Peter Kornfeld

Effects of thymectomy in myasthenia gravis.

Factors influencing onset of remission in myasthenia gravis were evaluated in 2062 patients, of whom 962 had had thymectomy. Multivariate analysis showed that appearance of early remissions among all patients was significantly and independently influenced by thymectomy, by milder disease, and by absence of coexisting thymomas. Patients with mild generalized symptoms treated with thymectomy reached remission more frequently, even when compared with those with ocular myasthenia treated without surgery. Short duration of disease before thymectomy in mild cases was another factor associated with earlier remissions. Mortality for all patients was significantly and independently influenced by severity of symptoms, age, associated thymomas, and failure to remove the thymus. Patients without thymectomy and with thymomas had, in addition, earlier onset of extrathymic neoplasms. Morbidity after the transcervical approach was minimal. This study demonstrates that early thymectomy by the transcervical approach, when technically feasible, has significant clinical advantages over the transthoracic approach and should be advocated for all patients with myasthenia gravis, including those with ocular disease.

Detection of Anti-Acetylcholine Receptor Factors in Serum and Thymus from Patients with Myasthenia Gravis

Since the blood and thymus of patients with myasthenia gravis may contain inhibitors of neuromuscular transmission that affect acetylcholine receptors of striated muscle, we used denervated rat muscle to test for inhibitors in 43 serums and 18 thymus glands from such patients. Seven per cent of serums inhibited the binding of 125l alpha-bungarotoxin to triton-solubilized receptors; 65 per cent interfered with binding of toxin-labeled receptors to concanavalin-A coupled to Sepharose gel, and 85 per cent formed IgG-receptor complexes detectable by immunoprecipitation. Serum inhibitory activity varied widely among patients with similar clinical manifestations and was not correlated with duration of myasthenia gravis or thymectomy. Among thymus extracts, 44 per cent were inhibitory in the concanavalin-A binding assay, whereas 72 per cent contained anti-receptor IgG. Thus, serums from patients with myasthenia gravis contain more than one anti-receptor factor.

Thymomas in patients with myasthenia gravis.

The records of 141 patients with myasthenia gravis who had thymomas were reviewed. In this series there were 69 noninvasive tumors and 52 invasive tumors. The five year survival for all patients was 60%, with the invasive group demonstrating a poorer prognosis than the noninvasive. The remission rates for the whole group (both invasive and noninvasive) of myasthenics was quite low (7%). Although the overall survival of this series of patients was relatively high, it is felt that by earlier diagnosis and a more aggressive surgical approach their prognosis will be even better.

Electrophysiologic diagnosis of myasthenia gravis and the regional curare test

Two hundred and fifty consecutive patients were evaluated for myasthenia gravis with repetitive supramaximal stimulation of peripheral nerves and regional curare administration when necessary. Among patients with definite generalized myasthenia gravis, 72 percent had abnormal responses to repetitive supramaximal stimulation alone and another 17 percent had abnormal responses after regional curare administration. Among those with possible generalized myasthenia gravis, 15 percent had abnormal responses to repetitive supramaximal stimulation and another 12 percent had abnormal responses after regional curare administration. Of those with only ocular symptoms, 46 percent had abnormal responses to repetitive supramaximal stimulation before or after regional curare administration, suggesting generalized involvement. Myasthenia gravis has not developed subsequently in any of the equivocal patients with negative electric tests. We have found these electric procedures to be simple, safe, and at least as effective as other methods in diagnosing myasthenia gravis.

A Study of the Usefulness and Limitations of Electrical Countershock, Cardiac Massage, Epinephrine and Procaine in Cardiac Resuscitation from Ventricular Fibrillation

The efficacy of electrical countershock, cardiac massage, epinephrine and procaine in stopping ventricular fibrillation and restoring a competent ventricular contraction was studied in anesthetized dogs. It was found that countershock is a reliable means of stopping fibrillation. However, it must be preceded by cardiac massage if not applied promptly after the initiation of fibrillation. Epinephrine helps restore a competent ventricular contraction once fibrillation has been stopped by countershock but it increases the incidence of recurrence of fibrillation. The doses of procaine which constitute a reliable means of stopping fibrillation depress the rhythmicity of the heart to such an extent that the cessation of fibrillation is followed by prolonged periods of cardiac standstill.

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-

The effect of chronic pyridostigmine administration on pyridostigmine‐14C metabolism in myasthenia gravis

RECENTLY, WE REPORTED the fate of intravenously injected single doses of pyridostigmine14C in myasthenia gravis patients in the basal state.l.2 We encountered great difficulty in securing an adequate number of severe myasthenic patients who could safely be kept off all anticholinesterase therapy for seventy-two hours, the time required for the body to excrete all pyridostigmineJ4C. For this reason, we repeated the above study in 3 myasthenic subjects without interrupting the patients’ therapeutic regimens.

Transcervical thymectomy for thymoma in myasthenia gravis

The results of thymectomy performed through a transcervical approach in 37 myasthenic patients with thymomas is reported and compared with results in 97 patients who had thymomas removed through a transsternal approach. In 29 of the former patients the thymomas were unsuspected and found at the time of thymectomy, and in 8 a preoperative chest roentgenogram was suspicious for the presence of a tumor. In the transcervical group there were only 4 invasive thymomas, while in the transsternal group there were 32. In the transcervical group there was no evidence of recurrence in the patients with unsuspected thymomas, and one recurrence in the group with suspected thymomas. In the transsternal group eight patients had known recurrence or persistent disease. The transcervical approach seems appropriate for the removal of small thymomas discovered at the time of thymectomy or suspected from the preoperative work-up.

Studies in myasthenia gravis Pyridostigmine‐C14 metabolism after thymectomy

Pyridostigmine-carbon14 (P-C14) excretion studies in myasthenia gravis patients who had had thymectomies failed to produce any significant difference from results observed in myasthenic patients who had not had thymectomies. Thus, change in P-C14 metabolism cannot help explain decreased anticholinesterase requirements and electromyographic changes observed in some patients following thymectomy.

Pathogenesis and treatment of myasthenia gravis

SIR,-Drs J K Cruickshank and C Mackenzie in their leading article (21 November, p 1349) rightly draw attention to the promising prospects opened up by the introduction of the enzyme-linked immunosorbent assay (ELI SA) technique and of monoclonal antibodies. We agree with this, yet think that a more critical approach is needed. The specificity required for diagnostic tests is high. In a series with 5%, true positives, an additional 1 I` of false positives would mean that one in six of all positives were false. Parasites are masters at antigenic disguise, either by mimicry or incorporation of host antigens. False-positives, therefore, are as likely to occur in diseases which cause the release of tissue antibodies as in patients with other parasitic diseases; yet in many evaluations of immunodiagnostic tests the controls are drawn only from the last group or from blood donors. Not surprisingly, in clinical practice the results may be less good than the claims. General hospital patients need to be included among the controls. The advantages of ELISA are its suitability for mass screening and the lack of subjectivity in interpretation. As regards parasitology, the former characteristic is of value for seroepidemiology but not as yet for serodiagnosis, which is almost always done on a small scale. The method has no inherent advantages as regards specificity; and unless purified antigen is available it may be less specific than, for instance, immunofluorescence, in which crossreactive structures in a parasite can be disregarded. In this department we find that even purified parasite antigens can give false-positives in conditions where, for example, there is liver damage. Nevertheless, purified antigens, if they were freely available, would be a great advance. Who is to provide them? Over and over again commercial firms have produced satisfactory parasite antigens; but many have not been made universally available, or else after a short time they have been withdrawn. To many people the obvious agency would appear to be the World Health Organisation, which could ensure international standardisation and offer the products at a price which the Third World could afford. However, except in isolated instances WHO has not so far seen this to be its role. These and other aspects of the subject are dealt with more fully in recent reviews.1 2 The hopes which your editorial raises are more likely to be realised if the problems are faced.