Myasthenia Gravis

Myasthenia gravis (MG) is a rare autoimmune disease characterized by pronounced weakness and rapid fatigue of the voluntary muscles, including the ophthalmic muscles.¹ 

History of Myasthenia Gravis in the Medical Literature

In the early 17th century, chroniclers in Virginia documented the first known case of MG, describing the presentation of Native American Indian Chief Opechankanough. They reported, “The excessive fatigue he encountered wrecked his constitution; his flesh became macerated; his sinews lost their tone and elasticity; and his eyelids were so heavy that he could not see unless they were lifted up by his attendants … He was unable to walk, but his spirit rising above the ruins of his body directed from the litter on which he was carried by his Indians.” Opechankanough, the uncle of Pocahontas, died in 1664.^2,3

In 1672, the English physician Thomas Willis documented the “habitual and spurious palsies” of a patient in De Anima Brutorum, which was translated from Latin into English in 1683. Willis hypothesized that the palsies resulted from a “fault of explosive Copula suffused everywhere from the blood into the moving fibres.” This insight accurately predicted the autoimmune nature of acetylcholine receptor destruction at the neuromuscular junction.²

The medical literature on MG stagnated for about 200 years following Willis’s publication, until Samuel Wilks, an English physician at Guy’s Hospital in London, in 1877 described bulbar weakness, but no peripheral muscle weakness, in a girl who died of respiratory paralysis. She failed to exhibit the abnormalities of the medulla oblongata typically associated with respiratory failure.² 

Ten years later, another physician, Eisenlohr, treated an 18-year-old girl with bulbar paralysis and progressive external ophthalmoplegia; in this patient also, no brainstem abnormalities were noted at autopsy after her death from cardiorespiratory failure. Like Willis and Wilks, Eisenlohr detailed day-to-day fluctuations in the severity of her symptoms, which seemed to abate with rest. These hallmark features of MG frequently led physicians of the time to a diagnosis of “hysteria” because they were skeptical that anything was truly wrong.²

Also in 1887, Lauriston E. Shaw, MD, reported the case of a 37-year-old baker with pronounced limb muscle weakness and atrophy, especially of the upper extremities; also noted were dysphagia for solid foods, dysarthria, and the expectoration of frothy mucus. At this patient’s autopsy, Shaw observed an enlarged mediastinal gland, presumably the thymus, as well as pus in the smaller bronchial tubes, but no central nervous system abnormalities.^2,4

History of the Name Myasthenia Gravis

In 1879, a German physician, Wilhelm Heinrich Erb, differentiated MG from progressive bulbar palsy, describing 3 hallmark features of MG rarely found in central nervous system disorders. The triad included isolated bilateral ptosis, paresis of the muscles of mastication, and cervical muscle paresis. Erb implied that these features distinguished a unique disease entity.²

In 1893, Samuel Goldflam, another German physician, supported Erb’s findings when he described 3 cases of his own of relapsing and remitting bulbar and extremity paresis. Goldflam also noted involvement of the diaphragm, facial muscles, abdominal muscles, and cervical muscles, with rapid fatigue and day-to-day variability in the severity of symptoms. Like Erb, Goldflam proposed that this disease entity rated a unique identity among neuromuscular conditions; as a result, it was designated the Erb-Goldflam symptom complex.²

In 1895, Friedrich Jolly coined the term myasthenia gravis pseudoparalytica while detailing the cases of 2 young boys with the disorder. He combined the Greek terms mya (“muscle”) and asthenia (“weakness”) and added the Latin descriptor gravis (“severe”). The term pseudoparalytica described the symptoms of paralysis without structural changes in the nervous system.^2,3  

History of Treatment

In 1934, Mary Broadfoot Walker recognized that the symptoms of MG coincide with those of curare poisoning, which is treated with physostigmine, a cholinesterase inhibitor. When she injected physostigmine to treat a patient with MG, the symptoms promptly improved; however, the use of this medication caused unpleasant side effects, so Walker considered neostigmine (Prostigmin) as an alternative.^3,5 

In Octoer 1934, a young woman with MG since 1928 that had been unresponsive to several treatments was transferred to St. Alfege’s Hospital, London, where she received hypodermic injections of neostigmine with atropine 3 times daily. Oral neostigmine was used successfully in place of the injected neostigmine in 1935, and eventually anticholinesterase medications became a mainstay of MG treatment.⁵

Henry R. Viets, a neurologist and medical historian (1890-1969), graduated from Harvard Medical School in 1916. Harvey Cushing mentored Viets, convincing him to accept a research fellowship at Oxford with the famed neurologist Sir Charles Sherrington. While in England, Viets heard of Mary Walker’s success in treating MG with anticholinergic drugs. He confirmed Walker’s research results in 1935 when he injected neostigmine to treat a patient with MG at Massachusetts General Hospital, with tremendous success. Viets went on to establish the first MG clinic in the world and did pioneer research and writing about the treatment of MG.⁶

In 1936, Alfred Blalock, a physician at Johns Hopkins, was the first to remove a mediastinal mass from a patient with MG, whose condition subsequently improved postoperatively. Blalock continued to operate on patients with MG in the early 1940s with similar positive results, establishing thymectomy as a successful treatment for MG.⁷

In the 1950s, researchers introduced edrophonium and pyridostigmine as effective treatments for MG.⁸ Pyridostigmine, a synthetic acetylcholinesterase inhibitor, targets acetylcholine in the synaptic cleft of the neuromuscular junction; central nervous system toxicity is limited because the drug is unable to cross the blood-brain barrier.⁹

In the 1970s, prednisone and azathioprine became established treatments for MG.^3,9

In the 1990s and 2000s, intravenous immunoglobulin (IVIG) and plasma exchange proved to be effective treatments for MG, particularly during acute exacerbations in patients with severe forms of MG.^3,9,10

History of the Etiology of Myasthenia Gravis

In 1959 and 1960, Nastuk and Simpson, respectively, independently proposed that MG is an autoimmune disease affecting the neuromuscular junction.^3,11,12

In 1973, Patrick and Lindstrom demonstrated an autoimmune response in rabbits against acetylcholine receptors in muscle tissue, which explained the structural and functional damage to the neuromuscular junction seen in patients with MG. This finding sparked the advent of immunosuppressant therapy in MG.³

References

1. Myasthenia gravis: symptoms and causes. Mayo Clinic. Accessed January 31, 2022. 
2. Nguyen-Cao TM, Gelinas D, Griffin R, Mondou E. Myasthenia gravis: historical achievements and the “golden age” of clinical trials. J Neurol Sci. 2019;406:116428. doi:10.1016/j.jns.2019.116428
3. Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest. 2006;116(11):2843-2854. doi:10.1172/JCI29894
4. Shaw LE. A case of bulbar paralysis without structural changes in the medulla. Brain. 1890;13(1):96-99. doi:10.1093/brain/13.1.96 
5. Pearce JMS. Mary Broadfoot Walker (1888–1974): a historic discovery in myasthenia gravis. Eur Neurol. 2005;53(1):51-53. doi:10.1159/000084268
6. Feibel RM. Henry R. Viets, MD, and the history of myasthenia gravis. Neurology. 2021;96(7):322-326. doi:10.1212/WNL.0000000000011239
7. Kirschner PA. Alfred Blalock and thymectomy for myasthenia gravis. Ann Thorac Surg. 1987;43(3):348-349. doi:10.1016/S0003-4975(10)60635-2
8. Pascuzzi RM. The history of myasthenia gravis. Neurol Clin. 1994;12(2):231-242.
9. Farmakidis C, Pasnoor M, Dimachkie MM, Barohn RJ. Treatment of myasthenia gravis. Neurol Clin. 2018;36(2):311. doi:10.1016/j.ncl.2018.01.011
10. Lehmann HC, Hartung HP, Hetzel GR, Stüve O, Kieseier BC. Plasma exchange in neuroimmunological disorders: part 2. Treatment of neuromuscular disorders. Arch Neurol. 2006;63(8):1066-1071. doi:10.1001/archneur.63.8.1066
11. Nastuk WL, Strauss AJ, Osserman KE. Search for a neuromuscular blocking agent in the blood of patients with myasthenia gravis. Am J Med. 1959;26(3):394-409. doi:10.1016/0002-9343(59)90248-7
12. Simpson JA. Myasthenia gravis: a new hypothesis. Scott Med J. 1960;5(10):419-436. doi:10.1177/003693306000501001

Reviewed by Hasan Avcu, MD, on 2/7/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.