Gabriel Genkins

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.

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

Studies in myasthenia gravis: Early thymectomy: Electrophysiologic and pathologic correlations

Indications for thymectomy in myasthenia gravis have been recently expanded to include all cases with extraocular symptoms as a result of the minimal morbidity and negligible mortality of the transcervical approach. As increasing numbers of patients with myasthenia gravis, covering the entire spectrum of generalized disease, have been added to the thymectomy population, a more accurate evaluation of the effects of the operation is possible. Our experience with 353 patients who have undergone thymectomy indicates that early thymectomy, particularly in patients who do not have germinal centers, is followed by early remission of the disease. Delayed remission after thymectomy is related to the duration and severity of the disease, and to presence of thymic germinal centers. Germinal centers were found more frequently in patients with long duration of the disease and in patients in whom the disease had progressed to respiratory involvement. Marked improvement in electromyographic findings immediately after thymectomy was observed in the majority of patients who had had the disease for 1 year of less and where germinal centers were absent. The percentage of malignant thymomas was higher in patients who underwent thymectomy 1 year or more after the onset of symptoms of myasthenia gravis. These data indicate the importance of early thymectomy while the disease is still in the mild stages. Transcervical thymectomy is the treatment of choice as it is followed by a higher percentage of remissions and by less morbidity than other forms of treatment.

THYMECTOMY IN MYASTHENIA GRAVIS: PATHOLOGIC, CLINICAL, AND ELECTROPHYSIOLOGIC CORRELATIONS*

Application of thymectomy in the treatment of myasthenia gravis was based originally on empirical observations. Similarly, indications for thymectomy were developed empirically from preliminary results reported by Keynes 2* and Harvey.4 Lack of knowledge of the etiology of myasthenia gravis and of the function of the thymus gland, and the small numbers of selected patients in most of the early series resulted in conflicting reports 5-7 on the role and value of thymectomy in myasthenia gravis. In recent years there has been a rapid expansion of knowledge concerning the thymus gland 8, 9 and its relationship to immune surveillance.10 The reports of the immunologic effects of neonatal thymectomy l1 were followed by the observations that adult experimental thymectomy has also delayed immunologic effects.lZ3 l3 Thymectomy was originally thought to result in an increase of the risk of oncogenesis, but as Allison pointed out in 1967 certain neoplasms decrease following thymectomy.14 Decrease in the risk of oncogenesis following thymectomy in patients with myasthenia gravis has been previously r e ~ 0 r t e d . l ~ Accumulating evidence that autoimmunity may play a major role in the pathophysiology of myasthenia gravis,l6V l7 the possibility that liability to autoimmunity might be a thymus-dependent state,’R and the experience with a large number of patients who have undergone the simplified transcervical thymectomy l9 permit a reevaluation of the role of thymectomy in myasthenia gravis. The present report is an evaluation of results obtained in 438 thymectomies of which 233 were via the transcervical approach and an analysis of factors related to immunity influencing the response to thymectomy and risk of oncogenesis. Results of thymectomy and risk of oncogenesis were correlated with thymic pathology, electromyographic findings, age, preoperative duration of disease, peripheral lymphocytes, 17-ketosteroid excretion, and carcinoembryonic antigen (CEA) titers.

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.

Analysis of false negative results in the immunoassay for anti-acetylcholine receptor antibodies in myasthenia gravis

Possible causes for the failure of immunoassays to detect anti-acetylcholine receptor activity in serum from confirmed myasthenia gravis (MG) patients were investigated. A more sensitive assay, using Protein A to trap immune complexes (ARIA), was applied to 65 MG sera which were negative in the usual assay and to 42 normal human sera. Normal and negative MG sera had antibody (Ab) activity in the same range (50-70 pM). Titers present in 70% of normal sera appeared to be specific antireceptor antibodies as defined by tests for antigen specificity. Thus, higher sensitivity assays did not improve discrimination of MG from normals. In a second group of 108 MG sera studied, 48 were negative by the usual assay criteria in a rat acetylcholine receptor immunoassay. Further detailed analysis of this negative group showed that 3/48 had IgG3 antibody not detectable in the test, 14/48 had Abs recognizing human receptor determinants exclusively, 29/48 had toxin blocking Abs not determined by immunoassays, and 6/48 were negative in all tests. The results indicate that the exclusive occurrence of toxin-blocking antibodies in MG subjects is a major factor contributing to false negatives in the ARIA test. Estimates of the amount of Abs with this functionality indicated that they are present in very much smaller amounts than other classes of anti-receptor Abs. Degree of blocking activity in patient serum showed a fair correlation with severity of disease. Thus, blocking antibodies appear capable of causing all degrees of disease severity in the absence of other types of antireceptor Abs. The development of a sensitive and quantitative in vitro assay for blocking antibodies combined with the usual immunoassay would be a major improvement for a MG diagnostic test, with greater than 94% positivity predicted.

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.