The history of acetylcholinesterase inhibitors in the treatment of myasthenia gravis.

The beneficial effects of acetylcholinesterase inhibitors for the treatment of myasthenia gravis (MG) was a major discovery that came about through one young physician putting together a string of previous observations. To understand how this discovery came to light, we must first go back to earlier times when men hunted by bow-and-arrow to capture their prey. The substance used to poison the prey was eventually was identified as curare. Centuries later, a connection was made between the physiological effects of curare and a disease entity with no known pathological mechanism or treatment, myasthenia gravis. In 1935, house officer Dr. Mary Walker was the first physician to try physostigmine in the treatment of MG, which had previously been used to treat curare poisoning. What she saw was a dramatic improvement in the symptoms experienced in patients with MG, and thus became the first documented case of use of physostigmine, an acetylcholinesterase inhibitor, in the treatment of MG. This article is a summary of the history of the use of acetylcholinesterase inhibitors in the treatment of myasthenia gravis. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

Henry R. Viets, MD, and the History of Myasthenia Gravis.

Henry R. Viets (1890-1969) was both a noted neurologist and medical historian. While at Harvard Medical School, from which he graduated in 1916, he attracted the attention of Harvey Cushing who directed Viets into these disciplines. Cushing arranged for Viets to take a fellowship in Oxford in the year after his graduation. With Cushing's recommendation, he lived with Sir William and Lady Osler and did research with the famous neurologist Sir Charles Sherrington. Viets was in London in 1935 when he heard about the remarkable success of Mary Walker in treating myasthenia gravis, first with physostigmine and then with neostigmine (Prostigmin). Securing an ampoule of this drug, he took it to the Massachusetts General Hospital where he was an attending neurologist and in March 1935 injected it into a myasthenic patient with great success. He established the first Myasthenia Gravis clinic in the world and was a pioneer in the treatment of this once obscure disease; he evaluated hundreds of patients and published many articles on myasthenia. He continued this association for more than 30 years. Under the tutelage of Cushing and Osler, Viets became a medical historian and bibliophile, publishing hundreds of articles and several books on many different subjects in the history of medicine. He was a president of the American Association for the History of Medicine and curator of the Boston Medical Library that eventually joined with the Harvard Medical School Library. Viets served on the Editorial Board of the New England Journal of Medicine for 40 years.

The Mary Walker effect: Mary Broadfoot Walker.

Mary Broadfoot Walker (1888-1974) was the first to demonstrate the 'Mary Walker effect' describing the weakness of other muscle groups following release of the arteriovenous occlusion of an unrelated exercising muscle group in patients with myasthenia gravis, which led to the search for a circulating causative agent for myasthenia gravis. She was the first to clearly demonstrate that strength temporarily improved in patients with myasthenia gravis with physostigmine or Prostigmin (neostigmine). This dramatic treatment response has been erroneously termed the 'Mary Walker effect'. Further, she noted hypokalaemia during attacks of weakness in familial periodic paralysis, pioneering treatment with potassium chloride. Although Mary Walker practiced in a nonacademic setting and trained at a time when women were not allowed to train alongside men, she was the first to convincingly demonstrate three life-changing treatments in the field of neuromuscular medicine, a feat that few physicians of any era can claim.

Clinical trials for myasthenia gravis: a historical perspective.

Symposia dedicated to myasthenia gravis and related disorders date back to 1947 and serve as markers of the progress for the field. We provide a brief historical review of therapy development through the lens of the publications that arose from the close to quinquennial meetings that have been supported nearly since their inception by the Myasthenia Gravis Foundation of America and the New York Academy of Sciences. One can appreciate great advances, false starts, and dead ends that are found in all fields of medicine. We tally up the score card for MG and find points scored, but the win is not yet close.

Mary Broadfoot Walker: 83 years since a historical discovery.

Mary Broadfoot Walker was a Scottish physician who, in 1935, described in great detail the effect of an anticholinesterase drug (physostigmine) on the signs and symptoms of myasthenia gravis. An original five-minutes movie is available online and the skepticism of her contemporary British medical doctors is understandable when the drastic effect of the treatment is shown in this movie. What Mary Walker taught us, more than eight decades ago, about myasthenia gravis continues to be the basis of a pharmacological diagnostic test and treatment of this disease.

Mary Broadfoot Walker: 83 years since a historical discovery / Mary Broadfoot Walker: 83 anos desde uma descoberta histórica

ABSTRACT Mary Broadfoot Walker was a Scottish physician who, in 1935, described in great detail the effect of an anticholinesterase drug (physostigmine) on the signs and symptoms of myasthenia gravis. An original five-minutes movie is available online and the skepticism of her contemporary British medical doctors is understandable when the drastic effect of the treatment is shown in this movie. What Mary Walker taught us, more than eight decades ago, about myasthenia gravis continues to be the basis of a pharmacological diagnostic test and treatment of this disease.

RESUMO Mary Broadfoot Walker foi uma médica escocesa que em 1935 descreveu em grande detalhe o efeito de uma droga anticolinesterásica (fisostigmina) nos sinais e sintomas da myasthenia gravis. Um filme original com cinco minutos de duração está disponível online e a reação cética dos colegas médicos contemporâneos de Mary é compreensível dado o drástico efeito terapêutico mostrado neste filme. O que Mary Walker nos ensinou mais de oito décadas atrás continua a ser a base de um teste diagnóstico farmacológico e do tratamento da myasthenia gravis.

Sensory aspects in myasthenia gravis: A translational approach.

Myasthenia gravis is a paradigmatic muscle disorder characterized by abnormal fatigue and muscle weakness that worsens with activities and improves with rest. Clinical and research studies done on nicotinic acetylcholine receptors have advanced our knowledge of the muscle involvement in myasthenia. Current views still state that sensory deficits are not "features of myasthenia gravis". This article discusses the gap that exists on sensory neural transmission in myasthenia that has remained after >300years of research in this neurological disorder. We outline the neurobiological characteristics of sensory and motor synapses, reinterpret the nanocholinergic commonalities that exist in both sensory and motor pathways, discuss the clinical findings on altered sensory pathways in myasthenia, and propose a novel way to score anomalies resulting from multineuronal inability associated sensory troubles due to eugenic nanocholinergic instability and autoimmunity. This medicine-based evidence could serve as a template to further identify novel targets for studying new medications that may offer a better therapeutic benefit in both sensory and motor dysfunction for patients. Importantly, this review may help to re-orient current practices in myasthenia.

[Myasthenia gravis: past, present and future].

Myasthenia gravis (MG) was first described in 17(th) century. It was after 1960s, when it became clear that MG was an autoimmune disease targeting AChR. Recently, anti-MuSK and anti-Lrp4 antibodies were found as novel antibodies in MG. In 1980s, in addition to cholinesterase inhibitors, high-dose corticosteroid treatment was introduced. This dramatically reduced the mortality rate of MG, but now we recognized that side effects of steroid have influenced patients significantly, and that high dose of steroid correlate with poor QOL. Since we have more means to treat MG at present, and also in the future, we should shift to the strategy in which steroid dose is kept low.

History of outcome measures for myasthenia gravis.

This review illustrates how measurements of clinical status in patients with myasthenia gravis have evolved from clinical descriptions and estimates of mortality rates to more sophisticated evaluative instruments, including numerical rating scales that measure strength, endurance, quality of life, and activities of daily living. The rationale and use of weighting and the importance of patient-reported outcomes are also discussed. The measurement of the steroid-sparing effect of an immunosuppressant is also reviewed.

Dr Lazar Remen (1907-74): a forgotten pioneer in the treatment of myasthenia gravis.

Dr Lazar Remen (1907-74) was the first, in 1932, to describe the beneficial effect of prostigmine on a myasthenia gravis patient. His observation actually preceeded by two years Mary Broadfoot Walker's (1888-1974) paper, which is considered to be the landmark article on this association.

Surgery of the thymus in Japan.

The thymus has long been an organ of mystery. Today, it is known to be central to the construction of our immune system. I focus on the days when no one was sure what the thymus's function was. I review the Japanese literature regarding the beginnings of surgery of the thymus, especially the surgery for thymoma and thymectomy, which was performed as a treatment for myasthenia gravis.