94 Myasthenia Gravis

Myasthenia gravis is a disorder of skeletal muscle characterized by weakness and easy fatigability due to autoimmune destruction of the acetylcholine re­ceptor in the postsynaptic membrane of the neuro­muscular junction.

Distribution and Incidence

The disease has a worldwide distribution and has been identified as the primary cause of death at the average annual rate of 1.5 per million in the United States. If cases coded as contributory or as a compli­cation are included, then the total would be 2 to 2.5. This seems to be the safest method of reckoning the actual incidence of myasthenia gravis, and previous estimates of 1 in 1,600 of the population probably vastly overestimate the incidence of myasthenia. There is no difference between whites and non­whites, and there is no difference in nationality. The death rate is slightly higher for women than men. In age-adjusted death rates for all ages, there is no appreciable difference in nine geographic regions of the United States. Thus myasthenia gravis seems to be uniformly distributed throughout the United States, and probably is uniformly distributed throughout the world. There is no difference be­tween city and country in the incidence of myas­thenia gravis, and the age-specific death rates for the United States, based on a survey of 675 death certificates listing myasthenia gravis as the primary cause of death, showed that 90 percent of the dece­dents were older than 15 years of age. For this popu­lation the age-specific death rate is less than 1 per million until age 35, when there is a steady increase in the incidence of death for myasthenia gravis up to age 75. There appears to be a twin-peaked incidence, with females peaking between the ages of 15 and 24, and men peaking between ages 40 and 60. But if all ages are considered together, the sex ratio is proba­bly close to 1. Morbidity data in surveys of the United States, Canada, England, Norway, and Ice­land over a 10-year period using retrospective analy­sis show that the incidence of myasthenia is proba­bly 0.2 to 0.5 per 100,000, with the prevalence being 3 to 6 per 100,000.

Etiology and Immunology

The overwhelming evidence is that myasthenia gravis is due to an immune system dysfunction that produces an autodirected antibody against the acetylcholine receptor in the postsynaptic mem­brane of the neuromuscular junction. The evidence is clinical, laboratory, serologic, and therapeutic. The clinical evidence that myasthenia is an auto­immune disease is based on the association of myas­thenia with vaccination, insect sting, infection, or trauma; and its association with autoimmune dis­eases such as hypothyroidism, systemic lupus, and polymyositis. Many laboratory abnormalities point to the immune system dysfunction in myasthenia gravis. These include serologic abnormalities, in­creased incidence of a specific human leukocyte anti­gen (HLA-B8) in certain types of disease, histologic abnormalities of thymus and skeletal muscle, and abnormal responsiveness of lymphocytes to mito­gens. Antinuclear antibodies are positive in uncom­plicated myasthenia in about 18 percent of cases and in 54 percent of myasthenic patients who have thymoma, a tumor derived from elements of the thy­mus. Antistriated muscle antibodies are present in about 11 percent of patients with uncomplicated myasthenia and in all patients who have myas­thenia associated with thymoma. Perhaps the most important serologic test in myasthenia is the IgG antibody directed against the acetylcholine receptor.

This antibody is probably positive in 70 to 95 percent of clinically diagnosed myasthenic patients and is the cause of the weakness and easy fatigability in the disease. Myasthenia gravis can be readily pro­duced in animals by immunizing them against their acetylcholine receptor. Experimental autoimmune myasthenia gravis usually develops 2 to 3 weeks after immunization with the receptor and has all the features of human myasthenia gravis. Myasthenia gravis responds to all of the manipulations against the immune system that one would expect to see if the disease were of autoimmune origin.

Clinical Manifestations

The single most important clinical feature of myas­thenia gravis is weakness of skeletal muscle wors­ened by exercise and relieved by rest. Without this feature there can be no diagnosis. Weakness with easy fatigability is the only constant in this disease; all other features are variable. For instance, the weak­ness is usually worse in the afternoon and evening, although some patients are weaker in the morning when they first awaken. Usually the muscles sup­plied by the cranial nerves are the first and most severely affected, with resultant diplopia, ophthal­moplegia, dysphagia, dysphonia, dyspnea, and dys- mimia. The disease may involve proximal lower- and upper-extremity muscles. In rare instances, however, proximal muscles weaken first. Involvement of indi­vidual muscles may be symmetrical, but is often asymmetrical with a dominant leg and arm usually weaker than a nondominant counterpart. Myasthe­nia gravis can also present as weakness of a single muscle - for example, the external rectus or superior oblique in one eye - or as a single complaint - for in­stancejaw ptosis from inability to close the mouth. It can also present as a symptom seemingly unrelated to the neuromuscular system - for instance, burning eyes from exposure to keratitis, from incomplete eye closure during sleep, or a sore throat on awakening from mouth breathing during sleep. The disease may affect people at any age or of either sex and varies in severity from mild nonprogressive disease involving the eyes only (ocular form) to severe cases that may be rapidly fatal such as acute myasthenia gravis af­flicting older men.

Diagnosis and Pathology

No two myasthenic patients look alike or have the same signs and symptoms. The classical appearance is unmistakable and is usually associated with bilat­eral ptosis, weakness of the face, and difficulty in smiling, chewing, and talking.

History

Seventeenth Century

Although myasthenia gravis was not described with any pretense of completeness as a clinical entity until the last quarter of the nineteenth century, a reference by Thomas Willis, an astute seventeenth­century English clinician, indicates that Willis probably knew of the disease and recognized the chief symptom of asthenia of the voluntary muscles with recovery after rest. The description of weakness in his patients occurs in his book on the physiology and pathology of disease with illustrated cases, De anima brutorum (1672), published in two separate editions the same year in Oxford and in London. The book was translated into English by S. Pordage in 1683 and published as “Two Discourses Concerning the Souls of Brutes” in Willis’s Practice of Physick (London 1684). The significant part is as follows:

There follows another kind of this disease i.e., the palsy, depending on the want and fewness of spirits in which although motion be not deficient in any part or member wholly, yet it is not performed in any but the weakly and depravedly only. For though the distempered are free from want of motion they are not able however to move their member strongly or to bear any weight. Moreover, in ev­ery motor endeavor, they labor with a trembling of their limbs which is only a defect of debility and of a broken strength in the mode of power.

He then goes on to say that the patients with this affliction, although languishing in their limbs, are well in their stomachs and have a good and laudable pulse and urine. “Yet, they are as if they were inner­vated and cannot stand upright and dare scarce en­ter upon local motions, or if they do cannot perform them long. Yea, some without any notable sickness are for a long time fixed in their bed as if they were everyday about to die” Willis then goes on to state what has been often quoted:

At this time I have under my charge a prudent and honest woman who for many years have been obnoxious to this sort of spurious palsy, not only in her members, but also in her tongue. She for sometimes can speak freely and readily enough, but after she has spoke long or hastily or eagerly, she is not able to speak a word but becomes mute as a fish, nor can she recover the use of her voice under an hour or two.

Thus did Willis note that his patients developed general, “although partial paralysis,” and that they were not able to move their members strongly or bear any weight. This seems to be a description of myasthenia gravis, although, of course, we will never really know.

Nineteenth Century

Nearly 200 years were to pass from the time of Willis before myasthenia gravis was again mentioned in the medical literature. The next recorded observa­tion appears to have been made by an English physi­cian, Samuel Wilks in 1877, one of the physicians to Guy’s Hospital, London, who, when describing some cases of bulbar paralysis, described a patient with symptoms slightly similar to myasthenia gravis. He talked about a woman who could scarcely walk and had defective extraocular movement. Her speech was slow and deliberate, and she fatigued easily. Subsequently, she developed trouble swallowing and was unable to cough and died of respiratory paraly­sis. This is an incomplete discussion, but is the first fatal case of myasthenia gravis ever described in the medical literature.

The first really complete report of myasthenia gravis was given by Wilhelm W Erb in 1879; he described a patient, age 55, who was seen in 1868,11 years prior to the publication of the case record. The patient’s illness had developed over a period of four months, and the first principal symptoms, which were clearly described, included ptosis, neck weak­ness, and dysphagia. Some atrophy was noticed in the neck muscles, and the patient seemed to respond to faradism (induced current). The patient was proba­bly one of the first to be treated by Erb with electric­ity. The patient, George Fuss, a day laborer, went into remission, and it was natural for Erb to attri­bute the improvement to his electrical treatment. Erb’s second case was Magdalene Meisel, a peasant 30 years of age, first seen in 1870. Her symptoms were double vision, ptosis, dysphagia, and weakness. She died suddenly at night, and no autopsy was done. She had clear-cut exacerbations and remis­sions. The third patient reported by Erb, August Thai, a merchant, age 47 years, had difficulty hold­ing his head up, and showed bilateral ptosis and facial weakness.

Subsequently, a score more cases were reported by 1893, when Samuel V. Goldflam reported a detailed study of myasthenia gravis. Goldflam mentions all of the currently accepted clinical signs and symp­toms of the disease, which he summarized as follows:

1. The disease occurs in early life.

2. Both sexes are equally affected.

3. It is a disease of the motor system.

4. Chewing, swallowing, and eye movements are most affected at first, followed by involvement of trunk extremity.

5. Trunk involvement is usually but not necessarily always symmetrical.

6. Most patients are worse in the afternoon and eve­ning and are improved by rest.

Goldflam also mentioned that daily exacerbations and remissions may occur, and that death may be due to respiratory impairment, and may occur sud­denly. His article in many ways is the most impor­tant ever written in the history of myasthenia gravis.

The next major advance occurred a year later, in an 1894 paper by F. Galle. He was the first to ana­lyze the reaction of muscles in myasthenia gravis to electrical stimulation and to name the disease. He also suggested physostigmine as a form of drug treat­ment, but he does not seem to have followed up on this important point; it was left to Mary Walker, 40 years later, to demonstrate the therapeutic value of physostigmine.

Twentieth Centiuy

Modem studies of the pathological physiology of myasthenia gravis started with the work of A. M. Harvey (1948), and a series of illustrious colleagues, including Richard Masland, D. Grob, and T R. Johns. These men recognized the characteristic re­sponse of the evoked muscle action potential to re­petitive stimulation of nerve, thereby localizing the defect of myasthenia gravis to the neuromuscular junction.

In 1964, E. Elmquist and colleagues, using mi­croelectrode techniques on human intercostal mus­cle, seemed to show that there was too little acetylcholine in each quantum released from the nerve terminal, an abnormality that could be ex­plained by the presence of a false transmitter or by an abnormal binding or packaging of acetylcholine quanta. This particular finding, as it subsequently turned out, was in error, and we now know that the postsynaptic membrane is poorly sensitive to in­fused acetylcholine and that the defect in myas­thenia gravis has nothing to do with any presynaptic defect. In fact, presynaptic release of acetylcholine in myasthenia gravis is normal.

In the meanwhile, evidence was accumulating that there was an immunologic disorder in myasthenia. This was first suggested by D. W. Smithers in 1959, who recognized the histological parallel between the thymus in myasthenia and the thyroid gland in thy­roiditis. The following year, J. A. Simpson drew atten­tion to the increased frequency, in myasthenia gravis, of other diseases regarded as autoimmune, especially rheumatoid arthritis. But the major advance oc­curred in 1973, when J. Patrick and J. M. Lindstrom injected rabbits with acetylcholine receptors purified from electric eel, intending to make antibodies to the acetylcholine receptor. In the process, they induced and recognized experimental autoimmune myasthe­nia gravis. This led to experiments indicating the na­ture of the human disease. We now know that the disease is caused by a circulating antibody directed against the acetylcholine receptor and that treat­ments directed against the abnormal antibody are effective in modifying the clinical signs and symp­toms of myasthenia gravis.

Bernard M. Patten

Harvey, A. M. 1948. Some preliminary observations on the clinical course of myasthenia gravis before and after thymectomy. Bulletin of the New York Academy of Medicine 24: 505-22.

Lindstrom, J. M., et al. 1976. Antibody to acetylcholine receptor in myasthenia gravis: Prevalence, clinical cor­relates and diagnostic value. Neurology 26: 1054—9.

Lisak, R. P., and R. L. Barchi. 1982. Myasthenia graυis. London.

Mann, J. D., T. R. Johns, and J. F. Campa. 1976. Long­term administration of corticosteroids in myasthenia gravis. Neurology 26: 729.

Newsom-Davis, J. 1979. Plasma exchange in myasthenia gravis. Plasma Therapy 1: 17.

Osserman, K. E. 1958. Myasthenia gravis. New York.

Patrick, J., and J. M. Lindstrom. 1973. Autoimmune re­sponse to acetylcholine receptor. Science 180: 871—2.

Patten, B. M. 1978. Myasthenia gravis. Muscle and Nerve 1: 190.

Schwab, R. S., and C. C. Leland. 1953. Sex and age in myasthenia gravis as critical factors in incidence and remission. Journal of the American Medical Associa­tion 153: 1270.

Simpson, J. A. 1966. Myasthenia gravis as an autoim­mune disease: Clinical aspects. Annals of the New York Academy of Sciences 135: 506-16.

Vincent, A. 1980. Immunology of acetylcholine receptor in relation to myasthenia gravis. Physiological Reviews 60: 756.

Walker, M. B. 1934. Treatment of myasthenia gravis with physostigmine. Lancet 1: 1200.

Whitaker, J. N. 1980. Myasthenia gravis and autoim­munity. Advances in Internal Medicine 26: 489.

Bibliography

Blalock, A., et al. 1941. The treatment of myasthenia gravis by removal of the thymus gland. Journal of the American Medical Association 117: 1529.

Brunner, N. E., T. Namba, and D. Grob. 1972. Cortico­steroids in management of severe, generalized myas­thenia gravis: Effectiveness and comparison with corticotropin therapy. Neurology 22: 603-10.

Elmquist, D., and J. O. Josefsson. 1962. The nature of the neuromuscular block produced by neomycin. Acta Physiologica Scandinavica 54: 105—10.

Grob, D., and A. M. Harvey. 1951. Effect of adrenocorti­cotropic hormone (ACTH) and cortisone administra­tion in patients with myasthenia gravis and report of onset of myasthenia gravis during prolonged corti­sone administration. Johns Hopkins Medical Journal 91: 125-36.