From the Guidelines
Myasthenia gravis is an autoimmune disorder characterized by antibody-mediated attack on the neuromuscular junction, primarily targeting acetylcholine receptors, leading to impaired neuromuscular transmission and fluctuating muscle weakness. The pathophysiology of myasthenia gravis involves the binding of antibodies to acetylcholine receptors on the postsynaptic membrane of skeletal muscles, causing receptor degradation, complement-mediated damage to the postsynaptic membrane, and physical blockade of receptor binding sites 1. This interference prevents acetylcholine from effectively binding to its receptors, disrupting signal transmission between nerves and muscles. In some patients without acetylcholine receptor antibodies, antibodies instead target muscle-specific kinase (MuSK) or lipoprotein receptor-related protein 4 (LRP4), which are proteins essential for clustering acetylcholine receptors at the neuromuscular junction.
The thymus gland plays a significant role in this pathology, with approximately 75% of patients showing thymic abnormalities including hyperplasia or thymoma 1. These thymic changes likely contribute to the breakdown in immune tolerance to acetylcholine receptors. The resulting impaired neuromuscular transmission manifests as fluctuating muscle weakness that typically worsens with repeated use and improves with rest, affecting ocular, bulbar, limb, and respiratory muscles to varying degrees. Key features of the disorder include:
- Variable weakness exacerbated by fatigue
- Ocular symptoms such as ptosis and diplopia
- Bulbar, limb, and respiratory muscle involvement
- Increased risk of thymoma and autoimmune thyroid disease 1
The primary goal of treatment is to minimize morbidity and mortality, reduce symptoms, and improve quality of life. Treatment is goal-directed and targeted outcomes may include recognition of disease, prevention of morbidity and mortality, reduction of diplopia, restoration of normal ocular alignment, and improvement of self-image 1. Thymectomy is indicated in certain cases, particularly in the presence of thymoma, and may substantially reduce clinical symptoms 1. Overall, the management of myasthenia gravis requires a comprehensive approach, taking into account the patient's individual needs and circumstances, to optimize outcomes and improve quality of life.
From the Research
Pathophysiology of Myasthenia Gravis
The pathophysiology of myasthenia gravis involves the impairment of the neuromuscular junction, which is caused by an autoimmune response against components of the muscle membrane localized at the neuromuscular junction 2, 3. The most common target of this autoimmune disease is the acetylcholine receptor (AChR), with antibodies against AChR found in 80%-85% of patients 3, 4. Other targets include the MuSK protein and the LRP4 protein 3, 4.
Autoimmune Response
The autoimmune response in myasthenia gravis is characterized by the presence of autoantibodies against the AChR or other components of the neuromuscular junction 3, 4. These autoantibodies lead to the destruction of the AChR, resulting in a decrease in the number of functional AChR at the neuromuscular junction 2. This decrease in AChR leads to a reduction in the transmission of nerve impulses to muscles, resulting in muscle weakness and fatigue 5, 6.
Key Features of Myasthenia Gravis
Some key features of myasthenia gravis include:
- Muscle weakness that worsens with activity and fluctuates over the course of the day 5
- Involvement of respiratory musculature can lead to life-threatening crisis requiring intensive care unit care 5
- Presence of autoantibodies against AChR or other components of the neuromuscular junction 3, 4
- Thymoma is present in 10%-20% of patients with AChR MG 4
Current Understanding and Treatment
The current understanding of the pathophysiology of myasthenia gravis has led to the development of new treatment options, including molecular therapies that target specific immune pathways 6, 4. These new treatments offer more selective, rapid, and safer alternatives to traditional immunosuppressants 6. Despite these advances, a large proportion of patients remain chronically dependent on corticosteroids, and new treatments are needed to reduce the chronic use of corticosteroids and diminish side effects 4.