Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society.

Nico Melzer,Björn Tackenberg,Peter Fuhr,Heinz Wiendl,Ralf Gold,Reinhard Hohlfeld,Arthur Melms,Fritz Zimprich,Alexander Marx,Berthold Schalke,Christiane Schneider-Gold,Sven G Meuth,Tobias Ruck

doi:10.1007/s00415-016-8045-z

Abstract

Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder of neuromuscular synaptic transmission. The clinical hallmark of MG consists of fluctuating fatigability and weakness affecting ocular, bulbar and (proximal) limb skeletal muscle groups. MG may either occur as an autoimmune disease with distinct immunogenetic characteristics or as a paraneoplastic syndrome associated with tumors of the thymus. Impairment of central thymic and peripheral self-tolerance mechanisms in both cases is thought to favor an autoimmune CD4+ T cell-mediated B cell activation and synthesis of pathogenic high-affinity autoantibodies of either the IgG1 and 3 or IgG4 subclass. These autoantibodies bind to the nicotinic acetylcholine receptor (AchR) itself, or muscle-specific tyrosine-kinase (MuSK), lipoprotein receptor-related protein 4 (LRP4) and agrin involved in clustering of AchRs within the postsynaptic membrane and structural maintenance of the neuromuscular synapse. This results in disturbance of neuromuscular transmission and thus clinical manifestation of the disease. Emphasizing evidence from clinical trials, we provide an updated overview on immunopathogenesis, and derived current and future treatment strategies for MG divided into: (a) symptomatic treatments facilitating neuromuscular transmission, (b) antibody-depleting treatments, and (c) immunotherapeutic treatment strategies.

Highlights

This manuscript has partially been adopted from the clinical guidelines ‘‘Diagnostik und Therapie der Myasthenia gravis und des Lambert-Eaton-Syndroms’’ of the German Neurological Society (DGN) published by some of the authors [44]
The clinical hallmark of Myasthenia gravis (MG) consists of fluctuating fatigability and weakness affecting ocular, bulbar and limb skeletal muscle groups
MG may either occur as an autoimmune disease with distinct immunogenetic characteristics or as a paraneoplastic syndrome associated with tumors of the thymus

Summary

Introduction

This manuscript has partially been adopted from the clinical guidelines ‘‘Diagnostik und Therapie der Myasthenia gravis und des Lambert-Eaton-Syndroms’’ of the German Neurological Society (DGN) published by some of the authors [44]. In 10–20 % of patients the combination of AZA and GCS does not lead to sufficient clinical stabilization or remission requiring GCS at dosages of more than 7.5 mg/day prednisolone equivalent and in the long term requiring other immunosuppressive treatment strategies (therapy resistance). A recent clinical trial compared MTX (17.5 mg/week) in 24 patients with generalized MG with AZA (2.5 mg/day/kg bodyweight) regarding its steroid-sparing effect and showed an equivalent effect within a treatment period of 2 years [68]. A randomized, placebo-controlled clinical trial in 80 patients with MG with minimal clinical disease under an oral prednisolone therapy (10–20 mg/day) studied the steroid-sparing effect of TCM (3 mg/day) over a period of 28 weeks. In severe and otherwise treatment resistant life-threatening MG, CPP can be used as ultima ratio as positive clinical evidence exist for several treatment regimens: 1. CPP pulse therapy: 500 mg/m2 body surface area every 4 weeks until remission under co-medication with mesna, based on a prospective, randomized, double-blinded study [31]

Immuno- or myeloablative CPP therapy

Line therapies:

Conclusion

Findings

Compliance with ethical standards