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PubMed2001

Difference in sensitivity to vecuronium between patients with ocular and generalized myasthenia gravis.

Patients with myasthenia gravis show sensitivity to non-depolarizing neuromuscular blocking drugs, but little is known about differences in this sensitivity between types of myasthenia. In 10 patients with ocular myasthenia gravis and 10 with generalized myasthenia gravis, twitch tension was monitored in the adductor pollicis muscle by supramaximal train-of-four stimulation of the ulnar nerve during anaesthesia with sevoflurane 2.5% and nitrous oxide 60%. After baseline measurement, an initial dose of vecuronium 10 microg kg(-1) was given. When the twitch height stabilized (maximum block after the first 10 microg kg(-1)), the next incremental dose of 10 microg kg(-1) was given and repeated until block, defined as [1-(first twitch/baseline first twitch)] x 100 reached 90%. Maximum block after the first dose of vecuronium in ocular patients was significantly less than that in generalized patients (median 51 vs 91%; P<0.05). Onset of block after the first dose of vecuronium was significantly slower in ocular than in generalized myasthenic patients (mean 300 vs 200 s; P<0.05). Doses required to attain a block of 90% or more were significantly higher in ocular than in generalized patients (median 20 vs 10 microg kg(-1); P<0.05). Clinicians should consider the type of disease according to the Osserman classification when using non-depolarizing neuromuscular. blocking drugs in patients with myasthenia gravis.

Adult↗
PubMed1999

Acetylcholinesterase activity of skeletal muscle in a non-immunogenic model for myasthenia gravis in rats.

Myasthenia gravis is caused by an autoimmune attack to acetylcholine receptors of skeletal muscle. Acetylcholine release from motor nerve terminals is upregulated in patients with myasthenia gravis and also in rat "myasthenic" models, dependent on the reduction of the number of acetylcholine receptors. This study addresses the question as to whether at "myasthenic" endplates there are changes in the activity of acetylcholinesterase. To this end we studied acetylcholinesterase activity in junctional and extrajunctional regions of dilator naris, extensor digitorum longus, and hemidiaphragm muscles from rats with alpha-bungarotoxin-induced myasthenia gravis. In all studied muscles from "myasthenic" rats there was no significant change of junctional acetylcholinesterase activity. In contrast, in dilator naris and extensor digitorum longus muscles, there was a 60% and 30% increase of extrajunctional acetylcholinesterase activity. There was no significant change in the extrajunctional activity in hemidiaphragm muscles. Velocity sedimentation analysis revealed that the increase in extrajunctional activity in extensor digitorum longus muscles could be attributed to an increase of the activity of the G4 form of acetylcholinesterase. Treatment of rats with 6.4 microgh(-1) neostigmine bromide for 29 days had no influence on junctional and extrajunctional acetylcholinesterase activity of extensor digitorum longus muscles from rats with alpha-bungarotoxin-induced myasthenia gravis.

Acetylcholinesterase↗
PubMed1997

Th1 epitope repertoire on the alpha subunit of human muscle acetylcholine receptor in myasthenia gravis.

In myasthenia gravis (MG), CD4+ T helper cells recognize the muscle acetylcholine receptor (AChR) alpha subunit. We investigated the epitope repertoire of anti-AChR blood CD4+ Th1 cells from 13 myasthenic patients and three healthy controls, using overlapping synthetic peptides screening the alpha subunit sequence and an enzyme-linked immunospot (ELISPOT) assay that detects antigen-induced interferon-gamma secretion of individual Th1 cells. All patients recognized a pool of the alpha subunit peptides. All but one patient recognized numerous peptides. Each patient had an individual pattern of peptide recognition, but most or all patients recognized four sequences (residues 48-67, 101-137, 304-322, and 403-437) that stimulated relatively large numbers of Th1 cells. They include previously identified "immunodominant" sequences recognized by AChR-specific CD4+ T cell lines from myasthenic patients. Peptide 1-14 was also recognized frequently. The controls recognized, with a low precursor frequency, the peptide pool and a few peptides that frequently included the immunodominant sequences described above. The present results demonstrate that Th1 cells are involved in the anti-AChR response in MG and that their epitope repertoire is very complex. This indicates that when MG is clinically evident, the AChR itself is the sensitizing antigen and the target of the autoimmune Th1 cells, although it does not exclude that molecular mimicry between one AChR epitope and a microbial structure may have triggered this autoimmune response. Although the complexity of the Th1 repertoire suggests that development of specific immunosuppressive treatments targeted on epitopes recognized by autoimmune T cells will be difficult, the existence of immunodominant T epitope sequences might facilitate that task.

Adolescent↗
PubMed1998

Antibodies against beta1 and beta2 adrenergic receptors in myasthenia gravis.

Patients with myasthenia gravis have antibodies and T cells that react with the beta1- and beta2-adrenergic receptors. These receptors, as well as other auto-antigens, are present on cardiomyocytes, skeletal muscle cells and lymphocytes and are of importance for the regulation of the functions of these organs. Antibodies against the beta1-adrenergic receptor have been implicated in dilated cardiomyopathies. Myasthenia gravis (MG) patients have been suggested to have a higher than normal prevalence of heart disease. We have analysed the isotypes, subclasses, and binding sites of the beta-adrenergic receptors antibodies in both MG patients and healthy individuals and the correlation between beta-adrenergic receptors antibodies and heart disease in MG patients. The patients have IgG antibodies that react with both beta1- and beta2-adrenergic receptors. The subclasses were predominantly IgG2 and IgG4. By using synthesised overlapping peptides representing the immunodominant regions on the receptors, it was shown that the antibodies bound to partially overlapping sites on both beta1- and beta2-adrenergic receptors, but not to peptides from the acetylcholine receptor. beta-adrenergic receptor antibodies were found in 34/125 MG patients. Seven out of these 34 patients had symptomatic heart disease, all seven were over 70 years of age and had arteriosclerotic heart disease. There was no difference in the prevalence of clinical heart disease in patients with and without beta-adrenergic receptor antibodies. However, patients with heart disease had significantly higher levels of antibodies than healthy individuals and other patients. Antibodies against beta-adrenergic receptors in patients with myasthenia gravis binds to both beta1- and beta2-adrenergic receptors and might be implicated in the few patients with myasthenia gravis who have heart disease.

Aged↗
PubMed1990

Myasthenia gravis poses a diagnostic problem for the otolaryngologist: a closer look at symptoms may alert the possibility of myasthenia gravis.

A nine-year retrospective study of the new cases of myasthenia gravis (MG) at Ramathibodi Hospital was done to find the incidence, the symptoms, and the physical signs at initial attendance (IA) and at the time of correct diagnosis (CD). In contrast to previous studies on MG, we found an incidence of only 1.1 patient with MG/year in the department of otolaryngology, representing only 3.3% of the new cases of MG seen at Ramathibodi Hospital. Ninety percent of patients with MG had five or more symptoms at the time of IA but only 30% had positive physical signs at the time of IA. However, all the patients had five or more symptoms at the time of CD and all the patients had five or more physical signs at the time of CD. Seven out of 10 patients were diagnosed as MG late, 8-182 days after the time of IA. The presence of five or more symptoms at the time of IA should have alerted the otolaryngologist to consider MG as a possible diagnosis. This emphasis has yet to be written in the otolaryngological literature.

Adolescent↗
PubMed2000

[Modulation of experimental myasthenia gravis by IVIg].

Myasthenia Gravis (MG) is an autoimmune disease mediated by antibodies directed against the acetylcholine receptor (AChR). Treatment by IVIg is effective in acute forms of myasthenia gravis. In order to determine the in vivo effects of the various fractions of human immunoglobulins, we used an experimental model of myasthenia gravis in SCID mice. To this end, thymic cells from MG patients are transferred to these mice according to a well defined protocol. When establishing of the model, we noticed the appearance of anti-AChR antibodies and the loss of AChR expression at the muscle level. After treatment with IVIgG or IVIgM, the mice displayed a lower anti-AChR antibody titer compared to control mice (albumin treated) and the loss of the AChR number at the muscle was significantly reduced. These results obtained from one MG patient indicate that the human immunoglobulin preparations induce significant effects on pathogenic parameters in the SCID mouse model. Therefore this model is interesting to approach the mechanisms of action of human immunoglobulins and deserves further investigation.

Acetylcholine↗
PubMed1995

Ventilatory muscle strength and endurance in myasthenia gravis.

Patients with generalized myasthenia gravis (MG) often have associated ventilatory muscle involvement. It is not known whether patients with isolated ocular muscle involvement have identifiable involvement of their ventilatory muscles. Most studies have assessed muscle involvement by measuring muscle strength; however, we hypothesized that measures of ventilatory muscle endurance may be more sensitive tests of ventilatory muscle involvement in myasthenia gravis. We studied 17 patients with myasthenia gravis (four with ocular involvement alone and 13 with varying degrees of generalized myasthenia gravis). Spirometry, ventilatory muscle strength (maximum inspiratory and expiratory pressures (MIP and MEP)) and endurance (2 min incremental threshold loading test) were measured before and 20 min after i.m. neostigmine. We compared the results with those of 10 normal controls. We found no difference between patients with isolated ocular involvement and controls. Ocular myasthenia gravis patients did not improve after neostigmine. The patients with generalized myasthenia gravis had reduced baseline ventilatory muscle strength (MIP 67 cmH2O (70% of predicted), MEP 86 cmH2O (50% of pred) and endurance (mean maximal load achieved = 246 g, mean pressure at highest load (P) = 19.4 cmH2O) compared with controls. After neostigmine, there was a significant increase in MIP in patients with generalized myasthenia gravis and a trend towards an increased MEP. As a group, the patients with generalized myasthenia gravis did not demonstrate a change in their ventilatory muscle endurance after neostigmine; however, there was considerable interpatient variability in response. We conclude that patients with isolated ocular MG have normal ventilatory muscle strength when tested conventionally.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

What's in a smile?: Quantification of the vertical smile of patients with myasthenia gravis.

Many patients with myasthenia gravis who experience bulbar symptoms show a vertical smile, which may have a considerable, and often underestimated, impact on social life. Peri-oral muscle function can be quantified by calculating lip-length and snout indices, which indicate the degree to which a person is capable of smiling and of pursing the lips, respectively. In the present study patients with bulbar myasthenia gravis were compared to patients with ocular myasthenia gravis, patients now in remission (but previously suffering from bulbar myasthenia gravis), and healthy subjects. The lip-length and snout indices of patients with bulbar myasthenia gravis were significantly lower than those of the other groups. The facial impairments were no longer detectable in patients with bulbar myasthenia gravis in remission and no subclinical impairments in lip-length and snout indices were found in the ocular myasthenia gravis group. These findings were consistent with the patients' reports of impairment of smiling and other oral functions. The patients suffering from a vertical smile or other oral impairments were well aware of their condition, most probably because of the social consequences of being unable to smile. The indices could be of importance in the longitudinal evaluation of therapy in individual patients and in pharmacotherapeutical research. We found a low correlation between the lip-length and snout indices, which reflects the capricious pattern of involvement of separate muscles in myasthenia gravis. Therefore both indices deserve special attention if they are used for monitoring myasthenic symptoms.

Adult↗
PubMed1997

Drugs and myasthenia gravis. An update.

Myasthenia gravis is a disease of the neuromuscular junction in which normal transmission of the neuron-to-muscle impulse is impaired or prevented by acetylcholine receptor antibodies. Several classes of drugs have been associated with clinical worsening of existing myasthenia gravis, and a small subset of drugs, most notably the antirheumatic agent penicillamine, have been implicated in the pathogenesis of a variant of the disease. Recent case reports and other documented evidence link a number of specific agents with clinical worsening of myasthenia gravis.

Adrenal Cortex Hormones↗
PubMed1981

Autoimmunity in ocular and generalised myasthenia gravis.

Restricted ocular myasthenia gravis (OMG) and generalised myasthenia gravis (GMG) have been shown to differ in a number of respects. In OMG, antiacetylcholine receptor, antistriational and antinuclear antibodies were rare relative to their frequency in GMG. In contrast, antithyroid antibodies and a history of thyroid disease were much more prevalent in OMG than in GMG, OMG was not associated with the female predominance seen in GMG and appeared to be relatively common in some races rather than others. It is suggested that different pathogenetic mechanisms are responsible for these two forms of MG.

Age Factors↗
PubMed1999

The role of B-cells in experimental myasthenia gravis in mice.

Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are caused by auto-antibodies against the nicotinic acetylcholine receptor (AChR) at the postsynaptic membrane. To evaluate the extent to which the humoral immune response against AChR operates in the pathogenesis of EAMG, we immunized B-cell knockout (microMT) and wild type C57BL/6 mice with AChR in complete Freund's adjuvant. The ability of AChR-primed lymph node cells to proliferate and secrete IFN-gamma in response to AChR and its dominant peptide alpha 146-162 were intact in microMT as in wild type mice. Similar levels of mRNA for IFN-gamma, IL-4 and IL-10 in AChR-reactive lymph node cells were detected in microMT and wild type mice. However, microMT mice had no detectable anti-AChR antibodies and never developed clinical EAMG. We conclude that B-cells are critically required for the genesis of clinical EAMG, but not for AChR-specific T-cell priming.

Animals↗
PubMed1997

Myasthenia gravis.

Adult-onset myasthenia gravis is an acquired autoimmune disorder of neuromuscular transmission in which acetylcholine receptor antibodies attack the postsynaptic membrane of the neuromuscular junction. Although the cause of this disease is unknown, the role of immune responses in its pathogenesis is well established. Circulating acetylcholine receptor antibodies are present in 80% to 90% of patients with the generalized form of myasthenia gravis. Most patients have ptosis, diplopia, dysarthria and dysphagia. The weakness and fatigue worsen on exertion and improve with rest. Respiratory muscle and limb weakness are rare at the onset of the disease. For the past two decades, there has been considerable progress in understanding the diagnosis and management of myasthenia gravis. The diagnosis is based on clinical presentation, neurologic examination, and confirmation by means of electrophysiologic testing and immunologic studies. Myasthenia gravis mimics many neuromuscular diseases and even illnesses such as depression and chronic fatigue syndrome. One should always exclude drug-induced myasthenia gravis for all patients. With the introduction of new modalities of treatment, particularly immunosuppressive or immunomodulating drugs, plasma exchange and thymectomy, the morbidity and mortality of myasthenia gravis have decreased dramatically to the point that myasthenia gravis should not be considered as serious a disease as it once was. Although the several therapeutic options are usually effective and have meant independence in daily life to many patients with myasthenia gravis, well-designed, controlled, prospective studies are still lacking.

Adult↗
PubMed2002

Dendritic cells exposed in vitro to TGF-beta1 ameliorate experimental autoimmune myasthenia gravis.

Experimental autoimmune myasthenia gravis (EAMG) is an animal model for human myasthenia gravis (MG), characterized by an autoaggressive T-cell-dependent antibody-mediated immune response directed against the acetylcholine receptor (AChR) of the neuromuscular junction. Dendritic cells (DC) are unique antigen-presenting cells which control T- and B-cell functions and induce immunity or tolerance. Here, we demonstrate that DC exposed to TGF-beta1 in vitro mediate protection against EAMG. Freshly prepared DC from spleen of healthy rats were exposed to TGF-beta1 in vitro for 48 h, and administered subcutaneously to Lewis rats (2 x 10(6)DC/rat) on day 5 post immunization with AChR in Freund's complete adjuvant. Control EAMG rats were injected in parallel with untreated DC (naive DC) or PBS. Lewis rats receiving TGF-beta1-exposed DC developed very mild symptoms of EAMG without loss of body weight compared with control EAMG rats receiving naive DC or PBS. This effect of TGF-beta1-exposed DC was associated with augmented spontaneous and AChR-induced proliferation, IFN-gamma and NO production, and decreased levels of anti-AChR antibody-secreting cells. Autologous DC exposed in vitro to TGF-beta1 could represent a new opportunity for DC-based immunotherapy of antibody-mediated autoimmune diseases.

Animals↗
PubMed1989

Immunologic studies on myasthenia gravis. II: A new chemotactic factor for lymphocytes found in patients with myasthenia gravis.

A specific chemotactic factor for lymphocytes was found in thymic tissue extract from myasthenic patients who had undergone thymectomy. Biologic activities and the biochemical nature of this factor were examined. The major findings were as follows: (1) The factor from myasthenic thymus was specifically chemotactic for T lymphocytes. Marker analysis of target cells revealed that only OKT4 positive cells (helper/inducer T cells) responded to the factor. Chemotactic activity was also found in the normal thymus, but its activity was different from that found in the myasthenic thymus. Interestingly, OKT8 positive cells (suppressor/cytotoxic T cells), as well as OKT4 positive cells, migrated toward the normal thymic extract (2) Chromatography of the extract by gel filtration gave three peaks with chemotactic activity; molecular size were 160,000 to 100,000, 25,000 to 15,000, and smaller than 1350 daltons (3) The factor was inactivated by heating for 30 minutes at 56 degree C and was also destroyed under conditions of pH 4 and pH 10. The factor was also sensitive to treatment by trypsin, sodium metaperiodata, 8 mol/L urea, reduction, or alkylation. (4) The chemotactic activity in the myasthenic thymus was distinct from other known chemotactic factors, including C5a, interleukin-1, and interleukin-2. (5) Chemotactic activity for lymphocytes was found in both the aqueous extract and the culture supernatant of thymic stromal cells, but not in thymocyte extract or in the serum. These findings indicate that the chemotactic factor specific for OKT4 positive cells may be secreted by stromal cells of the myasthenic thymus but not of the normal thymus.

Adolescent↗
PubMed1999

Preoperative preparation and anesthetic management of patients with myasthenia gravis.

Patients with myasthenia gravis have specific clinical problems that must be addressed by the anesthesiologist when surgery is contemplated. Optimal perioperative management of myasthenia gravis patients undergoing thymectomy requires careful preoperative assessment and preparation. This assessment and preparation includes evaluation for concomitant autoimmune, respiratory, and cardiac disorders as well as optimization of medical management for myasthenia. There are important intraoperative concerns to be addressed including appropriate monitoring, premedication, and other agents used during surgery including muscle relaxants and anesthetic agents. Postoperatively, attention must be directed specifically to pain relief, ventilatory management, and the appropriate titration of reversal agents and anticholinesterase inhibitors. Optimal management of all these factors maximizes the chance for successful and uncomplicated hospitalization.

Anesthesia, General↗
PubMed1976

Pathological mechanisms in experimental autoimmune myasthenia gravis. I. Immunogenicity of syngeneic muscle acetylcholine receptor and quantitative extraction of receptor and antibody-receptor complexes from muscles of rats with experimental automimmune myasthenia gravis.

Immunization of Lewis rats with acetylcholine receptor (AChR) purified from either Electrophorus electricus electric organ or syngeneic rat muscle induced experimental autoimmune myasthenia gravis (EAMG). This was demonstrated by clinical signs of weakness and by electromyographic evidence of imparied neuromuscular transmission. The amount of rat AChR required to induce an autoimmune response was comparable to the amount of eel AChR required. In vitro complexing of rat AChrR with antibody reduced its immunogenicity. Autoantibody to muscle AChR was present in serum and complexed with AChR in muscle. Antibody was not bound to the ACh binding site of AChR, since antibody-AChR complexes extracted from muscle could still bind 125I-alpha-bungarotoxin. The amount of AChR extracted from muscle of rats with EAMG was diminished. The amount of AChR and antibody-AChR complexes in muscle was measured at intervals after immunization with eel AChR. The amount of AChR decreased in rats with acute EAMG, then transiently increased to more than normal amounts during remission, and finally decreased to only about 20% of normal in rats with chronic EAMG. At least half of the AChR remaining in animals with chronic EAMG was complexed with antibody. Thus, both a decrease in amount of AChR and the formation of antibody-AChR complexes contribute to impairment of neuromuscular transmission in rats with EAMG. The possible mechanisms involved in the changes in AChR content are discussed.

Animals↗