Myasthenia gravis historical perspective
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D., Keanu Ngo[2]
Overview
Myasthenia gravis (MG) was first recognized as a distinct clinical entity by Thomas Willis in 1672, although his account was overlooked until 1903. Detailed clinical descriptions in the late 19th century by Samuel Wilks (1877), Wilhelm Erb (1879), Hermann Oppenheim (1887), and Samuel Goldflam (1893) established the characteristic picture of fluctuating, fatigable weakness, and Friedrich Jolly proposed the name "myasthenia gravis" around 1895. The autoimmune basis was hypothesized by John Simpson in 1960 and proven in the 1970s, when antibodies against the acetylcholine receptor (AChR) were shown to be pathogenic. Symptomatic treatment began with Mary Broadfoot Walker's demonstration of physostigmine (1934) and neostigmine (1935); thymectomy was introduced by Alfred Blalock, and modern respiratory support and immunotherapy reduced mortality from nearly 100% in severe early-20th-century cases to under 5% today. The regulatory approval of the complement inhibitor eculizumab in 2017 opened the current era of targeted biologic therapy.
Historical Perspective
Early Clinical Recognition
- The English physician Thomas Willis gave the first recognizable account of fatigable weakness with recovery after rest in 1672 (in Latin); this description was largely unnoticed until it was rediscovered in 1903.[1][2]
- The first modern clinical description is attributed to Samuel Wilks (London) in 1877. Toward the close of the 19th century, Wilhelm Erb of Heidelberg (1879) described a "new bulbar symptom complex," Hermann Oppenheim of Berlin (1887) reported similar cases, and Samuel Goldflam of Warsaw (1893) provided a detailed account emphasizing fatigability, diurnal and day-to-day fluctuation, and remissions and exacerbations.[1][3]
Origin of the Name
- Friedrich Jolly proposed the term "myasthenia gravis pseudoparalytica" — combining a Greek-derived term for muscle weakness with the Latin word for "grave" or "severe" — to describe progressive weakness on repetitive stimulation with recovery after rest. The modifier was later dropped, and "myasthenia gravis" became the accepted name worldwide. Most sources date this to 1895, although one account places Jolly's presentation to the Berlin Society for Psychiatry and Nervous Disease on November 13, 1899.[4][3]
Elucidation of the Autoimmune Basis
- The autoimmune nature of MG was hypothesized by John Simpson in 1960 (with related work by Nastuk and colleagues, 1959).[5]
- Definitive proof came in the 1970s: Patrick and Lindstrom (1973) showed that rabbits immunized with purified AChR developed myasthenic weakness, Drachman and colleagues demonstrated reduced AChR numbers in myasthenic muscle using radiolabeled snake toxin, and Lindstrom and associates (1976) detected serum anti-AChR antibodies in approximately 85–90% of patients. By 1977 the antibody-mediated character was established through passive IgG transfer, localization of IgG and complement on the postsynaptic membrane, and the benefit of plasmapheresis.[3][6]
- Muscle-specific kinase (MuSK) was identified as a second major autoantigen (Hoch et al., 2001), followed later by LRP4.[7]
Landmark Events in the Development of Treatment Strategies
Anticholinesterases
- In 1934, house officer Mary Broadfoot Walker, reasoning that MG resembled curare poisoning, produced a striking (though temporary) improvement with physostigmine, a partial curare antagonist. In 1935 she demonstrated relief with neostigmine (Prostigmin). Her observation both provided symptomatic therapy and localized the defect to the neuromuscular junction.[2][8]
- Edrophonium was introduced around 1950 and pyridostigmine in the mid-1950s.[5]
Thymectomy
- Alfred Blalock observed remission after removing a thymic tumor and subsequently proposed thymectomy even in patients without a tumor, establishing thymus-directed surgery for MG (reported around 1936–1940).[9][5]
- The benefit of thymectomy, long supported only by anecdotal case series, was confirmed by the randomized MGTX trial (reported 2016) in nonthymomatous AChR-antibody-positive MG.[9][10]
Respiratory Support and Immunotherapy
- Mechanical ventilation (1950s), building on the "iron lung" and positive-pressure ventilation, dramatically reduced death from myasthenic crisis.[11]
- Corticosteroids and plasmapheresis (1960s), azathioprine (1960s–1970s), cyclosporine (1980s), intravenous immunoglobulin (1980s–1990s), and mycophenolate mofetil (1990s–2000s) were introduced sequentially. MG mortality fell from approximately 30% before 1960 to under 5% in the modern era.[11][12]
Modern Targeted Era
- Rituximab was the first monoclonal antibody used in MG, chiefly for refractory and MuSK-antibody-positive disease.[12]
- A new era began with the approval of the complement inhibitor eculizumab in 2017 (REGAIN trial), followed by additional complement inhibitors (ravulizumab, zilucoplan) and neonatal Fc receptor (FcRn) antagonists (efgartigimod, approved 2021; rozanolixizumab; nipocalimab).[12][13]
Notable Historical Cases
- An often-cited putative early American case is Chief Opechancanough, described retrospectively from 17th-century Virginian chronicles as having fatigue and weakness; this is an anecdotal historical account rather than a formal first description of the disease.[10]
References
- ↑ 1.0 1.1 Hughes T (December 2005). "The early history of myasthenia gravis". Neuromuscul Disord. 15 (12): 878–86. doi:10.1016/j.nmd.2005.08.007. PMID 16289896.
- ↑ 2.0 2.1 Feibel RM (February 2021). "Henry R. Viets, MD, and the History of Myasthenia Gravis". Neurology. 96 (7): 333–338. doi:10.1212/WNL.0000000000011480.
- ↑ 3.0 3.1 3.2 Keesey JC (April 2004). "Clinical evaluation and management of myasthenia gravis". Muscle Nerve. 29 (4): 484–505. doi:10.1002/mus.20030. PMID 15052614.
- ↑ Keesey J (May 1998). "Myasthenia gravis". Arch Neurol. 55 (5): 745–6. doi:10.1001/archneur.55.5.745.
- ↑ 5.0 5.1 5.2 Pascuzzi RM (May 1994). "The history of myasthenia gravis". Neurol Clin. 12 (2): 231–42. PMID 8041339.
- ↑ Engel AG (November 1984). "Myasthenia gravis and myasthenic syndromes". Ann Neurol. 16 (5): 519–34. doi:10.1002/ana.410160502. PMID 6095730.
- ↑ Yoshikawa H, Adachi Y, Nakamura Y, et al. (January 2024). "Comparative study of Japanese nationwide epidemiological studies of myasthenia gravis using datasets of 2006 and 2018". PLoS One. 19 (1): e0296910. doi:10.1371/journal.pone.0296910.
- ↑ Katz NK, Barohn RJ (January 2021). "The history of acetylcholinesterase inhibitors in the treatment of myasthenia gravis". Neuropharmacology. 182: 108303. doi:10.1016/j.neuropharm.2020.108303. PMID 32918950 Check
|pmid=value (help). - ↑ 9.0 9.1 Ropper AH (August 2016). "RetroSternal - Looking Back at Thymectomy for Myasthenia Gravis". N Engl J Med. 375 (6): 576–7. doi:10.1056/NEJMe1607953.
- ↑ 10.0 10.1 Nguyen-Cao TM, Gelinas D, Griffin R, Mondou E (November 2019). "Myasthenia gravis: Historical achievements and the "golden age" of clinical trials". J Neurol Sci. 406: 116428. doi:10.1016/j.jns.2019.116428. PMID 31574325.
- ↑ 11.0 11.1 Barohn RJ (2008). "Treatment and clinical research in myasthenia gravis: how far have we come?". Ann N Y Acad Sci. 1132: 225–32. doi:10.1196/annals.1405.028. PMID 18567872.
- ↑ 12.0 12.1 12.2 Gerischer L, Doksani P, Hoffmann S, Meisel A (2025). "New and Emerging Biological Therapies for Myasthenia Gravis: A Focussed Review for Clinical Decision-Making". BioDrugs. 39 (2): 185–213. doi:10.1007/s40259-024-00701-1.
- ↑ Gwathmey KG, Ding H, Hehir M, Silvestri N (April 2024). "How should newer therapeutic agents be incorporated into the treatment of patients with myasthenia gravis?". Muscle Nerve. 69 (4): 372–384. doi:10.1002/mus.28038.