Myasthenia gravis

Myasthenia gravis is caused by autoantibodies that target proteins at the neuromuscular junction, most commonly the nicotinic acetylcholine receptor (AChR). These antibodies reduce the number of available receptors, impairing the end-plate potential and diminishing muscle contraction. In about 10–15% of patients, antibodies against muscle-specific kinase (MuSK) are found, often producing a distinct phenotype with prominent bulbar and respiratory weakness. A small subset harbors antibodies to LRP4 or agrin, and a minority are seronegative, suggesting other immune mechanisms. The thymus plays a central role: thymic hyperplasia is present in up to 65% of early-onset cases, and thymoma occurs in about 10% of all patients. The thymus may harbor autoreactive B cells that produce AChR antibodies, and thymectomy has been shown to improve outcomes in selected patients.¹²

The hallmark of MG is fatigable weakness: muscles tire with repeated use and recover after rest. Ocular symptoms—ptosis and diplopia—are the initial presentation in about 50% of patients, and most develop them within two years. Bulbar symptoms include dysarthria, dysphagia, and difficulty chewing. Limb weakness is typically proximal and asymmetric. The diagnosis is confirmed by the presence of AChR or MuSK antibodies, but seronegative cases may require electrodiagnostic testing. Repetitive nerve stimulation shows a decremental response, and single-fiber electromyography demonstrates increased jitter. The ice pack test, in which cooling the eyelid improves ptosis, is a simple bedside maneuver with high specificity. Edrophonium testing, once common, is now rarely used due to availability and cardiac risks.³⁴

Treatment is tailored to severity and includes symptomatic and immunomodulatory strategies. Acetylcholinesterase inhibitors, such as pyridostigmine, provide symptomatic benefit by increasing acetylcholine availability at the neuromuscular junction. Corticosteroids and steroid-sparing agents (azathioprine, mycophenolate, tacrolimus) are used for long-term immunosuppression. Thymectomy is recommended for patients with thymoma and is also beneficial in non-thymomatous AChR-positive early-onset MG, as demonstrated by the MGTX trial. For acute exacerbations, plasmapheresis and intravenous immunoglobulin are equally effective. Myasthenic crisis, defined as respiratory failure requiring intubation, occurs in 15–20% of patients and carries a mortality rate of less than 5% in modern series. Emerging therapies include complement inhibitors (eculizumab, ravulizumab) and neonatal Fc receptor antagonists (efgartigimod), which offer rapid improvement in refractory cases.⁵⁶

Beyond the classic presentation, MG has several underrecognized dimensions. Ocular MG progresses to generalized disease in about 50–60% of cases, usually within two years, but remains purely ocular in the rest. The disease can be triggered or exacerbated by certain drugs, including penicillamine, aminoglycosides, and beta-blockers, and by infections or stress. A rare form, seronegative MG, may involve antibodies to agrin or LRP4, and some patients have low-affinity AChR antibodies detectable only by cell-based assays. In MuSK-positive MG, patients often have severe bulbar and respiratory weakness with relative sparing of ocular muscles, and they may respond poorly to pyridostigmine. The historical figure of Thomas Willis is often credited with the first description of MG in 1672, but the term "myasthenia gravis" was coined by Friedrich Jolly in 1895. The association with thymoma was recognized in 1901, and the first successful thymectomy was performed by Alfred Blalock in 1939.⁷

AChR

Acetylcholine receptor, the main target of autoantibodies in MG.

MuSK

Muscle-specific kinase, a protein involved in AChR clustering; antibodies to it cause a distinct MG subtype.

Thymoma

A tumor of the thymus gland, present in about 10% of MG patients.

Myasthenic crisis

Respiratory failure due to severe weakness of respiratory muscles, requiring mechanical ventilation.