Tatsuji Namba

THE NATURAL COURSE OF MYASTHENIA GRAVIS AND EFFECT OF THERAPEUTIC MEASURES

Prior to the introduction in 1934 of anticholinesterase compounds for diagnosis and management of myasthenia gravis,’ the few patients recognized with the disease were mainly those with severe illness and high mortality.2* For example, the records of the Johns Hopkins and Maimonides Hospitals from 1900 to 1934 show a yearly average of two new patients, most of whom died within a year after onset. After 1934, the disease was much more frequently recognized (50 patients per year in these hospitals), but since almost all patients received anticholinesterase medication, and many had thymectomy and assisted ventilation after 1939,4 pressure or volume controlled respiration after 1960,5 and corticosteroids after 1966,6 it has not been possible to delineate the “natural” course of the disease. In 300 patients with generalized myasthenia gravis who were followed between 1940 and 1958, 30% died, 26% improved, 21 % remained unchanged, 13% went into remission, and 10% became w ~ r s e . ~ ~ Patients who had thymectomy did somewhat better (by about 7%) than those who did not. In reports from 1958 to 1971, death occurred in 31% and improvement in 52% of 726 patients who did not have thymectomy, death in 14% and improvement in 68% of 744 patients who had a nonthymomatous thymus removed (p < 0.001), and death in 43% and improvement in 31% of 169 patients who had a thymoma removed.1°-15 During the past 20 years, there has been a reduction in mortality and morbidity of the disease,lG attributed to improvement in management, but specific factors have been difficult to isolate. The present study describes the course of the disease during the past 40 years and factors affecting its’ outcome.

CORTICOTROPIN AND CORTICOSTEROIDS IN GENERALIZED MYASTHENIA GRAVIS: COMPARATIVE STUDIES AND ROLE IN MANAGEMENT

The effect of 310 courses of corticotropin, methylprednisolone, prednisone, and dexamethasone were studied in 62 patients with generalized myasthenia gravis who were poorly responsive to anticholinesterase medication and most of whom required assisted respiration. Improvement in strength and response to anticholinesterase medication occurred in 91% of the courses, and was moderate or marked in 63%. The incidence, degree, and duration of improvement appeared to be dose related. High doses of dexamethasone (20 mg orally each day for 10 days, repeated if necessary), which had 75% more glucocorticoid effect than any other regimen studied, produced the highest incidence of both improvement (100%) and moderate-to-marked improvement (75%), and the greatest duration of improvement (more than 3 months after 40% of the courses). The duration of improvement following intensive courses of any of the corticosteroids was approximately doubled by the subsequent administration of smaller doses of dexamethasone or prednisone on alternate days. Most patients with severe disease relapsed after 3 to 6 months of corticosteroid treatment, but increase in the dose of corticosteroid, and daily administration, which was more effective than alternate-day administratin, almost always again resulted in improvement. Corticotropin and corticosteroids were equally effective before and after thymectomy. High doses of corticotropin and corticosteroid produced an initial exacerbation of the disease in 80% of the courses, which was moderate or marked in 57%. Reduction in dose reduced the incidence of severe exacerbation, but did not prevent it, and also resulted in slower and less marked improvement. Withholding anticholinesterase medication did not prevent exacerbation or increase improvement, and afforded no advantage, though it was usually helpful to reduce the dose of this medication. Because of the hazard of initial exacerbation and the occurrence of other serious side effects in 15% of the patients. (bleeding ulcer, vertebral compression, aseptic necrosis of the femoral head or tibia, and subcapsular cataracts), it is recommended that corticosteroid treatment be limited to myasthenic patients who are not responding satifactorily to anticholinesterase medication, that smaller doses be employed in patients whose disease is not life threatening, and that higher doses be reserved for patients who are critically ill and are being managed, at least initially, in an intensive care unit.

Association of myasthenia gravis with pemphigus vulgaris, Candida albicans infection, polymyositis and myocarditis

Abstract A 52-year-old man developed generalized myasthenia gravis, with pronounced oculobulbar muscle weakness. At the age of 54, he developed pemphigus vulgaris, manifested by papulo-bullous eruptions in the skin and oral mucosa, and by the presence of serum globulin which bound to intercellular substance of the stratified squamous epithelium. Candida albicans was repeatedly cultured from the oral lesions. At the age of 56, the patient developed severe weakness of trunk and limb muscles, and elevation in the serum of enzymes originating from muscle. The electromyogram was compatible with both myasthenia gravis and polymyositis, and the muscle biopsy with polymyositis. The electrocardiogram indicated myocardial damage. The patient died suddenly. Post-mortem examination revealed degenerative changes in skeletal and cardiac muscle, with interstitial and perivascular round cell infiltration, round cell infiltration of the thyroid, and a normal thymus. The patient demonstrated the association of myasthenia gravis with polymyositis (58 reported patients) with pemphigus vulgaris (9 reported patients), with Candida albicans infection, and with lesions in the myocardium.

THE ROLE OF HUMORAL AND CELLULAR IMMUNE FACTORS IN NEUROMUSCULAR BLOCK IN MYASTHENIA GRAVIS

The neuromuscular block of myasthenia gravis appears to be due to decreased and abnormal responsiveness of the motor end plates to transmitter, and perhaps a decreased number of functioning end plates. The presence in myasthenic patients of serum globulins that bind to a bariety of cellular and subcellular components, and of thymic abnormalities, has encourage the search for humoral and cellular immune factors that may be responsible for the anatomic and functional defects. Attempts to demonstrate neuromuscular blocking activity in the serum have been inconclusive. While 30% to 48% of myasthenic patients have globulins that react with muscle membrane, striations, ribonucleporotein, and thymic epithelial cells, these globulins have not been shown to react with the end plate or acetylcholine receptor, or to impair neuromuscular transmission. Antinuclear, rheumatoid, antimitochondrial antithyroid, anti-smooth-muscle, and anti-gastric-parietal cell factors are found in the serum of 3% to 16% of myasthenic patients, but these are much more commonly present in other diseases. However, antibodies to acetylcholine receptor from electric tissue, which were recently reported in the serum of three fourths of myasthenic patients, may prove to be more directly related to the neuromuscular block. While the majority of myasthenic patients have thymic abnormalities, including thymoma in 9% of patients and hyperplastic thymus in 66% of patients, the remaining 25% of patients have normal, involuted, or undetectable thymus. Thymectomy has a favorable effect in about two thirds of myasthenic patients, but about one third of patients have no benefit. Thirty-two patients have been described who developed myasthenia gravis after total thymectomy and presumably in the absence of the thymus. Thymus lymphocytes of myasthenic patients have some differences from those of normal subjects, including a greater proportion of B cells, but their significance is not known. Attempts to demonstrate neuromuscular blocking activity in the thymus of myasthenic patients have been inconclusive. Blood lymphocytes of myasthenic patients also have some differences from those of normal subjects, including a lower proportion of T cells. The proportion of both T and B cells increased following thymectomy. While studies on the immunological reactivity of lymphocytes from myasthenic patients have shown some differences from those of normal subjects, neuromuscular blocking activity has not been demonstrated in these cells or in their extracts. There is increasing evidence that the neuromuscular block of myasthenia gravis is due to alteration of the acetylcholine receptor. The recent reports of antibodies to acetylcholine receptor in the serum of myasthenic patients suggests that these may be responsible for the neuromuscular block, but such action, and the cause of antibody release, remain to be determined.

DESENSITIZATION TO ACETYLCHOLINE AT MOTOR END PLATES IN NORMAL HUMANS, PATIENTS WITH MYASTHENIA GRAVIS, AND EXPERIMENTAL MODELS OF MYASTHENIA GRAVIS

Desensitization to ionophoretically applied ACh at the motor end plates of normal humans and patients with MG was studied. The pattern of desensitization at the normal human motor end plate was completely consistent with that observed in muscles of various animals. At motor end plates of MG patients there was greater desensitization and slower recovery from desensitization than in normals. A similar pattern of desensitization was observed at normal end plates when they were exposed to serum globulins of MG patients, and at end plates of muscles from mice than were repeatedly injected with serum globulins of MG patients. Despite the reported reduction in the number of ACh receptors, our calculations show that there is a large pool of spare receptors forming a sizeable margin of safety at the end plates of MG patients. The number of receptors may not show additional progressive reduction in number during repetitive motor activity. Our results indicate that desensitization could play a significant role in the development of neuromuscular block following repetitive motor activity in MG patients. The mechanism by which desensitization is augmented in MG patients in not yet clear.

Cholinesterase activity of muscle fibers and motor end plates: Comparative studies

Abstract Cholinesterase activity of skeletal muscle and its subcellular fractions, including motor end plates, was compared chemically and histochemically in man, mouse, guinea pig, rat, dog, and chicken. The total cholinesterase activity of muscle per milligram of nitrogen was highest in man (4,135 × 10 −9 moles of acetylcholine hydrolyzed in 30 min) and in descending order, decreased in mouse, chicken (red muscle), rat, and dog, to a value of 245 in chicken (white muscle). Cholinesterase was present in all subcellular components fractionated by differential centrifugation, and was greatest in the microsome fraction followed generally, in descending order, by the mitochondria, myofibril, and supernatant fractions. Each of these fractions had greater cholinesterase activity in human muscle than in mouse muscle, and in mouse muscle than in muscle of other species. The ratio of the activities of the microsome fraction and total muscle ranged from 9.5 in man to 2 in guinea pig. Greater concentration of cholinesterase activity was also demonstrated electron microscopically in the sarcotubular system in rat. Because of its relatively greater proportion, the myofibril fraction appears to contribute most to the total cholinesterase activity of muscle. Isolated muscle membrane contained high cholinesterase activity of motor end plates, and the activity was greater than the activity of the microsome fraction in guinea pig, rat, and chicken. The cholinesterase activity per motor end plate was in descending order from 0.805 in the rat, through man, guinea pig, and mouse, to 0.180 in dog, and the variation is less than the variation of the total muscle cholinesterase activity among these species.