Romanian Neurosurgery  |  Volume XXXI  |  Number 1 |  2017  |  January - March 

 
Article 

 
The miracle of St. Alfege’s Hospital and the 

history of the treatment of myasthenia gravis  

 

Cristina Croitoru, Dana Turliuc, Florentina Danciu, A. Cucu, Claudia Costea 
ROMANIA 

 

 

 

DOI: 10.1515/romneu-2017-0011 
 



 
 
 
 
 

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DOI: 10.1515/romneu-2017-0011   

The miracle of St. Alfege’s Hospital and the history of the 
treatment of myasthenia gravis 

Cristina Croitoru1, Dana Turliuc1,2, Florentina Danciu1, A. Cucu1, 
Claudia Costea1,2 
1“Prof. Dr. N. Oblu” Emergency Clinical Hospital Iasi, ROMANIA 
2“Grigore T. Popa” University of Medicine and Pharmacy Iasi, ROMANIA 

 
Abstract: Having a recent history, the neurological condition called myasthenia gravis 
has raised dilemmas and questions among doctors since it was first discovered in the 
16th century and it has not ceased to be a challenge. Nowadays, neuroscience 
researchers from around the world have been striving to perfect a modern treatment of 
this condition. Our paper is an incursion into the past, more precisely into the history 
of the treatment of this disease, from its origin to date, when immunological therapy 
has progressed.  
Key words: myasthenia gravis, treatment of myasthenia gravis, history of medicine 

 
Introduction 

The myasthenia gravis (MG) condition 
has had a relatively recent history, given its 
discovery as late as the 16th century (Figure 
1). Although it is full of misunderstandings 
and errors, the history of MG has acquired 
the value of truth later, thanks to neurologists, 
neuro-psychiatrists and neurosurgeons 
passionate about science, as they not only 
tried to understand its pathology, but also to 
find means of treatment (5). Despite these 
efforts, until as late as the 1930’s, the 
treatment of MG was empirical and only 
amount to: bed rest, administration of tonic 
preparations (iron, quinine, mercury, arsenic 
and strychnine) and various extracts from 

animal glands (thymus, ovary, testicle, 
adrenals), as well as radioactive substance 
injections and thymus and thyroid 
irradiations. Thus, we can say that the 
treatment of MG was in most cases 
ambiguous, which turned into “a source of 
discouragement to the patient and a cause of 
nightmare for the physician” (16). 
The first efficient substance: ephedrine 

The year 1930 marked an important 
progress in the history of the treatment of 
MG, as ephedrine proved to be the first 
efficient substance in the treatment of MG. 
This substance is still used as second-line 
medication in the treatment of this condition. 
The efficiency of ephedrine in MG was 



 
 
 
 
 
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discovered by the American chemist Harriet 
Isabel Edgeworth (1865-1916), who suffered 
from MG herself and who took ephedrine for 
menstrual cramps and accidently noticed an 
improvement in her muscle fatigue (9). 

In the light of the breakthroughs in the 
field of muscular contraction, neuroscience 
researchers focused their attention on 
creatinine metabolism. Thus, Dr. Walter 
Boothby published, between 1932 and 1936, 
various papers on the beneficial effect on the 
symptoms of the disease of the aminoacid 
glycine combined with ephedrine (4). 
The miracle of St. Alfege’s Hospital: 
physostigmine 

The year 1934 marked the beginning of a 
modern approach to the treatment of MG. 
While treating a patient suffering from MG, 
the British doctor Mary Broadfoot Walker 
(1888-1974) (Figure 2) discovered the 
beneficial effect of physostigmine on muscle 
fatigue and palpebral ptosis. The young 
doctor noticed that the effect lasted between 2 
and 5 hours, depending on the concentration 
of the physostigmine administered 
subcutaneously. She published her findings 
that same year in the prestigious journal 
Lancet: “I think that this effect of 
physostigmine on myasthenia gravis is 
important, though it is only temporary, for it 
improves swallowing and might tide the 
patient over respiratory crisis. It supports the 
opinion that fatigability is due to poisoning of 
the motor end-organs, or myoneural 
junctions” (31). Thus, physostigmine came to 
be known as “the miracle of St. Alfege’s 
Hospital”, named after one of the hospitals 
where Mary Walker worked (15).  

Table 
The main breakthroughs in the history of the 

treatment of MG, modified after Afifi (1) 

 

 
Figure 1 - Possible onset of myasthenia gravis with 
unilateral left ptosis (Pierrot - Amedeo Modigliani, 

Paris-1915) (public domain) 

Year Treatment 
1930 ephedrine 
1932 glycine 
1934 physostigmine 
1936 first thymectomy 
1949 ACTH 
1950s corticotherapy 
1966 reintroduced corticotherapy 

1967 azathioprine 
1973 acetylcholine receptor is autoantigen 
1976 plasma exchange 
1980 cyclophosphamide 
1984 intravenous immunoglobulin 
1987 cyclosporine 
2000s immunotherapies 



 
 
 
 
 

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Mary Broadfoot Walker 

 
Alfred Blalock 

 
Douglas Fambrough 

Figure 2 - Contributors to the treatment of 
myasthenia gravis 

In addition to physostigmine, Dr. Mary 
Walker also studied the effects of neostigmine 
and potassium chloride on MG patients with 
remarkable yet short-lasting results. She 
noted an improvement in muscle fatigue and 
the absence of central side effects of 
physostigmine (18, 30). 

Due to her pioneering in the treatment of 
MG, Mary Walkera still is one of the major 
contributors to the treatment of MG, with 
numerous incommensurable achievements: 
she is the first specialist who suggested the 
idea of “myasthenic crisis”, the first specialist 
to have noted that MG is located in the 
neuromuscular junction and also the first 
specialist to have discovered the clinical effect 
which was later called “the Mary Walker 
effect”. Of all of Dr. Mary Walker’s 
achievements, the most important is the use 
of physostigmine as primary therapy. This 
also stimulated the research of other 
acetylcholinesterase inhibitors like 
edrophonium in 1950 by MacFarlane (20) or 
pyridostigmine in 1954 by Kermit Osserman 
(23). These are still being used as first-line 
drugs in the treatment of MG.  

The use of neostigmine in the treatment of 
MG may be also credited to the German 
Lazar Remen (1907-1974), who published in 
German literature in 1932, that is 2 years 
before Mary Walker, a paper that claimed 
that the symptoms of a patient with MG 
improved after she had received neostigmine 
(26). 
Total resection of the thymus gland in the 
treatment of MG 

Being aware of Ernst Ferdinand 
Sauerbruch’s (1875-1951) post-thymectomy 



 
 
 
 
 
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results, the American surgeon Alfred Blalock 
(1899-1964) (Figure 2) performed the 
resection of a post-radiotherapy cystic tumor. 
The case was of a 19-year old girl with 
generalized MG, who underwent surgery 
during the remission period and who was 
administered prostigmin before and after the 
surgery. The case was published 3 years later, 
in 1939, in a paper in which Blalock claimed 
that the myasthenic symptoms were remitted. 
21 years later the patient was still alive (3, 13). 
Encouraged by this positive result, in 1941, 
Blalock started to practice thymectomy in 
MG patients without thymus tumors. Thus, 
he published reports on 6 cases of transsternal 
thymectomy and noticed that three of them 
did not subsequently require drug therapy 
(2). 

Inspired by Blalock’s promising results, 
the English surgeon Geoffrey Keynes, (1887-
1982) also performed 120 thymectomies 
between 1942 and 1949 in MG patients, and 
reported a 65% improvement in his cases 
(17). The treatment of MG through 
thymectomy had also crossed the ocean, as 
the American surgeon Oscar Theron Clagett 
(1908-1990) and the neurologist Lee Eaton 
(1905-1958), from the Mayo Clinic, had 
performed 72 thymectomies in MG patients, 
which they subsequently compared to the 142 
MG cases that had not undergone surgery (8). 
Later, that is between 1950 and 1954, there 
was a difference of opinion between the two 
continents as concerns thymectomy efficiency 
in MG patients. On the one hand, the 
Americans Clagett and Eaton from the Mayo 
Clinic, claimed that thymectomy was 
inefficient, on the other hand, the English 

Keynes argued against. It was later proven 
that this difference of opinion was due to the 
fact that most of the patients that had 
undergone surgery in the Mayo Clinic had 
thymus tumors, whereas in England they had 
thymic hyperplasia (1). This discrepancy was 
settled in 1955 when Clagett and Eaton set 
clear thymectomy criteria: absence of thymus 
tumors and patients’ age below 50 (7). 
ACTH and cortisol 

Wishing to achieve the same effect as 
thymectomy without the actual surgical 
procedure, in 1949, the Americans Clara 
Torda and Harold Wolff from the New York 
Hospital administered ACTH to 15 patients 
suffering from MG. Immediately after the 
administration of 500mg for 5 days, they 
noted a visible worsening of the symptoms in 
all the patients, including one dead; yet, they 
later noted the improvement of the symptoms 
of 10 out of 15 patients (29). After cortisol 
had been isolated and discovered in the 
adrenal glands and its effects had been 
studied by the chemists Edward Kendall 
(1886-1972) and Tadeus Reichstein (1897-
1996) (14), cortisone started to be 
administered to MG patients in 1950. 
Neuroscience researchers noted the same 
effect as in the case of ACTH, with a 
significant initial worsening and an 
improvement after a few days. Nevertheless, 
due to its life-threatening effects, they do not 
encourage the use of hydrocortisone in the 
treatment of MG.  

According to the German neuro-
psychiatrist Friedrich Jolly (1844-1904) and 
the British doctor Mary Broadfoot Walker 
(thirty nine years later) suggested that in MG 



 
 
 
 
 

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the impairment was located in the 
neuromuscular junction and that 
acetylcholine was the mediator involved (5), 
in 1956 the American David Grob et al. shed 
some more light on the matter by claiming 
that the seat of MG was at the post-synaptic 
level (10). A year later, that is in 1957, another 
neuroscientist, John Desmedt, published in 
the Nature journal a study in which he 
considered the post-synaptic component 
responsible for muscle fatigue in MG (6), and 
also suggested a possible acetylcholine 
depletion in the neuromuscular junction (22). 
Myasthenia gravis......an autoimmune 
disease? 

After the neuroscience researchers 
concluded that in MG the seat of impairment 
was located in the post-synaptic region, the 
medical world suggested that MG may be an 
autoimmune disease, as its association with 
autoimmune diseases has been noted. Thus, 
in 1954, in a review of 138 cases of systemic 
lupus erythematosus patients, Harvey et al. 
noted that 3 of them also suffered from MG 
(12). Nevertheless, the first specialist to 
officially launch in literature the assumption 
related to the autoimmune nature of MG was 
Dr. Smithers DW, in 1958 (1). That same 
year, Kermit Osserman, who had studied the 
effect of pyridostigmine, made a classification 
of MG and divided it into four groups 
depending on symptom severity and location 
(1). Smithers’ assumptions were confirmed in 
1960 by the Scottish doctor John Simpson. A 
review of all 404 cases of MG recorded 
between 1953 and 1955 enabled Simpson to 
reach three conclusions: that MG patients had 
thymus abnormalities, that thymectomy has a 
positive influence of disease prognosis and 

that there is a connection between MG and 
several other diseases like rheumatoid 
polyarthritis, systemic lupus erythematosus, 
hyperthyroidism, aplastic anemia, pernicious 
anemia or sarcoidosis. Thus, Simpson 
concludes that “myasthenia gravis is a 
muscular autoimmune response, in which an 
antibody of the protein in the end-plate can 
be involved as a reaction to an infection or 
thymus influenced by the pituitary gland” 
(27). That same year, i.e. is in 1960, Jacques 
Miller proved the immunological function of 
the thymus, in a series of studies that he 
published a year later in the Lancet (21). 

In 1968, in his attempt to discover a serum 
protein able to inhibit neuromuscular 
transmission, William Nastuk et al. focused 
on the study of the complement in MG. He 
found correlations between the serum 
complement level and disease activity and 
argued that “the levels of complement are 
decreased during the clinical activity of the 
disease, while during its remission, they 
increase. This suggests the possibility that MG 
is an autoimmune mediated disease” (28). 
Furthermore, in an attempt to identify the 
generator of these autoimmune reactions – an 
anti-striated muscle antibody, Arthur Strauss 
analyzed the serum of 1139 subjects, of 
whom: 129 were healthy, 386 had MG and 
674 suffered from inflammatory, 
endocrinological and carcinomatous 
myopathies, muscular dystrophies and 
thymomas not accompanied by MG (28). 
Since he discovered that in subjects with MG 
and thymomas, serum globulins retained the 
complement, Strauss established a certain 
connection between thymus abnormalities 
and impulse transmission alteration in the 



 
 
 
 
 
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neuromuscular junction. 
Thus, once the assumption according to 

which autoimmunity plays an essential role in 
MG pathogenesis was accepted, the 
reintroduction of corticotherapy, which had 
been abandoned for its life-threatening 
effects, was supported. Initially, cortisol and 
then prednisone started to be administered 
for their immunosuppressant functions, in 
more carefully calculated doses. Subsequent 
studies showed that symptom worsening was 
temporary and that an obvious disease 
symptom improvement was visible after 7 to 
10 days (1). “By borrowing” from the 
lymphoma and leukemia therapy, doctors 
started to focus their attention on other 
classes of medicines like: 
immunosuppressants, chemotherapy drugs or 
cytotoxic drugs. Thus, azathioprine started 
with 1967 to be administered to MG patients 
in Europe and cyclophosphamide since 1980 
(14). 
Reference year 1973 

1973 is considered a reference year in the 
history of the treatment of MG, since it marks 
two essential discoveries in understanding the 
pathology of this condition and its 
approaching the current level of knowledge. 
The first occurred in the Johns Hopkins 
Hospital, when Douglas Fambrough (Figure 
2) noted that acetylcholine receptors were 
located solely in the postsynaptic component 
after he had used a radioactively labeled from 
the cobra venom (alpha-bungarotoxin), with 
high binding affinity to the acetylcholine 
receptor (11). The second discovery belongs 
to Jim Patrick and Jon Lindstrom from the 
Salk Institute, who identified the 
acetylcholine receptor as the autoantigen 

responsible for triggering the autoimmune 
response (24). Lindstrom also isolated 
acetylcholine receptor antibodies in 1976. He 
injected rabbits with acetylcholine receptors 
sampled from electric eels and found that 
they exhibited flaccid paralysis and breathing 
difficulties and in addition that the symptoms 
were partially improved by prostigmin 
administration (19). The confirmation of the 
autoimmune pathogenesis and of the 
existence of acetylcholine receptor antibodies 
occurred in 1976, when Fueron treated three 
MG patients by plasmapheresis, with certain 
clinical improvement (25). This is actually the 
decisive breakthrough marking the transition 
towards a modern therapeutic approach and 
continuation of the immunological and 
genetic research of MG. 

Conclusion 
Having a relatively recent history, the 

treatment of MG has been a challenge for 
neuroscientists, and especially for doctors, 
who were faced with an unknown disease the 
therapy of which was even more unknown. 
Whereas the first disease description was 
done in England and the symptoms and name 
of the disease were later clarified in Germany, 
we can safely say that the treatment and 
immunopathological grounds originate in the 
United States. Although answers have been 
found to questions that seemed to have no 
answer, the complexity of MG is still very 
much visible nowadays, when the medical 
world has got involved in a process of 
continuous exploration, which focuses on the 
genes involved, on new autoantigenes and 
also on new immunotherapies of an 
extremely “complex” condition. 



 
 
 
 
 

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Correspondence 
Dana Turliuc 
“Prof. Dr. N. Oblu” Emergency Clinical Hospital 
Iasi, Romania 
E-mail: turliuc_dana@yahoo.com 

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