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Myasthenia gravis and the thymus
The American VOL.
Journal JANUARY
xxx11
of Medicine
1962
Editorial Myasthenia /
Gravis
and the Thymus sions. While these remissions are usually partial and temporary, occasionally they are complete and prolonged. Such a clinical course, together with the predominant occurrence in females in the childbearing age group, form a pattern reminiscent of that seen in systemic lupus erythematosus. Over the age of fifty this sex pattern in myasthenia disappears and male patients are seen more frequently. Neonatal myasthenia gravis, while not a common occurrence, is a unique condition in which the child of a mother with myasthenia gravis manifests, for an average period of three weeks, classic myasthenic weakness responsive to anticholinesterases. The infant’s myasthenia is uniformly transient and does not correlate well with the severity or duration of the maternal disease. The nature and mechanism of action of the substance crossing the placenta are important problems in the study of this disease. Certain diseases are associated with myasthenia gravis more often than can be explained by chance. Hyperthyroidism occurs in over 3 per cent of patients with myasthenia gravis [7,2]. The time of onset of the two disorders follows no consistent pattern. Further studies of this relationship are important, particularly in regard to antithyroid antibodies. Some patients with classic polymyositis or dermatomyositis have weakness of the myasthenic type with improvement after neostigmine therapy. In such cases the ocular muscles are uninvolved 1341, and the characteristic myasthenic defect in neuromuscular transmission has not been demonstrated electromyographitally [5]. On the other hand, some patients with
the past few years new observations have been made concerning the anatomic, physiologic and pharmacologic abnormalities in myasthenia gravis. Recent experiments provide information which suggests that the thymus is an immunologic rather than an endocrine organ. It seems important to review these developments in relation to the pathogenesis of myasthenia gravis.
D
URING
MYASTHENIA
GRAVIS
Clinically, there are certain features of this disease which occur with such regularity, or which are so unique, as to demand explanation by any hypothesis concerned with pathogenesis (Table I). Many of these features are widely known, but certain of them are worthy of special comment. With increasing severity of disease there is a progressive degree of basal weakness at rest and a progressive limitation in the ability of anticholinesterases to improve strength. Such observations indicate that these measures do not correct the basic defect in myasthenia gravis, a point which is widely known but often forgotten. While onset with ocular symptoms with subsequent involvement of other muscle groups is common, the disease in one-fifth of the patients remains limited to extraocular muscles [7]. At the other extreme are patients in whom the extent and severity of the disease progress steadily over a period of weeks, months or years. Most patients fall into an intermediate group whose course is initially one of progressive involvement which reaches a plateau after which there may be periodic exacerbations and remis1
Editorial
2 TABLE I FEATURESOF MYASTHENIA CRAWS
1. Female sex predominance 2. Predilection for ocular and bulbar muscles 3. Increased weakness on voluntary effort with rapid recovery upon rest 4. Residual weakness not responsive to rest or to anticholinesterase medication. 5. Dramatic spontaneous remissions 6. Transient neonatal myasthenia with maternal myasthenia 7. Association with thymic abnormalities and hyperthyroidism
myasthenia gravis have pronounced muscular wasting, and have muscle lesions suggesting myositis [6]. The evidence is not completely convincing that true myasthenia gravis occurs in polymyositis or dermatomyositis, but the possibility of a relationship is intriguing and deserves further study. Review of the cases reporting coincident systemic lupus erythematosus and myasthenia gravis reveals that while the diagnosis of lupus appears definite, the manifestations attributable to myasthenia gravis are atypical and respond poorly to anticholinesterase therapy [3,7]. A number of instances of the familial aggregation of myasthenia gravis have been reported [8]. There are at least fifteen examples of the disease in siblings. In one remarkable family seen at this hospital, four children had classic myasthenic weakness responsive to neostigmine therapy [9]. We have also seen the disease in identical twins. Certain anatomic changes in this disease have been clearly documented: (1) Alterations have been described in the muscle fiber itself consisting of an acute coagulative necrosis. Russell believes the lymphorrhage to be secondary to necrosis of the muscle fibers [IO], but we have seen it in a pericapillary or perivenular position as well. It is of interest that a typical finding in experimental autoimmune disease is the perivenular cuff of lymphocytes [ 7 71. (2) By means of supravital and cholinesterase-staining technics an abnormal branching or an elongation of the motor nerve terminals has been demonstrated [ 12,131. (3) Electron microscopic studies have revealed focal areas of decreased density of the end-plate sarcolemma within the secondary synaptic clefts. In severe myasthenia, there was also widening of the clefts, disruption of their basement membrane and focal deposits in the axoplasm of the nerve terminal [ 741.
Most investigators have focused their interest on the physiologic and pharmacologic aspects of myasthenia gravis. The electrophysiologic abnormalities are consistent with a decreased acetylcholine effect on the motor end-plate, but there is disagreement as to its cause. There are two major possibilities: (1) diminished synthesis or release of acetylcholine by the nerve ending; and (2) decreased sensitivity of endplates to acetylcholine liberated in normal amounts. Increased destruction of acetylcholine has been reasonably well excluded. Supporting the first possibility are the similarities between the neuromuscular block in myasthenia gravis and that produced by drugs known to interfere with acetylcholine synthesis or release [lg. Favoring the second is the reduced responsiveness in the patient with myasthenia gravis to injection of acetylcholine and similar drugs, for if the defect were in acetylcholine release, one would anticipate that an injection of acetylcholine would have its usual effect [ 76791. Direct evidence has been obtained by recording from myasthenic end-plates in vitro [ZO]. Miniature end-plate potentials (which result from the spontaneous release of packets of acetylcholine from nerve endings) were found to be of normal amplitude, indicating no decrease in end-plate responsiveness. The frequency of the release of these packets of acetylcholine was less than normal, and could not be increased by the usual maneuvers. This evidence weighs heavily in favor of a defect in the nerve ending. However, since these muscles were not clinically involved, one cannot exclude end-plate insensitivity in the involved muscles. Immunologic abnormalities have recently been described, using fluorescein-labeled serum globulin. The serum globulin in some patients with myasthenia was bound to skeletal muscle, while this fraction in normal subjects was not [21]. This binding was associated with the fixation of complement. Further studies indicated that this serum component was a 7S gamma globulin [22]. This material was found in the region of the A band of the muscle fiber but spared the H zone [23], suggesting that the binding site is in the area of overlap between the primary and secondary filaments of the myofibril. The myasthenic globulin fixes to normal human muscle and to the skeletal muscle of other species as well, but not to human cardiac muscle. Questions under investigation include the specificity of this reaction for myasthenia gravis, the correlation AMERlCAN
JOURNAL
OF
MEDICINE
Editorial with the clinical status of the patient, and the relationship to neonatal myasthenia gravis. The unique clinical characteristics of myasthenia gravis suggest that it is a uniform disease due to a specific functional defect. The anatomic, physiologic and pharmacologic studies demonstrate that this disorder is localized to the region concerned with neuromuscular transmission, and that nerve terminal, end-plate and muscle fiber may be involved. This is an area in which closely related and highly specific enzyme proteins play a vital role in normal function. The demonstration of an abnormal globulin which attaches to muscle, the phenomenon of neonatal myasthenia, together with the nature of the pathologic lesions raise the intriguing possibility than an immune mechanism may be involved in pathogenesis. THE
FUNCTION
OF THE
THYMUS
There has been renewed interest in the function of the thymus. In studies of the formation of a lymphoidal thymus from its epithelial rudiment it appears that lymphocytes can arise intrinsically during the embryonic development of this structure [Z]. This organ is a source of circulating lymphocytes [25], and has been demonstrated to contain a lymphocyte-stimulating factor thought to be produced by the epithelial cells [26]. This is of interest in relation to the observation that in the absence of the thymus the incidence of spontaneous [27] or induced [28] lymphocytic leukemia in mice is sharply reduced. Thymic lymphocytes are capable of eliciting the graft versus host reaction indicating that they are immunologically competent cells [29]. In the immature animal the thymus is necessary for the production of circulating antibodies to foreign protein [30]. While the adult thymus has not been demonstrated to produce antibody in response to the remote injection of antigen [31-331, it has been shown to be immunologically reactive to the direct injection of antigen [34]. The histologic response under these circumstances is similar to that seen in the myasthenic thymus with intense germinal center formation and to the secondary immune response in other lymphatic tissues exposed to antigen. The lack of antibody response to circulating antigen in the adult thymus may be attributed to failure of antigen to gain access to thymic cells except when the thymus is injured [34]. VOL.
32,
JANUARY
1962
These observations that the thymus plays an immunologic role take on added significance when one reviews the thymic changes in myasthenia gravis. THE
THYMUS
IN
MYASTHENIA
CRAWS
The coincidence of thymic hyperplasia or thymoma and myasthenia gravis is well established and far exceeds a chance relationship. When associated with thymoma the onset of myasthenia is later in life, there is a male sex preponderance [35], and in general the weakness is more severe and progressive [ 71, although there is considerable individual variability. In some instances detection of the thymoma precedes the onset of myasthenia by many years, and in at least three instances myasthenia appeared several years following apparent total thymectomy [ 1,36,37]. Histologically this tumor is composed of variable mixtures of epithelial and lymphocytic cells (thymocytes), which are the normal thymic constituents. The epithelial cells may be arranged in cords or clumps surrounded by lymphocytic cells giving a “glandular” appearance. Sometimes there are perivascular cuffs of lymphocytes [38] reminiscent of the perivenular lymphocytic accumulations in experimental autoimmune disease [II]. Thymic hyperplasia is even more commonly associated with myasthenia. Here the temporal relationship is more difficult to establish, for frequently the hyperplasia is not detectable clinically. The characteristic microscopic finding is the abnormal proliferation of lymphocytic elements with the formation of numerous germinal centers, even in the absence of gross enlargement of the thymus. It seems unlikely that the thymus is the source of the pathogenic material in neonatal myassince in three thenia, instances maternal thymectomy had been performed prior to pregnancy [39-471. More recently, other disorders have been reported in association with thymoma. Refractory anemia due to erythroid hypoplasia is the most common, but granulocytopenia and thrombocytopenia have been described as well. Some of these patients have had myasthenia gravis as well as cytopenia. Four cases are recorded of acquired agammaglobulinemia associated with thymoma. These patients did not have myasthenia gravis [42&U]. Two patients
Editorial with myositis in association with thymoma have been described, but neither responded to therapy with neostigmine [B&46]. The pathologic changes in thymic hyperplasia resemble those described in a thymus under antigenic stimulation, while the perivascular lymphocytic cuffing seen in the thymomas resembles the lesion associated with delayed hypersensitivity. That these thymus abnormalities are not the primary cause of myasthenia gravis is suggested by the instances in which neonatal myasthenia developed after maternal thymectomy prior to pregnancy and by the development of the disease following presumably total thymectomy. In our present state of knowledge the understanding of this collection of observations is still in a rather primitive state. The scanty evidence that myasthenia gravis may be a unique type of response to some as yet unknown immunologic abnormality, the growing indications that the thymus plays an immunologic role which may be under endocrinologic supervision, together with the well established thymic abnormality in this disease, provide a substantial direction for future research A coordinated approach to these problems using the anatomic, physiologic, pharmacologic and immunologic technics now available should be a productive one.
8.
9.
10.
11.
12. 13.
14.
15.
16.
A. MCGEHEE HARVEY, M.D. J. JOHNS, M.D.
17.
Department of Medicine The Johns Hopkins University School of Medicine and Hospital Baltimore, Maryland
18.
AND RICHARD
REFERENCES 1. GROB, D. Myasthenia gravis, current status of pathogenesis, clinical manifestations, and management. J. Chron. Dis., 8: 536, 1958. 2. SILVER, S. and OSSERMAN,K. E. Hyperthyroidism and myasthenia gravis. J. Mount Sinai Hosp., 24: 1214, 1957. 3. ROWLAND, L. P., HOEFER, P. F. A. and ARANOW, H., JR. Myasthenic syndromes. Res. Publ. A. New. @ Ment. Dis., 38: 548, 1958. 4. WALTON, J. N. and ADAMS,R. D. Polymyositis. Baltimore, 1958. Williams & Wilkins, Co. 5. RICHARDSON,A. T. Clinical and electromyographic aspects of polymyositis. Proc. Roy. Sot. Med., 49: 111,1956. 6. SIMPSON,J. A. Myasthenia gravis: a new hypothesis. Scot. M. J., 5: 419, 1960. 7. HARVEY, A. M., SHULMAN, L. E., TUMULTY, P. A., CONLEY, C. L. and SCHOENRICH, E. H. Systemic
19.
20.
21.
22. 23.
lupus erythematosus: Review of the literature and clinical analysis of 138 cases. Medicine, 33: 291, 1954. KURLAND,L. T. and ALTER, M. Current status of the epidemiology and genetics of myasthenia gravis. In: Myasthenia Gravis, pp. 307-336. Edited by Viets, H. R. Springfield Ill., 1961. Charles C Thomas. WALSH, F. B. and HOYT, W. F. External ophthalmoplegia: as a part of congenital myasthenia in siblings: myasthenia gravis in children: report of a family showing congenital myasthenia. Am. J. Ofihth., 47: 28, 1959. RUSSELL,D. S. Histological changes in the striped muscles in myasthenia gravis. J. Path. But., 65: 279,1953. WAKSMAN, B. H. A comparative histopathological study of delayed hypersensitivity reactions. In: Ciba Foundation Symposium on Cellular Aspects of Immunity. Edited by Wolstenholme, G. E. W. and O’Connor, M. Boston, 1960. Little, Brown & co. CGERS, C. and DESMEDT,J. E. Abnormal end-plates in myasthenic muscle. Lance& 2: 1124, 1958. C~ERS, C. and WOOLF, A. L. The Innervation of Muscle, a Biopsy Study. Springfield, Ill., 1959. Charles C Thomas. ZACKS, S. I., BAUER, W. C. and BLUMBERG,J. M. Abnormalities in the fine structure of the neuromuscular junction in patients with myasthenia gravis. Nature, London, 190: 280, 1961. DESMEDT,J. E. Myasthenic-like features of neuromuscular transmission after administration of an inhibitor of acetylcholine synthesis. Nature, London, 182: 1673, 1958. CHURCHILL-DAVIDSON, H. C. and RICHARDSON,A. T. Neuromuscular transmission in myasthenia gravis. J. Physiol., 122: 252, 1953. CHURCHILL-DAVIDSON, H. C. and RICHARDSON,A. T. A study of neuromuscular transmission in one hundred cases of myasthenia gravis. In: Myasthenia Gravis, pp. 199-207. Edited by Viets, H. R. Springfield, Ill., 1961. Charles C Thomas. GROB, D., JOHNS,R. J. and HARVEY, A. M. Studies in neuromuscular function. IV. Stimulating and depressant effects of acetylcholine and choline in patients with myasthenia gravis, and their relationship to the defect in neuromuscular transmission. Bull. Johns Hojkins Hosp., 99: 153, 1956. GROB, D., JOHNS,R. J. and HARVEY, A. M. Studies in neuromuscular function. VI. Effects of anticholinesterase compounds, d-tubocurarine, and decamethonium in patients with myasthenia gravis. Bull. Johns Hopkins Hosp., 99: 219, 1956. DAHLBKCK,O., ELMQVIST,D., JOHNS,T. R., RADNER, S. and THESLEFF,S. An electrophysiologic study of the neuromuscular junction in myasthenia gravis. J. Physiol., 156: 336, 1961. STRAUSS,A. J. L., SEEGAL, B. C., Hsu, J. C., BURKHOLDER, P. M., NASTIJK, W. L. and OSSERMAN, K. E. Immunofluorescence demonstration of a muscle binding, complement-fixing serum globulin fraction in myasthenia gravis. Proc. Sot. Exjer. Biol. &3 Med., 105: 184, 1960. STRAUSS,A. Personal communication. STRAUSS,A., DEITCH, A. and Hsu, K. Further obAMERICAN
JOURNAL
OF MEDICINE
Editorial
24.
25. 26.
27.
28.
29.
30.
31.
32.
33.
34.
servations on the localization of a muscle-binding, complement-fixing seruin globulin fraction in myasthenia gravis. Fed. Proc., 20: 38, 1961. BALL, W. D. and AUERBACH,R. In vitro formation of lymphocytes from embryonic thymus. Exfer. Cell Res., 20: 245, 1960. SCHOOLEY,J. C. and KELLY, L. S. The thymus in lymphocyte production. Fed. PYOC., 20: 71, 1961. METCALF, D. The thymic origin of the plasma lymphocytosis stimulating factor. &it. J. Cancer, IO: 442, 1956. LAW, L. W. and MILLER, J. H. Observations on the effect of thymectomy on spontaneous leukemia in mice of the high-leukemic strains, RIL and C58. J. Nat. Cancer Inst., 11: 253-262, 1950. LAW, L. W. and MILLER, J. H. The influence of thymectomy on the incidence of carcinogeninduced leukemia in strain DBA mice. J. Nat. Cancer Inst., 11: 425, 1950. BILLINGHAM,R. E. Cited in Burnet, Sir MacFarlane, The Clonal Selection Theory of Acquired Immunity, p. 88. Nashville, 1959. Vanderbilt University Press. ARCHER, 0. and PIERCE, J. C. Role of thymus in development of the immune response. Fed. PYOC., 20: 26, 1961. HARRIS, T. N., RHOADES, J. and STOKES, J., JR. Study of role of thymus and spleen in formation of antibodies in rabbit. J. Zmmunol., 58: 27, 1948. MACLEAN, L. D., ZAK, S. J., VARCO, R. L. and GOOD, R. A. Thymic tumor and acquired agammaglobulinemia; a clinical and experimental study of the immune response. Surgery, 40: 1010, 1956. THORBECKE,G. J. and KEUNING, F. J. Antibody formation in vitro by haemopoietic organs after subcutaneous and intravenous immunization. J. Zmmunol., 70: 129, 1953. MARSHALL, A. H. E. and WHITE, R. G. Experimental thymic lesions resembling those of myasthenia gravis. Lancet,1: 1030, 1961.
VOL.
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JANUARY
1962
35. CASTLEMAN,B. and NORRB, E. H. The pathology of the thymus in myasthenia gravis. A study of 35 cases. Medicine, 28: 27, 1949. 36. EHRENREICH, T. and ALLEN, A. C. Myasthenia gravis following extirpation of an asymptomatic thymoma. Cancer, 11: 173, 1958. 37. GRAY, H. K. in discussion of Effler, D. B. and McCormack, L. J. Thymic neoplasms. J. Thor& Surg., 31: 60, 1956. 38. CASTLEMAN, B. In: Atlas of Tumor Pathology: Tumors of the Thymus Gland, Sec. V, Fast. 19. Washington, 1955. National Research Council. 39. FORD, F. R. Diseases of the Nervous System in Infancy, Childhood and Adolescence, 4th ed., pp. 1298-1299. Springfield, Ill., 1960. Charles C Thomas. 40. GEDDES,A. K. and KIDD, H. M. Myasthenia gravis of the newborn. Canad. M. A. J.. 64: 152. 1951. 41. NILSBY, I. Myasthenia gravis oi newboin child. Acta paediat., 37: 489, 1949. 42. GAFNI, J., MICHAELI, D. and HELLER, H. Idiopathic acquired agammaglobulinemia associated with thymoma. Report of two cases and review of the literature. New England J. Med., 263: 536, 1960. 43. GOOD, R. A., ROTSTEIN,J. and MAZZITELLO, W. F. Simultaneous occurrence of rheumatoid arthritis and agammaglobulinemia. J. Lab. @3 Clin. Med., 49: 343, 1957. 44. MAWTIN, C. M., GORDON, R. S. and MCCULLOUOH, N. B. Acquired hypogammaglobulinemia in an adult: report of a case with clinical and experimental studies. New England J. Med., 254: 449, 1956. 45. BONDUELLE, M., BORDET, F., BOUYGUES, P. and CHARLES,F. Un cas de polymyosite avec thymome. Verification anatomique. Rev. Neural., 92: 551, 1955. 46. WALI.ER, J. V., SHAPIRO, M. and PALTAUF, R. Congestive heart failure in postmenopausal muscular dystrophy: myositis, myocarditis, thymoma. Am. Heart J.. 53: 479, 1957.
Journal JANUARY
xxx11
of Medicine
1962
Editorial Myasthenia /
Gravis
and the Thymus sions. While these remissions are usually partial and temporary, occasionally they are complete and prolonged. Such a clinical course, together with the predominant occurrence in females in the childbearing age group, form a pattern reminiscent of that seen in systemic lupus erythematosus. Over the age of fifty this sex pattern in myasthenia disappears and male patients are seen more frequently. Neonatal myasthenia gravis, while not a common occurrence, is a unique condition in which the child of a mother with myasthenia gravis manifests, for an average period of three weeks, classic myasthenic weakness responsive to anticholinesterases. The infant’s myasthenia is uniformly transient and does not correlate well with the severity or duration of the maternal disease. The nature and mechanism of action of the substance crossing the placenta are important problems in the study of this disease. Certain diseases are associated with myasthenia gravis more often than can be explained by chance. Hyperthyroidism occurs in over 3 per cent of patients with myasthenia gravis [7,2]. The time of onset of the two disorders follows no consistent pattern. Further studies of this relationship are important, particularly in regard to antithyroid antibodies. Some patients with classic polymyositis or dermatomyositis have weakness of the myasthenic type with improvement after neostigmine therapy. In such cases the ocular muscles are uninvolved 1341, and the characteristic myasthenic defect in neuromuscular transmission has not been demonstrated electromyographitally [5]. On the other hand, some patients with
the past few years new observations have been made concerning the anatomic, physiologic and pharmacologic abnormalities in myasthenia gravis. Recent experiments provide information which suggests that the thymus is an immunologic rather than an endocrine organ. It seems important to review these developments in relation to the pathogenesis of myasthenia gravis.
D
URING
MYASTHENIA
GRAVIS
Clinically, there are certain features of this disease which occur with such regularity, or which are so unique, as to demand explanation by any hypothesis concerned with pathogenesis (Table I). Many of these features are widely known, but certain of them are worthy of special comment. With increasing severity of disease there is a progressive degree of basal weakness at rest and a progressive limitation in the ability of anticholinesterases to improve strength. Such observations indicate that these measures do not correct the basic defect in myasthenia gravis, a point which is widely known but often forgotten. While onset with ocular symptoms with subsequent involvement of other muscle groups is common, the disease in one-fifth of the patients remains limited to extraocular muscles [7]. At the other extreme are patients in whom the extent and severity of the disease progress steadily over a period of weeks, months or years. Most patients fall into an intermediate group whose course is initially one of progressive involvement which reaches a plateau after which there may be periodic exacerbations and remis1
Editorial
2 TABLE I FEATURESOF MYASTHENIA CRAWS
1. Female sex predominance 2. Predilection for ocular and bulbar muscles 3. Increased weakness on voluntary effort with rapid recovery upon rest 4. Residual weakness not responsive to rest or to anticholinesterase medication. 5. Dramatic spontaneous remissions 6. Transient neonatal myasthenia with maternal myasthenia 7. Association with thymic abnormalities and hyperthyroidism
myasthenia gravis have pronounced muscular wasting, and have muscle lesions suggesting myositis [6]. The evidence is not completely convincing that true myasthenia gravis occurs in polymyositis or dermatomyositis, but the possibility of a relationship is intriguing and deserves further study. Review of the cases reporting coincident systemic lupus erythematosus and myasthenia gravis reveals that while the diagnosis of lupus appears definite, the manifestations attributable to myasthenia gravis are atypical and respond poorly to anticholinesterase therapy [3,7]. A number of instances of the familial aggregation of myasthenia gravis have been reported [8]. There are at least fifteen examples of the disease in siblings. In one remarkable family seen at this hospital, four children had classic myasthenic weakness responsive to neostigmine therapy [9]. We have also seen the disease in identical twins. Certain anatomic changes in this disease have been clearly documented: (1) Alterations have been described in the muscle fiber itself consisting of an acute coagulative necrosis. Russell believes the lymphorrhage to be secondary to necrosis of the muscle fibers [IO], but we have seen it in a pericapillary or perivenular position as well. It is of interest that a typical finding in experimental autoimmune disease is the perivenular cuff of lymphocytes [ 7 71. (2) By means of supravital and cholinesterase-staining technics an abnormal branching or an elongation of the motor nerve terminals has been demonstrated [ 12,131. (3) Electron microscopic studies have revealed focal areas of decreased density of the end-plate sarcolemma within the secondary synaptic clefts. In severe myasthenia, there was also widening of the clefts, disruption of their basement membrane and focal deposits in the axoplasm of the nerve terminal [ 741.
Most investigators have focused their interest on the physiologic and pharmacologic aspects of myasthenia gravis. The electrophysiologic abnormalities are consistent with a decreased acetylcholine effect on the motor end-plate, but there is disagreement as to its cause. There are two major possibilities: (1) diminished synthesis or release of acetylcholine by the nerve ending; and (2) decreased sensitivity of endplates to acetylcholine liberated in normal amounts. Increased destruction of acetylcholine has been reasonably well excluded. Supporting the first possibility are the similarities between the neuromuscular block in myasthenia gravis and that produced by drugs known to interfere with acetylcholine synthesis or release [lg. Favoring the second is the reduced responsiveness in the patient with myasthenia gravis to injection of acetylcholine and similar drugs, for if the defect were in acetylcholine release, one would anticipate that an injection of acetylcholine would have its usual effect [ 76791. Direct evidence has been obtained by recording from myasthenic end-plates in vitro [ZO]. Miniature end-plate potentials (which result from the spontaneous release of packets of acetylcholine from nerve endings) were found to be of normal amplitude, indicating no decrease in end-plate responsiveness. The frequency of the release of these packets of acetylcholine was less than normal, and could not be increased by the usual maneuvers. This evidence weighs heavily in favor of a defect in the nerve ending. However, since these muscles were not clinically involved, one cannot exclude end-plate insensitivity in the involved muscles. Immunologic abnormalities have recently been described, using fluorescein-labeled serum globulin. The serum globulin in some patients with myasthenia was bound to skeletal muscle, while this fraction in normal subjects was not [21]. This binding was associated with the fixation of complement. Further studies indicated that this serum component was a 7S gamma globulin [22]. This material was found in the region of the A band of the muscle fiber but spared the H zone [23], suggesting that the binding site is in the area of overlap between the primary and secondary filaments of the myofibril. The myasthenic globulin fixes to normal human muscle and to the skeletal muscle of other species as well, but not to human cardiac muscle. Questions under investigation include the specificity of this reaction for myasthenia gravis, the correlation AMERlCAN
JOURNAL
OF
MEDICINE
Editorial with the clinical status of the patient, and the relationship to neonatal myasthenia gravis. The unique clinical characteristics of myasthenia gravis suggest that it is a uniform disease due to a specific functional defect. The anatomic, physiologic and pharmacologic studies demonstrate that this disorder is localized to the region concerned with neuromuscular transmission, and that nerve terminal, end-plate and muscle fiber may be involved. This is an area in which closely related and highly specific enzyme proteins play a vital role in normal function. The demonstration of an abnormal globulin which attaches to muscle, the phenomenon of neonatal myasthenia, together with the nature of the pathologic lesions raise the intriguing possibility than an immune mechanism may be involved in pathogenesis. THE
FUNCTION
OF THE
THYMUS
There has been renewed interest in the function of the thymus. In studies of the formation of a lymphoidal thymus from its epithelial rudiment it appears that lymphocytes can arise intrinsically during the embryonic development of this structure [Z]. This organ is a source of circulating lymphocytes [25], and has been demonstrated to contain a lymphocyte-stimulating factor thought to be produced by the epithelial cells [26]. This is of interest in relation to the observation that in the absence of the thymus the incidence of spontaneous [27] or induced [28] lymphocytic leukemia in mice is sharply reduced. Thymic lymphocytes are capable of eliciting the graft versus host reaction indicating that they are immunologically competent cells [29]. In the immature animal the thymus is necessary for the production of circulating antibodies to foreign protein [30]. While the adult thymus has not been demonstrated to produce antibody in response to the remote injection of antigen [31-331, it has been shown to be immunologically reactive to the direct injection of antigen [34]. The histologic response under these circumstances is similar to that seen in the myasthenic thymus with intense germinal center formation and to the secondary immune response in other lymphatic tissues exposed to antigen. The lack of antibody response to circulating antigen in the adult thymus may be attributed to failure of antigen to gain access to thymic cells except when the thymus is injured [34]. VOL.
32,
JANUARY
1962
These observations that the thymus plays an immunologic role take on added significance when one reviews the thymic changes in myasthenia gravis. THE
THYMUS
IN
MYASTHENIA
CRAWS
The coincidence of thymic hyperplasia or thymoma and myasthenia gravis is well established and far exceeds a chance relationship. When associated with thymoma the onset of myasthenia is later in life, there is a male sex preponderance [35], and in general the weakness is more severe and progressive [ 71, although there is considerable individual variability. In some instances detection of the thymoma precedes the onset of myasthenia by many years, and in at least three instances myasthenia appeared several years following apparent total thymectomy [ 1,36,37]. Histologically this tumor is composed of variable mixtures of epithelial and lymphocytic cells (thymocytes), which are the normal thymic constituents. The epithelial cells may be arranged in cords or clumps surrounded by lymphocytic cells giving a “glandular” appearance. Sometimes there are perivascular cuffs of lymphocytes [38] reminiscent of the perivenular lymphocytic accumulations in experimental autoimmune disease [II]. Thymic hyperplasia is even more commonly associated with myasthenia. Here the temporal relationship is more difficult to establish, for frequently the hyperplasia is not detectable clinically. The characteristic microscopic finding is the abnormal proliferation of lymphocytic elements with the formation of numerous germinal centers, even in the absence of gross enlargement of the thymus. It seems unlikely that the thymus is the source of the pathogenic material in neonatal myassince in three thenia, instances maternal thymectomy had been performed prior to pregnancy [39-471. More recently, other disorders have been reported in association with thymoma. Refractory anemia due to erythroid hypoplasia is the most common, but granulocytopenia and thrombocytopenia have been described as well. Some of these patients have had myasthenia gravis as well as cytopenia. Four cases are recorded of acquired agammaglobulinemia associated with thymoma. These patients did not have myasthenia gravis [42&U]. Two patients
Editorial with myositis in association with thymoma have been described, but neither responded to therapy with neostigmine [B&46]. The pathologic changes in thymic hyperplasia resemble those described in a thymus under antigenic stimulation, while the perivascular lymphocytic cuffing seen in the thymomas resembles the lesion associated with delayed hypersensitivity. That these thymus abnormalities are not the primary cause of myasthenia gravis is suggested by the instances in which neonatal myasthenia developed after maternal thymectomy prior to pregnancy and by the development of the disease following presumably total thymectomy. In our present state of knowledge the understanding of this collection of observations is still in a rather primitive state. The scanty evidence that myasthenia gravis may be a unique type of response to some as yet unknown immunologic abnormality, the growing indications that the thymus plays an immunologic role which may be under endocrinologic supervision, together with the well established thymic abnormality in this disease, provide a substantial direction for future research A coordinated approach to these problems using the anatomic, physiologic, pharmacologic and immunologic technics now available should be a productive one.
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A. MCGEHEE HARVEY, M.D. J. JOHNS, M.D.
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Department of Medicine The Johns Hopkins University School of Medicine and Hospital Baltimore, Maryland
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REFERENCES 1. GROB, D. Myasthenia gravis, current status of pathogenesis, clinical manifestations, and management. J. Chron. Dis., 8: 536, 1958. 2. SILVER, S. and OSSERMAN,K. E. Hyperthyroidism and myasthenia gravis. J. Mount Sinai Hosp., 24: 1214, 1957. 3. ROWLAND, L. P., HOEFER, P. F. A. and ARANOW, H., JR. Myasthenic syndromes. Res. Publ. A. New. @ Ment. Dis., 38: 548, 1958. 4. WALTON, J. N. and ADAMS,R. D. Polymyositis. Baltimore, 1958. Williams & Wilkins, Co. 5. RICHARDSON,A. T. Clinical and electromyographic aspects of polymyositis. Proc. Roy. Sot. Med., 49: 111,1956. 6. SIMPSON,J. A. Myasthenia gravis: a new hypothesis. Scot. M. J., 5: 419, 1960. 7. HARVEY, A. M., SHULMAN, L. E., TUMULTY, P. A., CONLEY, C. L. and SCHOENRICH, E. H. Systemic
19.
20.
21.
22. 23.
lupus erythematosus: Review of the literature and clinical analysis of 138 cases. Medicine, 33: 291, 1954. KURLAND,L. T. and ALTER, M. Current status of the epidemiology and genetics of myasthenia gravis. In: Myasthenia Gravis, pp. 307-336. Edited by Viets, H. R. Springfield Ill., 1961. Charles C Thomas. WALSH, F. B. and HOYT, W. F. External ophthalmoplegia: as a part of congenital myasthenia in siblings: myasthenia gravis in children: report of a family showing congenital myasthenia. Am. J. Ofihth., 47: 28, 1959. RUSSELL,D. S. Histological changes in the striped muscles in myasthenia gravis. J. Path. But., 65: 279,1953. WAKSMAN, B. H. A comparative histopathological study of delayed hypersensitivity reactions. In: Ciba Foundation Symposium on Cellular Aspects of Immunity. Edited by Wolstenholme, G. E. W. and O’Connor, M. Boston, 1960. Little, Brown & co. CGERS, C. and DESMEDT,J. E. Abnormal end-plates in myasthenic muscle. Lance& 2: 1124, 1958. C~ERS, C. and WOOLF, A. L. The Innervation of Muscle, a Biopsy Study. Springfield, Ill., 1959. Charles C Thomas. ZACKS, S. I., BAUER, W. C. and BLUMBERG,J. M. Abnormalities in the fine structure of the neuromuscular junction in patients with myasthenia gravis. Nature, London, 190: 280, 1961. DESMEDT,J. E. Myasthenic-like features of neuromuscular transmission after administration of an inhibitor of acetylcholine synthesis. Nature, London, 182: 1673, 1958. CHURCHILL-DAVIDSON, H. C. and RICHARDSON,A. T. Neuromuscular transmission in myasthenia gravis. J. Physiol., 122: 252, 1953. CHURCHILL-DAVIDSON, H. C. and RICHARDSON,A. T. A study of neuromuscular transmission in one hundred cases of myasthenia gravis. In: Myasthenia Gravis, pp. 199-207. Edited by Viets, H. R. Springfield, Ill., 1961. Charles C Thomas. GROB, D., JOHNS,R. J. and HARVEY, A. M. Studies in neuromuscular function. IV. Stimulating and depressant effects of acetylcholine and choline in patients with myasthenia gravis, and their relationship to the defect in neuromuscular transmission. Bull. Johns Hojkins Hosp., 99: 153, 1956. GROB, D., JOHNS,R. J. and HARVEY, A. M. Studies in neuromuscular function. VI. Effects of anticholinesterase compounds, d-tubocurarine, and decamethonium in patients with myasthenia gravis. Bull. Johns Hopkins Hosp., 99: 219, 1956. DAHLBKCK,O., ELMQVIST,D., JOHNS,T. R., RADNER, S. and THESLEFF,S. An electrophysiologic study of the neuromuscular junction in myasthenia gravis. J. Physiol., 156: 336, 1961. STRAUSS,A. J. L., SEEGAL, B. C., Hsu, J. C., BURKHOLDER, P. M., NASTIJK, W. L. and OSSERMAN, K. E. Immunofluorescence demonstration of a muscle binding, complement-fixing serum globulin fraction in myasthenia gravis. Proc. Sot. Exjer. Biol. &3 Med., 105: 184, 1960. STRAUSS,A. Personal communication. STRAUSS,A., DEITCH, A. and Hsu, K. Further obAMERICAN
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24.
25. 26.
27.
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29.
30.
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33.
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servations on the localization of a muscle-binding, complement-fixing seruin globulin fraction in myasthenia gravis. Fed. Proc., 20: 38, 1961. BALL, W. D. and AUERBACH,R. In vitro formation of lymphocytes from embryonic thymus. Exfer. Cell Res., 20: 245, 1960. SCHOOLEY,J. C. and KELLY, L. S. The thymus in lymphocyte production. Fed. PYOC., 20: 71, 1961. METCALF, D. The thymic origin of the plasma lymphocytosis stimulating factor. &it. J. Cancer, IO: 442, 1956. LAW, L. W. and MILLER, J. H. Observations on the effect of thymectomy on spontaneous leukemia in mice of the high-leukemic strains, RIL and C58. J. Nat. Cancer Inst., 11: 253-262, 1950. LAW, L. W. and MILLER, J. H. The influence of thymectomy on the incidence of carcinogeninduced leukemia in strain DBA mice. J. Nat. Cancer Inst., 11: 425, 1950. BILLINGHAM,R. E. Cited in Burnet, Sir MacFarlane, The Clonal Selection Theory of Acquired Immunity, p. 88. Nashville, 1959. Vanderbilt University Press. ARCHER, 0. and PIERCE, J. C. Role of thymus in development of the immune response. Fed. PYOC., 20: 26, 1961. HARRIS, T. N., RHOADES, J. and STOKES, J., JR. Study of role of thymus and spleen in formation of antibodies in rabbit. J. Zmmunol., 58: 27, 1948. MACLEAN, L. D., ZAK, S. J., VARCO, R. L. and GOOD, R. A. Thymic tumor and acquired agammaglobulinemia; a clinical and experimental study of the immune response. Surgery, 40: 1010, 1956. THORBECKE,G. J. and KEUNING, F. J. Antibody formation in vitro by haemopoietic organs after subcutaneous and intravenous immunization. J. Zmmunol., 70: 129, 1953. MARSHALL, A. H. E. and WHITE, R. G. Experimental thymic lesions resembling those of myasthenia gravis. Lancet,1: 1030, 1961.
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35. CASTLEMAN,B. and NORRB, E. H. The pathology of the thymus in myasthenia gravis. A study of 35 cases. Medicine, 28: 27, 1949. 36. EHRENREICH, T. and ALLEN, A. C. Myasthenia gravis following extirpation of an asymptomatic thymoma. Cancer, 11: 173, 1958. 37. GRAY, H. K. in discussion of Effler, D. B. and McCormack, L. J. Thymic neoplasms. J. Thor& Surg., 31: 60, 1956. 38. CASTLEMAN, B. In: Atlas of Tumor Pathology: Tumors of the Thymus Gland, Sec. V, Fast. 19. Washington, 1955. National Research Council. 39. FORD, F. R. Diseases of the Nervous System in Infancy, Childhood and Adolescence, 4th ed., pp. 1298-1299. Springfield, Ill., 1960. Charles C Thomas. 40. GEDDES,A. K. and KIDD, H. M. Myasthenia gravis of the newborn. Canad. M. A. J.. 64: 152. 1951. 41. NILSBY, I. Myasthenia gravis oi newboin child. Acta paediat., 37: 489, 1949. 42. GAFNI, J., MICHAELI, D. and HELLER, H. Idiopathic acquired agammaglobulinemia associated with thymoma. Report of two cases and review of the literature. New England J. Med., 263: 536, 1960. 43. GOOD, R. A., ROTSTEIN,J. and MAZZITELLO, W. F. Simultaneous occurrence of rheumatoid arthritis and agammaglobulinemia. J. Lab. @3 Clin. Med., 49: 343, 1957. 44. MAWTIN, C. M., GORDON, R. S. and MCCULLOUOH, N. B. Acquired hypogammaglobulinemia in an adult: report of a case with clinical and experimental studies. New England J. Med., 254: 449, 1956. 45. BONDUELLE, M., BORDET, F., BOUYGUES, P. and CHARLES,F. Un cas de polymyosite avec thymome. Verification anatomique. Rev. Neural., 92: 551, 1955. 46. WALI.ER, J. V., SHAPIRO, M. and PALTAUF, R. Congestive heart failure in postmenopausal muscular dystrophy: myositis, myocarditis, thymoma. Am. Heart J.. 53: 479, 1957.