Myasthenia gravis (MG) is a chronic neuromuscular disease defined by fluctuating muscle weakness and fatigue that worsens with activity and improves with rest. This condition can affect any voluntary muscle, including those controlling eye movement, facial expression, and breathing. The history of understanding MG involved recognizing its unique clinical pattern, naming it, and finally uncovering its underlying biological cause. This journey involved multiple physicians across different centuries, each adding a crucial piece to the puzzle of this complex disorder.
Early Descriptions of the Disorder
The earliest known description of symptoms consistent with MG came from the English physician Thomas Willis in 1672. In his book, De Anima Brutorum, Willis detailed the case of a woman whose speech was temporarily lost and whose fatigue was so severe that she could not speak for long periods. Willis’s account clearly captured the hallmark symptom of fatigable weakness that defines MG.
Over a century later, in 1878, German neurologist Wilhelm Erb provided clinical recognition of the disorder. Erb described patients presenting with bilateral eyelid droop (ptosis), severe neck weakness, and difficulty swallowing, with symptoms that fluctuated and improved after rest. He was the first to recognize that this specific pattern of weakness was distinct from other forms of paralysis, such as progressive bulbar palsy, which lacked the fluctuating course. His work helped establish the condition as a unique neurological entity.
Solidifying the Clinical Definition and Naming
The clinical features of the condition were solidified by the work of Polish neurologist Samuel Goldflam. In 1893, Goldflam published a review documenting the disease’s symptoms, severity, and prognosis. His detailed analysis emphasized the pathological symptom of muscular fatigue, known as apokamnosis, as a central characteristic of the illness.
Goldflam’s work was so important that the disorder was often referred to as Erb-Goldflam disease for a time. Just two years later, in 1895, German neurologist Leopold Jolly formally introduced the name Myasthenia Gravis pseudoparalytica. The term, which was later shortened, combines the Greek word for muscle weakness (myasthenia) with the Latin word for severe (gravis).
Jolly also conducted early experiments using repetitive nerve stimulation in his patients. He observed a decrement, or reduction, in muscle response with repeated electrical impulses. This observation suggested that the problem lay not in the central nervous system but in the communication junction between the nerve and the muscle.
The Autoimmune Mechanism
Despite the clear clinical definition and name, the cause of MG remained unknown until the mid-20th century. The breakthrough came with the realization that MG is an autoimmune disorder, where the body’s immune system mistakenly attacks its own healthy tissues. This understanding began to form in the 1950s but was definitively established in the 1970s.
The mechanism centers on the neuromuscular junction, where a nerve cell transmits a signal to a muscle fiber using acetylcholine. In the most common form of MG, the body produces autoantibodies that target the nicotinic acetylcholine receptors (AChRs) located on the muscle side of the junction. These antibodies effectively block, alter, or destroy the receptors, preventing acetylcholine from binding properly.
This destruction reduces the number of functioning receptors by up to 70 to 90 percent, leading to a failure of nerve impulses to adequately stimulate muscle contraction. This causes the characteristic fatigable weakness, as the available receptors are quickly overwhelmed with repeated activity. The discovery of circulating anti-AChR antibodies provided a clear biological marker and confirmed the autoimmune nature of the disease.
Current Methods for Diagnosis
Today, the diagnosis of MG relies on clinical evaluation and specific laboratory tests that confirm the defect at the neuromuscular junction.
Blood Tests
Blood tests are a cornerstone of diagnosis, identifying specific autoantibodies. Most commonly, these are anti-acetylcholine receptor (AChR) antibodies, present in about 85% of cases. Tests also look for antibodies targeting Muscle-Specific Kinase (MuSK) or Lipoprotein-related protein 4 (LRP4) in seronegative patients.
Electrodiagnostic Testing
Electrodiagnostic testing, such as repetitive nerve stimulation (RNS), is frequently used. This technique involves delivering small electrical shocks to a nerve and recording the resulting muscle contraction. Diagnosis is supported by observing a characteristic decrement in the muscle’s compound action potential after repetitive stimuli.
Pharmacological Testing
The Edrophonium test, which involves injecting a short-acting drug to temporarily improve muscle strength, was historically common. It is now used less often due to potential side effects and the improved accuracy of other testing methods.