A Short History of Myasthenia Gravis

Historical Perspective

The first described case of MG is likely that of the Native American Chief Opechancanough, (1554-1646) was a tribal chief of the Powhatan Confederacy who died in 1646, as reported by Virginian chroniclers: “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… hew 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.”

Dr. Geoffrey Keynes in his “The History of Myasthenia Gravis*” I have recently come across an unpublished Latin letter written in 1658 by Dr. John Maplet, a physician working in Bath, to Dr. Thomas Browne of Norwich, the celebrated author of Religio Medici.  Maple reports that he is in charge of “a little boy of seven who cannot speak; his limbs also and all his joints are so wanting in strength that he can neither stand nor walk.”

In 1672, the English physician Thomas Willis described a patient with the “fatiguable weakness” of limbs and bulbar muscles characteristic of MG (3).  Many other physicians treating patients described this condition; however, no treatment was available and death resulted in the majority of cases.

The name myasthenia gravis suggested by Jolly was accepted at a meeting of the Berlin Society of Psychiatry and Neurology in November 1899, and it has been generally adopted, through without the appendage pseudoparalytica, added by Jolly to indicate the absence of any structural changes.  They name myasthenia graves is, of course, an unfortunate mongrel, being derived from Greek words, vc, a muscle, and dcOVvem weakness, while gravis is Latin for heavy or severe.

John Carl Keesey, in his “A History of Treatment of Myasthenia Gravis“, documented around 1900, “for the next decade MG was also treated with “organotherpy” (organic extracts of suprarenal, thyroid, pituitary, and ovarian glands) on the supposition that MG might be an endocrine function and that these glands, especially the thyroid and thymus counteracted each other.”

Attempts at rational treatments of MG began in the 1930s.  A major step forward occurred in 1934 when Dr. Mary Broadfoot  Walker realized that MG symptoms were similar to those of curare poisoning, which was treated with physostigmine, a cholinesterase inhibitor. She showed that physostigmine promptly improved myasthenia symptoms (5), making anticholinesterase drugs a staple in MB management. Dr. Walker also demonstrated that parenteral Prostigmin (neostigmine), another cholinesterase, was very effective in temporarily alleviating the symptoms of MG.  She postulated in her letter to LANCET, that “It may be significant that physostigmine inhibits the action of the esterase that destroys acetylcholine.”

In 1936, Sir Henry Dale reported further work to show that acetylcholine was liberated at motor nerve endings (now termed ligand-gated ion channels) to produce the same effect in ordinary muscles and that its action was limited by the ferment, cholinesterase.

in 1936, “Percy Lavon Julian, an African-American chemist, who was a research fellow at DePauw University in Greencastle, Indiana” finally “was readily able to convert his eserethole to the final intermediate, eseroline” (1) or the natural calabar alkaloid physostigmine.  It is still available today as Eseroline sulphate.” Julian also synthesized cortisone from soy bean extract.

Because thymus pathology is common in MG patients, as fist noted in the late 1800s (3), in 1937, Black removed a mediastinal mass from a young woman who had MG (3); the patient improved postoperatively. Later, Black reported other myasthenic patients who improved after thymus removal (3), establishing thymectomy as a treatment for MG.

In 1944 Professor Andrew Wilson demonstrated the presence of a curare-like substance in the serum of myasthenics. He also made 324 extracts of the thymus glands removed at operation with the same results, the potency being related to the effectiveness of the thymectomy.

In 1945, pyridostigmine bromide (PB) PB, a reverible cholinesterase (ChE) inhibitor, is a carbamate compound, specifically, the dimethylacarbamate ester of 3-hydroxy-1-methylphyidinium bromide was synthesized by Hoffman-La Roche Laboratories in Basle, Switzerland and is sold under the trade name Mestinon.

In 1955, Mestinon was approve by the Food and Drug Administration (FDA) as safe for the treatment of myasthenia gravis ten years after the synthesis of Mestinon in Switzerland.

In 1959-1960, Simpson and Nastuck proposed independently that MG has an autoimmune etiology (6,7) based on several observations: (a) MG patients’ sera compromise contraction in nerve-muscle preparations; (b) the level of serum complement correlates inversely with the severity of MG symptoms: (c) infants of myasthenic mothers may present transient myasthenic symptoms (neonatal MG): (d) inflammatory infiltrates may occur in muscles of MG patients, and pathologic changes are common in their thymi; and (e) MG may be associated with other putative autoimmune disorders.

Mogen Kjaer, in Arhus, Denmaerk, was the first, in 1971, to report his experience with prednisone treatment for MG, begun in 1965. In the 1970s, prednisone and azathioprine became established treatments for MG (9), and plasma exchange was introduced as an effective acuter treatment for sever MG (10), further proving that circulating factors caused MG symptoms.

In 1973, Patrick and Lindstrom demonstrated that rabbits immunized with purified muscle-like AChR developed MG-like symptoms (experimental autoimmune MG [EAMG]) (8). After that seminal discovery, many studies demonstrated an autoimmune response against muscle AChR in MG and the role of anti-AChR Abs in causing the structural and functional damage of the NMJ. These findings promoted the use of immunosuppressants in MG.

Plamapheresis was pioneered in the United States by Perer Dau at Children’s Hospital in San Francisco, who published his favorable results on five MG patients in 1977.

Globunlin, in February 1984, Edward Arsura and associates from the Maimonides Medical Center in Brooklyn, New York were the first to report IVIG in the United States, describing rapid and temporary improvement in 12 MG patients.

Getman et al (1992 AM J Human Genetics) found the human acetylcholinesterase gene (ACHE) on the long arm of chromosome 7q22.  Acetylcholinesterase is found in all innervated tissues (and on the surface of red blood cells) and has the function of stopping nerve impulse transmissions; and, with MG impeding muscle contraction by destroying acetylcholinase.

The first case report of the successful treatment of severe refactory MG mycophenlate mofetil (Cellcept by Roche) appeared in 1998.  Mycophenolic acid was originally isolated in 1896 from a penicillium culture, and in the 1940s through the 1970s it was found to have antineoplastic, antibacterial, antifungal and antiviral properties.  Its innunosuppressive action, inhibiting proliferative of T & B lymphocytes was only discovered in the 1980s.

Now underway, “this (MGFA) study involves analysis of a very large number of genes from more than 1,000 MG patients… we are collecting DNA from saliva samples… at the National Institues of health, under the direction Dr. Bryan Traynor. They will analyze 700,000 genes from each patient’s DNA… to determine which genes are associated with MG.”

The future

Sources:
http://www.jci.org/articles/view/29894
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1034650/
http://www.myasthenia.org/LinkClick.aspx?fileticket=xLve7q3eT2s%3D&tabid=97
http://www.ncbi.nlm.nih.gov/pmc/articels/PMC1682033/pdf/ajhg00063-0082.pdf

(note: MG treatment by bloodletting, electroshock and radiation were not covered in this history)

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