THYROID DISEASE AND MUSCLE DYSFUNCTION IAN RAMSAY M.D.(Edin.), M.R.C.P.(Lond.), M.R.C.P.(Edin.) Consultant Physician, Regional Endocrine Centre, North Middlesex Hospital, London, N.18 WILLIAM HEINEMANN MEDICAL BOOKS LTD. First published 1974 © Ian Ramsay 1974 ISBN 0 433 272 554 PRINTED IN ENGLAND BY THE WHITEFRIARS PRESS LTD, LONDON AND TONBRIDGE To Patty and Augustus for their help FOREWORD Some ten years ago a young clinician, Ian Ramsay, came to my laboratory. He was well trained and had the critical attitude of the British school at its best. He was determined to study thyrotoxic myopathy by all available methods. In record time he acquainted himself thoroughly with quantitative electromyography. In the intervening years he has used this and other methods to study muscle dysfunction in a unique consecutive series of patients with thyro- toxicosis. His papers on the subject mark real advances in the under- standing of metabolic muscle disease. Two of Ramsay's findings are rare in muscle disease and impressed me as being of basic importance: (i) Structural changes were mild or absent although weakness and wasting and electromyographic evidence of "fibre loss" were pronounced. (ii) There was a remarkable return to normal of the electro- myographic abnormalities and of weakness and wasting a few months after successful treatment of hyperthyroidism. These findings indi- cate transient block of muscle fibres rather than destruction and repair. Muscle disorders in thyroid disease are a fascinating subject, bordering as they do on endocrinology, neurology, pathology and neurophysiology. Since Dr. Ramsay has been one of the pioneers in this area he is exceptionally qualified to present the state of knowledge, which he does from his own work and by a critical evaluation of the work of others. It gives me pleasure to introduce his lucid account of muscle dysfunction in thyroid disease. The book fills a need. FRITZ BUCHTHAL Institute of Neurophysiology, University of Copenhagen. PREFACE This book is written in an attempt to clarify one of those areas in medicine where specialities overlap, namely endocrinology and neurology, though many of the clinical problems to be considered are encountered by the general physician. In the last decade or so increasing attention has been drawn to the association between abnormalities of skeletal muscle and derangement of thyroid function. Thus thyrotoxic myopathy, previously thought to be rare, is now known to be common; muscular abnormalities are being more frequently described in patients with hypothyroidism; and the association of Myasthenia Gravis and Periodic Paralysis with hyperthyroidism is also well recognized. That there are these associations is not surprising considering that thyroid hormone plays a major part in regulating the production of energy in the body, and indeed it is to be hoped that investigation of these diseases will throw more light on the controlling mechanisms of muscle metabolism. My thanks are due to the two thyrotoxic patients with severe myopathy who first stimulated my interest in the subject and to the Royal Victoria Hospital, Belfast, which generously supported my initial researches. I am also grateful to Miss G. Pentelow of King's College Hospital Medical School Library and her staff for helping to check the references. I. R. December 1973 ACKNOWLEDGEMENTS Grateful acknowledgements are made to the following publishers for allowing their illustrations to be reproduced. Chapter 1 Fig. 3 : The Lancet Figs. 4 and 7: The Clarendon Press, Oxford Figs. 8, 9, 10 and 11 : The Mayo Clinic Proceedings Chapter 2 Figs. 3, 4 and 6: Act a Neurologica Scandinavica Fig. 5 : The Royal Australasian College of Physicians Fig. 7 : Archives of Neurology Figs. 8 and 9 : The Muscular Dystrophy Group of Great Britain Chapter 3 Figs. 1 and 2: The British Medical Journal Fig. 3: Neurology Fig. 4: The American Medical Association Figs. 5, 6, 7, 8, 9 and 10: The Johns Hopkins Medical Journal Chapter 4 Fig. 2: Archives of Physical Medicine and Rehabilitation Figs. 3, 4 and 5: Mayo Clinic Proceedings Fig. 6: Journal of Clinical Endocrinology and Metabolism Figs. 7, 8, 9, 10 and 12: American Medical Association Fig. 11 : Excerpta Medica Foundation Figs. 13, 14, 15 and 16: Journal of Cell Biology CHAPTER 1 THYROTOXIC MYOPATHY Severe muscular weakness and wasting occurring in patients with thyrotoxicosis has, comparatively recently, been regarded as rare (Whitfield and Hudson, 1961). The association however was first noticed by both Graves (1835) and Basedow (1840) in their descrip- tions of hyperthyroidism. Quite a long time elapsed after their observations before du Cazal in 1885 (Sattler, 1952) and Bathurst in 1895 specifically described patients who presented with severe muscular atrophy and weakness as the first indication of their thyro- toxicosis. Bathurst noticed the predominantly proximal involvement of the arms and legs and described how his patient found it difficult to rise from the lying or kneeling positions without using his arms. Possibly because of the protean nature of thyrotoxic symptoms and signs and because of the ease with which florid hyperthyroidism can be diagnosed, the presence of myopathy was neglected and in the years between 1895 and 1962 only 73 cases could be found by Ramsay (1964) in the English, German and French literature.* Waldenström said in 1945 that thyrotoxic myopathy was extremely uncommon and Whitfield and Hudson (1961) thought that it was of considerable rarity. Without a doubt the severe form, presenting with myopathie symptoms which overshadow all else, is relatively uncommon, but recent work done in the last decade and a half suggests that these 73 published cases represent the visible top of the iceberg and that if thyrotoxic patients are carefully examined clinically and electromyographically, a majority will be found to have muscle involvement (Pipberger, Kälin and Wegmann, 1955; * Bathurst (1895), Ayer, Means and Lerman (1934), Starling and Brain (1938), Darke, Hunt and Brain (1938), Parsons and Twort (1939), MacKenzie (1940), del Castillo, de la Baize and Caul (1940), Morgan and Williams (1940), McEachern and Ross (1942), Devic et al. (1942), Bartels and Pizer (1944), Thorn and Eder (1946), Froment, Gallavardin and Devic (1946), Devic et al. (1947), Sanderson and Adey (1949), Quinn and Worcester (1951), Zierler (1951), Sanderson and Adey (1952), Millikan and Haines (1953), Kite, McClintock and Graves (1954), Sacrez, Lausecker and Isch (1955), Hoffenburg and Eales (1956), Collings and Lienhard (1957), Boström and Hed (1958), Hed, Kirstein and Lundmark (1958), Melville (1959), Ellis and Carey (1961), Whitfield and Hudson (1961) and Havard (1962). 2 Thyroid Disease and Muscle Dysfunction Hed, Kirstein and Lundmark, 1958; Gimlette, 1959; Havard et al, 1963; Satoyoshi, Murakami and Torii, 1963; Ramsay, 1965, 1966). Analysis of the literature on 73 patients with "chronic thyrotoxic myopathy" (Ramsay, 1964) The age at presentation was the same for both sexes, with an average of 47-7 years. Normally in an unselected group of thyrotoxics one would expect at least a 3: 1 female : male ratio, but 38 of the patients were male, making virtually a 1: 1 ratio. The female patients had had symptoms of thyrotoxicosis for an average of 25-3 months and weakness for 22-5 months compared with 11-3 months and 11-1 months respectively for the men. It is interesting to note that the symptoms of myopathy were an early feature of the illness. The mean weight loss was rather similar in the two groups, being 16-6 kg for the males and 15-1 kg for the females, but of course this represents a greater percentage weight loss in the female sex and would accord with the much longer duration of their symptoms. Although the patients were reported in the literature because of their myopathie features, in fact in only 23 % were they the presenting complaint. In most of the other patients the onset of muscular weak- ness was concurrent or followed shortly after the onset of the usual features of hyperthyroidism. The characteristic complaints were difficulty in climbing stairs, rising from a kneeling position or from a low chair, getting up out of bed, lifting the arms for such tasks as combing the hair, hanging curtains or putting things on shelves. Some patients experienced enormous fatigue while walking even on the level and a few noticed weakness of every muscle movement. There was no relationship between the muscle weakness and the nresence or absence of exophthalmos or of ophthalmoplegia. In 49-3% of the patients the only muscles affected were the proximal muscles of the shoulder and pelvic girdles. In 34-3% distal as well as proximal muscles were involved. In the remaining 16-4% of the patients there was dysfunction of the bulbar muscles in addition to involvement of all skeletal muscles. There were no differences between the two sexes as to the groups of muscles affected by the myopathie process. Muscle pain, stiffness and contractions were noted in one patient by Hoffenburg and Eales (1956), cramps were described in two patients (Sanderson and Adey, 1952; Millikan and Haines, 1953) and were the presenting feature in a recent case (Araki, Terao, Matsumoto, Narazaki and Kuroiwa, 1968). Muscular aching was prominent in one of Whitfield and Hudson's (1961) patients. Thyrotoxic Myopathy 3 In the patients with bulbar weakness, difficulty in speaking was the most prominent symptom. There was an inability to pronounce words properly, hoarseness or an alteration in the quality of the voice. Dysphagia was the second common problem and in one patient there was nasal régurgitation when swallowing fluids. Spontaneous muscle movements were seen in 41-7% of the men with thyrotoxic myopathy, but in only 3-2% of the women. It is possible that this difference could be due to the preservation of a thicker layer of subcutaneous fat in women. The movements were variously described as being fasciculation or fibrillation, though the latter is rather a misnomer since strictly speaking it is an electro- myographic phenomenon produced by the contraction of single muscle fibres and cannot be seen through the skin (Thomas, 1963). There is no clear explanation so far for these spontaneous muscle movements. Abnormally sensitive motor end plates were thought by some to be the cause of the phenomenon (McEachern and Ross, 1942; Kite, McLintock and Graves, 1954). Harman and Richardson (1954) thought that the movements were identical to the myokymia which may occur in normal people, especially when fatigued. Characteristically this is seen as coarse muscular twitching. It is not affected by spinal or high nerve block, is not made worse by pro- stigmine but is abolished by curare. Electromyographic studies show an increased excitability of nerve tissue. Unselected thyrotoxic patients The findings in the above group of patients, selected because of the prominence of their myopathy, can be compared with several series of unselected thyrotoxic patients (see Table 1.1). It can be seen that about 5 % of all thyrotoxic patients have weakness as their presenting complaint, a third to a half have it as a symptom and 60 to 80% are weak on clinical examination. The type of weakness noted is similar to that described in the patients with chronic myopathy, namely difficulty in walking upstairs, rising out of a chair, brushing or combing the hair without resting, lifting things from high shelves, putting up curtains, playing the piano and carrying shopping baskets; some of the men who were engaged in manual labour noticed that they required help in lifting heavy objects which previously they could manage by themselves (Havard et al, 1963; Ramsay, 1966). A few patients noticed aching in their muscles (Ramsay, 1964). In Ramsay's series (1966) 63% of the patients had proximal muscle involvement alone. This was usually both weakness and Figure 1.1. Female thyrotoxic patient with well preserved fat stores who had such a severe proximal myopathy that she was un- able to stand unaided. (Patient of Dr. C. G. McKerron).