Epilogue

The history of myasthenia gravis reflects that of general medicine. In the last quarter of the 19th century a few German doctors gradually delineated a new disease of which the clinical features did not fit in the diseases known at that time. Apart from the younger age of the patients and the fluctuating course with remissions and exacerbations, the absence of macroscopic or microscopic lesions in the central nervous system was an important argument for the concept of a new disease. The negative argument could be used because many diseases of the central nervous system could be diagnosed at that time by neuro-pathological examination, which was nearly the only way to verify or to refute the clinical diagnosis. In the patients suffering from the new disease the single abnormalities were tumors of the thymus and lymphorrhagic infiltrates in skeletal muscles which later were also found in other organs (1, 2). A relationship of these abnormalities with the clinical symptoms was far from clear. It was therefore realistic to choose a name that expressed the most striking symptom: muscle weakness (asthenia) although not true paralysis. That this weakness increased by faradic stimulation of the nerve, a therapeutic modality advocated by Duchenne (3), was demonstrated by Jolly (fig. 1.2). Although it was known by physiologists (Foster 1876) that the propagation velocity of the nerve impulse slows down to about 10% when arriving at the muscle endplates, the notion of discontinuity between nerve and muscle and the existence of a transmitter substance, acetylcholine, emerged only in the 1930's by the discovery of Dale (4). It was in the same period that the effect of physiostigmin in MG was described by Mary Walker (1.4) and the idea of a curarizing substance impeding muscle function at the endplates, revived. In the first quarter of the 20th century the function of the endocrine glands producing circulating hormones 1 was detected. This gave the impetus for the search of a circulating substance that might cause the muscle weakness in MG.

The main source of this substance was sought in the thymus but experiments never gave convincing results and were abandoned in the late 1950's. In the 1930's thoracic operations became possible with lesser risks. Since thymic tumors had an unusual high frequency in severe myasthenia patients, a causative role was assumed so that surgical removal was a logical consequence. However the extension of surgery to the non-tumorous thymus was more intuitive than based on firm scientific arguments. In the 1950's auto-immunity was introduced as a pathophysiological concept. In 1956 Roitt et al (5) demonstrated auto-antibodies against thyroglobulins in patients with Hashimoto's thyroiditis. Burnet (6) proposed a clonal selection theory: in embryonal life immunocompetent lymphocytes are formed which are able to recognize all kind of antigens, but the lymphocytes directed against the body's own proteins are normally deleted. If this elimination mechanism fails, lymphocytes are retained in postembryonal life that may attack the body's own cells by specific antibodies. Later Burnet (7) suggested that the thymus is the site where 'forbidden clones' of immunologically competent cells are destroyed. Simpson's suggestion that MG was an auto immune disease with an attack on the muscle-endplates, was based on analogous reasoning and clinical intuition. Female preponderance, the fluctuating course of the disease, lymphorrhages in muscles (but not at the endplate), thymic abnormalities (not known then in other diseases) and concomitant occurrence of RA and diseases of the reticuloendothelial system (of which the cause was unknown) were his main arguments.The proposed antibodies could not been demonstrated.I That the pathophysiological abnormality was caused by a postsynaptic defect was not the prevaling opinion in the 1960's; rather a deficit in ACh-production or a disturbance in ACh-resynthesis was incriminated (8) although some investigators defended a postsynaptic disturbance. (9, 10) This discussion became trivial when in 1973 the loss of AChR was visualized (11). In fact the knowledge of receptor-pathology in general was not yet developed in the 60's. It is now known that ACh-production is increased in MG (12). Increase of transmitters by upregulation is a common event in postsynaptic disturbances.