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.     

Giant cell myositis associated with concurrent myasthenia gravis: a case-based review of the literature

The term “giant cell myositis” has been used to refer to muscle diseases characterized histologically by multinucleated giant cells. Myasthenia gravis is an autoimmune neuromuscular junction disorder. The rare concurrence of giant cell myositis with myasthenia gravis has been reported; however, the clinical and histological features have varied widely. Here, we present such a case and a review of the literature. An 82-year-old woman admitted for subacute, progressive, proximal muscle weakness developed acute-onset dysphagia, dysphonia, and respiratory distress 5 days after admission. Laboratory findings were positive for acetylcholine receptor binding antibodies and striational muscle antibodies against titin. Muscle biopsy demonstrated widespread muscle fiber necrosis with multinucleated giant cells, consistent with giant cell myositis. She died despite treatment with pulse methylprednisolone and plasma exchange. A literature review of the PubMed and Scopus databases from 1944 to 2020 identified 15 additional cases of these co-existing diagnoses. We found that giant cell myositis with myasthenia gravis primarily affects female patients, is typically diagnosed in the 6–7th decades, and is characterized by the presence of thymoma. Muscle histology predominantly shows giant cell infiltrate without granulomas. The onset of myasthenia gravis symptoms may precede, follow, or coincide with symptoms of myositis. Treatment with thymectomy, anticholinesterase inhibitors, or immunosuppressive therapy may lead to favorable clinical outcomes.

     

Modulation of acetylcholine receptor by antibody against the receptor

Antibody against acetylcholine receptor induces an increase in the rate of degradation of acetylcholine receptors on a mouse cell line (BC(3)H-1) and cultured rat skeletal muscle. The increased rate of degradation results in a lowered density of acetylcholine receptors on muscle membrane and a lowered sensitivity to iontophoretically applied acetylcholine. The modulation of acetylcholine receptor is energy, temperature, and time dependent and may be related to antigenic modulation found in other systems. Acetylcholine noise analysis demonstrates that antibody against acetylcholine receptor reduces the channel mean conductance and mean open time slightly.It is concluded that antibody binds to the acetylcholine receptor, impairs its function, and induces receptor degradation. This results in a lowered density of acetylcholine receptor and a lowered sensitivity to acetylcholine. Patients with myasthenia gravis have antibodies to their acetylcholine receptor in their serum. Antigenic modulation of receptor in the muscle of patients with myasthenia gravis could contribute to the observed decrease in amplitudes of miniature endplate potentials and in muscle acetylcholine sensitivity, and the symptoms of muscular weakness.     

Comparative Study of Clinical Effects Between Plasma Adsorption and Double Filtration Plasmapheresis in Patients with Myasthenia Gravis

Abstract: Plasma exchange (PE) has been one of the most powerful treatments for patients with myasthenia gravis (MG) since Pinching et al. reported its clinical usefulness in 1976, despite the need for supplemental human plasma. However, new apheresis techniques, e.g., plasma adsorption (PA) and double filtration plasmapheresis (DFPP), which do not need human plasma, were developed and have been introduced for clinical use in MG. We compared the effects of these plasma purification therapies in patients with MG and found that DFPP improved such subjective symptoms as chest compression and general fatigue better than PA while both of them could decrease the serum level of acetylcholine receptor (AChR) antibodies and relieve objective muscle weakness to a similar degree. It may be that DFPP can remove some circulating pathogenic factors other than AChR antibodies more efficiently than PA.—     

Discordant thymectomy in identical twins concordant for myasthenia gravis

BACKGROUND: Thymectomy is standard therapy fornonthymomatousmyasthenia gravis despite the absence of randomized clinical trials (1). Myasthenia gravis is uncommonly reported in monozygous twins; disease concordance occurs in approximately one third of such identical twin pairs; and treatment for myasthenia gravis, when described,is usually concordant in identical twin pairs (2).OBJECTIVE: To report an 11-year clinical course of a pair of identical twins concordant for generalized acetylcholine receptor antibody–positive nonthymomatous myasthenia gravis in whom only 1 was treated with extended transsternal thymectomy. CASE REPORT: Twin A was a 19-year-old white woman who presented with an 8-week history of intermittent leg weakness, causing her to fall during activities, such as climbing stairs. On examination,she had moderately severe fatigable proximal muscle weakness and ptosis. Her weakness improved with intravenous edrophonium administration.Initial binding acetylcholine receptor antibody titer was 1.22 nmol/L (normal value, 0.03 nmol/L). Repetitive 2-Hz nerve(median, ulnar, and facial) stimulation studies demonstrated up to a 16% decremental response. Chest computed tomography showed residual thymic tissue without thymoma. An extended transsternal thymectomy was performed 11 weeks after the onset of symptoms.     

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.     

Therapeutic Apheresis in Myasthenia Gravis

Abstract: Plasma exchange (PE) is an easily applicable technique for rapid and massive removal of antibodies, and its beneficial role is well established in the management of myasthenia gravis (MG), an antibody‐mediated disorder of the neuromuscular junction. PE is useful in myasthenic crisis, in most severe forms of MG before thymectomy, in the early postoperative period, and in cases of symptom worsening during tapering or initiation of immunosuppressive therapy. Clinical efficacy varies from 55% to 100%, and improvement rarely persists for more than 4–10 weeks; thus immunosuppressive therapy has to be associated. New apheretic techniques (double filtration plasmapheresis, immunoadsorption systems with staphylococcal protein A columns or thryptophan‐polyvinyl alcohol gel columns) that allow the selective removal of IgG and anti‐AChR antibody were recently used in the management of MG with positive effects. Whether their therapeutic effect and cost effect prove more favorable than those obtained by PE still must be demonstrated.     

Steroids induce acetylcholine receptors on cultured human muscle: implications for myasthenia gravis.

Antibodies to the acetylcholine receptor (AChR), which are diagnostic of the human autoimmune disease myasthenia gravis, block AChR function and increase the rate of AChR degradation leading to impaired neuromuscular transmission. Steroids are frequently used to alleviate symptoms of muscle fatigue and weakness in patients with myasthenia gravis because of their well-documented immunosuppressive effects. We show here that the steroid dexamethasone significantly increases total surface AChRs on cultured human muscle exposed to myasthenia gravis sera. Our results suggest that the clinical improvement observed in myasthenic patients treated with steroids is due not only to an effect on the immune system but also to a direct effect on muscle. We propose that the identification and development of pharmacologic agents that augment receptors and other proteins that are reduced by human genetic or autoimmune disease will have broad therapeutic applications.     

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.     

Advanced age enhances the sepsis-induced up-regulation of the γ- and α7-nicotinic acetylcholine receptors in different parts of the skeletal muscles

BackgroundThe muscle mass decreases with age, leading to frailty and weakness; however, the role of acetylcholine receptors in this process has not been properly studied. In this article, we hypothesize that diaphragmatic as well as peripheral muscle weakness may be caused by the up-regulation of gamma and alpha 7 nicotinic acetylcholine receptors (nAChRs) on muscle cell membranes.MethodAdult male rats were randomly divided into sham and sepsis groups. Sepsis was induced by cecal ligation and puncture (CLP). Blood specimens and biopsies of tibialis anterior muscle and diaphragm were obtained at 24 h post CLP.ResultsUp-regulation of gamma and alpha 7 nAChRs was detected in both sham and septic groups; however, this response was more robust in septic animals. Compared to tibialis anterior muscle, the diaphragm expressed a higher number of both receptor types.ConclusionsMuscle weakness in old age and sepsis may have common molecular underpinnings. Loss of diaphragmatic strength may explain hypoxia and respiratory failure often encountered in frail elderly.     

Early and late results after thymectomy in myasthenia gravis: a retrospective study [correction of analysis]

BACKGROUND: This study aims to evaluate the early and late outcome of patients treated by surgery for myasthenia gravis and the diagnostic value of the Besinger Score, which is based on a correlation of severity of symptoms with specific antibodies to acetylcholine receptors, in the follow-up investigation after surgical therapy. METHODS: Between June 1984 and April 1992 thoracotomy was performed in 51 myasthenia gravis cases at our department. The retrospective analysis considered patients with (n = 13) or without thymoma (n = 38). The Besinger score was used to describe the severity of disease preoperatively and up to 5 years postoperatively. RESULTS: The Besinger score fell continually post surgery. Changes in relative serum concentrations of antibodies were similar to the Besinger score. Five years after thymectomy complete remission was diagnosed in 40% of the patients. The required dosage of pyridostigmine had fallen by two thirds after 5 years. Patients with follicular hyperplasia had significantly higher remission rates than those with thymoma. CONCLUSIONS: Surgery for myasthenia gravis is successful. The Besinger score well quantifies the severity of the disease.     

Monozygotic twins with Klinefelter's syndrome discordant for systemic lupus erythematosus and symptomatic myasthenia gravis

Monozygotic twins with Klinefelter's syndrome were evaluated for two distinct illnesses. One subject had clinical and serologic evidence of systemic lupus erythematosus and no symptoms of muscle weakness. His identical twin had typical symptoms and laboratory evidence of myasthenia gravis. Antibodies to acetylcholine receptors were present in both subjects. These patients are discussed in relation to genetic, hormonal, and immunologic mechanisms involved in the pathogenesis of these two disorders.     

Sevoflurane for trans-sternal thymectomy in myasthenia gravis

Myasthenic gravis (MG) is an autoimmune disease associated with acetylcholine receptor deficiency. Patients with MG exhibit increased sensitivity to non-depolarising muscle relaxants. In an attempt to avoid neuromuscular blockers, we used sevoflurane in two myasthenic patients undergoing trans-sternal thymectomy. Inhalation of 8% sevoflurane in oxygen using vital capacity technique produced rapid, pleasant and smooth induction and provided good tracheal intubating conditions. In both patients anaesthesia was maintained with 1.5-2% end-tidal concentration of sevoflurane and nitrous oxide in oxygen without adjunctive neuromuscular blocking agents. There were minimal changes in cardiovascular variables and recovery was faster. It is suggested that sevoflurane may be the main anaesthetic for both induction and maintenance in myasthenic patients undergoing trans-sternal thymectomy.     

A case of dermatomyositis associated with thymic abnormalities]

A case of dermatomyositis (DM) associated with thymic cyst with lymphoid follicle formations has been reported. A 57-year-old man developed polyarthralgia, muscle weakness, heliotrope rash and Gottron's sign. Laboratory findings showed elevated values of creatine-phosphokinase, aldolase and transaminase. He was diagnosed as DM and was treated with prednisolone 50 mg/day. Muscle weakness was improved immediately, although rash persisted unchangeably. He was examined for coexistence of malignant tumor which had been reported frequently as associated with DM. Enlargement of thymus was found by computer tomography and then thymectomy was performed. In his thymus, lymphoid follicle formations, which are as often encountered in other autoimmune diseases, were found. So far, the beneficial effect of thymectomy on the improvement of immunological abnormalities not only in patients with myasthenia gravis but also in patients with other autoimmune diseases has been recognized. In this case, intractable rash in DM improved after thymectomy. Further study needs to clarify the relationships between DM and thymic abnormalities.     

Immunoadsorption in Guillain‐Barré Syndrome and Myasthenia Gravis

Elimination of circulating antibodies by hemapheresis is an empirical treatment concept in various neuroimmunological diseases. Plasma exchange (PE) has been shown to be superior to symptomatic treatment in Guillain‐Barré syndrome (GBS) in two large multicenter studies. It is also effective in myasthenia gravis (MG), although no comparative studies have been performed. Immunoadsorption (IA) using polyvinyl alcohol gel columns to which phenylalanin (IM‐PH) or tryptophan (IM‐TR) are covalently bound is an alternative to PE, and seems to have equal efficacy and comparable side effects. This method also obviates the need for replacement of plasma with human albumin or plasma. We compared the treatment results of 11 patients with GBS treated by PE to those of 13 patients treated by IA using an IM‐TR column. Here, we found no statistically significant differences with regard to efficacy and clinical or procedural complications. From these data we conclude that immunoadsorption can be used as an equal alternative to PE. A large multicenter study comparing PE, intravenous immunoglobulins (IVIG), and the combination of both in the treatment of GBS revealed no significant difference between the 3 treatment groups. In MG, only 2 small studies have been performed using IA, and no studies comparing PE or other treatments to IA have been conducted. Both investigations of IA therapy demonstrated a marked reduction in the acetylcholine receptor (AchR) antibodies and a sustained improvement of the clinical signs. These results therefore show that IA is an effective treatment for myasthenia gravis.     

Structure and superorganization of acetylcholine receptor–rapsyn complexes

The scaffolding protein at the neuromuscular junction, rapsyn, enables clustering of nicotinic acetylcholine receptors in high concentration and is critical for muscle function. Patients with insufficient receptor clustering suffer from muscle weakness. However, the detailed organization of the receptor–rapsyn network is poorly understood: it is unclear whether rapsyn first forms a wide meshwork to which receptors can subsequently dock or whether it only forms short bridges linking receptors together to make a large cluster. Furthermore, the number of rapsyn-binding sites per receptor (a heteropentamer) has been controversial. Here, we show by cryoelectron tomography and subtomogram averaging of Torpedo postsynaptic membrane that receptors are connected by up to three rapsyn bridges, the minimum number required to form a 2D network. Half of the receptors belong to rapsyn-connected groups comprising between two and fourteen receptors. Our results provide a structural basis for explaining the stability and low diffusion of receptors within clusters.     

Resolution of autoimmune oophoritis after thymectomy in a myasthenia gravis patient

Myasthenia gravis (MG) is an autoimmune disorder characterized by autoantibodies against acetylcholine receptors. MG is generally an isolated disorder but may occur concomitantly with other autoimmune diseases. We describe an eighteen-year-old girl with MG who was admitted to our clinic with secondary amenorrhea and diagnosed as autoimmune oophoritis. Since her myasthenic symptoms did not resolve with anticholinesterase therapy, thymectomy was performed. After thymectomy, her menses have been regular without any hormonal replacement therapy. To our knowledge, this is the first report on a patient with autoimmune ovarian insufficiency and MG in whom premature ovarian insufficiency resolved after thymectomy, without hormonal therapy.     

Marked Respiratory Failure in an Ambulant Patient with Immune-mediated Necrotizing Myopathy and Anti-Kv1.4 and Anti-titin Antibodies

We herein report a case of seronegative immune-mediated necrotizing myopathy (IMNM) concurrent with anti-Kv1.4 and anti-titin antibodies. A 72-year-old Japanese woman presented with a 29-year history of fluctuating high serum creatine kinase (CK) levels followed by intermittent ptosis and respiratory muscle weakness. This case highlights the fact that marked respiratory muscle weakness requiring intubation can be seen in an ambulant patient with IMNM. Marked respiratory muscle weakness, rhabdomyolysis-like acute elevation of CK levels, and anti-striational muscle antibodies may be a characteristic constellation of findings in a distinct subgroup of patients with inflammatory myopathy with myasthenia gravis or similar symptoms.     

Myasthenia Gravis and Lambert‐Eaton Syndrome

Abstract: Myasthenia gravis is a common autoimmune disorder characterized by the presence of pathogenic antibodies directed against the acetylcholine receptor. Patients present with variable degrees and distribution of fluctuating weakness at times life threatening. Clinical manifestations, establishment of diagnosis, the natural history of myasthenia gravis, and therapeutic options are herein reviewed. Far less common is Lambert‐Eaton syndrome (the myasthenic syndrome), another autoimmune disorder due to the presence of antibodies directed against the PQ‐type voltage‐gated calcium channels. Clinical features and treatment options are summarized.