POLYMYOSITIS AND MYASTHENIA GRAVIS: IMMUNODEFICIENCY DISORDERS INVOLVING SKELETAL MUSCLE

200 cases of multiple sclerosis, and the use of sunflower oil (which has 66 °; linoleic esters) has been advocated for its prophylaxis and treatment.30 Secondly, some plant oils and other lecithin-rich foods such as egg-yolk seem to contain pharmacologically active trace substances with anti-inflammatory effects comparable to, or more powerful than, those of cortiOf special interest to us was the demonstration sone. by Long and Martin 31 that the arachis oil base of a supposedly anti-inflammatory drug contained an antiinflammatory substance which when partially purified was shown to be maximally effective, at doses of 6 ng. per kg., in depressing the allergic hypersensitivity of guineapigs infected with B.c.G. (i.e., about a million times as active as cortisone). Subsequently, another, much less active component from arachis oils and egg yolk was isolated and identified as N-ethylpalmitamide, which was effective at 5 mg. per kg. (i.e., similar to cortisone) .12, 11 However, Long and Martin are not convinced that this is the same substance as the one they originally detected in arachis extracts, which remains unidentified (D. A. Long, personal com-

reported in

munication).

POLYMYOSITIS AND MYASTHENIA GRAVIS: IMMUNODEFICIENCY DISORDERS INVOLVING SKELETAL MUSCLE R. L. DAWKINS

P. J. ZILKO Clinical Immunology Division, Royal Perth Hospital Perth Medical Centre, Perth, Western Australia

and

Human polymyositis and aspects of myasthenia gravis may be conof subtle sequences immunodeficiency states. Autoimmune processes leading to inflammatory muscle disease and the presence of associated tumours may reflect the partial loss of antibody-mediated homœoSummary

static mechanisms. INTRODUCTION

As a consequence of experiments designed to define the relationships between experimental autoallergic myositis and human diseases of skeletal muscle it is suggested that polymyositis and some features of

myasthenia gravis may be specific complications of subtle immunodeficiency states.

CONCLUSION

These findings do not seem to have received the attention that they deserve. The possibility that the biological activity of polyunsaturated fatty acids is due to very potent trace contaminants must be added to the better known hypotheses of action such as fluidising of membranes 34 or modification of prostaglandin metabolism.35,36 Furthermore, if the changed pathogenesis of scrapie in mice treated with arachis oil is due to the anti-inflammatory effect of the oil (which could also be the basis of the effect of prednisone), this provides us with yet another tool with which to investigate the early steps in the pathogenesis of these agents, suggesting as it does that the relevant cell types are a part of the inflammatory defences of the host. This work was supported in part by Association of Scottish Branches of the

a

grant from the

Multiple Sclerosis

Society. Requests for reprints should be addressed to G. W. 0., A.R.C. Animal Breeding Research Organisation, West Mains Road, Edinburgh EH9 3JQ. REFERENCES 1. 2.

3. 4. 5. 6.

Thormar, H. Z. Neurol. 1971, 199, 1. Gibbs, C. J., Gajdusek, D. C. Res. Publ. Ass. nerv. ment. Dis. 1971, 49, 383. Stamp, J. T. Br. med. Bull. 1967, 23, 133. Porter, D. D., Porter, H. G., Cox, N. A. J. Immun. 1973, 111, 1407. Pattison, I. H., Jones, K. M. Res. vet. Sci. 1967, 8, 160. Beck, E., Daniel, P. M. in Slow, Latent and Temperate Virus Infections (edited by D. C. Gajdusek and others); p. 85. Washington, 1965.

7.

8. 9. 10. 11. 12. 13. 14. 15. 16.

Fraser, H., Bruce, M., Dickinson, A. G. VIIth int. Congr. Neuropath. (in the press). Zlotnik, I. Acta neuropath. 1962, suppl. 1, p. 363. Fraser, H. Res. vet. Sci. 1969, 10, 338. Fraser, H., Bruce, M. Lancet, 1973, i, 617. Fraser, H., Dickinson, A. G. J. comp. Path. 1973, 83, 29. Horta-Barbosa, L., Fuccillo, D. A., Sever, J. L. J. Am. med. Ass. 1971, 218, 1185. Worthington, M., Clark, R. J. gen. Virol. 1971, 13, 349. McFarlin, D. E., Raff, M. C., Simpson, E., Nehlsen, S. H. Nature, 1971, 233, 336. Eklund, C. M., Kennedy, R. C., Hadlow, W. J. J. infect. Dis. 1967, 117, 15. Dickinson, A. G., Fraser, H. J. comp. Path. 1969, 79, 363.

EXPERIMENTAL AUTO ALLERGIC MYOSITIS

This disease may be produced in various species by immunisation with skeletal muscle and is characterised by a widespread inflammatory myopathy.1-3 Cell-mediated immunity to muscle has been demonstrated by skin-testing,l,4 lymphocyte transformation,5 and migration inhibition.6 Spleen-cell suspensions from affected animals are cytotoxic to 51Cr-labelled chick-muscle cultures, apparently by means of a reaction involving T -cells,7 and the disease can be passively transferred with lymphoid cells rather than

serum.8,9 In addition

to

a

cell-mediated reaction directed

against muscle, animals generally possess antibodies which bind react with

to

skeletal muscle."-"

Such antibodies

cytoplasmic muscle-specific antigens of cultured muscle-cells,13-15 and are not cytotoxic to

51Cr-Iabelled muscle-cells.16

17. Fraser, H., Dickinson, A. G. Nature, 1970, 226, 462. 18. Clarke, M. C., Haig, D. A. Res. vet. Sci. 1971, 12, 195. 19. Dickinson, A. G., Fraser, H. Heredity, 1972, 29, 91. 20. Outram, G. W., Dickinson, A. G., Fraser, H. Nature, 1973, 241, 536. 21. Outram, G. W., Dickinson, A. G., Fraser, H. ibid. 1974, 249, 855. 22. Outram, G. W., Fraser, H., Wilson, D. T. J. comp. Path. 1973, 83, 19. 23. Hotchin, J. Symp. quant. Biol. 1962, 27, 379. 24. Miller, G., Enders, J. F. J. Virol. 1968, 2, 787. 25. Duc-Nguyen, H., Henle, W. J. J. Bact. 1966, 92, 250. 26. Edelman, R., Wheelock, E. F. Science, 1966, 154, 1053. 27. Outram, G. W. PH.D. thesis, University of Edinburgh, 1972; and

unpublished. 28. Clausen, J., Møller, J. Acta neurol. scand. 1967, 43, 375. 29. Mertin, J., Hughes, D., Shenton, B. K., Dickinson, J. P. Klin. Wschr. 1974, 52, 248. 30. Miller, J. H. D., Zilkha, K. J., Langman, M. J. S., Payling Wright, H., Smith, A. D., Berlin, J., Thompson, R. H. S. Br. med. J. 1973, i, 765. 31. Long, D. A., Martin, A. J. P. Lancet, 1956, i, 464. 32. Kuehl, F. A., Jacob, T. A., Ganley, O. H., Ormond, R. E., Meisinger, M. A. P. J. Am. chem. Soc. 1957, 79, 5577. 33. Ganley, O. H., Robinson, H. J., Rahway, N. J. J. Allergy, 1959, 30, 415. 34. Singer, S. J., Nicolson, G. L. Science, 1972, 175, 720. 35. van Dorp, D. A., Beerthuis, R. K., Nugteren, D. H., Vonkeman, H. Biochim. biophys. Acta, 1964, p. 204. 36. Bergström, S., Danielsson, H., Samuelsson, B. ibid. p. 207.

201

These data suggest that experimental autoallergic myositis (E.A.M.) involves aT-cell reaction directed against muscle-specific antigen, and that the presence of serum antibody reflects immunisation without implying a specific and direct role for humoral mechanisms in the pathogenesis of the disease. HUMAN POLYMYOSITIS

This disease is characterised by the presence of inflammatory myopathy with or without dermal involvement (dermatomyositis) and with or without The form in children is an associated neoplasm. often considered to be a specific subtype because of the presence of vasculitis 1’ing and calcinosis and the relative absence of an associated neoplasm, but more work on these aspects is required. The adult form of polymyositis has been relatively well studied and provides some striking similarities and contrasts when compared with E.A.M. The pathological picture is similar, and lymphocyte transformation and cytotoxicity studies have suggested that there is a T-cell-mediated process analogous to that found in the experimental disease.19.20 In contrast, however, patients with polymyositis do not have anti-muscle antibodies if exception is made for rare patients with an associated thymoma and myasthenia 21 The prevalence of nonmuscle autoantibodies such as antinuclear factor is often said to be increased, but this may be due to the inclusion of patients with connective-tissue disorders which overlap with polymyositis.22 These findings suggested that there could be some restraint on humoral-antibody formation in human polymyositis. In this way the similarities in the Tcell compartment and the differences in the B-cell Immunological compartment could be explained. function tests performed on patients with polymyositis have indicated that antibody responses to tetanus toxoid, immunoglobulin concentrations, and isohxmagglutinin titres are often depressed, suggesting a mild form of humoral immune deficiency.7.23 Cellmediated immunity is normal except in treated patients. Patients with low immunoglobulin concentrations did not have immunoglobulin and complement deposited in vessel walls as has been found in some patients with juvenile dermatomyositis?4 Thus, although deposition or hypercatabolism cannot be excluded absolutely, hyposynthesis of antibody appears more likely and this possibility is supported by reports of polymyositis occurring in association with X-linked hypogammaglobulinaemia’25 and perhaps penicillamine therapy 2s Accordingly, it is suggested that polymyositis may be a consequence of a humoral deficiency state which predisposes to the development of a T-cell-mediated inflammatory myopathy. The same defect could also predispose to the development of neoplasia. It is relevant that the prevailing view identifying T-cells with immuno-surveillance and the maintenance of tolerance and thence, via a failure of these functions, with the development of neoplasia and autoimmune disease requires re-examination in view of the mounting evidence that humoral antibody may be equally significant. MYASTHENIA GRAVIS

It is well known that

some

patients with myasthenia

have an antistriational antibody, and our own evidence suggests that this is similar to the antibody found in the experimental disease." In view of the findings in E.A.M. it appeared necessary to consider the possibility that antibody might be an indicator of autoimmune muscle disease occurring in some, but not all, patients with myasthenia gravis. The antibody is known to be correlated with the presence of thymomas and inflammatory lesions in muscle.21,27 Other situations linking thymoma, myositis, and anti-muscle antibody are known in man and animals.28 We have therefore compared patients with and without antimuscle antibodies in terms of lymphocyte-mediated myotoxicity, serum-complement, and the presence of

gravis

non-muscle

autaantibodies lz

Comparisons of competence and HL-A antigens were also undertaken in view of our findings in polymyositis and because of neglected reports of defective humoral responses in myasthenia gravis.29 It was found that antibody-positive patients have cell-mediated myotoxicity similar to that found in polymyositis and that the titre of antibody is related to the degree of lymphocyte cytotoxicity 11 Patients without the antibody do On the other not have cell-mediated myotoxicity. either the occurrence of hypocomplementaemia hand, or non-muscle autoantibodies was unrelated to the presence or absence of anti-muscle antibody and may be more relevant to a separate antibody which reacts with the acetylcholine receptor and actually induces neuromuscular block.3O On these grounds it is concluded that a certain group of patients with myasthenia gravis have autoimmune disease of skeletal muscle in addition to neuromuscular block, and it is this group which is associated with thymomas and perhaps HLAZ,u,31 Interestingly, subtle humoral immunodeficiency occurs in the same group and, although this could be a consequence of the thymomas, the association with HL-A antigens suggests that patients may be susceptible to autoimmune and neoplastic disease because of some inherited characteristic possibly determined by immune-response genes. It is not yet possible to determine whether the immunodeficiency associated with this type of myasthenia gravis is similar to that found in polymyositis; but some differences might be expected since anti-muscle antibodies, irrelevant autoantibodies, and a specific type of tumour are found in the former, but not the latter, disorder.

immunological

We are grateful to the Muscular Dystrophy Associations of America and the West Australian Arthritis and Rheumatism Foundation for support. P. J. Z. is the W.A.A.R.F. (Merck Sharp and Dohme) research fellow for 1973-75. Requests for reprints should be addressed to R. L. D., Clinical Immunology Division, Royal Perth Hospital, Box X2213, G.P.O. Perth, Western Australia 6001. REFERENCES 1. 2. 3.

Dawkins, R. L. J. Path. Bact. 1965, 90, 619. Kakulas, B. A. ibid. 1966, 91, 495. Morgan, G., Peter, J. B., Newbould, B. B. Arthr. Rheum. 1971, 14,

599. 4. Webb, J. M. J. reticuloendothelial Soc. 1970, 7, 305. 5. Esiri, M. M., MacLennan, I. C. M. Clin. exp. Immun. (in the press). 6. Partridge, T., Smith, P., Sloper, J. C. Proceedings of Third International Congress of Muscle Diseases, 1974 (in the press). 7. Dawkins, R. L. Cytotoxicity, Muscle-specific Antigens and Their Relevance to Diseases of Muscle. University of Western Australia, 1973.

202

Methods and Devices PREVENTION OF PEROPERATIVE PRESSURESORES DURING PELVIC SURGERY G. D. OATES General

Hospital, Bimingham B4 6NH, England

OPERATIONS in which the lithotomy or Lloyd-Davies is maintained for a long time may result, especially in elderly subjects, in significant pressure ischaemia of the skin and subcutaneous tissues in the area bearing most weight-usually over the upper part of the posterior aspect of the sacrum. If the patient is turned on his side on being returned to bed after the operation, the area in question will almost invariably show characteristic dusky changes which coincide with the site of pressure against the operating-table mattress, or the firm, wedge-shaped, anti-static cushion often used by surgeons in procedures such as abdomino-perineal excision of the rectum. Prompt rubbing of the affected area, until normal circulation returns, usually prevents frank skin breakdown, but the very early development of open pressure-sores in two elderly patients led me to pay much closer attention to the avoidance of this complication. Some improvement was first achieved by the use of a dry polyurethane-foam supporting cushion, followed by careful rubbing of the reddened area immediately the operation was completed. However, such an open cushion was not ideal from the hygiene point of view, and there were still some visible pressure changes in the skin over the sacrum. The problem was solved by the employment of a fluid flotation cushion, placed on top of the firm mattress of the operating-table in such a position that it supported the entire sacral and lower lumbar areas. Thus at the same time it also provided good operative exposure of the perineum when the legs were raised on to the Lloyd-Davies supports.

position

Path. 1971,

8. Currie, S. J. 105, 169. 9. Esiri, M. M., MacLennan, I. C. M. Clin. exp. Immun. 1974, 17, 139. 10. Dawkins, R. L., Eghtedari, A. A., Holborow, E. J. ibid. 1971, 9, 329. 11. Dawkins, R. L., Robinson, J., Wetherall, J. D. Proceedings of Third International Congress of Muscle Diseases, 1974 (in the press). 12. Partridge, T. A., Manghani, D., Sloper, J. C. Lancet, 1973, i, 676. 13. Dawkins, R. L., Lamont, M. Exp. Cell. Res. 1971, 67, 1. 14. Dawkins, R. L., Aw, E. J., Simons, P. J. Immunology, 1972, 23, 961. 15. Dawkins, R. L., Holborow, E. J. J. immun. Meth. 1972, 2, 1. 16. Dawkins, R. L., Loewi, G. J. Path. 1973, 110, 67. 17. Banker, B., Victor, M. Medicine, Baltimore, 1966, 45, 261. 18. Dawkins, R. L., Mastaglia, F. L. New Engl. J. Med. 1973, 289, 108. 19. Dawkins, R. L., Mastaglia, F. L. ibid. 1973, 288, 434. 20. Currie, S., Saunders, M., Knowles, M., Brown, A. E. Q. Jl Med. 1971, 40, 63. 21. Rowland, L. P., Lisak, R. P., Schotland, D. L., De Jesus, P. V., Berg, P. Neurology, Minneap. 1973, 23, 282. 22. Dawkins, R. L., Mastaglia, F. L. Aust. N.Z. J. Med. 1972, 2, 11. 23. Dawkins, R. L., Zilko, P. J. Abstracts, Australian Society for Immunology, 1973. 24. Whitaker, J. N., Engel, W. K. New Engl. J. Med. 1972, 286, 333. 25. Gotoff, S. P., Smith, R. D., Sugar, O. Am. J. Dis. Child. 1972, 123, 53. 26. Schraeder, P. L., Peters, H. A., Dahl, D. S. Archs Neurol. 1972, 27, 456. 27. Oosterhuis, H. J., Bethlem, J., Feltkamp, T. E. W. J. Neurol. Neurosurg. Psychiat. 1968, 31, 460. 28. Strauss, A. J., Snell, K. C., Duntley, B. J., Soban, E. J., Stewart, H. L. Lancet, 1968, i, 1126. 29. Kornfeld, P., Seigal, S., Weiner, L. B., Osserman, K. E. Ann. intern. Med. 1965, 63, 416. 30. Almon, R. R., Andrew, C. G., Appel, S. H. Science (in the press). 31. Feltkamp, T. E. W., van den Berg-Loonen, P. M., Nijenhuis, L. E., Engelfreit, C. P., van Rossum, A. L., van Loghem, J. J., Oosterhuis, H. J. G. H. Br. med. J. 1974, i, 131.

The cushion (’Hydro-medica’ flotation cushion) works the principle of rotation. When a body floats in water the pressure of the water against the submerged parts is equalised, as described in Pascal’s Law which states that "the pressure at any part in a fluid is the same in all directions ". Obviously, it would be unsuitable to submerge patients in water for extended periods, and impossible to operate on them under such conditions, but if they can be placed in a floating state and yet be kept dry an excellent compromise is attained. The cushion we have employed consists of a core of cavity-linked polyether foam, surrounded by a very thin plastic envelope. Free air has been extracted from the foam and the bag and replaced by fluid. The bag is then sealed in such a way as to maintain a negative pressure within it. When the patient is placed on the cushion the pressure thereby applied displaces the fluid equally all over the interior of the bag, and through its contained cellular foam. Thus, it is possible to redistribute this pressure over the lower spine and upper parts of the buttocks equally and with little compression. Since we started using this cushion three years ago we have had no further problems from peroperative pressure ischaemia. An additional advantage of this cushion is that it is easily washed and disinfected, as its envelope is of smooth nylon-polyvinyl material. on

TheHydro-medica’ flotation cushion is obtainable from Hunter Laboratories Ltd., Clifton Heights, Triangle West, Bristol.

RULER FOR MEASURING PHYSIOLOGICAL TRACINGS WITH A VARIABLE STANDARD DOUGLAS PICKERING Departments of Pœdiatrics and Cardiology, Radcliffe Infirmary, Oxford OX2 6HE PRESSURE measurements from a cardiac-catheter trace require a series of small-proportion calculations, or a card marked with the height of the standard; this is then equally subdivided, and subsequent pressures are read off the side of the calibrated card. However, every time the