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PubMed2002

The role of antibodies in myasthenia gravis.

Myasthenia gravis is an autoimmune disease associated with antibodies directed to the postsynaptic acetylcholine receptor. These antibodies reduce the number of receptors. Autoantibodies against AChR and other muscle antigens can be used for the diagnosis of myasthenia gravis and related disorders. The origin and the role of these antibodies in the disease are discussed. Experimental autoimmune myasthenia gravis, an experimental model closely mimicking the disease, has provided answers to many questions about the role of antibodies, complement macrophages and AChR anchor proteins. Genetically modified anti-AChR antibodies may also be used in the future to treat myasthenia.

Autoantibodies↗

PubMed1979

The role of acetylcholine receptor antibodies in myasthenia gravis.

Myasthenia gravis is an autoimmune disease of man characterized by remitting and relapsing muscle fatigability. Although the etiology and pathogenesis are incompletely understood, the presence of circulating antibodies directed against the nicotinic acetylcholine (ACh) receptor in 80--90% of patients with myasthenia gravis and the identification of immune complexes at their neuromuscular junction have helped explain the altered neuromuscular transmission. The ACh receptor antibodies do not block access of ACh to the receptor, but do decrease the number of receptors by accelerating their degradation both in rat myotube cultures and in vivo models. In vitro these antibodies play a major role in myasthenia gravis. However, correlations of antibody titers with the clinical state following thymectomy or in neonatal myasthenia suggest that host factors may be equally important in determining whether the ACh receptor antibodies will result in clinical myasthenia.

Acetylcholine↗

PubMed1976

Audiotympanometric findings in myasthenia gravis.

Myasthenia gravis can be a difficult diagnostic and therapeutic problem. Our study on six patients consisted of pure-tone audiograms, tympanometry, and acoustic reflex tests. Positive findings in the myasthenia gravis patients prior to medication included hyperacusis and increase in the intensity of sound required to elicit an acoustic reflex. Following medication, the hyperacusis lessened and the intensity of sound required to elicit the acoustic reflex decreased. During follow-up of two of the patients we encountered cholinergic (overdosage) crisis in one patient and myasthenic (underdosage) crisis in the other patient. Muscle weakness can be a common factor in both conditions. The acoustic reflex test can differentiate between the two types of crises. We believe audiotympanometric tests can aid in diagnosis and treatment of myasthenia gravis patients.

Acoustic Stimulation↗

PubMed1980

Myasthenia gravis.

Myasthenia gravis is characterized by muscle weakness, which is alleviated by rest and by anticholinesterase drugs. There are two forms of the disease in the dog, acquired and congenital. The acquired form occurs either in young adults, or in older animals that have developed mediastinal tumors. Clinically, there is weakness of the muscles of the limbs, neck, and head, together with dilatation of the esophagus. In some cases, circulating antibody to acetylcholine receptor is present and the amount of receptor in the end-plates is decreased. It is thought to be an autoimmune disease. The congenital form of canine myasthenia gravis occurs most frequently in Jack Russell terriers from six to eight weeks of age. The clinical manifestations are similar to those accompanying acquired myasthenia, although dilatation of the esophagus is not a feature. Raised antibody levels to acetylcholine receptor have not been noted, although the amount of receptor in the end-plates is decreased. Thus, the congenital form does not appear to be an autoimmune disease and the pathophysiology has yet to be established. Both forms of canine myasthenia gravis provide useful models analogous to the disease in man.

Animals↗

PubMed2005

The early history of myasthenia gravis.

Myasthenia gravis was first recognised as a distinct clinical entity by Thomas Willis, a 17th century Oxford physician, whose 1672 account in Latin was largely unnoticed until 1903. The first modern description was made in 1877 by Samuel Wilks, a London physician. Towards the close of the 19th century, primary muscle diseases and diseases due to denervation of muscle were studied by English, French, and German physicians. The first full descriptions of myasthenia gravis were by Wilhelm Erb, of Heidelberg, and Samuel Goldflam of Warsaw. The account by Willis, and the 19th century literature of myasthenia gravis are reviewed, revealing the dominance of German physicians and neuropathologists in the early understanding of the disease. The development in pathology, aetiology, and therapy in the first half of the 20th century are described.

History, 17th Century↗

PubMed2005

[An experience of nursing a client with myasthenia gravis].

Myasthenia gravis is an autoimmune disease. It causes the formation of certain antibodies that attack acetylcholine receptors. The consequent reduction in the number of acetylcholine receptors causes impairment in the transduction of neural pulses (Cross, 1999). Clients usually present with ineffective breathing patterns, high risk of aspiration, and activity intolerance. Myasthenia gravis poses a threat not only to the lives of clients, but also of psychological and social impairment. The author describes the nursing evaluation undertaken during the process of caring for a client with myasthenia gravis, and, using Gorden's functional health assessment guide, summarizes six nursing problems, including high risk of aspiration, activity intolerance, knowledge deficit, powerlessness, ineffective breathing pattern and high risk of injury. Nursing intervention using multiple measures improved this client's symptoms of adjustment and understanding of the disease, while also raising the caring ability and quality of life of both client and family.

Adult↗

PubMed1991

Extraocular muscle surgery in myasthenia gravis.

Myasthenia gravis is typically a disease of young people in active employment who need a field of binocular single vision. Although it is systemically controllable with a good chance of spontaneous remission, persistent loss of binocularity may cause chronic disability. We report our experience of extraocular muscle surgery in five patients with stable myasthenia gravis and persistent double vision. Extraocular muscle involvement was selective, giving rise to incomitant and concomitant squints, with individual muscle overactions as well as underactions. Treatment was by conventional recession and resection procedures with the additional use of Faden and adjustable sutures where appropriate. In all five cases a larger, stable field of binocular single vision was established. It is concluded that extraocular muscle surgery may be beneficial in selected cases of myasthenia gravis.

Adolescent↗

PubMedDate not supplied

[ORL manifestations of myasthenia gravis].

Myasthenia gravis is an illness of insidious onset whose first manifestation often is dysphagia. We report the case of a 25 year-old woman who consulted for nosebleed. On her first visit she referred progressive dysphagia, but the results of endoscopic digestive examination and indirect laryngoscopy were normal. The condition evolved until the appearance of weakness of the extremities suggested myasthenia. Myasthenia gravis was diagnosed by means of electromyography and determinations of antibodies against acetylcholine receptors. We reviewed the literature on the clinical manifestations, diagnostic procedures, and treatment of this condition. This case highlights the importance of suspecting myasthenia gravis in young women with dysphagia and a family or personal history of autoimmune disease in order to reach an early diagnosis and treatment.

Adult↗

PubMed1997

[Thymectomy in myasthenia gravis].

Myasthenia gravis is a relatively uncommon autoimmune disorder of neuromuscular transmission. Surgical therapy plays an important role in addition to medical treatment. Follow-up results of 52 patients with thymectomy are presented. Between 1984-1996 thymectomy via median sternotomy was performed in 52 patients with myasthenia gravis (female = 28, male = 24). The score described by Ossermann and Genkins was used for classification. According to this classification, we found 12 patients in class II(I), 21 in class IIA, 17 in class IIB and 2 in class III, respectively. A thymoma was found in 19, follicular lymphoid hyperplasia in 24 and an atrophic thymus in 9 cases, respectively. There was no mortality. Severe postoperative complications consisted of bleeding and reoperation in one patient and another patient developed a sternal instability with consecutive operative refixation. Follow-up evaluation after a mean period of 36 months (min. 6 months, max. 130 months) revealed a relief of myasthenic symptoms in 37 patients. Thymectomy is effective in the treatment of myasthenia gravis with a low complication rate.

Adult↗

PubMed2005

Increased expression of rapsyn in muscles prevents acetylcholine receptor loss in experimental autoimmune myasthenia gravis.

Myasthenia gravis is usually caused by autoantibodies to the acetylcholine receptor (AChR). The AChR is clustered and anchored in the postsynaptic membrane of the neuromuscular junction (NMJ) by a cytoplasmic protein called rapsyn. We previously showed that resistance to experimental autoimmune myasthenia gravis (EAMG) in aged rats correlates with increased rapsyn concentration at the NMJ. It is possible, therefore, that endogenous rapsyn expression may be an important determinant of AChR loss and neuromuscular transmission failure in the human disease, and that upregulation of rapsyn expression could be used therapeutically. To examine first a potential therapeutic application of rapsyn upregulation, we induced acute EAMG in young rats by passive transfer of AChR antibody, mAb 35, and used in vivo electroporation to over-express rapsyn unilaterally in one tibialis anterior. We looked at the compound muscle action potentials (CMAPs) in the tibialis anterior, at rapsyn and AChR expression by quantitative radioimmunoassay and immunofluorescence, and at the morphology of the NMJs, comparing the electroporated and untreated muscles, as well as the control and EAMG rats. In control rats, transfected muscle fibres had extrasynaptic rapsyn aggregates, as well as slightly increased rapsyn and AChR concentrations at the NMJ. In EAMG rats, despite deposits of the membrane attack complex, the rapsyn-overexpressing muscles showed no decrement in the CMAPs, no loss of AChR, and the majority had normal postsynaptic folds, whereas endplates of untreated muscles showed typical AChR loss and morphological damage. These data suggest not only that increasing rapsyn expression could be a potential treatment for selected muscles of myasthenia gravis patients, but also lend support to the hypothesis that individual differences in innate rapsyn expression could be a factor in determining disease severity.

Action Potentials↗

PubMed1986

Decreased autologous mixed lymphocyte reaction in myasthenia gravis.

Myasthenia gravis is an autoimmune disease in which the autoantigen, the acetylcholine receptor at the neuromuscular junction, is well characterized. As with many other autoimmune diseases, however, the basic cause of immune malfunction is unknown. The autologous mixed lymphocyte reaction (AMLR) involves the proliferation of T lymphocytes when co-cultured with autologous non-T cells and may reflect in vivo mechanisms of immune control. We have measured the AMLR in 22 patients with myasthenia gravis and found the magnitudes of the peak responses to be significantly depressed compared to those of 41 normal healthy controls. Proliferative responses of T cells from myasthenic patients to the mitogens, Concanavalin A and Phytohaemagglutinin-P, were also found to be significantly depressed relative to controls. These abnormal immune cell responses can be, in part, interpreted in terms of defective suppressor cell functions in myasthenia gravis.

Acetylcholinesterase↗

PubMed1996

Peptide analogs to pathogenic epitopes of the human acetylcholine receptor alpha subunit as potential modulators of myasthenia gravis.

Myasthenia gravis is an autoimmune disease in which T cells specific to epitopes of the autoantigen, the human acetylcholine receptor, play a role. We identified two peptides, p195-212 and p259-271, from the alpha subunit of the receptor, which bound to major histocompatibility complex (MHC) class II molecules on antigen-presenting cells (APCs) from peripheral blood lymphocytes of myasthenia gravis patients and stimulated lymphocytes of >80% of the patients. We have prepared analogs of these myasthenogenic peptides and tested their ability to bind to MHC class II determinants and to interfere specifically with T-cell stimulation. We first determined relative binding efficiency of the myasthenogenic peptides and their analogs to APCs of patients. We found that single substituted analogs of p195-212 (Ala-207) and p259-271 (Lys-262) could bind to human MHC molecules on APCs as efficiently as the original peptides. Moreover, dual analogs containing the two single substituted analogs in one stretch (either sequentially, Ala-207/Lys-262, or reciprocally, Lys-262/Ala-207) could also bind to APCs of patients, including those that failed to bind one of the single substituted analogs. The single substituted analogs significantly inhibited T-cell stimulation induced by their respective myasthenogenic peptides in >95% of the patients. The dual analogs were capable of inhibiting stimulation induced by either of the peptides: They inhibited the response to p195-212 and p259-271 in >95% and >90% of the patients, respectively. Thus, the dual analogs are good candidates for inhibition of T-cell responses of myasthenia gravis patients and might have therapeutic potential.

Adult↗

PubMed1995

Leflunomide prevents the development of experimentally induced myasthenia gravis.

Myasthenia gravis is an autoimmune disease in which autoantibodies specific to the acetylcholine receptor (AChR) are formed, leading to a gradual destruction of the receptors in muscles that are responsible for picking up nerve impulses, and results in weakness and eventual loss of muscle function. The novel immunomodulating drug leflunomide (HWA 486) has been shown to be very effective in preventing and halting ongoing disease in an array of experimental autoimmune disorders and reactions leading to organ graft rejection. Further, recent data from phase II clinical trials indicate that this drug is efficacious and is safe in humans with rheumatoid arthritis. In the studies reported here, we found that rats immunized with AChR-protein and not receiving leflunomide developed experimental myasthenia gravis (EMG) between day 7 and 11 post-immunization, and about 79% of these animals expressed clinical signs of disease. Treatment of AChR-protein immunized rats with leflunomide, from the day of disease induction, totally suppressed the development of EMG. Thus, the results we have obtained using leflunomide in EMG indicate that this drug could be beneficial in combating myasthenia gravis in humans.

Animals↗

PubMed2004

Myasthenia Gravis.

Myasthenia gravis is a disorder of neuromuscular transmission, manifest by variable weakness of skeletal muscle. The disorder has a range of therapies that differ with respect to efficacy, timing, and side effects. The physician treating myasthenia gravis must be well versed in understanding the evidence basis for using these agents, as well as the trade-offs between persistent disease manifestations and their costs and expected benefits. Diagnosis of myasthenia gravis depends on recognizing the pattern of weakness, which typically involves some combination of extraocular, bulbar, facial, limb, and neck muscles. Management relies on some combination of medications that influence the function of the neuromuscular junction and treatments that alter the immune response. Thymectomy is commonly used, although trends in evidence-based medicine are leading expert clinicians to look closely at its efficacy. Plasma exchange is useful for patients in crisis, who require rapid improvement. The exact role for high-dose intravenous immunoglobulin in this setting is still being studied, although the agent is gaining popularity. Knowing that the treatments are effective is not enough. It is still important to determine the treatment that has a more rapid onset, because these patients often require intensive care or respiratory assistance.

Journal Article↗

PubMed1993

T cell reactivity to acetylcholine receptor in rats orally tolerized against experimental autoimmune myasthenia gravis.

Myasthenia gravis and its animal model experimental autoimmune myasthenia gravis (EAMG) represent T cell-dependent autoimmune diseases mediated by antibodies against the nicotinic acetylcholine receptor (AChR) of the neuromuscular junction. Oral administration of Torpedo AChR to Lewis rats prior to immunization with the myasthenogenic Torpedo AChR and complete Freund's adjuvant results in the prevention of clinical EAMG, and the suppression of AChR-specific B cell responses. To examine the influence of oral tolerance to EAMG on AChR-reactive T cells, we determined and enumerated such cells in the popliteal, inguinal, and mesenteric lymph nodes, spleen, and thymus by a T cell immunospot assay that is based on the secretion of interferon-gamma (IFN-gamma) by antigen-reactive T cells. A diminution of such cells was detected in popliteal, inguinal, and mesenteric lymph nodes of rats orally tolerized to EAMG compared to unfed or vehicle-fed animals. We conclude that oral administration of AChR, in addition to preventing clinical signs of EAMG and suppressing AChR-specific B cell responses, also counteracts the development of AChR-reactive IFN-gamma-secreting cells in certain lymphoid organs.

Administration, Oral↗

PubMed1994

[Tumor-associated myasthenia gravis and myasthenia syndrome].

Out of 700 patients operated on account of myasthenia gravis, 144 cases with tumours (20.57%) were evaluated. Classification took place in five groups: 1. Thymoma and myasthenia gravis; 2. Thymic cysts and myasthenia gravis; 3. Thymoma and latent myasthenia gravis; 4. Paraneoplastic myasthenia-syndrome; 5. Thymoma, myasthenia gravis and myasthenia-syndrome. Up-to-date classification of thymomas is: epithelioma with minimal, marked or overwhelming lymphatic reaction. Dark-cell and light-cell epitheliomas equally associate with myasthenia. Concerning prognosis, location of the tumour to thymic capsula, surrounding, perithymic tissue is more important than the histologic structure of the tumour. Previous examination in the case of mediastinal tumour can reveal latent, mild myasthenia which was not known till that time. Term of postthymectomic myasthenia can be excluded on the basis of these examinations. Heterogeneity is considerable among myasthenia-syndromes concerning both histopathologic and clinical features. There is a double indication of operation in the case of myasthenia with tumour: the tumour and the disease. Good results can be achieved in myasthenia gravis associated with tumour by means of total operation, post-operative radiation and by other up-to-date therapeutical procedures. The results are hardly beyond those of non-tumours myasthenia gravis.

Adolescent↗

PubMed2003

Decreased expression of Src homology 2 domain-containing protein tyrosine phosphatase 1 reduces T cell activation threshold but not the severity of experimental autoimmune myasthenia gravis.

Myasthenia gravis (MG) and its murine model experimental autoimmune myasthenia gravis (EAMG) are T cell-dependent, antibody-mediated autoimmune diseases. Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) is a cytosolic tyrosine phosphatase that is involved in regulating the T cell activation cascade from signals initiated through the TCR. To study the role of SHP-1 in EAMG pathogenesis, we immunized C57BL/6 (B6) mice heterozygous for deletion of the SHP-1 gene (me(v+/-)) and their littermate wild type B6 mice with torpedo acetylcholine receptor (TAChR). T cell proliferation and IFNgamma production were significantly increased in B6.me(v+/-) mice after immunization with AChR compared to that of wild type littermates. However, clinical incidence and severity of the disease were not changed. There also were no significant differences in AChR-specific antibodies produced between wild type and me(v+/-) mice. These data suggest that deficiency in SHP-1 expression does decrease the activation threshold of autoreactive T cells in EAMG, but the increased frequency of autoreactive T cells does not aggravate EAMG in terms of clinical score, incidence, or antibody titers.

Animals↗

PubMed1997

Cytokines and the pathogenesis of myasthenia gravis.

Myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG) are caused by autoantibodies against nicotinic acetylcholine receptor (AChR) in skeletal muscle. The production of anti-AChR antibodies is mediated by cytokines produced by CD4+ and CD8+ T helper (Th) cells. Emerging investigations of the roles of cytokines in MG and EAMG have revealed that the Th2 cell related cytokine interleukin 4 (IL-4), an efficient growth promoter for B-cell proliferation and differentiation, is important for anti-AChR antibody production. IL-6 and IL-10 have similar effects. The Th1 cytokine IFN-gamma is important in inducing B-cell maturation and in helping anti-AChR antibody production and, thereby, for induction of clinical signs and symptoms. Results from studies of time kinetics of cytokines imply that IFN-gamma is more agile at the onset of EAMG, probably being one of the initiating factors in the induction of the disease, and IL-4 may be mainly responsible for disease progression and persistance. Even though other Th1 cytokines like IL-2, tumor necrosis factor alpha (TNF-alpha), and TNF-beta as well as the cytolytic compound perforin do not directly play a role in T-cell-mediated help for anti-AChR antibody production, they are actually involved in the development of both EAMG and MG, probably by acting in concert with other cytokines within the cytokine network. In contrast, transforming growth factor beta (TGF-beta) exerts immunosuppressive effects which include the down-regulation of both Th1 and Th2 cytokines in MG as well as EAMG. Suppressive effects are also exerted by interferon alpha (IFN-alpha). Based on elucidation of the role of cytokines in EAMG and MG, treatments that up-modulate TGF-beta or IFN-alpha and/or suppress cytokines that help B-cell proliferation could be useful to improve the clinical outcome.

Animals↗