Kermit E. Osserman

Myasthenia gravis: Evaluation of treatment in 1,355 patients

The Myasthenia Gravis Clinics of Massachusetts General Hospital and The Mount Sinai Hospital were established in 1935 and 1951, respectively. Patients have been seen regularly at each clinic to the present time, and standardized methods of diagnosis, treatment, and follow-up have been carried out over the years. Details concerning diagnosis and treatment are available in previous publications from each clinic.l.2 Thymectomy, in selected cases, has been employed at Massachusetts General Hospital since 1941 and at The Mount Sinai Hospital since 1951. Eight cases were lost to follow-up in Boston before 1942, and 21 cases were lost to follow-up in New York before 1952. Therefore, surgical therapy was available to all but 29 of the total number of patients. Patients in each clinic were surveyed to determine eligibility for inclusion in the study. Adequate information concerning the initial diagnostic evaluation and at least one followup visit were the criteria for inclusion. Pertinent data concerning each patient from the onset of disease to the most recent evaluation or death were processed separately by each clinic, and the information was coded in a uniform manner on IBM cards. The information included sex, race, age at onset, type and

THE ROLE OF THYMECTOMY IN THE TREATMENT OF MYASTHENIA GRAVIS

Vincent P. Perlo, Barry Amason,* David Poskanzer, Benjamin Castleman, Robert S. Schwab, Kermit E. Osserman, Angelo Papatestis, Lawrence Alpert and Alan Kark The Myasthenia Gravis Clinic of the Massachusetts General Hospital; the Neurology and Pathology Departments, Harvard Medical School, Boston, Mass.: the Myasthenia Gravis Clinic and Departments of Medicine, Pathology and Surgery, the Mount Sinai Hospital, New York, N . Y .

Critical reappraisal of the use of edrophonium (tensilon) chloride tests in myasthenia gravis and significance of clinical classification.

Our original communication in 1952 describing the use of edrophonium (Tensilon) chloride as a rapid diagnostic test for myasthenia gravis’ was soon followed by reports of its dual use in management and regulation of anticholinesterase drug therapy2 and in the differential diagnosis of crisis.’ Over the course of a decade, the test has proven t o be a simple, accurate. rapid and valuable tool in the clinical management of this difficult disease. In 1956< a further manuscript from The Mount Sinai Hospital suggested definitive changes in dosage schedules based on which one of the three tests was being used. Following this, there were a number of report,s in the literatures ’ illustrating the value of edrophoniiim chloride as a diagnost,ic aid. By the time of The Second International Symposium on Myasthenia Gravis in 1959, the edrophonium diagnostic test had received world-wide acceptance.’ Since then it continues to be used for diagnosis, management and differentiation of crisis. Specific instructions for its use regarding dosages, administration and timing are to be found only in extensive review articles on myasthenia gravis. In these reportsg and from personal communications with workers in t,he field, there appear to be no unanimous criteria for use of edrophonium. Each physician uses his own modification which has led to variable interpretation of responses. I t was felt that this would be a good point in time to reappraise the test, its various uses and the proper dosages which will give it maximum efficiency. We are now citing our experience based on more than 25,000 edrophonium tests.

Metabolism of 14C‐labeled pyridostigmine in myasthenia gravis: Evidence for multiple metabolites

THE AIM of this investigation is to study the metabolism and excretion pattern of pyridostigmine in normal and myasthenic subjects. Approximately 10% of patients with myasthenia gravis develop resistance or insensitivity to anticholinesterase drug therapy. The reasons for this are only conjectural. Pyridostigmine is currently the most widely used drug. There is considerable variation among patients in the doses required for relief of symptoms. The varying doses required by different patients are related to several factors: duration and severity of the disease, as well as absorption, metabolism, and excretion of the drug. The factor of absorption can be eliminated by using a parenteral form of the drug. Previous investigations have demonstrated that, after oral administration of pyridostigmine, the urine excretion pattern per patient remains quite constant but considerable difference exists in the urine excretion pattern of different patients.1 Previous animal studies have dealt with pyridostigmine-14C metabolism in the rat.2~3 Following oral administration of the drug, about 42% of the dose is absorbed and excreted in urine.3 About 75% of excreted radioactivity represents intact pyridostigmine, while 25% is metabolite.3 Following intramuscular injection of pyridostigmine-14C in the rat, there is rapid elimination of the drug, chiefly by renal tubu-

Über die Myasthenia gravis

Wghrend ieh diesen zussmmenfassenden Artikel fiber die :Fortsehritte in der Behsndlung der Myssthenis grsvis~, ~ schreibe, linden sich in tier Literstur Beitrgge sus allen grSl~eren Lgndern der Erde. Die meisten dieser Berichge befsssen sich mit den Grundlagen der Pathophysielogie der Myssthenis grsvis, den ktinischen Beobschtungen mi~ verschiedenen antieholinergisehen Drogen und mit den Versuchen, die Indikstion zur Thymektomie herauszuarbeiten.

CONCLUDING COMMENTS: CLINICAL COMMENTARY

Although knowledge of etiology and basic disturbance in myasthenia gravis is still in exploratory phases in several areas of physiology and immunology, clinical management of the myasthenic patient by means of drug therapy, surgery and adjuvant modalities has progressed to nearly optimal controls in most centers. Results of survivorship and clinical improvements have shown remarkable gains. Whereas clinical emphasis in previous monographs revolved primarily around application of new and different types of drug therapy, this has now shifted to more effective methods involving the use of established drugs. In particular, as discussed by Glaser, Osserman and Genkins, there has been general disavowal of drugs of long therapeutic effect with more widespread recognition and management of drug overdosage and resistance or insensitivity both early and late in the course of the disorder. Despite the negative result obtained in the recent national co-operative study of ACTH in ocular myasthenia, some interest, as seen in the papers of Von Reis and colleagues, Grashchenkov and Perelman, is being focused anew on the use of steroid hormones and ACTH in regimens designed to restore drug responsiveness and terminate the so-called “brittle” state. There also appears to be more general agreement regarding the histopathology of the thymus gland in states of hyperplasia and tumor (Castleman, Lattes), compared with the confused state of nomenclature in earlier monographs. Incidence and relationship to myasthenia gravis of other systemic diseases, particularly those of the collagen group and thyroid gland, may shed further light on the questions of myasthenia as a singular entity or a syndrome (Simpson, Wolf et al . ) . In a group of papers concerning syndromes simulating myasthenia gravis, Schwab and Perlo using the best of controls, described the occurrence of some false-positive responses to anticholinesterase drugs. Johns and McQuillan reported a group of six females proven not to have myasthenia gravis, who were able to tolerate large dosages of anticholinesterases. Lambert added a new neuromuscular syndrome seen in a patient who did not have myasthenia gravis or the myasthenic syndrome associated with a small oat-cell carcinoma of the lung. Effects of myasthenia gravis analyzed on thepre-it& postmorbid personality structure of the af-

Thymectomy for Myasthenia Gravis

Excerpt The report from Blalock, Mason, Morgan, and Rivin in 1939 (1) of thymectomy for patients with myasthenia gravis and thymoma created hope that this was the therapeutic answer for this diseas...