Myasthenia gravis (MG) is a chronic, immune-mediated disorder affecting the neuromuscular system. It is characterized by fluctuating muscle weakness that improves with rest and worsens with activity. This condition impairs communication between nerves and skeletal muscles, leading to fatigue in voluntary muscles such as those controlling the eyes, face, throat, and limbs. The underlying issue involves a breakdown in the process that initiates muscle contraction at the junction where nerve cells transmit signals to muscle cells.
Initial Clinical Descriptions
The earliest documentation of a condition resembling myasthenia gravis dates back to 1672. English physician Thomas Willis described a patient in De Anima Brutorum who experienced profound fatigue, noting she could speak well in the morning but was unable to utter a word by evening. This account established the characteristic of fluctuating, exertion-dependent weakness, though it went largely unnoticed for nearly two centuries.
The condition gained significant attention in the late 19th century as neurologists began classifying muscle disorders. German neurologist Wilhelm Erb published a definitive clinical description in 1878, detailing the characteristic oculobulbar symptoms, such as droopy eyelids and difficulty swallowing. Erb’s work provided the first clear medical delineation, distinguishing MG from other paralytic conditions.
Polish neurologist Samuel Goldflam solidified the clinical understanding in 1893 with a comprehensive review of cases, emphasizing muscular fatigue. The disease was sometimes referred to as the Erb-Goldflam syndrome in recognition of their work. The modern name was coined in 1895 by Friedrich Jolly, who proposed the term myasthenia gravis pseudoparalytica. The simpler myasthenia gravis was eventually adopted, identifying the disease based purely on clinical signs.
Identifying the Autoimmune Mechanism
The cause of the weakness remained a mystery until the mid-20th century. The first major breakthrough occurred in the early 1970s when researchers, including Jon Lindstrom and Vanda Lennon, developed an animal model by injecting rabbits with purified acetylcholine receptors (AChR). This work led to the discovery that the serum of most MG patients contained autoantibodies directed against the AChR at the neuromuscular junction. The 1976 publication of this finding firmly established MG as an autoimmune disorder, where the immune system mistakenly attacks healthy tissue.
These autoantibodies bind to the AChR on the muscle cell surface, blocking the chemical signal, acetylcholine, from reaching its target. This binding also causes the receptors to be destroyed and internalized, severely reducing the number of functional receptors available to trigger muscle contraction. The thymus gland, located in the chest, plays a central role in this process. It is often enlarged (hyperplasia) or contains a tumor (thymoma) in many patients, serving as a site for initiating the autoimmune response.
The AChR antibody discovery did not account for all patients, prompting a search for other targets. In 2001, a second major subgroup was identified with the discovery of antibodies against Muscle-Specific Kinase (MuSK). MuSK is a protein that helps cluster and maintain the AChR, and its blockade causes a different, often more severe, clinical presentation. A third autoantibody was identified in 2011, targeting the Low-Density Lipoprotein Receptor-Related Protein 4 (LRP4), which works with MuSK to organize the neuromuscular junction.
Evolution of Diagnostic Confirmation
Before antibody testing, diagnosis relied on the temporary pharmacological Edrophonium test, introduced in the 1950s. This test involved injecting the short-acting drug edrophonium, which temporarily prevents the breakdown of acetylcholine in the neuromuscular junction. A rapid, temporary improvement in muscle strength, particularly in the eyes, supported the diagnosis of MG.
The Edrophonium test has largely been replaced by modern, safer methods, especially serum antibody testing. Detecting antibodies against AChR, MuSK, or LRP4 in the blood is now the gold standard for confirmation. For the minority of patients who are “seronegative,” electrodiagnostic studies are instrumental in confirming the diagnosis.
Repetitive Nerve Stimulation (RNS) measures the muscle’s electrical response to repeated nerve stimulation. In MG, RNS typically shows a characteristic decrement, or drop, reflecting the failure of neuromuscular transmission. The most sensitive method is Single-Fiber Electromyography (SFEMG), which detects subtle abnormalities in the timing of muscle fiber activation, known as “jitter.” This increased variability in signal transmission is a reliable marker for impaired function at the neuromuscular junction.
Key Therapeutic Milestones
The first major therapeutic milestone occurred in 1934 when physician Mary Walker noted the similarity between MG symptoms and curare poisoning, which is reversed by physostigmine. She successfully treated an MG patient with physostigmine, a drug that improves neuromuscular transmission by inhibiting the enzyme that breaks down acetylcholine. This led to the development of longer-acting anticholinesterase inhibitors, such as pyridostigmine (Mestinon), which remain the first-line symptomatic treatment today.
A second major treatment class, immunosuppressive agents, was introduced in the mid-20th century. Corticosteroids, such as prednisone, were used starting in the 1950s to suppress the underlying autoimmune attack. Other immunosuppressants like azathioprine were later integrated into treatment protocols for long-term disease management, helping to reduce the production of pathogenic antibodies.
Surgical intervention became a recognized therapeutic option with the refinement of thymectomy, the removal of the thymus gland. The procedure was established as a formal treatment in the 1930s and 1940s, notably by Alfred Blalock. Thymectomy can lead to sustained improvement or remission, even in patients without a thymoma. For acute, life-threatening exacerbations, rapid-acting immunotherapies emerged in the 1980s, including plasmapheresis and intravenous immunoglobulin (IVIg).