Harriet Edgeworth: A Mysterious Story in the History of Myasthenia Gravis

A young woman contracts a respiratory virus during a pandemic, followed by a debilitating illness with dizziness and tachycardia – so severe that she can’t get out of bed. Her tests are normal, and her doctors minimize her illness, telling her she could stand to lose some weight.  Eventually, she gets a diagnosis, but no treatments seem to help her symptoms. She is left to figure it out on her own.

It could be a story from 2021, but it happened a hundred years earlier. Harriet Edgeworth, PhD, was diagnosed with myasthenia gravis while working in science and medicine, and pursued a diagnosis for years.  When she tried an over-the-counter stimulant for her menstrual cramps, her symptoms improved, and she published the results in the Journal of the American Medical Association (JAMA).

Aside from her famous paper, little is known about Harriet Isabel Edgeworth. She was born in 1892 in Eureka, Utah. She went to the University of Chicago for undergraduate studies, and obtained a Masters of Science there in 1916. In 1917 – the fourth year of the first World War – she worked with the Food Administration in Washington D.C. on techniques of canning and preservation.

D.C. was hit hard by the H1N1 influenza virus in August of 1918, during the deadly global influenza pandemic often called the “1918 flu.” By October 1918, schools in D.C. closed, patients overwhelmed the hospitals, and every day 3,000 new cases were reported. In her 1930 JAMA article, Edgeworth reports that she came down with an “influenzal pneumonia” that year.

The influenza virus of 1918 was thought to cause a variety of post-infectious symptoms, notably encephalitis lethargica, a disease characterized by catatonia, lethargy, facial nerve palsy, and even coma. Based on other case reports from the 1920s that describe myasthenia gravis without with the precedence of flu-like symptoms, the 1918 flu most likely was not a common trigger of the disease. Still, after Edgeworth had the flu, she couldn’t get out of bed. She had a “tachycardia which in the absence of organic disease was attributed to a toxic depression of the vagus” – presumably a dysautonomia.

She wrote that despite her symptoms, she continued working in a research laboratory. She finished her PhD in chemistry at Columbia in 1921, with a thesis on “Experiments with Two Methods for the Study of Vitamin B,” with Henry C. Sherman.

A year later, she enrolled at Rush Medical College, then affiliated with the University of Chicago. But in the summer of 1924, she developed double vision and intermittent diplopia. She saw a doctor, who noted her weight, and recommended “daily and persistent exercise.” She tried to return to medical school, but after working in obstetrics all night, found she could not raise her foot to climb onto a curb. She left medical school for her health, and would never return.

She went to a neurologist, and although the “myasthenic electrical reaction” was absent, she was diagnosed with myasthenia gravis, a disease characterized by intermittent muscle weakness, worsened by activity. Edgeworth was treated with an “autologous vaccine” – typically an injection of the body’s own tissues, though in this case it is not clear what was injected – which helped with her frequent sinus infections, and with sleep. Various preparations were made from animal organs, including thyroid and renal cortex, without benefit. Her symptoms worsened. By 1927, she writes, she struggled to breathe, chew, or swallow.

Edgeworth also suffered from menstrual cramps, and in the summer of 1929, she tried ephedrine – a stimulant medication that affects the adrenergic receptors, at the time available without a prescription – along with aminopyrine, an analgesic (no longer produced in most countries due to risk of serious side effects).

The effect was miraculous. She recognized the possibility of a placebo effect, but noted that whenever she took ephedrine, her symptoms improved dramatically, and whenever she stopped, they worsened. The improvement was cumulative: the longer she took the medication, the better she felt.

She wrote:

“In the past three months, I have taken 6/8 grains daily except for a few days. I am now able to walk the distance of several rooms, to get into and out of a car with a small amount of help, and to speak and chew without difficulty. I can raise my arms to my head for a few minutes, write a short letter, and read the daily newspaper without diplopia occurring.”

She was living in Tucson, Arizona when her article was published in 1930. Despite her PhD and initial start in medical school, she was listed as a homemaker in the 1930 United States Federal Census. According to that same census, she lived with and employed a nurse, Gunda Engen (1902-1990), a Norwegian immigrant who had been a Head Nurse in the Medical Department at the Presbyterian Hospital of the City of Chicago, and who published articles in the American Journal of Nursing in 1929 and 1931.

Three years after her first report, Edgeworth published a follow-up, noting that her symptoms had continued to improve on her miracle drug. She found if she increased the dose, she felt better temporarily, then had severe side effects. She did use more ephedrine when her body was stressed: when exposed to heat or cold, during her menses, or during a respiratory infection. She pointed out in the second paper that she didn’t know whether the medication would have long-term effects on her health – but given that there was nothing else to help her feel better, she planned to continue it anyway.

A year later, in 1934, another woman – the Scottish physician Mary Broadfoot Walker – found an even better treatment for myasthenia gravis: physostigmine, the precursor to pyridostigmine bromide (Mestinon), which is still used today.

Walker noted that the symptoms of myasthenia gravis looked similar to those of poisoning with curare, a paralyzing agent using as an “arrow poison” by indigenous people in Central and South America. Walker was on to something. Curare works by inhibiting acetylcholine receptors at the neuromuscular junction. We now know that myasthenia gravis is an autoimmune disease in which those same receptors are affected by auto-antibodies.

Walker tried an injection of physostigmine salicylate, a “partial antagonist to curare,” in a 56-year-old woman with myasthenia gravis. Physostigmine inhibits breakdown of acetylcholine at the neuromuscular junction. The woman’s ptosis, jaw drop, and swallowing improved – temporarily. (Walker also tried giving the woman ephedrine, with no improvement.)

Ephedrine has been used for almost a century as an adjunct therapy to cholinesterase inhibitors for myasthenia gravis, but mechanistically it’s not clear how the medicine works to improve symptoms in this disease. A recent Cochrane review pointed out a paucity of randomized controlled clinical trials to show safety and efficacy of ephedrine in myasthenia gravis. As ephedrine can have serious side effects, including cardiovascular disease and stroke, and can be used in the illegal production of methamphetamine, it is tightly regulated, and can be difficult to procure.

Did Edgeworth ever try physostigmine for her symptoms? If so, she didn’t tell JAMA. After her 1933 report, Edgeworth disappears from the literature. In 1950, she was listed in the US Census as living with her mother, Amy Edgeworth, in Kankakee, Illinois, with the occupation: “keeping house” – and she was listed as married, though this seems to be an error, as there is no other record of a marriage, and her obituary lists no children or spouse.

She died in Illinois, February 2, 1971, at the age of 78.

Notable references:

Edgeworth H. A report of progress on the use of ephedrine in a case of myasthenia gravis. JAMA. 1930;94(15):1136.

Edgeworth H. The effects of ephedrine in the treatment of myasthenia gravis: second report. JAMA. 1933;100(18):1401.

Walker, M.B. Treatment of myasthenia gravis with physostigmine. The Lancet. 1934;i:1200-1201