In the 60's of the last century, myasthenia indeed was a "gravis" disease. It used to be treated with anticholinesterase drugs and thymectomy, the kinds of therapy, that used to raise numerous controversies. Thymectomy was at that time an operation with a high degree of probability for a postoperative deterioration. Myasthenic crises were very frequent and tracheotomies repeatedly indicated.
Thanks to Professor Albrecht Struppler, my teacher of electromyography from Münich, I met K. Osserman, during the World Congress of Neurology, New York, 1969. At that time he was regarded as top MG expert, active at the Mount Sinai Hospital, New York.
He was the first to start treating MG with a series of ACTH injections. At first, the course would cause deterioration, followed by a significant and long-lasting improvement. Upon my return to Zagreb, I tried to introduce that kind of therapy at my unit. The deterioration would sometimes reach to the respiratory crisis, so there was no way of treatment on a "regular" neurological department. I started to alocate the patients on the Intensive Care of the Department for Infectious Diseases chaired by J. Rulnjević, where we usually sent the patients during myasthenic crises. Upon the constitution of the Thoracic Surgery , Jordanovac, Zagreb, with LJ. Topalović, the head, I would transfer them there.
Our ACTH course was followed by azathioprin (Imuran), introduced into therapy of myasthenia gravis in 1969 at the Neurological Department, Hamburg, Germany. Applied as first and only therapy no convincing positive effects were found. However, after ACTH series, it prolonged the remission. The ACTH therapy was a complicated one, risky, and in the end, the results were not as desired.
In 1973 I visited the Bethesda hospital, where I met W. King Engel. He gave me a very useful information about HSDAD (High Single Dose Alternate Day) prednisone therapy (1
). Prednisone was administered in a single high dose, in the morning, every other day. I introduced that scheme upon my return to Croatia, and very soon we got to modify it.
A corticosteroid with the highest concentration in one pill, and with a long enough half-time was looked for. It was fluocortolon (Ultralan oral), 20 mg a pill, with 24 hours decomposition half-time. However, on the day without corticosteroid, in serious cases, the significant deterioration appeared. The smaller dose of fluocortolon was necessary on the second day, too.
In more difficult cases, we would treat with unchanged high doses of fluocortolon, every day, until the stabilization of the clinical signs and symptoms. Then we would gradually decrease dosage of the second day, decrescendo, into the every other day administration. The phase like this one, would last for several weeks, exceptionally for months. The single morning (until 8 o'clock) dose proved to be crucial, because, within the circadian rhythm of concentration of cortisol in blood, the physiological level of cortisol in blood is the highest at that time. Lack of respect for the physiological rhythms, and for natural laws in general, has bad consequences. The evening dose, so frequently used, had insomnia as the smallest of side effects.
Due to such administration, especially in combination with azathioprin I changed the prognosis of myasthenia gravis in Croatia significantly. The patient's mobility would quickly improve and the hospitalization would shorten. Myasthenic crises, especially tracheotomies. became rare. The possibility of plasmapheresis was the further significant step towards better prognosis of MG.
By the way, I also used the ACTH therapy to try to cure a young woman with a verified Porphyria Acuta Intermittens, in a very bad condition. The result was exceptional and remission complete. After the series of injections, fluocortolon was administered. The remission with fluocortolon was achieved even with the patient's sister who became ill several years later. The result was published in European Neurology (2
). The administration of fluocortolon also in patients with Sclerosis Multiplex started. We reported the first results in polimyositis 1978 (3
) and in myasthenia gravis 1979 (4
Many specialists persisted to refuse the corticosteroid therapy, considering it very dangerous. Their choice was the dexamethason, eventualy pronison several times a day. Its side effects were really significante, from pronounced Cushing Syndrome to isolated arterial hypertension, hyperglycemia, osteoporosis etc.
Endocrinological research for side- effects
Very early we started looking for the side effects with prof. Vanja Mikuličić and Danilo Tepavčević and later on with prof. Mirko Koršić. (Department of Endocrinology, KBC, Zagreb) At the same time we started analyzing the bone system with ing. Magda Harmut, Institute for Medical Research and Work Medicine of JAZU (Yugoslav Academy of Sciences and Arts). The preliminary results were reported at the First Symposium on Neuromuscular Diseases, Zagreb, 1977, and The Second Symposium on Neuromuscular Diseases, Dubrovnik, 1979 and printed (5
In the article from 1978, entitled Studying the Influence of Corticosteroids Therapy of HSDAD Type on Daily Rhythm of 11-OHCS Secretion, the Metabolites of Cortisol and Calciuria in Patients with Myasthenia Gravis, in the Summary, there is the following statement: "The first results of our research show that the corticosteroids therapy administered according to HSDAD scheme is less dangerous than it is generally thought, especially if the rare side effects are compared to the positive effects of this form of therapy. The values of 11-OHCS, 17-OH, secretion of cortisol, calciuria, OGTT do not differ from the normal significantly. As an exception, the type IV of differential lipidogramme according to Friedrichson can develop, as well as hypertension and facies lunata, but they disappear after the end of therapy. Lower calciuria was sometimes found before starting the therapy."