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

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.

A 49-Year-Old Man with Combined Myasthenia Gravis, Autoimmune Thyroiditis and IgG4 Orbitopathy

“…Azathioprine has been reported to help prevent the exacerbation of general MG [7]. Unfortunately, the patient's ocular symptoms recurred under oral immunosuppressants including azathioprine, hydroxychloroquine, and prednisolone.…”

“…Therefore, one diagnosis could be insufficient while making the decision on treatment choices in patients with combined eyelid ptosis, proptosis and ophthalmoplegia. Meanwhile, steroid-induced symptom exacerbation should be taken into consideration while initially treating the relatively elderly patients with severe MG [7]. However, the phenomenon of persistent ocular symptoms disappeared after repeated doses of IV pulse steroid, indicating that early deterioration should not preclude this beneficial treatment option during later followups of these patients [13].…”

“…The benefits of pulse steroids have been documented [5], but often require the combination with plasmapheresis and/ or other immunosuppressants [6]. Besides, the possibility of steroid-induced symptom exacerbation, especially deterioration to generalized MG, should be taken into consideration while treating either mild MG or myasthenic crisis [7].…”

Management of Immune-Mediated Paraneoplastic Neurological Disorders

“…With regard to facultative paraneoplastic syndromes which are more frequently of autoimmune origin, such as neuromyelitis optica or myasthenia gravis, the reader should refer to pertinent reviews [5,6].…”

Developing an international consensus guidance for myasthenia gravis using RAND/UCLA appropriateness method

“…[6][7][8][9][10][11] The following three assumptions were agreed a priori: (1) treatment costs and availability would not be considered; (2) clinical examination is performed by experienced physicians for the evaluation of neuromuscular disease; (3) the MGFA Clinical Classification refers to the state of the patient at the time of evaluation. Guidance statements were developed for the following seven topics: MG symptomatic and immunosuppressive (IS) treatment, IV immunoglobulin (IVIg) and plasma exchange (PLEX), impending and manifest myasthenic crisis, thymectomy, juvenile MG (JMG), muscle-specific tyrosine kinases (MuSK) antibody-positive MG and MG in pregnancy.…”