Thomas Willis (1621-1675), English physician, published a book, De anima brutorum(1) in 1672 in which he wrote about "a woman who temporarily lost her power of speech and became 'mute as a fish.'"(1) This has been interpreted as being the first written description of myasthenia gravis. Thomas Willis was born in Great Bedwin, a Wiltshire village in England. He graduated from Oxford University Legion with a Bachelor of Medicine in 1646. In 1660 he was appointed Sedleian Professor of Natural Philosophy at Oxford and given the M.D.(2)
"Chief Opechancanough, a warrior chief, was responsible for several massacres in the (American) colonies. He was captured in 1644 and the description of his condition is documented in colonial correspondence with England. “The excessive fatigues he encountered wrecked his constitution; his flesh became macerated; his sinews lost their tone and elasticity and his eyelids were too heavy that he could not see unless they were lifted up by his attendants. Further, we are told that he was unable to walk; but his spirit rising above the ruins of his body, directed them from litter on which he was carried by his Indians, the onset and retreat of his warriors.” While in captivity in Jamestown he was able to rest. After this inactivity he was able to raise himself from the ground to the standing position. Perhaps this warrior in his later years had developed MG. The clinical features of ptosis and extremity weakness would be consistent. The extremity weakness may have improved by rest. Therefore, the first description of MG may be from North America, but we will never be certain." (4)
"Samuel Wilks, English physician, 1824-1911, is said to have been the first to describe a case of myasthenia gravis, in 1877."(3) It is believed to be a case of "bulbar paralysis" described in Guy's Hospital Reports 22:7.(5)
Aleksei Kozhevnikov, Russian physician, (1836-1902) described "progressive familial spastic diplegia and wrote on the neuropathology of nuclear ophtalmoplegia, myasthenia, and bulbar paralysis. His textbook on nervous diseases was a popular manual because of its brevity and lucidity."(2) He was born in Ryazan and entered the University of Moscow in 1853 and received his M.D. in 1860. He later studied abroad in Germany, England, Switzerland and France.(3)
Heinrich Erb (1840-1921), German neurologist, was responsible (in part) for the delineation of myasthenia gravis (called Erb-Goldflam-Oppenheim disease at the time).(2) Heinrich Erb "was born in Winweiler, in the Bavarian Palatinate, studied medicine in Heidelberg, Erlangen, and finally Munich, where he received his doctorate in 1864."(2) He "described myasthenia gravis pseudoparalytica in 1878."(3) "For a half a century Wilhelm Heinrich Erb ruled over German Neurology with an imperial hand."(2) Published in Archiv fur Psychiatrie und Nerven Krankheiten 9:172.(5)
"Johann Ignaz Hoppe, Swiss physiologist, nineteenth century, described myasthenia gravis pseudoparalytica, in 1892."(3)
"Samuel V. Goldflam, Polish neurologist, 1852-1932, described myasthenia gravis pseudoparalytica, in 1893. Known as Erb-Goldflam disease and Hoppe-Goldflam symptom complex."(3) Published in Deutssche Zeitschrift fur Nervenheilkunde 1:96 3:427. (5)
Photo of
Mary B. Walker, ca. 1950 "Photo courtesy of Mrs. Pamela
Furtek"
Mary Broadfoot Walker (1896-1974), born at Croft-an-Righ, Wigtown, Scotland she became a salaried Assistant Medical Officer in 'Poor Law Service' at St. Alfege's Hospital, Greenwich, England.in 1920(13) and was later a medical officer in London hospitals(7). She introduced the use of physostigmine in the treatment of myasthenia gravis. Recorded in 1934.(3)(13)
According to writings of Jane Ellsworth (the Founder of the Myasthenia Gravis Foundation of America in 1952): "Surmising that, since MG had symptoms like curare poisoning, the curare antidote Physostigmine might help it, she injected some into her very droopy patients. Then, with utter drama, like Lazarus rising from the grave, they rose and walked across the room. Dr. Mary Walker had made one of those great medical discoveries of a "specific" medicine for a specific disease (like a key turning in a lock). ... A complete version of Jane Ellsworth writing is available(6).
The research of Dr. John Keesey added a different slant on the efforts of Dr. Walker when he wrote: "Although Mary Walker's 1934 report on physostigmine for myasthenia gravis was ignored by most of those in clinical medicine at the time, those responsible for the financing of British medical research vainly hoped that it could be used as an example of the practical outcome of basic research. ...
Her 1935 demonstration (17) (click on the above video of this demonstration) of the beneficial effect of Prostigmin (a.k.a. neostigmine) was greeted with general skepticism because of the rapidity with which the patient's symptoms of myasthenic weakness improved, but she was soon vindicated by rapidly published confirmatory reports by several contemporaries. .... Her 1938 demonstrations of what came to be known as the "Mary Walker effect" may have helped her reputation, since subsequent published opinions of her contributions were favorable, although she continued to be disparaged by some in private."(7)
Dr. Keesey's conclusion is that "Mary Walker, with her brief case reports and her frequent demonstrations, not only offered symptomatic treatment for MG that has stood the test of time, but also provided the most convincing evidence at the time that the neuromuscular junction was the focus of the disease."(7)
In 1997, a paper written by A.H. Keeney and V. T. Keeney stated: "In an era
when women were not admitted to the University of Edinburgh and when England's first
female physician (Elizabeth Garrett Anderson, 1836-1917) had to venture to Paris, France,
to earn her M.D. in 1870, the career of Mary Broadfoot Walker (..... .) (1988-1974) stands
out for truly remarkable achievement. She is credited with making the most significant
discovery in medical therapeutic within the British empire."(16)
Editorial Comments: It seems likely that other historic writings, still
unresearched, may shed more light on the period between 1934 when the initial discovery
was made and 1938 when Dr. Walker's discovery was formally demonstrated to the Royal
Society of Medicine. A thorough search of published works on
myasthenia, physostigmine and prostigmin reveal numerous related papers, published shortly
after Dr. Walker's first published work in 1934 (Lancet).
Sir Henry Dale (1875-1968), English physiologist-pharmacologist, showed that "the actions of acetylcholine are both muscarinic and nicotinic, and that at different synapses there are different effects which can be differently antagoinized. ... Another application came in the recognition of drugs such as physostigmine, drugs that block the enzymatic destruction of acetylcholine, and so allow this substance to accumulate in cases of deficiency, as in myasthenia gravis."(2) Dale shared in the Nobel Prize in 1936 for developing the theory of neurohumoral transmission. He was knighted in 1932 and gave many lectures in England and the United States. He was president of the Royal Society from 1940 to 1945.(2)
"Carl Weigert, German pathologist and histologist, 1845-1904, is credited with drawing attention to the relation between hypertrophy of the thymus and myasthenia gravis. Recorded in 1901."(3) Published in Neurologisches Zentralblatt, 20:597. (5) "The report of a thymus tumor in a patient with myasthenia gravis was the first, according to Weigert, of such an association, with the suggestion that the tumor might be related to muscle function." (11)
"Harriet Isabel Edgeworth, American biochemist, 1892 - , discovered the beneficial effect of ephedrine upon myasthenia gravis. Recorded in 1930."(3) Dr. Edgeworth noticed the first symptoms of myasthenia gravis in 1918 while she was employed as a chemist. Over the following years her symptoms slowly worsened until the winter of 1925 when she was hospitalized for the first time and a diagnosis of myasthenia gravis was confirmed. Over the following year she consulted with various researchers and volunteered herself as a subject for experimental treatment. Over the following three years she became increasingly worse until she was "totally helpless, had constant diplopia, was unable to chew, and had difficulty in talking, swallowing and breathing." "In the summer of 1929, while taking (for an entirely different purpose) tablets containing 1/8 grain (0.008 gm) ephedrine and 1 1/2 grain (0.1 gm.) amidopyrine, I noted a surprising improvement." Over the following years Dr. Edgeworth collaborated with researchers in a trial and error testing of ephedrine which showed conclusively that ephedrine was effective in the treatment of myasthenia gravis.(8) Her first report was published in the Journal of the American Medical Association (J.A.M.A.). (9)
Lazar Reman, 1907 - , introduced the use of neostigmine in the treatment of myasthenia gravis. Published, Deutssche Zeitschrift fur Nervenheilkunde 128:66 in 1932. (5)
Photograph Courtesy Andy Lucas, Mayo Clinic Archives
"Walter Meredith Boothby, American surgeon, 1880-1953(14), introduced aminoacetic acid (also known as glycine and glycocoll) in the treatment of myasthenia gravis. First published in 1932."(3, 8, 10) Dr. Boothby worked at the Mayo Clinic and published a series of reports describing his results with using both ephedrine and glycine in the treatment of myasthenia gravis. He collaborated with others including Harriet Edgeworth in some of these reports which were mainly positive concerning the results of glycine in the reduction of fatigue. (8, 10) In a published study in 1940, Nathan Schlezinger stated that aminoacetic acid and anterior pituitary extract did not work on a group of seven (7) patients he included in a trial.(12) He concluded that ephedrine was beneficial and "prostigmine" was dramatic.(12)
