La myasthénie du côté de l’interniste

Myasthenia gravis is an autoimmune disease due to specific antibodies inducing a neuromuscular transmission defect causing muscle fatigability. If onset of the disease may be at any age, myasthenia gravis concerns mostly young adults, in majority females. The disease characteristic features are the following: ocular symptoms (ptosis or diplopia) as main initial manifestation, extension to other muscles in 80 % of the cases, variability of the deficit, effort induced worsening, successive periods of exacerbation during the disease course, severity depending on respiratory and swallowing impairment (if rapid worsening, a myasthenic crisis is to be suspected), association with thymoma in 20 % of patients and with other various autoimmune diseases, most commonly hyperthyroidism and Hashimoto's disease. Diagnosis relies on the clinical features, improvement with cholinesterase inhibitors, detection of specific autoantibodies (anti-AChR or anti-MuSK), and significant decrement evidenced by electrophysiological tests. The points concerning specifically the internist have been highlighted in this article: diagnostic traps, associated autoimmune diseases, including inflammatory myopathies that may mimic myasthenia gravis, adverse effects of medications commonly used in internal medicine, some of them inducing myasthenic syndromes. The treatment is well codified: the treatment is well codified: (1) respect of adverse drugs contra-indications, systematically use of cholinesterase inhibitors, (2) thymectomy if thymoma completed with radiotherapy if malignant, (3) corticosteroids or immunosuppressive agent in severe or disabling form, (4) intensive care unit monitoring, plasmapheresis or intravenous immunoglobulins for patients with myasthenic crisis.     

Humoral and cellular immunity to intrinsic factor in myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease often associated with other autoimmune disorders. A case history of MG with a coexisting atypical megaloblastic anaemia with vitamin B12 deficiency and anti Intrinsic Factor (IF) antibodies, led to a study of humoral and cellular immunity to IF in 81 MG patients. Within this series, 3 other patients had a disturbed humoral and cellular immunity to IF. These 3 patients presented no other features of pernicious anaemia. The possible origins and significance of the anti IF antibodies in MG patients are discussed.     

Myasthenia gravis und myasthene Syndrome

Neuromuscular transmission is compromised in a variety of disorders due to immunological, toxic or congenital mechanisms. Myasthenia gravis (MG) is the most frequent among these disorders. In about 15% of cases, MG is associated with a second autoimmune disorder mainly seen in rheumatologists. Some of the drugs used in rheumatology can exacerbate MG or even trigger immunologically the occurrence of MG. In most MG patients, antibodies to the acetylcholine receptor (AChR) are present, but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-specific kinase antibodies which define a different subgroup of myasthenia. Among those MG patients with anti-AChR antibodies, a number of clinical subtypes can be identified including early-onset MG (onset ≤ 40 years), late-onset MG (onset after 40 years) and thymoma-associated MG. Even though less common, it is important to recognize Lambert Eaton myasthenic syndrome (LEMS). The abnormality in LEMS is a presynaptic failure to acetylcholine release caused by antibodies to voltage-gated calcium channels. More than half of LEMS patients have small-cell lung cancer.     

Dysphonia as first symptom of late-onset myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction that causes muscle weakness and fatigue. Fluctuating fatigue of skeletal muscles is the key clinical feature. Late-onset MG is more frequent in elderly men and is often misdiagnosed. While involvement of oropharyngeal musculature has been described with symptoms of dysphagia and slurred speech, the presence of fluctuating dysphonia as the first symptom of late-onset MG has not been emphasized. The case of an elderly man, who demonstrated voice changes and later swallowing impairment with weight loss, is reported. This case presentation of late-onset MG emphasizes that this form of the disease should be considered in the differential diagnosis of acute onset dysphonia in elderly persons.     

Robotic thymectomy for myasthenia gravis surgical techniques and outcomes

Myasthenia gravis (MG) is an autoimmune disorder in which antibodies are produced against post-synaptic acetylcholine receptors, thereby causing impairment of neuromuscular transmission. Diagnosis of MG is confirmed with the AChR antibody test and via an Electromyography. Although medical treatment with acetylcholinesterase inhibitors remains the main treatment of MG, in recent years thymectomy has become an integral part of the treatment algorithm. Numerous factors such as the Patient’s age, presence of AChR antibodies, or MuSK antibody, the severity of disease affect the decision of preforming the thymectomy. Historically thymectomy was preformed via sternotomy associated with significant morbidity. Advancement in the minimally invasive approaches to thymic resection has led to more acceptance of thymectomy in the management of MG. Among these approaches, robotic thymectomy is gaining popularity across the globe due to the unique advantages of the robotic platform like 3D visibility, enhanced dexterity, and wrist like articulating movements of instruments. This has led to less post-operative pain and morbidity; faster recovery and shorter hospital stay. Successful treatment of MG requires a multi-modality approach, which has led to the formation of MG teams in most academic centers, comprising of a specialist neurologist, intensivist, and thoracic surgeon. In this article, we describe the techniques and outcomes of the robotic thymectomy for MG.     

Acetylcholine receptors and myasthenia gravis

Recent years have seen considerable progress in understanding the nature of the molecular events involved in neuromuscular transmission. The acetylcholine receptor (AChR) has been purified to homogeneity and acetylcholine-induced ion transport has been reconstituted by incorporation of pure AChR into artificial membranes. Immunization against purified AChR induces a condition, clinically and physiologically similar to the human disease myasthenia gravis, which is due to circulating anti-AChR antibodies. This model, experimental autoimmune myasthenia gravis, is proving useful for investigating the role of genetic factors in determining the immune response to AChRs and for testing various experimental approaches to specific treatment. Myasthenia gravis is an autoimmune disease in which there is loss of acetylcholine receptors at the neuromuscular junction. Anti-AChR antibodies can be detected in the majority of patients and they cause loss of AChR by a variety of mechanisms. Anti-AChR antibody is heterogeneous and not restricted in idiotype. The role of the thymus in MG is still uncertain, but recent experiments implicate the presence of a cell type in MG thymus which may be involved in autosensitization to AChR.     

Myasthenia gravis

Myasthenia gravis is an autoimmune disease, which leads to load-dependent weakness of voluntary skeletal muscles with recovery of function after resting. The disease is caused by autoantibodies directed against the postsynaptic nicotinic acetylcholine receptors (AChR) leading to a reduction of neuromuscular transmission. Muscles and nerves are not affected. Disorders of the thymus play a role in the pathogenesis of AChR antibody-positive myasthenia. The clinical symptoms include exercise-induced fatigue either of the ocular muscles alone (ocular myasthenia) or striated skeletal muscle and the ocular, facial and bulbar musculature (generalized myasthenia). Treatment of myasthenia gravis involves administration of acetylcholine esterase inhibitors and immunosuppressive drugs. A myasthenic crisis is characterized by life-threatening complications with severe weakness, swallowing difficulties and respiratory failure, which requires intensive care treatment.     

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.     

MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4

Myasthenia gravis (MG) is a severely debilitating autoimmune disease that is due to a decrease in the efficiency of synaptic transmission at neuromuscular synapses. MG is caused by antibodies against postsynaptic proteins, including (i) acetylcholine receptors, the neurotransmitter receptor, (ii) muscle-specific kinase (MuSK), a receptor tyrosine kinase essential for the formation and maintenance of neuromuscular synapses, and (iii) low-density lipoprotein receptor-related protein 4 (Lrp4), which responds to neural Agrin by binding and stimulating MuSK. Passive transfer studies in mice have shown that IgG4 antibodies from MuSK MG patients cause disease without requiring complement or other immune components, suggesting that these MuSK antibodies cause disease by directly interfering with MuSK function. Here we show that pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation. In contrast, these IgG4 antibodies have no direct effect on MuSK dimerization or MuSK internalization. These results provide insight into the unique pathogenesis of MuSK MG and provide clues toward development of specific treatment options.Myasthenia gravis (MG) is an autoimmune disease caused by autoantibodies to proteins in the postsynaptic membrane at neuromuscular synapses. Most MG patients carry antibodies to acetylcholine receptors (AChRs), the neurotransmitter receptor at vertebrate neuromuscular synapses (1, 2). Autoantibodies to AChRs are largely of the IgG1 and IgG3 subclass (3), which causes muscle weakness by three mechanisms: (i) complement-mediated membrane lysis (4), (ii) cross-linking and depletion of cell-surface AChRs (5), and (iii) to a lesser extent, functional blocking of the ACh-binding site (6). The ability of antibodies to AChRs to recruit complement, dimerize, and modulate AChR expression is an important component of their pathogenic mechanism: animals with experimental autoimmune MG (EAMG) can be rescued from disease with monovalent Fab fragments generated from AChR IgG antibodies, and complement-deficient mice are protected against EAMG (5, 7, 8).Approximately 20% of patients with MG lack antibodies to AChRs, and ∼40% of these AChR-negative patients carry autoantibodies to muscle-specific kinase (MuSK), a receptor tyrosine kinase that is essential for all aspects of synaptic differentiation and maintenance (9–11). The synaptic defects in MuSK MG overlap with those in AChR MG, including a reduction in the number of functional AChRs at synapses and unreliable synaptic transmission, resulting in muscle fatigue and weakness. In contrast to AChR MG, MuSK MG is caused in large part by IgG4 antibodies (12–14) that fail to engage complement and are considered functionally monovalent (12–15). Consequently, the accumulation of complement and muscle membrane damage, hallmark pathological features of AChR MG, appear insignificant in MuSK MG (12, 16). Despite the paucity or absence of complement and cell damage in MuSK MG, the structural and functional deficits of synapses are extensive in MuSK MG, which highlights the key role that MuSK plays in organizing all aspects of synaptic differentiation (9, 17).AChR clustering and synapse formation are orchestrated by neuronally released Agrin, which binds to low-density lipoprotein receptor-related protein 4 (Lrp4), a member of the lipoprotein receptor-related protein family, causing Lrp4 to bind and activate MuSK (18–20). Once tyrosine-phosphorylated, MuSK recruits Dok-7, an adaptor protein that becomes phosphorylated and recruits additional signaling molecules essential for synapse formation (21–23).The extracellular region of MuSK contains three Ig-like domains and a Frizzled-like domain (9). The first Ig-like domain in MuSK is required for MuSK to bind Lrp4. Mutation of a single residue, I96, on a solvent-exposed surface of the first Ig-like domain, prevents MuSK from binding Lrp4 and responding to Agrin (20, 24). A hydrophobic surface on the opposite side of the first Ig-like domain mediates MuSK homodimerization, which is essential for MuSK transphosphorylation (24). Although MuSK is expressed by muscle and not by motor neurons, MuSK is critical for presynaptic as well as postsynaptic differentiation (9). In mice lacking MuSK, motor axons fail to stop and differentiate and instead wander aimlessly throughout the muscle (10). MuSK regulates presynaptic differentiation, at least in part, by clustering Lrp4 in muscle, which functions bidirectionally by serving not only as a receptor for Agrin and as a ligand for MuSK but also as a direct retrograde signal for presynaptic differentiation (25). In addition to its role during synapse formation, MuSK is also required to maintain adult synapses, because inhibition of MuSK expression in adult muscle leads to profound defects in presynaptic and postsynaptic differentiation (26, 27).Because IgG4 antibodies do not engage complement and are thought to be incapable of cross-linking and modulating expression of cell-surface antigens, we reasoned that pathogenic IgG4 autoantibodies to MuSK may directly interfere with MuSK function.Here we demonstrate that human IgG4 MuSK antibodies bind to the first Ig-like domain in MuSK and prevent Lrp4 from binding MuSK, thereby inhibiting Agrin-stimulated MuSK phosphorylation. We show that inhibiting the association between Lrp4 and MuSK seems to be the major mechanism by which the MuSK IgG4 antibodies disrupt MuSK signaling and cause MG, because these antibodies neither modulate MuSK surface expression nor have a direct effect on MuSK dimerization.     

Semiquantitative measurement of acetylcholine receptor at the motor end-plate in myasthenia gravis

OBJECTIVE: The purpose of this study was to investigate whether this semiquantitative measurement of the motor end-plate acetylcholine receptors (AChRs) can be used to confirm the diagnosis of myasthenia gravis (MG), and in particular ocular MG. METHODS: Motor point biopsies were performed from the biceps brachii muscles. Measurement of AChRs was made in peroxidase-labeled alpha-bungarotoxin stained muscle specimens. PATIENTS: Twenty patients with ocular MG, 37 with generalized MG, 5 with Lambert-Eaton myasthenic syndrome, 3 with botulism, 8 with amyotrophic lateral sclerosis, and 8 controls were included in this study. RESULTS: AChRs were decreased in all patients with generalized MG and in 80% of ocular MG including patients without detectable circulating anti-AChR antibodies, as compared with the control subjects. CONCLUSION: This method is useful to confirm the diagnosis of MG, in particular ocular MG without detectable anti-AChR antibodies.     

Pericarditis in myasthenia gravis

Myasthenia gravis is an autoimmune disorder with antibodies to the acetylcholine receptors (Ach R) in skeletal muscles. Myocardial involvement can present as a myocarditis or with arrhythmias. To our knowledge, there is no documentation in the literature of pericardial involvement in myasthenia gravis. We report the presence of pericardial effusion and atrioventricular conduction block in a patient with myasthenia gravis that responded appropriately to immunosuppressive therapy and plasma exchanges.     

Plasma Exchange for Treatment of Myasthenia Gravis: Pathophysiologic Basis and Clinical Experience

Abstract: Myasthenia gravis is an autoimmune disease characterized by production of antibodies to acetylcholine receptors located at the motor end plate in skeletal muscles. The antibodies bind and subsequently induce degeneration of these receptors. Loss of acetylcholine receptors results in inadequate contraction of muscle fibers in response to acetylcholine released from nerve terminals and clinically apparent muscle weakness. Plasma exchange removes the circulating antibodies in myasthenic patients with short‐term clinical improvement. Plasma exchange may be indicated in patients with acute exacerbation of neuromuscular weakness with bulbar or respiratory compromise, preoperative optimization prior to thymectomy, and postoperative deterioration following thymectomy or other surgical procedures. Long‐term, intermittent plasma exchange for patients who do not adequately respond to standard treatment is another evolving indication.     

Increased frequency of euthyroid ophthalmopathy in patients with Graves' disease associated with myasthenia gravis.

We previously showed that myasthenia gravis (MG) has a mild clinical expression when associated with autoimmune thyroid diseases (AITD). In the present study we have investigated the frequency of thyroid-associated ophthalmopathy (TAO) in patients with Graves' disease (GD) associated with MG as compared with GD patients without MG. A total of 418 patients with GD were studied, 31 with MG and 387 without MG. TAO was evaluated by physical examination, exophthalmometry, computerized tomography, and computerized visual fields assessment. The overall prevalence of TAO was similar in GD patients with MG (61.2%) and in those without MG (56.4%). When the analysis was restricted to GD patients with ocular MG, a greater frequency of TAO was found (84.6%), compared with GD patients without MG or with GD patients with generalized MG, although the differences did not reach the statistical significance. GD patients with MG had a significantly greater prevalence (12.9%) of euthyroid ophthalmopathy (clinically overt ophthalmopathy without previous and/or current hyperthyroidism) than those without MG (3.1%; p = 0.003). The results suggest a preferential association between the ocular manifestations of GD and MG, which may be due to immunological cross-reactivity against common autoimmune targets in the eye muscle as well as to a common genetic background.     

Contribution of intravenous immunoglobulins to the treatment of myasthenia

Myasthenia Gravis (MG) is an autoimmune disease characterized by the production of auto antibodies directed against the acetylcholine receptor of the neuro-muscular synapse. The signs and symptoms are a muscular deficit involving the spinal or cranial muscles. The degree of weakness changes spontaneously over shorter or longer periods. Some exacerbations, called myasthenia crisis, involve the respiratory muscle and are life-threatening. The prognosis of these crisis has been transformed by the use of mechanical ventilation. Treatments directed on immune-regulation such as thymectomy, corticosteroids or immunossupressive drugs contribute to the improvement in functional status and reduce the risk of exacerbation. Plasma exchanges lead to a rapid improvement of weakness during exacerbations. They are, despite the lack of controlled study, the reference treatment for acute exacerbations. More recently, high doses of immunoglobulins have been proposed and a controlled study has shown that they could be an alternative for the treatment of acute exacerbations of MG. Indication of immunoglobulin in the long term management of MG is not established.     

Dysphagia with Multiple Autoimmune Disease

Myasthenia gravis (MG) and polymyositis (PM) are organ-specific autoimmune diseases. Occasional reports describe patients with clinical and pathologic features of both. Achalasia is idiopathic in nature, but autoimmune and inflammatory mechanisms have been proposed for this disorder as well. We describe a patient with dysphagia who was diagnosed at different points in time with all these three rare conditions. Despite at least putatively having immune mechanisms in common, an association between the three has not been previously described. Received: 6 July 1999 / Accepted: 18 January 2000     

A comparative study of ocular and generalized myasthenia gravis

We compared the relations and therapeutic outcomes of ocular and generalized types of myasthenia gravis (MG) and used retrospective analysis for 65 patients with myasthenia gravis during a mean follow-up time of 30.4 months. There were 35 ocular and 30 generalized MG patients. Items of comparison included sex, age, clinical presentations, serum antibody titer, the association with thymus status, and therapeutic outcome. Of the patients with generalized MG, males were significantly older than females. Ptosis and diplopia were the most common symptoms in patients with MG, but there were no significant differences between the two types of MG. The eyelid levator muscle and lateral rectus muscle were the most commonly involved extraocular muscles in patients with MG. The associations with thymoma or thymus hyperplasia were more common in generalized MG than in ocular MG, and more common in younger than in older patients. The result of positive neostigmine test was 93.8% in all patients, but there were no significant differences between the two types of MG. Acetylcholine receptor antibody (AchRAb) presented an 81.1% positive rate and was significantly higher in generalized MG than that in ocular MG (96.2% vs 66.7%). There were no significant differences between the two types of MG regarding successful treatment strategies in both initial therapy and maintenance therapy. Only two of 16 patients had complete remissions after thymectomy. From the viewpoint of clinical presentations or from the therapeutic strategy outcome, the boundary between both types of MG seems to be vague. Both types of MG probably share the same entity in nature and the difference is just a matter of degree of severity. The benefit of thymectomy in treatment of MG needs further investigation.     

Clinical characteristics and prognosis of myasthenia gravis in older people

OBJECTIVES: To investigate the characteristics of myasthenia gravis (MG) in older people and to evaluate the benefits of immunosuppressive treatments at this age. BACKGROUND: Myasthenia gravis in older adults has not been extensively studied. In patients with disease onset after the age of 60, treatment mainly relies on medical therapy because thymectomy is generally not performed unless a thymoma is present. METHODS: Of 837 myasthenic patients followed since 1978, we identified 172 cases with onset after age 60. All patients were treated with anticholinesterases. In the decade from 1978 to 1988, immunosuppressive therapy was performed mainly with corticosteroids (prednisone); since 1989, azathioprine alone or, more often, associated with prednisone, has been increasingly used in MG patients. Long-term outcome was evaluated in 149 cases with follow-up longer than 1 year. Remission, pharmacological remission, and marked improvement with reduction in drug dosage were considered good results. RESULTS: Patients older than age 60 at onset of the disease were 20.5% of our series, male/female ratio was 1.9, age at onset ranged from 61 to 86 years, 87.2% patients had generalized disease, thymoma was detected in 37 patients (21.5%). Of 149 cases with sufficient follow-up data, 9 were in remission, 111 achieved good results, 3 died of MG, and 120 required immunosuppressive therapy at some time. Sixty-seven patients had been treated with prednisone for 0.5-16 years (mean, 5 years); good results were recorded in 51 patients (76.1%) and severe side effects in 12 (17.9%). Forty-six patients had received combined therapy with prednisone and azathioprine for 1 to 12 years (mean, 3.9 years); good results were recorded in 41 patients (89.1%) and severe side effects in six (19.5%). Seven patients had been treated with azathioprine alone for 1 to 4 years (mean, 2.3 years) with good results in five and with no side effects. CONCLUSIONS: The prognosis of MG in older people seems to be favorable, although full remission is rare and MG weakness, treatment side effects, and associated thymoma can contribute to mortality rate. In our experience, the combined therapy with prednisone and azathioprine was more effective than prednisone alone, and steroid-related side effects were more frequent than those related to azathioprine.     

Antigen-specific modulation of experimental myasthenia gravis: Nasal tolerization with recombinant fragments of the human acetylcholine receptor α-subunit

Myasthenia gravis (MG) and experimental autoimmune myasthenia gravis (EAMG) are antibody-mediated autoimmune diseases in which the nicotinic acetylcholine receptor (AcChoR) is the major autoantigen. The immune response in these diseases is heterogeneous and is directed to a wide variety of T and B cell epitopes of AcChoR. Candidate molecules for specific immunotherapy of MG should, therefore, have a broad specificity. We used recombinant fragments of the human AcChoR, encompassing the extracellular domain of the alpha-subunit, or shorter fragments derived from it, in experiments to modulate EAMG. We have demonstrated that intranasal administration of these recombinant fragments, which represent a major portion of epitopes involved in MG, prevents the induction of EAMG in rats and immunosuppresses an ongoing disease, as assessed by clinical symptoms, weight loss, and muscle AcChoR content. These effects on EAMG were accompanied by a marked reduction in the proliferative T-cell response and IL-2 production in response to AcChoR, in reduced anti-self AcChoR antibody titers and in an isotype switch of AcChoR-specific antibodies, from IgG2 to IgG1. We conclude that nasal tolerance induced by appropriate recombinant fragments of human AcChoR is effective in suppressing EAMG and might possibly be considered as a therapeutic modality for MG.