What is the pathophysiology of Myasthenia Gravis (MG)?

From the Guidelines

Myasthenia gravis is an autoimmune disorder characterized by antibodies targeting the neuromuscular junction, primarily affecting the acetylcholine receptors, as demonstrated in a study published in 2020 1. The pathophysiology of myasthenia gravis involves antibodies that reduce the number of functional acetylcholine receptors through several mechanisms: direct blocking of receptor binding sites, accelerated receptor degradation through cross-linking and endocytosis, and complement-mediated destruction of the postsynaptic membrane. The thymus gland plays a crucial role in this pathology, with thymic hyperplasia present in about 65% of patients and thymomas in 10-15%, as noted in a study from 2012 1. The resulting defect in neuromuscular transmission leads to the hallmark symptoms of muscle weakness and fatiguability, typically affecting ocular muscles first (causing ptosis and diplopia) before potentially progressing to other muscle groups including bulbar, limb, and respiratory muscles. Some key points to consider in the pathophysiology of myasthenia gravis include:

• The role of antibodies in reducing functional acetylcholine receptors
• The involvement of the thymus gland in the pathology of the disease
• The characteristic symptoms of muscle weakness and fatiguability, particularly affecting ocular muscles
• The potential for progression to other muscle groups, including bulbar, limb, and respiratory muscles The most recent and highest quality study on this topic, published in 2020 1, provides the most relevant information for understanding the pathophysiology of myasthenia gravis. This understanding of the pathophysiology guides treatment approaches, which include acetylcholinesterase inhibitors to increase acetylcholine availability, immunosuppressive therapies to reduce antibody production, thymectomy to remove potential antigenic sources, and in acute crises, plasma exchange or intravenous immunoglobulin to remove circulating antibodies. It is essential to recognize the disorder to initiate appropriate workup and referral to other subspecialties, including neurology, as noted in a study from 2020 1. Treatment is goal-directed, and targeted outcomes may include recognition of disease and prevention of morbidity and mortality from generalized myasthenia gravis, reduction of diplopia, restoration of normal ocular alignment, appearance, and improved self-image, restoration of binocular function, and reduction of compensatory head position. Overall, the pathophysiology of myasthenia gravis is complex and involves multiple factors, including antibodies, the thymus gland, and characteristic symptoms. Understanding these factors is crucial for providing effective treatment and improving patient outcomes, as demonstrated in a study published in 2020 1.

From the Research

Pathophysiology of Myasthenia Gravis

• Myasthenia gravis is a rare disease that causes impairment of the neuromuscular junction, characterized by dysfunction of the neuromuscular junction resulting in skeletal muscle weakness 2, 3.
• The basic abnormality in myasthenia gravis is a reduction in acetylcholine receptors (AChRs) at neuromuscular junctions due to the effects of autoantibodies that are directed against the AChRs in most patients, or against neighboring proteins involved in the clustering of AChRs (MuSK, LRP-4, or agrin) 4.
• Acetylcholine receptor is the most common target of this autoimmune disease, with AChR antibodies found in 80%-85% of patients 3.

Autoantibodies and Their Role

• Autoantibodies against the acetylcholine receptor, muscle-specific kinase (MuSK), and low-density lipoprotein receptor-related protein 4 (Lrp4) play a crucial role in the pathophysiology of myasthenia gravis 3, 4.
• Approximately 10% of patients are seronegative for antibodies binding the known disease-related antigens 3.

Clinical Presentation and Diagnosis

• Clinical presentation of myasthenia gravis includes muscle weakness and fatigue, often in typical patterns, with ptosis, diplopia, facial bulbar weakness, and limb weakness being the most common symptoms 3, 4.
• Diagnosis can be established with additional tests, including repetitive nerve stimulation, single fiber EMG, and the ice pack test, besides the typical clinical features and serologic testing 3.

Treatment Options

• Treatment options for myasthenia gravis consist of symptomatic treatment (such as pyridostigmine), immunosuppressive treatment, or thymectomy 3, 5.
• Pyridostigmine represents the first-line symptomatic treatment, while ambenonium and beta adrenergic agonists are second-line options 5.
• Early thymectomy should be undertaken if a thymoma, and in non-thymoma patients up to the age of 50-65 years if not obtaining remission on symptomatic treatment 5.