG with thymitis B cells are increased in the medulla forming germinal centers or diffuse B cell infiltrates. Intrathymic production of AChR-specific autoantibodies is the result of a classical antigen-driven immune reaction that occurs completely inside the thymus and involves AChR on myoid cells as the triggering (myasthenogenic) antigen. In thymomas no intratumorous immune reaction occurs and the AChR is not the myasthenogenic antigen. Instead, an abnormal neurofilament that shares epitopes with the AChR is expressed in thymomas and may trigger AChR-specific, non-tolerogenic T cell selection by molecular mimicry. These data support the hypothesis that initial steps in the pathogenesis of MG take place within abnormal thymic microenvironments, be they inflammatory or neoplastic. The etiology of MG remains enigmatic.

Adolescent↗

PubMed1999

Antibody dependent cell-mediated cytotoxicity--an additional mechanism in human autoimmune myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease characterised by serum anti-acetylcholine receptor (AChR) antibodies and several pathogenic mechanisms for the action of these antibodies have been elucidated. In this study, we have analysed a possible additional mechanism for these antibodies, namely antibody-dependent cell-mediated cytotoxicity (ADCC). Using as target cells a cell line expressing AChR, we could show an increased ADCC mediated by sera from MG patients. Sera with AChR antibodies induced a higher cytotoxicity than sera from patients without these antibodies or healthy individuals. Sera from MG patients with thymoma induced a higher cytotoxic effect than sera from other patients. There was a strong positive correlation between the concentration of AChR antibodies and cytotoxicity mediated by purified IgG fractions from thymoma patients. In addition, there was a higher cytotoxicity mediated by sera from thymoma patients with extended dinucleotide repeats, (AT)n repeats, in the CTLA-4 gene. ADCC mediated by AChR antibodies may thus be another possible pathogenic mechanism that could operate in MG patients, especially in patients with thymoma.

Antibody-Dependent Cell Cytotoxicity↗

PubMed1997

The effects of T cell subpopulations and recombinant interleukin (IL)-2 on peripheral B cell function in patients with myasthenia gravis.

Myasthenia gravis is an autoimmune disease mediated by antibodies to acetylcholine receptors (AChR) of skeletal muscle. The production of anti-AChR antibodies has been shown to be T cell dependent. To elucidate the mechanism(s) of anti-AChR antibody production in myasthenic patients, we studied the effects of regulatory T cells and/or IL-2 on the differentiation of AChR-primed B cells, with use of AChR stimulation for the induction of anti-AChR antibodies in vitro. Our data suggest that CD8+ T cells possess some complicated functions. CD8+ T cells could not only provide help for B cells to secrete anti-AChR antibody, but also possibly inhibit response of CD4+ T cells or kill B cells, then repress anti-AChR antibody production in MG patients. There might be some defect either in the number or function of CD8+ T cell in MG patients. Exogenous IL-2 could completely restore the suppression activity of CD8+ T cells in anti-AChR antibody production in vitro.

Adult↗

PubMed2000

Antigen mimicry in autoimmune disease. Can immune responses to microbial antigens that mimic acetylcholine receptor act as initial triggers of Myasthenia gravis?

Myasthenia gravis (MG) is an autoimmune disease caused by autoantibodies against self acetylcholine receptor (AChR). Although a great deal of information is known about the molecular and cellular parameters of the disease, its initial trigger is not known. In order to study the possibility of the involvement of microbial antigens that mimic AChR in triggering MG, we have searched the microbial proteins in the data bank for regions that are similar in structure to the regions of human (h) AChR alpha chain recognized by autoAbs in MG patients. Hundreds of candidate structures on a large number of bacterial and viral proteins were identified. To test the feasibility of the idea, we synthesized four microbial regions similar to each of the major autodeterminants of hAChR (alpha12-27, alpha111-126, alpha122-138, alpha182-200) and investigated their ability to bind autoAbs in MG and normal sera controls. It was found that MG sera recognized a significant number of these microbial regions. The results indicate that in some MG cases immune responses to microbial antigens may cross-react with self antigen (in this case hAChR) and could constitute initial triggers of the disease.

Amino Acid Sequence↗