Postgrad. med. J. (May 1968) 44, 385-397. Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from

Thyrotoxic muscle disease IAN RAMSAY M.D., M.R.C.P., M.R.C.P.E. Lecturer in Medicine, King's College Hospital Medical School, Denmark Hill, London, S.E.5 Summary and may be Evidence suggests that most hyperthyroid added. patients have a proximal . The more severe this is the more frequently are distal Chronic thyrotoxic myopathy muscles, and ultimately, bulbar muscles involved. Seventy-three cases of marked muscular Probably acute thyrotoxic myopathy or encepha- atrophy and weakness associated with hyperthy- lopathy supervenes on a previous chronic back- roidism which were reported in the literature be- ground or occurs concurrently with tween 1895 and 1962 have been analysed (Ram- involvement. Using careful electromyographic say, 1964). techniques evidence of myopathy may be found Clinical features in most it with The mean of of cases of thyrotoxics; disappears adequate age presentation Protected by copyright. treatment of the primary disease. chronic thyrotoxic myopathy was 47-7 years Myasthenia gravis and periodic paralysis are with no significant sex difference. The age range also associated with thyrotoxicosis and their was 20-69 years for males and 11-70 for females. differentiation is discussed. Infiltrative ophthalmo- The women had longer histories of thyrotoxi- pathy is not related to the effects of excess cosis than the men, an average of 25-3 months hormone, but is possibly due to EPS working compared with 11-3 months, and they had also in conjunction with LATS. noticed myopathic symptoms for a longer period of time (22-5 months and 11 1 months). The Introduction mean weight loss was rather similar, being 16-6 Although muscular weakness was recognized kg for males and 15-1 kg for females. by both Graves (1835) and Basedow (1840) as a Proximal muscles alone were affected by weak- symptom of and the first case ness and/or wasting in 49-3% of the cases. In of muscular was described in 34-3% and distal muscles were in- thyrotoxic atrophy proximal http://pmj.bmj.com/ 1885 by Du Cazal (Sattler, 1952), the syndrome volved, and in the remaining 16-4% there was of thyrotoxic myopathy was thought to be ex- generalized muscle disease involving also bulbar tremely rare (Waldenstrom, 1945; Whitfield & muscles. There was no significant difference be- Hudson, 1961). Only seventy-three cases could tween the sexes as to the groups of muscles be found in the literature between 1895 and picked out by the myopathic process. 1962 (Ramsay, 1964). Recent work, however, In 23% of the patients the muscle lesion was suggests that muscular involvement may be pre- the presenting complaint. In most of the rest, sent in the majority of thyrotoxic patients (Havard however, the onset of muscle symptoms was on September 26, 2021 by guest. et al., 1963; Satoyoshi et al., 1963a; Ramsay, concurrent with those of hyperthyroidism. Char- 1966). acteristically, patients had noticed difficulty in In 1945 Waldenstrom reviewed a group of climbing stairs or trying to rise out of a chair. patients who had presented with acute muscular Some could not hold their arms up long enough weakness involving particularly the bulbar mus- to comb their hair, some experienced great fati- cles. Since then there has been argument as to gue even while walking along the level, while a whether these patients had acute thyrotoxic myo- few just experienced generalized weakness. pathy or encephalopathy or whether they had Two patients (Sanderson & Adey, 1952; Milli- myasthenia gravis (Millikan & Haines, 1953). An kan & Haines, 1953) had had cramps in their attempt will be made in this review to show that legs, while Hoffenburg & Eales (1956) des- there is probably one primary muscle disorder cribed a man with pain and stiffness in his of hyperthyroidism, of varying severity, to which muscles and contractures, and muscular aching occasionally the effects of other diseases such as was a feature noted by Whitfield & Hudson 386 Ian Ramsay Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from (1961) in one patient. In the patients with bul- portion of men in the reported cases is higher bar involvement difficulty in speaking was the than would normally be expected in an unselected most common symptom and consisted of dys- group of thyrotoxics, but this can probably be phonia, hoarseness and weakness of speech or explained by the importance of normal muscle- an alteration in the quality of the voice. Dys- power in enabling a man to perform his job. phagia was the second commonest source of Half of the patients in the author's series (Ram- trouble and the nasal regurgitation of fluids say, 1966) had a history of some muscle weak- occurred in one patient. 41-7% of the men ness. The majority complained of difficulty in were noted to have spontaneous muscle move- walking upstairs, while the remainder had noti- ments, compared with only 3-2% of the women. ced principally arm weakness. The women among Although the movements were variously des- them had noticed great fatigue in trying to comb cribed by the authors as fasciculation or fibril- their hair. The men who were engaged in lation, the latter were unlikely to have been seen manual labour had noticed a decline in their since fibrillation consists of the contraction of ability to lift heavy objects and often required individual muscle fibres and cannot be seen assistance for tasks they had previously been through the skin (Thomas, 1963). McEachern & able to manage alone. There were no symptoms Ross (1942) and Kite, McLintock & Graves suggestive of bulbar muscle weakness. (1954) postulated that the 'fasciculations' in the The onset of typical thyrotoxic symptoms was thyrotoxics were due to an undue sensitivity of the presenting feature in 79.6% of the author's the motor end-plate in a state of abnormal meta- patients. In 3-7% weakness was the first symp- bolism. Harman & Richardson (1954) considered tom noted and in 16-7% this was concurrent that in many of these patients the phenomenon with thyrotoxic symptoms. No sex differences observed was, in fact, a of were discernible in of the three and myokymia, type any groups Protected by copyright. movement which may occur in normal people, in the patients with weakness, the duration of especially under conditions of fatigue. It is seen this symptom was much the same as that of the as coarse muscular twitchings, easily visible general features of thyrotoxicosis. through the skin. The spontaneous activity con- As can be seen in Table 1, 63% had proximal tinues after spinal or high nerve block, but is muscle involvement, usually weakness and wast- stopped by curare and is not increased by pros- ing, occasionally weakness without atrophy, tigmine. Electromyographic studies show that rarely atrophy without weakness (two patients). nerve excitability is increased, but that there is Distal muscles in addition to the proximal ones no evidence of a lower motor neurone lesion. were affected in 18-5%. No bulbar weakness However, if these findings in cases recorded was detected and in 18-5% the skeletal were as 'chronic thyrotoxic myopathy' are compared judged to be clinically normal. There was no (Table 1) with the findings in unselected thyro- variation in the findings between the two sexes, nor was there difference between those TABLE 1 any age http://pmj.bmj.com/ who had and those who had not A comparison between seventy-three patients with chronic muscle involve- thyrotoxic myopathy and fifty-four unselected thyrotoxics ment. An analysis of the muscles involved (Ramsay, 1964) showed that muscles of the shoulder girdle were more often affected than those of the pelvic Seventy-three Fifty-four and that 'chronic thyrotoxic unselected girdle extensors were involved twice as myopathy' patients thyrotoxics commonly as flexors. Havard et al. (1963) noted in their that the muscles Mean age (years) 47-7 47.9 fifty thyrotoxic patients most involved were on September 26, 2021 by guest. Male/female ratio 38 : 35 14: 40 commonly the deltoid, the Mean duration of thyro- supraspinatus and the quadriceps. toxic symptoms (months) 18-5 6-6 Table 2 compares the incidence of weakness Mean duration of weakness in the seventy-three patients reported as 'chronic (months) 16-4 5-0 with Mean weight loss (kg) 15-9 8-0 myopathy' six series of hyperthyroid patients. Ophthalmoplegia (%) 62 7.4 It can be seen that even in unselected thyro- Muscles affected: toxic patients weakness may be the presenting Proximal alone (%) 49 3 63 feature, that it is a symptom in about a third to Proximal and distal (%) 34-3 18-5 a half of cases and that it may be detected clini- Generalized and bulbar(%) 16-4 0 cally in 60-80%. The figures are remarkably uni- form in the unselected groups considering that toxics (Ramsay, 1966) it can be seen that the dif- the patients are drawn from Switzerland, Britain ferences are ones of degree only. The mean age and Japan. at presentation is virtually the same. The pro- Tendon reflexes were unremarkable in the Thyrotoxic muscle disease 387 Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from

TABLE 2 A comparison of the symptoms and signs of weakness in seventy-three patients with chronic thyroxtoxic myopathy and in several series of unselected thyrotoxic patients Weakness as Series No. of the presenting Weakness as Weakness patients complaint (%) a symptom (%) clinically (%) Recorded cases of myopathy (see above) 73 23 100 100 Pipberger, Kailin & Wegmann (1955) 13 61*5 69-2 Gimlette (1959) 40 32-5 60 Havard et al. (1963) 50 6 34 80 Satoyoshi et al. (1963a) 240 61 Ramsay (1965, 1966) 54 3-7 50 81-5 thyrotoxic myopathy patients. As nearly an Other workers, however, have denied a decrease equal number were hyperactive as were in muscle cell potassium and the matter is not diminished and in a small number of cases they yet resolved (Staffurth & Thompson, 1965; Shis- were absent. In a series of ordinary thyrotoxic hiba et al., 1966). patients (Ramsay, 1966) the reflexes were con- sidered to be normal in 53 7%, brisk in 42-6% Creatine and creatinine metabolism and reduced in 3-7%. Sensory abnormalities Creatine is synthesized in the liver from gly- have not been described. cocyamine which originates in the kidneys. It is then taken up by the muscles and converted by Protected by copyright. Prostigmine or edrophonium testing phosphocreatine kinase into phosphocreatine. Prostigmine or edrophonium (Tensilon) was Phosphocreatine is necessary for normal muscle given to twenty-seven of the cases of chronic contraction, its probable role being in the im- myopathy described in the literature. No increase mediate resynthesis of adenosine triphosphate in power was noticed in twenty-four instances (ATP) by the transfer of a phosphoryl group to and it produced a good response in only one adenosine diphosphate. Satoyoshi and his co- patient (McEachern & Ross, 1942) and a slight workers (1963a, b) found significantly reduced response in a further two (Sanderson & Adey, muscle creatine, phosphocreatine and ATP in 1949; Melville, 1959). Havard et al. (1963) as- thyrotoxics and showed that there was a corre- sessed muscular strength in forty-nine thyro- lation between muscle ATP concentrations and toxics before and 30 min after 1-5 mg of intra- muscular strength. Phosphocreatine in muscle muscular neostigmine. Forty-three patients may be lowered because of the inhibiting effect showed no increase in power, though six were of thyroxine on phosphocreatine kinase (Ask- http://pmj.bmj.com/ thought to be stronger. Ramsay (1966) found no onas, 1951) or because a normal intracellular significant difference in the length of time for potassium may be necessary for its formation which thyrotoxic subjects could maintain their (Grob, Liljestrand & Johns, 1957). legs at an angle of 45 degrees to the horizontal Because the degenerating muscle is unable to before and after the intravenous injection of store the creatine the serum level rises (Kuhl- edrophonium chloride. back, 1957; Satoyoshi et al., 1963a), the renal threshold is exceeded and urinary excretion in- on September 26, 2021 by guest. Biochemistry creases. It follows from this that thyrotoxic Apart from the usual indices of hyperthy- patients have a reduced tolerance to ingested roidism there have been no constant biochemical creatine (Thorn & Eder, 1946; Wilkins & Fleisch- features either in patients reported on as having mann, 1946). Urinary creatine is virtually absent myopathy or in unselected thyrotoxics. Generally in normal adult males, though values of up to speaking there is normocalcaemia, though a few 50 mg/day may be found in women (Documenta have slightly elevated values, and normal levels Geigy, 1962). In thyrotoxics with and without of serum potassium, sodium and chloride (Sato- obvious myopathy the excretion is generally yoshi et al., 1963a, b; Ramsay, 1964). Satoyoshi raised, though the high levels in serum and and his colleagues (1963a, b) found that muscle urine may be reduced, usually within one day, cell potassium was reduced and sodium increased by the administration of potassium chloride and noted a strong positive correlation between (Satoyoshi et al., 1963a, b). intracellular potassium levels and muscle strength. Creatine is broken down to creatinine by an- 388 Ian Ramsay Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from hydration, so it is not surprising that the amount myograms (EMGs), though since their report of creatinine found in the urine of hyperthyroid Bostrom & Hed (1958), Hed, Kirstein & Lund- patients is usually diminished. It must be em- mark (1958), Whitfield & Hudson (1961) and phasized, however, that the increased urinary ex- Havard (1962) have all reported typical myo- cretion of creatine and the diminished excretion pathic patterns in their patients with clinical of creatinine are not specific for thyrotoxics, but thyrotoxic myopathy. occur in other sorts of muscular dystrophies Since 1955 seven series of thyrotoxic patients and and are found in normal old age have been studied electromyographically and the (Zierler, 1951). Moreover, in some patients with results are summarized in Table 3. Most of the thyrotoxic myopathy there is no significant crea- previously published papers have given quantita- tinuria (Zierler, 1951). This has been explained tive estimations of the electromyographic find- by Hoch (1962) as being due to a failure of syn- ings in thyrotoxicosis, and so the results are thesis. In the liver ATP is required for the trans- subject to observer error. This may explain the fer of a methyl group from methionine to gly- normal EMGs in the patients of Millikan & cocyamine in order to form creatine (Kuhl- Haines (1953). If, however, a quantitative method back, 1957). of is used (Ramsay, 1965; Yates, 1965) in which twenty to twenty-seven Muscle enzymes different areas in each muscle are sampled and Aldolase, lactic dehydrogenase and total thi- the mean action-potential duration is compared amine were found to be decreased in thyrotoxic to the normal for that patient's age, then a muscle (Satoyoshi et al., 1963a). Phosphocreatin- higher degree of accuracy may be achieved. By ine kinase also tended to be lower than in controls this method 92-6% of Ramsay's (1965) patients and to be significantly increased in the serum. were shown to have evidence of a myopathy in The amounts of free thiamine and glutamic proximal muscles and 42-9% in distal musclesProtected by copyright. oxaloacetic transaminase were normal. also. Fig. 1(a) and (b) show the shortened mean Electromyography action potential duration in thyrotoxic patients Sanderson & Adey (1949, 1952) were the first compared to controls and the return towards to describe electromyographic abnormalities in normality on re-testing 4 months after the chronic thyrotoxic myopathy, namely a signifi- patients had become euthyroid. In addition the cant reduction in mean action potential duration, thyrotoxic patients had a significantly higher per- low voltage of the motor unit potentials and an centage of polyphasic potentials than the con- increased incidence of polyphasic potentials. trols, with again a return to normality after Millikan & Haines (1953) found normal electro- treatment had been effective. Havard et al. (1963)

TABLE 3 http://pmj.bmj.com/ Reports of electromyograms (EMGs) done on thyrotoxic patients EMG No. of evidence of Characteristic EMG patients myopathy (%) features Pipberger et al. (1955) 13 92-3 Shortening of action potentials, in- crease in polyphasicity, decrease in amplitude. Normal interference pat- on September 26, 2021 by guest. tern. Hed et al. (1958) 17 100 In areas sampled 75-100% of poten- tials were of short duration or polyphasic. 'Dense' or'scanty' inter- ference pattern. Gimlette (1959) 40 'Myopathic' pattern in the majority. Havard et al. (1963) 50 88 Motor units either polyphasic or shorter than normal. Satoyoshi et al. (1963b) 39 61-5 Unspecified. Yates (1963, 1965) 10 70 Shortened action potential duration. Ramsay (1965) 54 92 6 Statistically significant reduction in action potential duration and increase in percentage polyphasicity. Thyrotoxic muscle disease 389 Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from and Yates (1965) noted normal EMGs in their severity of the thyrotoxicosis and the degree of patients following clinical recovery. Fibrillation EMG change. was very rarely, and fasciculation never, found (Havard et al., 1963; Ramsay, 1966). Both the Nerve conduction patients with fibrillation potentials reported by No abnormalities in nerve conduction were Hed et al. (1958) probably had a lower motor found in thyrotoxics (Ramsay, 1965), though de- neurone lesion. myelinization and vacuolization of minor nerves (Hed et al., 1958), terminal sprouting of nerve fibres (Coers & Wolf, 1959), and swelling and 14 x beading of terminal nerve fibres (Havard et al., x~ ~~~~K 13 0-(a) _ x 1963) have been described histologically. x 21 Kx x K Muscle pathology XK S Askanazy (1898) was the first to describe 10 _ changes in the muscles of thyrotoxic patients. 9 ~~ 0 He noticed infiltration of fat cells between 8 - muscle fibres, atrophy of muscle fibres with a * 0~~~~~0 fi 7 decrease in their diameter, proliferation and clumping of muscle nuclei, loss of striation and c 6 .2 vacuolisation. Cardiac and smooth muscle showed no abnormality. Since 1898 a few further re- ports have appeared. Many described much the C t43 x _b K~~~~~~~xyX same findings as Askanazy (Dudgeon & Urqu- b x~~~K Protected by copyright. xI - x hart, 1926; Morgan & Williams, 1940; Bartels & 12 xx K Pizer, 1944; Quinn & Worcester, 1951; Bostrom 11 _ x * & Hed, 1958; Havard, 1962; Satoyoshi et al., 10 _ 1963a), but in addition aggregations of lym- 9 _ phocytes, or lymphorrhages, have been noted (Dudgeon & Urquhart, 1926; Liechti, 1938; 8 _ Thorn & Eder, 1946; Hed et al., 1958; Whit- 7- field & Hudson, 1961). Devic et al. (1947) des- 6 _ cribed an alteration of the mitochondria in the region of the motor end-plates and degeneration 0 20 30 40 50 60 70 of muscle mitochondria has recently been ob- Age (years) served by Engel (1966) who also noted altera- FIG. 1. (a) Deltoid EMGs. Graph showing the relation- tions of the cell surface and of the transverse ship between age and mean action potential duration tubular system. http://pmj.bmj.com/ in control subjects (X) and the shortening of the mean Coers & Wolf (1959), using an intravital stain- action potential duration in thyrotoxic patients (0). ing technique, found changes in the terminal (b) Deltoid follow-up EMGs. Graph showing a return to a normal action potential duration in the majority of nerve fibres, mainly profuse distal sprouting, the euthyroid patients (0). (Reproduced by kind per- often with the formation of multiple end-plates mission of the Editors of the Quarterly Journal of on single muscle fibres. Havard et al. (1963) des- Medicine.) cribed diffuse axonal swelling with multiple bead- ing, rounded or oval swellings of the terminal The shorter action potential duration in myo- axon and clubbing of the end-plate. However, on September 26, 2021 by guest. pathies does not occur in disuse atrophy (Buch- since neither Coers & Wolf (1959) nor Havard thal, 1957) and has been attributed to a decrease et al. (1963) published adequate control data, it in the number of fibres in each sub-unit (Buch- is difficult to assess the significance of their thai & Rosenfalck, 1963). Since the EMGs re- findings. turn to normal in thyrotoxicosis after treatment Hed et al. (1958) noticed the presence in the it seems likely that the myopathy is due to a muscle tissue of iron-loaded phagocytes. The sub- reversible decrease in functioning muscle fibres. sarcolemmal semilunar accumulations of meta- Havard et al. (1963) found a reasonable corre- chromatic substance observed by Asboe-Hansen, lation between muscle weakness and electro- Iversen & Wichmann (1953) in thyrotoxics, but myographic findings and this was confirmed most markedly in those with progressive exo- quantitatively by Ramsay (1964, 1965) who also phthalmos, have been confirmed by Kirchheiner found no relationship between the duration or (1962). This phenomenon can only be seen in 390 Ian Ramsay Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from muscles which have been fixed in basic lead (McEachern & Ross, 1942; Morgan & Williams, acetate; this precipitates acid mucopolysaccha- 1940) died of respiratory paralysis, but it is likely rides (Iverson, Asboe-Hansen & Carlsen, 1953). that their patients had myasthenia gravis (Milli- There have also been quite frequent reports kan & Haines, 1953). A patient of Thorn & of normal histological findings in patients with Eder (1946) with some evidence of bulbar in- thyrotoxic myopathy (Morgan & Williams, 1940; volvement succumbed. Three of Devic et al.'s Sanderson & Adey, 1949; Millikan & Haines, (1947) patients died following thyroidectomy, but 1953; Kite et al., 1954; Collings & Lienhard, apart from one patient (Hed et al., 1958) who 1957) and this has been confirmed in a recent died of an unrelated disease, not a single death series of thyrotoxic patients by Havard et al. in a patient with chronic thyrotoxic myopathy (1963), though some abnormalities were found has been reported since 1947. This reflects the in 23.3% and 68% of their cases, respectively, introduction of more effective treatment for by Ramsay (1966) and by Satoyoshi et al. (1963a, hyperthyroidism in the last 25 years. Full re- b). The Japanese workers found that when thyro- covery of muscle strength was noted in fifty- toxic symptoms were present for less than a year three of the reports in the literature and full abnormalities were present in 50% of cases, but power returned in 100% of thyrotoxic patients rose to 85% if the patients had been ill for lon- in recent series (Havard et al., 1963; Satoyoshi ger than 1 year. There was, however, no corre- et al., 1963a; Ramsay, 1964, 1966). Muscle lation between the muscle biopsy findings and power became normal in about the same time the severity of the thyrotoxicosis. as it took for the patients to become euthyroid Ramsay (1964) used a muscle-biopsy techni- after the start of treatment although atrophy que designed to prevent distortion of the muscle took significantly longer to disappear (Ramsay, architecture (Buchthal, Guld & Rosenfalck, 1966). Creatine and creatinine excretion returned 1955). Muscle-fibre diameters were measured to normal (Ramsay, 1966) as did electromyograms Protected by copyright. with a micrometer gauge and it was found that (Havard et al., 1963; Coomes, 1965; Ramsay, the mean diameter was 12 ,u smaller than in the 1965; Yates, 1965). controls. The apparent increase in the number of sarcolemmal nuclei, described by many Aetiology of myopathy authors, was attributed to the reduction in dia- Three factors have to be considered as possible meter of the fibres and their closer crowding causes of thyrotoxic muscle dysfunction. They together, for, on cross-section a normal number are thyroid stimulating hormone (TSH), LATS of nuclei was seen (Ramsay, 1966). and the (triiodothyronine and Muscle pathology similar to that described in thyroxine). Although TSH stimulates the normal thyrotoxic myopathy has been found by Dud- thyroid to produce hormone, its production by geon & Urquhart (1926) in the extrinsic eye the anterior pituitary is usually suppressed in muscles of patients suffering from malignant thyrotoxicosis (Lemarchand-Beraud, Vanotti & exophthalmos and it has been observed that Scazziga, 1967; Blum et al., 1967). LATS has http://pmj.bmj.com/ these changes could be produced by an anterior been shown to be present in up to 90% of thyro- pituitary extract in thyroidectomized guinea-pigs toxic patients (Blum et al., 1967), and it seems (Paulson, 1939; Dobyns, 1946). Recent work likely, in at least the majority of instances of (Kinderen, 1967) has isolated this pituitary fac- Graves' disease, that this --globulin is respon- tor and it has been called exophthalmos produc- sible for the excessive thyroid stimulation. Since ing substance (EPS). The role of long-acting LATS may persist after the successful control of stimulator in the thyroid (LATS) eye changes of thyrotoxicosis, though the myopathy always re- on September 26, 2021 by guest. thyrotoxicosis is not yet clear (Pimstone, Hoffen- mits, one is left with the conclusion that thyroid burg & Black, 1964), though Kinderen (1967) hormone is responsible for the muscle lesion. thinks that it may act as a facilitator in the pres- The mode and site of action of thyroid hor- ence of EPS. It may well be that the histological mone has recently been reviewed (Hoch, 1962, changes seen in thyrotoxicosis are nothing to 1968; Tapley, 1964; Parsons & Ramsay, 1968). do with the myopathy per se, but are caused Most of the evidence points to the mitochondrial by either EPS or LATS, for whereas the myo- membrane as being primarily involved, for ex- pathy remits with the achievement of euthyroid- perimentally physiological concentrations of thy- ism, the concentration of the latter two sub- roxine can be shown to cause mitochondrial stances may remain elevated in the serum. swelling (Tapley, 1964). Mitochondrial alteration (Devic et al., 1947) and degeneration (Engel, Prognosis 1966) have been seen in muscle from thyrotoxic Two of the earlier cases in the literature patients. Mitochondria are important in muscle muscle disease 391

Thyrotoxic Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from metabolism because they contain the mechanisms disintegrated or polyphasic potentials seen in the of oxidative phosphorylation and the production EMGs of thyrotoxic patients (Ramsay, 1965). of the high-energy phosphate bonds of adeno- The fact that muscle strength returns so quickly sine triphosphate (ATP). The muscles most following treatment and that the EMGs become affected by weakness in thyrotoxicosis are the normal suggests that the myopathy is essentially proximal ones, particularly the extensors; these metabolic in nature rather than structural. rely to a much greater extent on mitochondrial mechanisms as a source of energy than do the Acute thyrotoxic myopathy distal muscles, served largely by anaerobic gly- Acute thyrotoxic myopathy will be considered colysis (Ramsay, 1966). Hoch (1962) has sum- together with encephalopathy, because both titles marized the evidence that thyroxine produces seem to be ascribed to the same clinical situation 'uncoupling' of the reaction which transforms by different authors. The first papers in English oxidative to phosphorylative bond energy, the on the acute paresis of thyrotoxicosis were by net result being a decrease in the production Laurent (1944), Waldenstrom (1945), Sheldon & of high-energy bonds and the dispersion of energy Walker (1946) and Strong (1949). However, Wal- as heat. Chappell & Greville (1958) have shown denstrom, in addition to describing his own ten that thyroxine-induced swelling of mitochondria cases, quoted a large number of patients with can be reversed by the addition of ATP. Sato- similar features which had been gathered mainly yoshi and his colleagues (1963a) found a decreased from the German literature of the previous 50 amount of ATP in thyrotoxic muscles and demon- years. The clinical picture was of the sudden strated a relationship between this and the muscu- onset of bulbar palsy in a patient who may have lar strength of their patients. had antecedent thyrotoxic symptoms for several Other factors probably play a part in the de- months or even years. In many of the cases cited

creased production of ATP. Phosphocreatine by Waldenstrom (1945) there was severe diarr- Protected by copyright. kinase is inhibited by excess thyroxine (Askonas, hoea and vomiting and also clear evidence of 1951) and thus phosphocreatine, which normally thyrotoxic crisis and coma, and this latter asso- donates a phosphoryl group to adenosine dipho- ciation has also been described in subsequent sphate, is synthesized in diminished amounts. case-reports (Chapman & Maloof, 1956; Gimlette, Cell potassium depletion also adversely affects 1959; Heinrich et al., 1962). Eight out of Walden- the manufacture of phosphocreatine (Grob et strom's ten patients had atrial fibrillation com- al., 1957; Satoyoshi et al., 1963a). pared with 14% in an unselected thyrotoxic Another result of ATP-lack is a breakdown population (Ramsay, 1964), and this possibly in the energy-dependent control of membrane reflects the severity of the disease. Other features permeability. As a result water and sodium may which have been noted are aching in the limbs enter the muscle cell and potassium and enzymes and paraesthesiae (Gimlette, 1959). In most of may leave it (Satoyoshi et al., 1963a, b). Cer- the articles written since 1945 the authors have

tainly Green & Matty (1962), using thyroxine, noted that in addition to the symptoms of ptosis, http://pmj.bmj.com/ were able to demonstrate an increase in mem- difficulty with speech, dysphagia and the nasal brane permeability to water. Staffurth & Thomp- regurgitation of fluids, there was also generalized son have recently (1965) found an increase in muscle weakness. Ophthalmoplegia does not ap- muscle cell water in patients with thyrotoxic pear to be a particularly common feature, occur- myopathy, but were unable to demonstrate a ring in only two cases (Waldenstrom, 1945; drop in the potassium content. Although the Strong, 1949) out of fifty-five (3-6%). The ten- effect of thyroxine on mitochondria seems to be don reflexes were variable, being reported as important in producing the weakness, other mech- brisk or totally absent, and in one case there on September 26, 2021 by guest. anisms may play a part. For instance, Engel was evidence of an upper motor neurone lesion (1966), in electron-microscopic studies, has (Heinrich et al., 1962). shown that there are alterations of the muscle- Fasciculation was seen in the patient of Hein- cell surface and of the transverse tubular system rich et al. (1962) and fibrillation was reported which may be important in the local activation in Strong's (1949) case, though, for reasons of striated muscle fibre (Huxley & Taylor, 1958). which are discussed above, it was probably fas- The metabolically inefficient muscle fibres are ciculation or myokymia. not capable of proper contraction and they Pathological reports are scanty, but in Walden- atrophy. This leads to a decrease in the number str6m's review an enlarged thymus was noted of functioning fibres in each motor unit and in three patients and degeneration and haemorr- probably explains the reduction in mean action hage into the cranial nerve nuclei in three cases. potential duration and the increased number of Microscopic examination of the brain in Chap- D 392 Ian Ramsay Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from man & Maloof's (1956) second patient revealed incidentally with overactivity of the thyroid gland slight to moderate swelling of oligodendroglia for it may also occur in Cushing's syndrome, in the sub-cortical white matter. There have been acromegaly, and in apparently two reports on muscle histology. Strong (1949) euthyroid individuals. It is characterized by pro- found only evidence of oedema in biopsies of gressive exophthalmos, oedema of the lids and ocular and temporal muscles, whereas Gimlette's conjunctivae, weakness of the extraocular muscles, (1959) first case showed widespread degeneration particularly those showing elevation (Hall, Ford of muscle fibres with foci of lymphocytes. & Manson, 1967), convergence and lateral move- Electromyography appears to have been done ment, and occasionally papilloedema and cor- on only two occasions and in both patients the neal ulceration. pattern was that of a myopathy (Gimlette, 1959). The administration of thyroid extract or thy- A fatal outcome was almost the rule in the roxine to experimental animals does not, by earlier cases, but Waldenstrom (1945) was able and large, produce exophthalmos, but the latter to obtain a full remission of symptoms using can be initiated by the administration of anterior iodine followed by partial thyroidectomy. Later, pituitary extracts, particularly post-thyroidectomy with the development of effective antithyroid (Brain, 1959). This tallies closely with clinical drugs and radioactive iodine, complete recovery experience, for severe involvement of the eye has been obtained with medical treatment (Strong occurs more frequently following successful 1949; Chapman & Maloof, 1956; Gimlette, 1959; treatment of the thyrotoxicosis than during the Heinrich et al., 1962). course of the disease itself (Asboe-Hansen, Iver- It is difficult to decide whether this condition sen & Wichmann, 1952; Brain, 1959). The thy- should be called acute thyrotoxic myopathy or roid hormones thus do not seem to be the cul- encephalopathy. In favour of the lesion being a prits. myopathy, it has been noted that the patients Asboe-Hansen et al. (1952, 1953) found raisedProtected by copyright. did have skeletal muscle weakness as well as serum levels of thyrotropin in nine out of ten bulbar symptoms and it has already been re- patients with progressive exophthalmos. Kinderen marked upon that 16*4% of the patients des- Houtstra-Lanz & Schwarz (1960) and Dobyns, cribed as having chronic thyrotoxic myopathy Wright & Wilson (1961) have isolated a sub- also had bulbar weakness. The evidence for en- stance which they call 'exophthalmos producing cephalopathy rests on three cases (Waldenstrom, substance' (EPS) and which they believe to be 1945) with haemorrhage into cranial nerve nuclei an entity quite separate from thyrotropin. They and slight to moderate swelling of oligoden- also found a good correlation between the pres- droglia in another patient (Chapman & Maloof, ence or absence of exophthalmos and of EPS in 1956). It is of course known that patients may the serum of thyrotoxic patients (Schwarz, Kin- die of thyrotoxic crisis or in coma without any deren & Houtstra-Lanz, 1966). Improvement in preceding bulbar paralysis and the same non- some patients' exophthalmos following pituitary- specific pathological changes are found at stalk section or hypophysectomy (McCullagh, http://pmj.bmj.com/ autopsy. The proposition is therefore made that Clamen & Gardner, 1957) seemed to indicate the 'acute thyrotoxic myopathy' may represent the pituitary origin of ophthalmopathy and recently stage at which bulbar weakness complicates a workers in Utrecht have shown EPS activity in the chronic myopathy. However, if the thyrotoxic pituitaries of exophthalmic patients (Kinderen, process is severe enough the phase of generalized 1967). Moreover, they found that the activity of muscle weakness may be short and the bulbar EPS in serum dropped markedly following hypo- involvement, with its dramatic symptoms, becomes physectomy or pituitary irradiation. EPS has also the most pronounced feature. It must not be been demonstrated in the serum of exophthalmic on September 26, 2021 by guest. forgotten, however, that the patient could have patients with Cushing's syndrome and acromegaly myasthenia gravis in addition to thyrotoxic myo- so there is good evidence for it being the causa- pathy. Millikan & Haines (1953) thought that tive factor. LATS is usually present in addition many of the earlier cases described in the litera- to EPS in patients with infiltrative ophthalmo- ture probably had coincident myasthenia gravis pathy and thyrotoxicosis and Kinderen (1967) and thyrotoxicosis, and neostigmine gave drama- has suggested that it may act as a facilitatory tic relief from the bulbar symptoms in three of factor. the more recent cases (Laurent, 1944; Sheldon It is interesting to compare the pathological & Walker, 1946). changes described in the extrinsic eye muscles with those found in muscle tissue elsewhere. Infiltrative ophthalmopathy Askanazy (1898) found similar changes in both This condition is probably connected only (see above). Dudgeon & Urquhart (1926) ob- muscle disease 393

Thyrotoxic Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from served lymphorrhages, which were sometimes Myasthenia gravis perivascular, proliferation of interstitial cells and The combination of myasthenia gravis and atrophy of muscle fibres. These abnormalities thyrotoxicosis was first described by Remak in were most marked in the eye muscles, less so 1899 (Logothetis, 1961) and since then it has in the deltoid and biceps and least in the myo- been reported in more than fifty cases (Adams, cardium; the changes were similar to those found Denny-Brown & Pearson, 1962). in the muscles of thyroidectomized guinea-pigs It has been estimated that during the course injected with thyrotrophic anterior pituitary ex- of their disease 1% of thyrotoxics will develop tracts (Paulson, 1939; Dobyns, 1946). myasthenia gravis (Grob, 1963) and that the in- The semi-lunar accumulations of mucopoly- cidence of thyrotoxicosis preceding, accompany- saccharides situated under the sarcolemmal cover- ing or following the clinical onset of myasthenia ing of skeletal muscle fibres of patients with gravis is 5% (Millikan & Haines, 1953). Osser- progressive exophthalmos (Asboe-Hansen et al., man & Silver (1961) tested ninety of their myas- 1952) were also found in the extra-ocular mus- thenic patients and diagnosed thyrotoxicosis in cles (Wegelius, Asboe-Hansen & Lamberg, 1957). eight. Millikan & Haines (1953) found that 80% Mucopolysaccharides, particularly hyaluronic of the patients with this combination of two acid, were present in the orbital tissue of these diseases were women and that the type of myas- patients (Ludwig, Boas & Soffer, 1950; Asboe- thenia was the same as that in patients without Hansen & Iverson, 1951) and have been pro- thyrotoxicosis. The diplopia, ptosis, facial weak- duced in both intact and thyroidectomized ani- ness, bulbar palsy, etc., respond well to anti- mals by the injection of thyrotropin. cholinesterase drugs (Millikan & Haines, 1953), It is therefore proposed that the histological but the myopathy of thyrotoxicosis remains un- features described in thyrotoxic myopathy, apart altered (Havard et al., 1963; Ramsay, 1964). Fig. from muscle atrophy, are probably due to the 2 shows a patient (Ramsay, 1964) who presented Protected by copyright. effect of a pituitary factor. Thyrotropin itself with the simultaneous onset of thyrotoxicosis cannot be implicated since its concentration in and myasthenia gravis. Her diplopia and ptosis the blood of thyrotoxics is either normal or low responded dramatically to edrophonium chlo- (Lemarchand-Beraud et al., 1967; Blum et al., ride intravenously, but produced no change in 1967) and it is possible that the changes are her myopathic proximal limb muscles. produced by a synergistic action of EPS and Some authors have tried to find factors which LATS. are common to both myasthenia gravis and thyro- The mechanism whereby the eyes are pro- toxicosis. Cohen & King (1932) commented on truded in exophthalmos has been explained by the hypertrophy of lymphatic tissue, the occa- Iverson & Asboe-Hansen (1952) as being the sional lymphocytosis and the finding of lymphor- result of the water-binding qualities of the muco- rhages in muscle tissue. An enlarged thymus is polysaccharides in the orbital tissues. The muscle found in half the thyrotoxic patients who come paralysis could be secondary to stretching and to post-mortem examination (Williams, 1962) and http://pmj.bmj.com/ venous occlusion caused by the proptosis and thymic abnormalities are found in about 60% retro-orbital oedema, but it is more likely to be of myasthenics (Castleman & Norris, 1949; Row- due to a primary muscle disease, since ophthal- land, Aranow & Hoefer, 1957; Grob, 1961). In moplegia may occur without any demonstrable 15-33% of patients there is a thymoma; in 25- exophthalmos (Naffziger, 1932; Dobyns, 1950; 35% the thymus is hyperplastic. The thyrotoxi- Logothetis, 1961). cosis appears first in about half the patients. Treatment is unsatisfactory, though the con- Myasthenia gravis precedes the thyroid disease dition usually either regresses or stabilizes within in a third to just under a half and in 9-20% on September 26, 2021 by guest. a few months or years. Prednisone in large doses the onset of both is simultaneous (Millikan & (30-100 mg/day) may be successful in diminish- Haines, 1953; Grob, 1963). Although McEachern ing the severity of the ocular changes, but it is & Parnell (1948) described a 'see-saw' relation- difficult to continue with this because of the ship between the diseases, the myasthenia in- occurrence of steroid side-effects. Tarsorrhaphy creasing as the thyrotoxicosis diminishes and vice- may be performed in order to prevent corneal versa, only three reports have supported this ulceration and orbital decompression or hypo- concept (Thorner, 1939; Cohen, 1946; Maclean physectomy is sometimes done as a last resort. & Wilson, 1954). The majority of opinion con- A recent report of the beneficial effects of metro- cludes that both diseases move in parallel or nidazole in the treatment of exophthalmos (Har- show no obvious pattern of interaction (Thorn den, Chisholm & Cant, 1967) sounds promising, & Tierney, 1941; Kowallis, Haines & Pemberton, but further work is needed for evaluation. 1942; Flynn, 1944; Greene, 1949; Millikan & 394 Ian

Ramsay Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from Haines, 1953; Engel, 1961b, Osserman & Sil- toxic myopathy is fairly straightforward. The ver, 1961). Adams et al. (1962) take the view most prominent symptoms of the patient with that whatever the factors are which link the two myasthenia gravis will be ptosis, diplopia, dysar- diseases, the thyrotoxicosis does not make the thria and dysphagia and there will be a variation myasthenia gravis worse per se, but merely adds in the degree of weakness throughout the day, the weakness of thyrotoxicosis to that of the whereas the patient with myopathy will have latter. In support of this is Grob's (1961) ex- complaints associated mainly with proximal perience that myasthenia gravis may be precipi- muscle weakness. Only rarely will bulbar muscles tated, or be aggravated, by the treatment of other be involved and when they are the possibility of diseases with thyroid extract. myasthenia gravis must be carefully considered. The simplest test to perform is to inject 10 mg of edrophonium chloride (Tensilon) intraven- ously, having given the first milligram as a test dose. Within a minute the muscles involved by myasthenia gravis will have become stronger in 95% of cases (Osserman & Silver, 1961). The muscles affected by thyrotoxic myopathy remain just as weak. If the results are equivocal, further tests are available (Osserman & Silver, 1961; Simpson, 1964). Patients with myasthenia gravis become much weaker after receiving one-fifth to one-tenth of a normal curaring dose of D-tubo- curarine, but this has no effect on thyrotoxics.

In normal subjects and in hyperthyroid patients Protected by copyright. electromyographic potentials do not decrease in amplitude following repetitive nerve stimulation, but they do in myasthenics and this decrease can be reversed by giving edrophonium. Periodic paralysis More than 200 cases of concurrent thyro- toxicosis and periodic paralysis were reviewed by Engel in 1961 (Engel, 1961a) Okinaka and his colleagues (1957) in Japan found a 1-9% incidence of periodic paralysis in their thyro- toxic patients with a relatively higher incidence

for male patients (8-2%) than for females http://pmj.bmj.com/ (0-4%), giving a male-female ratio of 20-5: 1 compared with a ratio of 3: 1 in uncompli- cated periodic paralysis. They found a family history of periodic paralysis in only one out of 119 subjects and discovered that the major in- cidence of associated with FIG. 2. Female aged 35 with concurrent thyrotoxicosis periodic paralysis and thyrotoxicosis was in the third and fourth de- myasthenia gravis: (a) showing ptosis, (b) following on September 26, 2021 by guest. the intravenous injection of edrophonium. cades compared with the first and second for the uncomplicated disease. Seventy-five patients The suggestion has been made that both myas- were followed up and all but three of them re- thenia gravis (Simpson, 1960, 1966) and thyro- mitted after effective treatment of hyperthyroid- toxicosis (Anderson et al., 1964) are autoimmune ism. The Japanese workers felt that the simul- diseases. Simpson (1966) believes that the relation- taneous occurrence of the two diseases was pro- ship, which is similar to that between thyroditis bably due to pre-existing latent periodic paralysis and idiopathic Addison's disease (Blizzard, Chee becoming unmasked by the development of & Davis, 1967; Irvine, Stewart & Scarth, 1967), thyrotoxicosis (Okinaka et al., 1957). They have, may be the result of a genetic defect in immuno- in fact, recently shown that the mechanism of logical control. the paralysis is the same in patients with and Clinically the differentiation between myasth- without thyrotoxicosis, namely an influx of pot- enia gravis with hyperthyroidism and pure thyro- assium into the cells from the extracellular space Thyrotoxic muscle disease 395 Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from (Shizume et al., 1966). It is known that the ad- ANDERSON, J.R., GRAY, K.G., MIDDLETON, D.G. & YOUNG, ministration of adrenaline causes the movement J.A. (1964) Autoimmunity and thyrotoxicosis. Brit. med. J. ii, 1630. of potassium from the extracellular fluid into ASBOE-HANSEN, G. & IVERSEN, K. (1951) Influence of thyro- muscle cells (Grob et al., 1957). Since an effect trophic hormones on connective tissue; pathogenic of excess thyroid hormone is to sensitize body significance of mucopolysaccharides in experimental tissues to normal circulating amounts of adren- exophthalmos. Acta endocr. (Kbh.), 8, 90. ASBOE-HANSEN, G., IVERSEN, K. & WICHMANN, R. (1952) aline (Brodie et al., 1966) this may explain the Malignant exophthalmos; muscular changes and thyro- linkage between the two diseases. Certainly at- tropin content in serum. Acta endocr. (Kbh.), 11, 376. tacks of paralysis in uncomplicated periodic ASBOE-HANSEN, G., IVERSEN, K. & WICHMANN, R. (1953) paralysis can be initiated by the administration Progressive exophthalmos; muscular changes and thyro- of thyroid hormone (Shinosaki, quoted by tropin content of serum. Ugeskr. Laeg. 115, 889. ASKANAZY, M. (1898) Pathologische-anatomische Beitrage Okinaka et al., 1957). zur Kenntniss des Morbus Basedowii, insbesondere uber The weakness of periodic paralysis can be die dabei auftretende Muskelkrankung. Dtsch. Arch. klin. distinguished from that of myasthenia gravis in Med. 61, 118. that it tends to occur in the morning or after a ASKONAS, B.A. (1951) Effect of thyroxine on creatine large carbohydrate meal. The weakness involves phosphokinase activity. Nature (Lond.), 167, 933. BARTELS, E.C. & PIZER, E. (1944) Muscular atrophy in the legs, then the arms, trunk and face. Swallow- hyperthyroidism; report of a case. Lahey Clin. Bull. 4, 52. ing, movement of the eyes and respiration are BASEDOW, C.A. VON (1840) Exophthalmos durch Hyper- preserved until the last. trophie des Zellgewebes in der Augenhohle. Wschr. ges. Heilk. 6, 197. BLIZZARD, R.M., CHEE, D. & DAvIs, W. (1967) The incidence Conclusions of adrenal and other antibodies in the sera of patients with Most patients who have thyrotoxicosis suffer idiopathic adrenal insufficiency (Addison's disease). Clin. from some degree of myopathy, whether or not exp. Immunol. 2,19. it is obvious clinically. Occasionally, and especi- BLUM, A.S. GREENSPAN, F.S., HARDGADINE, J.R. & LOWEN- Protected by copyright. STEIN, J.M. (1967) Simultaneous detection of thyroid ally in the elderly patients who have Plummer's stimulating hormone (T.S.H.) and long acting thyroid disease and therefore no exophthalmos, the myo- stimulator (LATS). Metabolism, 16, 960. pathy may be the presenting feature. Thyrotoxi- BOSTROM, H. & HED, R. (1958) Thyrotoxic myopathy and cosis, therefore, should be always high up on polymyositis in elderly patients; differential diagnostic the differential diagnosis of myopathy. If ade- viewpoints. Acta med. scand. 162, 225. BRAN, R. (1959) Pathogenesis and treatment of endocrine quate treatment is given for the hyperthyroidism exophthalmos. Lancet, i, 109. the myopathy will remit completely in just about BRODIE, B.B., DAVIEs, J.I., HYNIE, S., KRIsHNA, G. & the same time as it takes for the patient to be- WEISS, B. (1966) Interrelationships of catecholamines with come clinically euthyroid. other endocrine systems. Pharmacol. Rev. 18, 273. Bulbar myopathy ('acute thyrotoxic myopathy') BUCHTHAL, F. (1957) An Introduction to Electromyography, is an indication of the severe p. 34. Glydendal, Copenhagen. nature of the BUCHTHAL, F., GULD, C. & ROSENFALCK, P. (1955) Propa- patient's hyperthyroidism and may be either the gation velocity in electrically activated muscle fibres in end-stage of chronic thyrotoxic myopathy or part man. Acta physiol. scand. 34, 75. http://pmj.bmj.com/ of a more acute involvement of most of the BUCHTHAL, F. & ROSENFALCK, P. (1963) muscles in the body. The situation is serious and in Man and Animals (Ed. by G. H. Bourne and M. N. treatment must be Golarz). Karger, Basel. instituted immediately to con- CASTLEMAN, B. & NORRIS, E.H. (1949) The pathology of the trol the hypermetabolic state with iodine, car- thymus in myasthenia gravis. Medicine (Baltimore), 28, 27. bimazole, propranalol and cooling. Maintenance CHAPMAN, E.M. & MALOOF, F. (1956) Bizarre clinical mani- of a good airway, the administration of oxygen festations of hyperthyroidism. New Engl. J. Med. 254, 1. and the prevention of aspiration of food are CHAPPELL, J.B. & GREVILLE, G.D. (1958) Mitochondrial measures. In swelling and its reversal. Proc. 4th int. Congr. Biochem., on September 26, 2021 by guest. important addition it is advisable Vienna, 15, 71. to give supplementary cortisol intravenously, es- COERS, C. & WOOLF, A.L. (1959) The Innervation of Muscle: pecially if the blood pressure is low. A Biopsy Study, p. 118. Blackwell Scientific Publications, Finally it is important to remember that a Oxford. patient with gross chronic thyrotoxic myopathy COLLINGS, H. & LIENHARD, W.F. (1957) Thyrotoxic myo- pathy with disturbance of potassium metabolism. Neuro- who also has bulbar symptoms may have myas- logy (Minneap.), 7, 667. thenia gravis, and the appropriate investigations COHEN, B. (1946) Thyrotoxicosis and myasthenia gravis: must therefore be carried out. report of a case. S. Afr. med. J. 20, 408. COHEN, S.J. & KiNG, F.H. (1932) Relation between myas- thenia gravis and exophthalmic . Arch. Neurol. References Psychiat. (Chic.), 28, 1338. ADAMS, R.D., DENNY-BROWN, D. & PEARSON, C.M. (1962) CooMEs, E.N. (1965) The rate of recovery of reversible Diseases of Muscle. A Study in Pathology. Kimpton, myopathies and the effects of anabolic agents in steroid London. myopathy. Neurology (Minneap.), 15, 523. Ian Ramsay

396 Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from

DEVIC, A., FROMENT, R., GUINET, P. & DEVIC, M. (1947) HUXLEY, A.F. & TAYLOR, R.E. (1958) Local activation of Les dystrophies musculaires hyperthyroldiennes. A propos striated muscle fibres. J. Physiol. (Lond.), 144, 426. de 14 observations personelles de myopathie basedowienne. IRVINE, W.J., STEWART, A.G. & SCARTH, L. (1967) A J. Med. Lyon. 28, 155. clinical and immunological study of adrenocortical in- DOBYNS, B.M. (1946) Studies on exophthalmos produced by sufficiency (Addison's disease). Clin. exp. Immunol. 2, 31. thyrotropic hormone; study of exophthalmos produced by IVERSEN, K. & ASBOE-HANsEN, G. (1952) Studies on the fat- various thyrotropic hormones and influence of testes on mobilising factor of the anterior pituitary gland; sup- exophthalmos. Surg. Gynec. Obstet. 82, 609. pressive action of thyroxine. Acta endocr. (Kbh.), 11, 111. DOBYNS, B.M. (1950) Present concepts of pathologic physio- IVERSEN, K., ASBOE-HANSEN, G. & CARLSEN, F. (1953) logy of exophthalmos. J. clin. Endocr. 10, 1202. Electron microscopy of certain muscle lesions in patients DOBYNS, B.M., WRIGHT, A. & WILSON, L. (1961) Assay of with pituitary-thyroid disorders. Acta endocr. (Kbh.), 14, the exophthalmos-producing substance in the serum of 177. patients with progressive exophthalmos. J. clin. Endocr. KINDEREN, P.J. DER (1967) EPS, LATS and exophthalmos. 21, 648. Thyrotoxicosis, Proceedings ofan International Symposium, Documenta Geigy (1962) Ed. by Konrad Diem, p. 530. Edinburgh, p. 221. Livingstone, Edinburgh. Geigy, Manchester. KINDEREN, P.J. DER, HOUTSTRA-LANz, M. & ScHwARz, F. DUDGEON, L.S. & URQUHART, A.L. (1926) Lymphorrhages (1960) Exophthalmos-producing substance in human in the muscles in exophthalmic goitre. Brain, 49, 182. serum. J. clin. Endocr. 20, 712. ENGEL, A.G. (1961a) Thyroid function and periodic paralysis. KIRCHHEINER, B. (1962) Specific muscle lesions in pituitary- Amer. J. Med. 30, 327. thyroid disorders. Acta med. scand. 172, 539. ENGEL, A.G. (1961b) Thyroid function and myasthenia gravis. KITE, W.C., McLINTOCK, J.C. & GRAVEs, R.W. (1954) Arch. Neurol. 4, 663. Chronic thyrotoxic myopathy. N. Y. St J. Med. 54, 1613. ENGEL, A.G. (1966) Electron microscopic observations in KowALLIs, G.F. HAINES, S.F. & PEMBERTON, J.J. (1942) thyrotoxic and corticosteroid induced myopathies. Proc. Goiter with associated myasthenia gravis: Report of three Mayo Clin. 41, 785. cases of exophthalmic goiter and one case of adeno- FLYNN, R. (1944) Graves' disease with disassociation of matous goiter with hyperthyroidism. Arch. intern. Med. thyrotoxicosis and ophthalmopathy associated with 69,41. myasthenia gravis. Med. J. Aust. i, 344. KUHLBACK, B. (1957) Creatine and creatinine metabolism in GIMLETTE, T.M.D. (1959) The muscular lesion in hyperthy- thyrotoxicosis and hypothyroidism. A clinical Acta

study. Protected by copyright. roidism. Brit. med. J. ii, 1143. med. scand. 159, Suppl. 331. GRAvEs, R.J. (1835) Clinical Lectures. Lond. med. surg. J. 7, LAURENT, L.P.E. (1944) Acute thyrotoxic bulbar palsy. 516. Lancet, i, 87. GREEN, K. & MATTY, A.J. (1962) Effect of thyroxine on the LEMARcHAND-BERAUD, T., VANNOTn, A. & SCAZZIGA, B-R. permeability of the isolated toad bladder. Nature (Lond.), (1967) Plasma TSH levels in the different forms of thyro- 194, 1190. toxicosis. Thyrotoxicosis, Proceedings of an International GREENE, R. (1949) Thyrotocicosis, exophthalmic ophthalmo- Symposium, Edinburgh, p. 48. Livingstone, Edinburgh. plegia, myasthenia gravis and vitiligo. Proc. roy. Soc. Med. LBIcHr, H. (1938) Zur Frage der Muskelveralnderungen bei 42, 263. Morbus Basedowii. Endokrinologie, 20, 81. GROB, D. (1961) Myasthenia gravis. A review ofpathogenesis LOGOTHETIS, J. (1961) Neurologic and muscular manifesta- and treatment. Arch. intern. Med. 108, 615. tions of hyperthyroidism. Arch. Neurol. (Chic.), 5, 533. GROB, D. (1963) Metabolic diseases of muscle. Ann. Rev. LUDWIG, A.W., BOAS, N.F. & SOFFER, L.I. (1950) Role of Med. 14, 151. mucopolysaccharides in pathogenesis of experimental GROB, D., LILJESTRAND, A. & JOHNS, R. (1957) Potassium exophthalmos. Proc. Soc. exp. Biol. (N. Y.), 73, 137. movement in normal subjects. Effect on muscle function. MCCULLAGH, E.P., Clamen, M. & GARDNER, W.J. (1957) Amer. J. Med. 23, 340. Clinical prognosis in the treatment of exophthalmos of HALL, R., FORD, J. & MANSON, N. (1967) Ophthalmic Graves' disease, with particular reference to the effect of http://pmj.bmj.com/ Graves' disease. Thyrotoxicosis, Proceedings of an Inter- pituitary surgery. J. clin. Endocr. 17, 1277. national Symposium, Edinburgh, p. 210. Livingstone, McEAcHERN, D. & PARNELL, J.L. (1948) The relationship Edinburgh. of hyperthyroidism to myasthenia gravis. J. clin. Endocr. HARDEN, R.McG., CHISHOLM, C.J.S. & CANT, J.S. (1967) 8, 842. The effect of Metronidazole on thyroid function and McEACHERN, D. & Ross, W.D. (1942) Chronic thyrotoxic exophthalmos in man, Metabolism, 16, 890. myopathy: a report of three cases with a review of pre- HARMAN, J.B. & RICHARDSON, A.T. (1954) Generalized myo- viously reported cases. Brain, 65, 181. kymia in thyrotoxicosis. Report of a case. Lancet, ii, 473. MACLEAN, B. & WILSON, J.A.C. (1954) See-saw relationship

HARVARD, C.W.H. (1962) Thyrotoxic myopathy; a reappraisal between hyperthyroidism and myasthenia gravis. Lancet, on September 26, 2021 by guest. and report of three cases. Brit. med. 1. i, 440. 1, 950. HARVARD, C.W.H., CAMPBELL, E.D.R., Ross, H.B. & MELVILLE, I.D. (1959) Chronic thyrotoxic myopathy. Scot. SPENCE, A.W. (1963) Electromyographic and histological med. J. 4, 318. findings in the muscles of patients with thyrotoxicosis. MILLIKAN, C.H. & HAINEs, S.F. (1953) The thyroid gland Quart. J. Med. 32, 145. in relation to . Arch. intern. Med. HED, R., KIRSTEIN, L. & LUNDMARK, C. (1958) Thyrotoxic 92, 5. myopathy. J. Neurol. Neurosurg. Psychiat. 21, 270. MORGAN, H.J. & WILLIAMS, R.H. (1940) Muscular atrophy HEINRICH, W.D., MCCABE, E.B., NICELY, D.A. & ELDER, and weakness in thyrotoxicosis (thyrotoxic myopathy; J.C. (1962) Encephalopathic hyperthyroidism manifesting exophthalmic ophthalmoplegia). Sth. med. J. (Bgham, as dysphagia. Amer. J. Roentgenol. 88, 336. Ala.), 33, 261. HOCH, F.L. (1962) Thyrotoxicosis as a disease of mitochon- NAFFZIGER, H.C. (1932) Discussion ofpaper by J. L. McCool dria. New Engl. J. Med. 266, 498. and H.C. Naffziger. Trans. Amer. ophthal. Soc. 30, 103. HOCH, F.L. (1968) Biochemistry of hyperthyroidism and OKINAKA, S., SmzumE, K., IINO, S., WATANABE, A., IRIE, M., hypothyroidism. Postgrad. med. J. 44, 347. NOGUCHI, A., KuMA, S., KUMA, K. & ITO, T. (1957) The HOFFENBURG, R. & EALES, L. (1956) Chronic thyrotoxic association of periodic paralysis and hyperthyroidism in myopathy; a report of two cases. S. Afr. med. J. 30, 1246. Japan. J. clin. Endocr. 17, 1454. Thyrotoxic muscle disease 397 Postgrad Med J: first published as 10.1136/pgmj.44.511.385 on 1 May 1968. Downloaded from OSSERMAN, K.E. & SILVER, S. (1961) Transactions of the SHISIBA, Y., SHIZUME, K., SAKUMA, M., YAMANCHI, H., Fourth International Goitre Conference (Ed. by R. Pitt- NAKAO, K. & OKINAKA, S. (1966) Studies on electrolyte Rivers), p. 100. Pergamon Press, Oxford. metabolism in idiopathic and thyrotoxic periodic paralysis. PARSONS, V. & RAMSAY, I. (1968) Thyroid and adrenal III. Metabolism, 15, 153. relationships. Postgrad. med. J. 44, 377. SHizuME, K. SHISHIBA, Y., SAKUMA, M., YAMANCHI, H., PAULSON, D.L. (1939) Experimental exophthalmos and NAKAO, K. & OKINAKA, S. (1966) Studies on electrolyte muscle degeneration induced by thyrotropic hormone. metabolism in idopathic and thyrotoxic periodic paralysis. Proc. Mayo Clin. 14, 828. I. Metabolism, 15, 138. PIMSTONE, B.L., HOFFENBERG, R. & BLACK, E. (1964) SIMPSON, J.A. (1960) Myasthenia gravis: a new hypothesis. Parallel assays of thyrotrophin, long acting thyroid stimu- Scot. med. J. 5, 419. lator and exophthalmos-producing substance in endocrine SIMPSON, J.A. (1964) Disorders of Voluntary Muscle (Ed. exophthalmos and pretibial myxoedema. J. clin. Endocr. by John N. Walton), p. 336. Churchill, London. 24, 976. SIMPSON, J.A. (1966) Myasthenia gravis as an autoimmune disease: clinical aspects. Ann. N. Y. Acad. Sci. 135, 506. PIPBERGER, H., KALIN, R. & WEGMANN, T. (1955) Muskulare STAFFURTH, J.S. & THOMPSON, J.C. (1965) Muscle potassium Storungen bei der Hyperthyreose. Schweiz. med. Wschr. in thyrotoxicosis. Metabolism, 14, 241. 85, 390. STRONG, J.A. (1949) Thyrotoxicosis with ophthalmoplegia, QuiNN, E.L. & WORCESTER, R.L. (1951) Chronic thyrotoxic myopathy, Wolff-Parkinson-White syndrome, and peri- myopathy; report of a case. J. clin. Endocr. 11, 1564. cardial friction. Lancet, i, 959. RAMSAY, I.D. (1964) The muscle lesion in thyrotoxicosis. TAPLEY, D.F. (1964) Mode and site of action of thyroxine. M.D. thesis, University of Edinburgh. Proc. Mayo Clin. 39, 626. RAMSAY, I.D. (1965) Electromyography in thyrotoxicosis. THOMAS, P.K. (1963) Clinical Physiology (Ed. by E. J. M. Quart. J. Med. 34, 255. Campbell, C. J. Dickinson and J. D. H. Slater), p. 315. RAMSAY, I.D. (1966) Muscle dysfunction in hyperthyroidism Blackwell Scientific Publications, Oxford. Lancet, H, 931. THORN, G.W. & EDER, H.H. (1946) Studies on chronic ROWLAND, L.P., ARANOW, H. & HOEFER, P.F. (1957) thyrotoxic myopathy. Amer. J. Med. 1, 583. Myasthenia gravis appearing after the removal ofthymoma. THORN, G.W. & TIERNEY, N.A. (1941) Myasthenia gravis Neurology (Minneap.), 7, 584. complicated by thyrotoxicosis; creatine studies; case report. SANDERSON, K.V. & ADEY, W.R. (1949) Chronic thyrotoxic Bull. Johns Hopk. Hosp. 69, 469.

myopathy, with report of case including electromyo- THORNER, M.W. (1939) Relation of myasthenia gravis to Protected by copyright. graphic studies. Med. J. Aust. i, 797. hyperthyroidism. Arch. intern. Med. 64, 330. SANDERSON, K.V. & ADEY, W.R. (1952) Electromyograph WALDENSTROM, J. (1945) Acute thyrotoxic encephalo- or and endocrine studies in chronic thyrotoxic myopathy. myopathy, its cause and treatment. Acta med. scand. 121, J. Neurol. Neurosurg. Psychiat. 15, 200. 251. SATOYOSHI, E., MURAKAMI, K., KOWA, H., KINOSHITA, M., WEGELIUS, O., ASBOE-HANSEN, G. & LAMBERG, B-A. (1957) NOGucHi, K., HOSHINA, S., NISnMYAMA, Y. & ITO, K. Retrobulbar connective tissue changes in malignant (1963a) Myopathy in thyrotoxicosis, with special emphasis exophthalmos. Acta endocr. (Kbh.), 25, 452. on an effect of potassium ingestion on serum and urinary WHITFIELD, A.G.W. & HUDSON, W.A. (1961) Chronic creatine. thyrotoxic myopathy. Quart. J. Med. 30, 257. Neurology (Minneap.), 13, 645. WILKINS, L. & FLEISCHMANN, W. (1946) Effects of thyroid SATOYOSHI, E., MuRAKAMI, K. & TORII, J. (1963b) Thyro- on creatine metabolism with a discussion ofthe mechanism toxic myopathy. Lancet, ii, 843. of storage and excretion of creatine bodies. J. clin. Invest. SATTLER, H. (1952) Basedow's Disease (English translation 25, 360. by J. W. and J. F. Marchand). Grune & Stratton, New WILUAMS, R.H. (1962) Textbook of Endocrinology (Ed. by York. R.H. Williams), p. 157. Saunders, Philadelphia. SCHWARZ, F., KINDEREN, P.J. DER & HouTsTRA-LANZ, M. YATES, D.A.H. (1963) The estimation of mean potential (1966) The correlation between endocrine exophthalmos duration in endocrine myopathy. J. Neurol. Neurosurg. http://pmj.bmj.com/ and exophthalmos producing substance. Acta endocr. Psychiat. 26, 458. (Kbh.), 51, 359. YATES, D.A.H. (1965) Electrodiagnosis of myopathic dis- SHELDON, J.H. & WALKER, R.M. (1946) Acute thyrotoxic orders. Postgrad. med. J. 41, 325. myopathy; recovery after partial thyroidectomy. Lancet, ZIRLER, K.L. (1951) Muscular wasting of obscure origin i, 342. and the thyroid gland. Bull. Johns Hopk. Hosp. 89, 263. on September 26, 2021 by guest.