Dogs and cats can get typical MG, with the usual antibodies that weaken nerve » muscle triggering in human patients. So we think that MG must have always been with us. The earliest clear description comes from Dr Thomas Willis, a well known London physician, who wrote in 1672:-
in the mornings, they are able to walk firmly or to take up any heavy thing. Before noon, the stock of the spirits being spent, which had flowed into the muscles, they are scarce able to move hand or foot. A prudent and honest woman has this spurious palsie since many years, not only in her members (limbs) but also in her tongue. Some time she can speak freely, .. but, after she has spoke long, hastily or eagerly, she becomes as mute as a fish; nor can she recover the use of her voice under an hour or two
In Europe, Neurology only became a separate speciality in about 1860, and MG was first recognised in its own right around 1880 by the German Neurologists Wilhelm Erb and Friedrich Jolly. They noticed that, unlike motor neuron disease, MG was not remorselessly progressive, and the weakness was fatiguable the harder you try, the weaker you get. It was first called myasthenia gravis in about 1895.
Since then, the story has progressed in a series of jumps along two tracks, which ran in parallel for decades, and came together only in the 1970s.
The first is the study of how nerves trigger muscles, and it starts with the French physiologist Claude Bernard. In the 1850s, he showed that the arrow poison Curare works by blocking this triggering. (It is now used to relax muscles during surgery). In the 1860s, TR Fraser and his team in Edinburgh found that the Calabar bean poison protects against curare, and they then purified physostigmine from it.
It was only in May 1934 that our heroine, Dr Mary Walker, when faced with a new MG patient, put two and two together and showed that physostigmine helped to strengthen her muscles. (That led to the development of its longer-acting cousin, pyridostigmine (ie Mestinon), which came into use in 1954). Her breakthrough also helped to explain the underlying defect: it proved that MG results from a defect in nerve » muscle triggering. Acetylcholine (ACh) had been a front-runner among the possible chemical ignition keys for triggering. In 1921, the Nobel prize-winner Otto Loewi finally proved its importance in nerve » heart muscle control. Again in that eventful month of May 1934, Sir Henry Dale showed that ACh is the vital signal in nerve » muscle ignition; the ACh is released from nerve endings like a shower of ignition keys, and somehow triggers the muscle into action. Dale and Loewi already knew that the spare ACh must be broken down, and that the stigmine drugs block that destruction. Finding the ignition locks took another 30 years or so (see III).
The starting point for the second track was the thymus, an organ behind the breast-bone whose function was then a mystery. Thymic tumours (thymomas) were first noticed in some myasthenics in 1899 (by H Oppenheim in Berlin and C Weigert in Frankfurt). Then, in 1917, E Bell in Minnesota looked in other myasthenics and saw different thymic changes rather like those in lymph glands draining an infection, as HE Sloan (Baltimore) recognised in the 1940s.
Back in 1900, it was too dangerous to operate on the chest, because there was no way to keep the patients breathing when the rib cage had been opened. But, in the mid 1930s, surgeons had developed positive pressure ventilation via a tube in the windpipe. So, in 1939, the American surgeon Alfred Blalock (Nashville) was able to remove a thymoma from a patient whose MG improved strikingly afterwards (that is unusual, as was soon found). Capitalising on this success, Blalock then thymectomised several more myasthenics without thymomas, and the results seemed even better (1941).
The baton was quickly taken up in this country by Sir Geoffrey Keynes (from 1942); he was not only a very distinguished surgeon already, and a greatly respected writer, but also the brother of the famous economist Maynard Keynes (of the New Deal). In 1949, he summarised his first 155 thymectomies. The improvements were almost confined to myasthenics without thymomas, whereas the MG sometimes got worse or even began after thymomas had been removed. Many of you will fondly remember his successor, our beloved former Vice-President, Mr Nick Lange
It was only in the 1960s that Drs Jacques Miller (London and Australia) and Bob Good (USA) finally showed that the thymus was a key immune organ. It generates T cells, the control freaks that help to switch on other immune cells to make antibodies and/or destroy germs. At the same time, it had become clear that several other disorders were caused by an immune attack on the patients own tissues, for example thyroid disease. In 1959, another beloved former Vice-President, Prof Iain Simpson, was reviewing all the thymectomies he could trace in Glasgow and London (404 in all). He noticed that such autoimmune diseases are specially common in relatives of myasthenics. He remembered that short-term MG could also be transferred from mother to newborn baby, just like protective antibodies are passed across. So he proposed, in 1960, that MG was autoimmune too. He was 12 years ahead of his time.
These two tracks finally came together in 1973. By then, physiologists realised that the ACh, the ignition keys, must somehow latch into specialised ACh receptors (AChRs) the ignition locks. Basic scientists were using snake venoms* to purify AChR (from electric fish). When they tried making antibodies against it by immunising rabbits*, they noticed that the rabbits became myasthenic, and got better with physostigmine. That proved that MG could be caused by antibodies ie by an immune attack, so confirming Prof Simpsons predictions. It was soon shown that most MG patients had similar antibodies so giving us a valuable diagnostic test, which is now in routine use around the world.
That breakthrough, in turn, led on to the use of plasma exchange, to wash the antibodies out of the patients blood-stream (by our President, John Newsom-Davis in 1979), and of other immune-suppressive drugs like Azathioprine (Imuran). It also provided sound logic for treating MG with steroids. These were already in use for MG by the 1960s, but now it became clear that they reliably lower the antibody levels within about two months.
There is still a lot we dont understand, especially about how the immune attack gets started and how it might be selectively switched off without clobbering all our protective immune responses. That is hard, but these questions are much easier to approach in MG, because its targets and mechanisms are so unusually well defined. We can see thus far because we stand on the shoulders of giants (as Newton once said). With your help, we must press on to the promised land now in our view.
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