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SOME DISEASES OF MUSCLE
Saturday
SOME DISEASES OF MUSCLE *
JOHN N. WALTON M.D.
Durh., F.R.C.P.
NEUROLOGIST, REGIONAL NEUROLOGICAL CENTRE, NEWCASTLE GENERAL HOSPITAL; PHYSICIAN IN NEUROLOGY, ROYAL VICTORIA INFIRMARY, NEWCASTLE UPON TYNE " " and " muscular dysSINCE the terms myopathy trophy " have different meanings for different people, I must begin by explaining how I apply them. In my " " view, the term myopathy may justifiably be used to describe any disorder of muscular structure or function in which the primary abnormality-structural, electrical, or biochemical-is in the muscle-fibre or its membrane or myoneural junction, or in the connective tissue within the muscle itself. Muscular dystrophy ", on the other hand, should be reserved for those forms of progressive muscularweakness and wasting which fall into the category of genetically determined, primary, degenerative "
myopathy (Walton 1961). Progressive Muscular Dystrophy
Though modifications have become necessary (Walton 1961, 1963), the classification of progressive muscular dystrophy proposed by Professor Nattrass and myself (Walton and Nattrass 1954) now seems generally acceptable. If one excludes cases with myotonia, and the relatively uncommon distal and ocular forms of dystrophy, most of the remaining cases fall into three groupsnamely, the Duchenne (pseudohypertrophic), limb-girdle, and facioscapulohumeral varieties. I shall here confine myself to the Duchenne type. This is, of course, the most severe form of the disease. Unlike so many other neurological disorders in childhood (e.g., cerebral palsy) which either remain static or tend to improve, muscular dystrophy is an insidious process of progressive deterioration. Beginning with a tendency to fall frequently and to waddle, with difficulty in climbing stairs and in rising from the floor, the child has increasing difficulty in walking, is confined to a wheelchair at about the age of 10, goes on to develop progressive skeletal distortion and atrophy (Walton and Warrick 1954), and usually dies before the age of 20. It is now apparent that in over 90% of families this form of the disease is inherited by a sex-linked recessive mechanism: it is manifest in males and transmitted by females. Support for this view comes not only from a study of affected pedigrees (Stevenson 1953, Walton 1955, 1956, Morton and Chung 1959) but also from the fact that the disease has been described in children born of the same mother but by different fathers. Final confirmation is given by the description of the disease in a female " who was found to be suffering from Turner’s syndrome (ovarian agenesis) and who had an XOchromosome constitution (Walton 1956), and from the *From the Savill memorial lecture delivered at the West End Hospital for Nervous Diseases, London, on Oct. 17, 1963. 7331
29
February 1964
fact that in one family crossing-over with the gene for red-green colour-blindness has been described (Walton et al. 1956). Attempts to demonstrate linkage or crossing-over between the gene responsible for this form of muscular dystrophy and the genes responsible for other sex-linked recessive traits have so far been unsuccessful. Recent work suggests, however, that not all cases are inherited by a sex-linked recessive mechanism; even within the sex-linked recessive variety, Becker and Kiener (1955) and Gresham and Cruickshank (1960) identify a sub-variety which is clinically milder, often of later onset, and in many respects more benign. Also it seems that in up to 10% of families the Duchenne-type muscular dystrophy may be inherited by an autosomal recessive mechanism (Lamy and de Grouchy 1954, Kloepfer and Talley 1958, Blyth and Pugh 1959, Dubowitz 1960, Jackson and Carey 1961). This form of inheritance unquestionably accounts for the great majority of cases in girls, and this subvariety is also more benign than the sex-linked recessive form.
Serum-enzyme Studies. In 1949 Sibley and Lehninger pointed out that the serum-aldolase level was raised in patients who had muscular dystrophy. While the normal activity of this enzyme is usually less than 10 Bruns units per millilitre, figures over 100 are frequently encountered in muscular dystrophy (Thomson et al. 1960), declining as the disease progresses. Pearson (1957) showed that in the preclinical stage of the disease the serum-aldolase may be much above normal. In 1959 Ebashi et al. found a pronounced increase in creatine-kinase activity in the serum of such cases, and it is now apparent that this enzyme is the most sensitive indicator of muscular dystrophy of the Duchenne type. While the average normal level is about 2 units per ml., with an upper level of 3-5 (Pearce et al. 1964b), values of up to several hundred units have been found in early cases. The highest serum-creatine-kinase value (1060 units) yet encountered by us was in a clinically normal younger brother of an affected boy; and we now believe it possible to identify, shortly after birth, those males who will later develop the clinical features of this disease. Pearson (1962) has shown that in preclinical cases the changes in serum-enzyme levels are associated with recognisable pathological change in muscle biopsy
specimens. Detection of Carriers In genetic counselling it is clearly important to be able to identify female carriers of the sex-linked recessive gene responsible for muscular dystrophy of the Duchenne type. Chung et al. (1960) and Dreyfus et al. (1956) found the serum-aldolase to be elevated in a small portion of carriers. Later Dreyfus et al. (1961) detected 23 out of 26 carrier females using serum-enzyme determinations and measurements of circulation-time, while Aebi et al. (1962) found a raised serum-creatine-kinase activity in
448 8 of 9 carriers. Leyburn et al. (1960) reported no significant rise in creatine output or in serum-aldolase in a series of carriers, but Hughes (1963) and Pearce et al. (1964c) say that 70-80% of female carriers can be accur-
identified by creatine-kinase estimation. In a proportion of carriers, slight but probably significant electromyographic (E.M.G.) abnormalities have been discovered (van den Bosch 1963, Barwick 1963). These findings can be correlated with the observations of Dubowitz (1963), of Pearson (1963), and of Pearce, Pearce, and Walton (1964), all of whom have shown that, in a proportion of known female carriers, slight histological abnormalities compatible with early dystrophic change can be discerned in muscle-biopsy specimens. These observations give modest support to the Lyon hypothesis (Lyon 1961) which suggests that in a proportion of female cells one X-chromosome may be inactivated. This may mean that in the cells in question the X-chromosome carrying the gene responsible for the Duchenne-type dystrophy has a phenotypic effect; and this is why biochemical, electrical, and pathological evidence of patchy muscle-fibre degeneration can be detected by the tests referred to. The proportion of cells in which these changes occur is small; and this is why clinical evidence of muscular weakness is usually lacking in these female carriers, even though minor clinical abnormalities have been reported in a small proportion of them (Chung et al. 1960, Emery 1963).
ately
Treatment When one considers treatment, it is difficult not to be despondent. Among the many forms tried and found wanting one can include glycine, vitamin E and its analogues, polyvitamin therapy, ’mixed aminoacids, and many others. Recently, Dowben (1963) has recommended anabolic steroid drugs with digitoxin. He had previously found (Dowben 1959) that these prolonged the lives of dystrophic mice of the Bar Harbor strain. Using similar anabolic steroid drugs in 40 cases, Barwick et al. (1963), in a double-blind trial, found no improvement in the disease and no evidence of arrest. Yet more recently, a mixture of nucleotides and nucleosides known commercially as ’Lasvadosin’ has been said to improve a proportion of patients with muscular dystrophy of the Duchenne type and to arrest of the disease in others (Thomson and Guest 1963). As the trial was uncontrolled, this report must be treated with reserve; but the numerous controlled trials of lxvadosin now in progress should determine whether it has any permanent place in treatment. I believe that the discovery of an effective remedy for the disease depends on elucidation of its primary biochemical cause.
Denny-Brown (1960), on the other hand, preferred a pathological classification, and suggested that only cases with histological evidence of inflammation should be called polymyositis. He would recognise as separate entities such disorders as necrotising myopathy, chronic progressive vacuolar myopathy, and progressive granular degeneration of muscle. Neither of these proposals seems to me satisfactoryfirst because the aetiology of the illness often remains obscure despite full investigation, and secondly because a response to steroid therapy (suggesting a relationship with disease of the collagen or connective-tissue group) may be seen in patients who show no clinical sign of disease other than the myopathy and in whom biopsy reveals only a necrotising myopathy or (rarely) a vacuolar myopathy without inflammatory change. Hence I still favour the purely clinical and empirical grouping of cases proposed by Walton and Adams (1958):
..J
Polymyositis with dominant muscular weakness but with some evidence of an associated collagen disease, or dermatomyositis with severe muscular disability and with slight or transient skin changes. III. Polymyositis complicating severe collagen diseasee.g., rheumatoid arthritis, or dermatomyositis with florid skin changes and minor muscle weakness. iv. Polymyositis complicating malignant disease (including carcinomatous myopathy and dermatomyositis in patients with malignant disease). Ill.
I would agree that
some
of the
cases
here classified
arbitrarilyand particularly some of the acute cases with myoglobinuria, the progressive cases of late onset, and indolent cases associated with carcinoma-may be due to metabolic abnormalities unrelated astiologically to the collagen or connective-tissue disorders to which most cases of polymyositis belong. And here I should mention the concept of carcinomatous myopathy. I believe that many patients presenting with a myopathic syndrome in relation to carcinoma are in fact suffering from polymyositis. I would, however, exclude the characteristic myasthenicmyopathic syndrome described particularly in relation to bronchogenic carcinoma, in which there are certain relatively specific clinical and electrophysiological abnormalities (Rooke et al. 1960, Wise and MacDermot 1962), A series of 52 cases of polymyositis seen in the Newcastle area between 1958 and 1962 has recently been reported TABLE I—CLASSIFICATION OF
52 CASES
OF POLYMYOSITIS
(Newcastle series 1958-1962, from Barwick and Walton 1963)
Current Trends in Research In this country, techniques being used to study the disease process include electron microscopy (Pearce 1963, Mair 1963), tissue culture and interference microscopy (Geiger and Garvin 1957, Pearce 1963, Ross 1963), histochemistry (Pearse 1963), phospholipid studies of the fibre membrane (McArdle 1963), and muscle-enzyme studies
(Pennington 1961, 1964). Polymyositis Classification of polymyositis remains somewhat controversial. Shy (1962) proposed that the late-life myopathies should simply be called polymyopathies, and should be identified separately by specifying the astiological factors known to operate in the particular case.
*These figures in the right-hand column indicate the number of case; c: carcinomatous myopathy which would fall into each of the first ihK: groups if the presence of malignancy was ignored or overlooked.
449 TABLE II AGE AT ONSET IN 432 CASES OF POLYMYOSITIS
(From Barwick and Walton 1963)
the remainder improved. The results were most satisfactory in group-n cases (i.e., polymyositis with very little evidence of other collagen disease, or polymyositis with dermatomyositis in which skin changes were slight); but they were only a little less good in patients in group I (" pure " polymyositis) and group ill (florid dermatomyositis or diffuse collagen disease with polymyositis as a
with Dr. Barwick (Barwick and Walton 1963). Table i arranges them according to our clinical classification, and in table n I give the age-incidence of 432 reported cases. In table in I have listed the signs and symptoms reported in 152 cases including the present series. Muscular pain and tenderness is noted in only about half, as is dysphagia. Two-thirds show cutaneous manifestations and a third a Raynaud phenomenon, while " rheumatic features " occur in less than a third. Muscular weakness involves the proximal limb muscles in almost all cases and the distal muscles in under a third, whereas two-thirds of the patients have weakness of neck muscles, and a third develop contractures at some stage of the illness. The erythrocyte-sedimentation rate was raised in less than half of the cases and comparatively few showed any increase in serum gamma-globulin. The serum transaminase (S.G.O.T.) and aldolase were raised in about half the cases in our series, and less than a quarter showed electrocardiographic abnormalities. In half the patients, however, there were electromyographic abnormalities which, by the criteria of Walton and Adams (1958), were strongly suggestive of polymyositis, whereas in several more the appearances were those of a non-specific myopathy. It is interesting that the electromyogram was normal or only slightly abnormal in 10 of the 52. Muscle
biopsy, too, may give relatively non-specific findings. In half the cases subjected to a single biopsy the changes TABLE III-SIGNS AND SYMPTOMS IN 152 CASES OF POLYMYOSITIS
(From Barwick
and Walton
1963)
secondary effect). The period of follow-up
is now between 9 months and five years. I agree with Pearson (1964) that the response to treatment is on the whole better in patients whose symptoms are of comparatively short duration. I would also stress that many patients require high dosage of prednisone, which must be given, irrespective of side-effects, until a response is obtained. Several of our patients TABLE IV-CLINICAL RESPONSE TO ADRENAL STEROIDS IN 52 PATIENTS WITH POLYMYOSITIS ACCORDING TO INITIAL CLINICAL GROUPING
(From Barwick and Walton 1963)
received 60 mg. of prednisone daily for weeks before improving. In 2 there was no clinical improvement with prednisone, but a satisfactory response was obtained with corticotrophin 80 units daily. We have not found any of the newer steroids (e.g., betamethasone and dexamethasone) superior to prednisone; and indeed, compared to prednisone and prednisolone, they are more likely to cause steroid myopathy. In several of our patients it has been possible to withdraw treatment without relapse after eighteen months to three years; but in several others a small maintenance dose is being continued for more than three years after the onset. One patient has been under treatment for over four years and relapses whenever an attempt is made to withdraw the drug. Nevertheless, the outlook for patients has been immeasurably improved since steroid treatment was introduced.
Polymyalgia Rheumatica Polymyalgia rheumatica (Bagratuni 1953, Gordon 1960, Todd 1961) must often have been overlooked in the
characteristic of polymyositis, and in were those of a myopathy, not characteristic of though polymyositis. In 14 of 32 cases so examined, however, the muscle biopsy gave completely normal findings. In assessing the results of treatment we used a classification of disability in which seven grades of muscular weakness are recognised (Swinyard et al. 1957). All 52 patients were treated with steroid drugs and all but 1 received prednisone or prednisolone. Table IV shows that, if one excludes patients with malignant disease, the results are much more satisfactory than is generally supposed. They do not depend entirely on the clinical category. Only 5 (11%) of the 46 patients who did not have malignant disease died as a direct result of the polymyositis ; more than half recovered completely, while most of were
regarded
as
3 others the appearances
past; for I have seen no fewer than 7 cases in the past year. All the patients were elderly and their principal complaint was of widespread muscular pain, often with local tenderness, minor constitutional upset, and general malaise. No muscular weakness was demonstrable, though movement was often restricted by the pain. None showed any evidence of cranial arteritis (Paulley and Hughes 1960) of joint involvement, and electromyography gave normal findings in all. Muscle biopsy was done in several, again with negative results. The serum enzymes were normal in all, but in every patient the erythrocytesedimentation rate was raised, usually to more than 50 mm. in the first hour, and the response to steroid therapy was immediate and dramatic. In many patients, steroids have been withdrawn, after three to six months’ treatment, without relapse. I regard this condition as a disorder of the intramuscular connective tissue, not involving the muscle-fibres. It is likely to be confused with polymyositis, but the absence of clinical, biochemical, electrical, and pathological evior
450
dence of muscle-fibre degeneration, combined with the finding of a high E.S.R., is sufficient to establish the clinical diagnosis when the pattern is otherwise characteristic. Myasthenia Gravis
aetiology In 1960
Simpson suggested that myasthenia gravis was autoimmune disorder and that the thymus probably might produce an antibody against muscle end-plate protein. In the same year Strauss et al. (1960) demonstrated a muscle-binding globulin in myasthenic serum, and further evidence supporting this concept has accumulated since (Harvey and Johns 1961, Burnet 1962). Also of importance are the observations of Coers and Desmedt (1959), Bickerstaff and Woolf (1960), and MacDermot (1960) upon the intramuscular nerve-endings in this disease : definite pathological changes are seen in terminal arborisations of nerve-fibres, and it has been suggested that the primary abnormality may be in the nerve-fibres themselves. Despite the constancy of these findings, it seems more likely that they are secondary to the antigenantibody reaction taking place at or near the motor end-plate. Relationship with Carcinoma A second point of interest is the relation between true myasthenia gravis and the myasthenic syndrome occurring in patients with bronchogenic carcinoma (Anderson et al. 1953) and occasionally in those with carcinoma elsewhere. In this syndrome the changes in the motor end-plate are quite different from those in true myasthenia gravis (Wise and MacDermot 1962). Furthermore, there are distinctive clinical and electrophysiological differences. For instance, the tendon reflexes are generally diminished in the carcinomatous syndrome but are often normal or even increased in true myasthenia (Simpson 1960). Again, patients with the carcinomatous myasthenic-myopathic syndrome show a poor response to treatment with neostigmine and are abnormally sensitive to decamethonium, whereas patients with myasthenia are resistant to this drug (Churchill-Davidson and Richardson 1952). In addition, Rooke et al. (1960) have demonstrated that after an initial period of muscular fatigue following exercise, patients with the disorder related to malignant disease may show a progressive potentiation in muscular strength. Electrically this is mirrored by a post-tetanic increment in the amplitude of the evoked action potentials produced by electrical stimulation of the motor nerve at rates of more than 50 per second (Rooke et al. 1960). Simpson (1964), however, has observed a similar phenomenon occurring occasionally in patients with true myasthenia; so it is not completely specific. Clearly, in patients found to have a myasthenic syndrome different from myasthenia gravis and showing the positive features described, thorough search for a bronchogenic neoplasm is advisable. Treatment and Prognosis I agree with Ferguson et al. (1955) when they say that myasthenia sometimes remains limited to the external ocular muscles and never spreads to involve the bulbar muscles and limbs. I agree also with Simpson’s view that an
the disease tends to burn itself out, or at least to reach a static phase, within five years of the onset (Simpson 1960). Two points about the management are not sufficiently recognised. The first is that different muscles and muscle groups within the same person may be differentially responsive to neostigmine. Thus while certain muscles
remain clinically weak and require more of the drug, others may be so sensitive to it that any increase in dose will increase the weakness by depolarisation block. In one patient, for example, the limb muscles remained weak on a small dose of neostigmine, but, if this was increased, the diaphragm became paralysed and respiratory embarrassment ensued. Secondly, in many patients with longstanding myasthenia, permanent muscular weakness and wasting supervenes. This is particularly true in the external ocular muscles; after several years of responsiveness to neostigmine these muscles may become totally resistant, with permanent partial paralysis. In the upper limbs it is the triceps especially which is affected (Simpson 1960), and the pattern of muscular wasting is usually quite different from that of progressive muscular dystrophy, though the irreversible changes in the muscles are not dissimilar, both electrically and pathologically, from those of muscular dystrophy. Simpson (1964) has found that most patients prefer pyridostigmine to neostigmine, because of its longer effect and comparative freedom from side-effects. However, many miss the quick boost experienced with neostigmine, and most patients seem to be satisfactorily stabilised on a combination of the two remedies. Ambenonium chloride (’ Mytelase ’) seems to be little, if at all, superior to neostigmine; and aldosterone inhibitors, which have been tried by Gottlieb and Laurent (1961), seem at present unlikely to be of lasting value. On the other hand, the new remedy lycoramine (Somers et al, 1963) may well prove useful. As regards thymectomy, I can only agree with Simpson that it may sometimes have to be performed in desperation, and even as an emergency, in patients failing to respond to medical treatment-particularly those requiring assisted respiration. As an elective operation, its results seem to be best by far in young women whose disease is severe and of comparatively short duration. Metabolic
Myopathies
Under this heading I shall say something about some recent advances in our understanding of the various forms of periodic paralysis. In passing, I may mention that the uncommon form which sometimes complicates hyperthyroidism and which seems to be particularly common in Japan (Okinaka et al. 1957), and chronic thyrotoxic myopathy, are disorders which invariably improve when the hyperthyroidism is treated. (In 1952 Asboe-Hansen et al, reported a pathological change which they regard as specific for chronic thyrotoxic myopathy-namely, crescent-shaped areas within muscle-fibres. But I have not yet seen it in pathological material.) Another form of metabolic myopathy is the generalised muscular weakness of Addison’s disease and hypopituitarism; but the changes in the muscle-fibres have yet to be elucidated.
Cushing’s Syndrome and Steroid Myopathy In 1959 Miiller and Kugelberg described 6 patients with Cushing’s syndrome, of whom 5 had weakness of the muscles of the pelvic girdle and thighs. Electromyography demonstrated myopathic changes but histological abnormalities in the muscle were few. In the same year Perkoff et al. reported similar muscular weakness in patients under treatment with steroids. Since then both naturally occurring myopathy and the iatrogenic disorder have been frequently reported; and it seems that the latter is most often caused by steroids with a fluorine atom in the 9-alpha position. Triamcinolone is particularly
451
likely to have this effect and should in my view no longer be used. In patients with steroid myopathy due to dexamethasone or betamethasone, the weakness has resolved when prednisone was substituted. .lfcArdle’s Syndrome In 1951 McArdle described the case of a man of 30 with increasing muscular pain and stiffness during slight exertion. McArdle showed that the blood lactate and pyruvate failed to rise after exercise, and he suggested that the disorder was due to a defect of glucose utilisation. In 1959 two additional cases were reported (Schmid and Mahler 1959, Mommaerts et al. 1959). In at least one of these cases there was also myoglobinuria; in both, muscle glycogen was increased and myophosphorylase activity was absent. Recently another case has been described by Mellick et al. (1962) in which there was some permanent muscular weakness indicating that a limb-girdle type of myopathy was developing. Schmid and Hammaker (1961) described three cases in a single family; they thought the disorder might be due to an autosomal recessive gene. Probably some patients previously described as having myotonia paradoxa were suffering from this syndrome. Although rare, it is noteworthy as the first clinical form of muscle disease in which a single enzyme defect has been conclusively demonstrated. No curative treatment is possible, but many patients can be improved by taking glucose, or preferably 50-100 mg. of fructose, before exertion. We must hope that many other obscure myopathies may eventually be shown to be due to a specific enzyme defect which can be ameliorated by an
appropriate remedy. Periodic Paralysis Syndromes The classical or hypokalaemic variety of periodic paralysis is well known. It gives rise to attacks of flaccid weakness of the voluntary muscles, usually sparing those of speech, swallowing, and respiration. As a rule, they begin in the second decade and are most frequent in early adult life; usually they last for several hours, and commonly they come on early in the morning on waking, or after a period of rest following exertion, or after a heavy carbohydrate meal. During the attacks the plasmapotassium is usually found to be low-i.e., less than 3 mEq. per litre. There is positive balance of potassome or all of the retained potassium passes into the muscle cell (Grob et al. 1957, Zierler and Andres 1957). Recent work (Shy et al. 1961) has shown that the resting membrane potential is normal during an attack of paralysis, but electron microscopy of muscle specimens has revealed that the vacuoles which can be seen in the muscle cell with the light microscope are due to dilatation of the sarcoplasmic reticulum. The normal resting membrane potential during an attack, even when potassium has moved into the cell, is probably due to a concomitant inward movement of water. Recently, Conn and Streeten (1960) suggested that this hypokalaemic form of periodic paralysis might be due to intermittent aldosteronism. Increased aldosterone excre-
sium, and it seems that
tion, however, is seen in comparatively few cases (Shy et al. 1961); and, although patients with primary aldosteronism due to aldosterone-secreting tumours of the adrenal (Conn 1955) do have attacks of muscular weakness, the role of aldosterone in the xtiology of periodic paralysis has probably been exaggerated. Patients with true aldosteronism generally have polyuria and polydipsia in addition, and can be cured by removal of the tumour. For an attack of this form of periodic paralysis the
appropriate treatment is administration of chloride, though it does not often seem to shorten an attack significantly. When attacks are frequent, it may be useful to give maintenance does of potassium; and, if these do not prevent the attacks, a possible alternative is spironolactone, which has been found to reduce their frequency and severity (Poskanzer and Kerr 1963a). However, the condition does improve spontaneously with age, and one of my patients who is a policeman now has only occasional mild attacks; he has managed a satisfactory career in the Police Force without the authorities ever knowing that he has the disease. The fact that
potassium is often given to these patients brought light a group of cases in which the serumpotassium does not fall during the attacks and in which the condition is actually made worse by potassium chloride (Tyler et al. 1951). Gamstorp (1956) studied two to a
families with this form of the disorder and gave it the name of adynamia episodica hereditaria (hyperkalsemic periodic paralysis might be more appropriate). It is closely related to paramyotonia; for some of the patients show definite myotonia (Drager et al. 1958), though in others the myotonia seems curiously limited to the muscles around the eye (van’t Hoff 1962). The typical attack usually occurs immediately after exercise, and it is usually shorter than those of the hypokalaemic variety, lasting on an average thirty to forty minutes and seldom more than one to two hours. Gamstorp (1962) and McArdle (1962) have shown that as a rule the attacks are associated with a rise in the serum-potassium, though some patients have severe weakness when the serumpotassium is no higher than 4 mEq. per litre:certainly weakness is usually severe when the level reaches 5 mEq., whereas in normal people a serum-potassium of 8 mEq. is needed before weakness develops. Electromyography in such cases often shows slight myopathic changes during the attacks as well as hyperirritability of myotonic type (Buchthal et al. 1958, Creutzfeldt 1961, Gamstorp 1962). Recently Abbott et al. (1962) have shown that the musclefibre membrane potential is lowered during attacks. The attacks themselves are rarely long enough to require treatment, though they can be shortened by intravenous calcium gluconate. Acetazolamide and hydrochlorothiazide have both been used successfully for prophylaxis; and, in the hands of McArdle (1964), the dichlorphenamide (50-100 mg. daily) has been even more successful. It will be interesting to see whether, by preventing attacks of paralysis, such maintenance treatment will prevent the development of the mild but irreversible muscular weakness or myopathy which supervenes eventually in most cases.
A third type of periodic paralysis is described by Poskanzer and Kerr (1961b). It bears in many respects a close resemblance to the hyperkalsemic variety, but the attacks commonly lasted for days or even weeks and often occurred at night. Even in severe attacks the serumpotassium remained normal and there was a positive potassium balance. However, paralysis was made worse or precipitated by giving potassium, and was always improved by large doses of sodium chloride. In these cases 9-fx-nuorohydrocortisone (0-1 mg. daily), when combined with acetazolamide, prevented attacks. Though these disorders are not common, it is important to recognise the different varieties and to bear in mind that a form of hypokalaemic periodic paralysis may complicate thyrotoxicosis and can be cured by the treatment
452 of the thyroid disorder. Careful investigation of every such case is necessary, because effective treatment depends on accurate diagnosis. Clearly the abnormalities in potassium metabolism are but one facet of a disease process whose nature we do not yet understand. Attempts to demonstrate a primary enzyme defect or a specific disorder of carbohydrate metabolism have so far been unsuccessful. For the present, changes in the serumpotassium remain one of the most reliable indices to diagnosis and treatment.
Lyon, M. (1961) Nature, Lond. 190, 372. Mair, W. (1963) Research in Muscular Dystrophy. London. McArdle, B. (1951) Clin. Sci. 10, 13. (1962) Brain, 85, 121. (1963a) Research in Muscular Dystrophy. London. (1964) in Disorders of Voluntary Muscle (edited by J. N. Walton); chap. 15. London. MacDermot, V. (1960) Brain, 83, 24. Mellick, R. S., Mahler, R. F., Hughes, B. P. (1962) Lancet, i, 1045. Mommaerts, W. F. H. M., Illingworth, B., Pearson, C. M., Guillory, R. J., Seraydarian, K. (1959) Proc. nat. Acad. Sci. 45, 791. Morton, N. E., Chung, C. S. (1959) Amer. J. hum. Genet. 11, 360. Müller, R., Kugelberg, E. (1959) J. Neurol. Psychiat. 22, 314. Okinaka, S., Shizume, K., Iino, S., Watanabe, A., Irie, M., Noguchi, A., Kuma, S., Kuma, K., Ito, T. (1957) J. clin. Endocrin. 17, 1454. Paulley, J. W., Hughes, J. P. (1960) Brit. med. J. ii, 1562. Pearce, G. W. (1963) Research in Muscular Dystrophy. London. Pearce, J. M. S., Walton, J. N. (1964) In preparation. Pennington, R. J., Walton, J. N. (1964a) J. Neurol. Psychiat. (in the press). (1964b) ibid. (in the press). (1964c) ibid. (in the press). Pearse, A. G. E. (1963) Research in Muscular Dystrophy; p. 189. London. Pearson, C. M. (1957) New Engl. J. Med. 256, 1069. (1962) Brain, 85, 109. (1963a) Rev. canad. Biol. 21, 533. (1964) in Disorders of Voluntary Muscle (edited by J. N. Walton); chap. 12. London. Pennington, R. J. (1961) Nature, Lond. 192, 884. (1964) in Disorders of Voluntary Muscle (edited by J. N. Walton); chap. 10. London. Perkoff, G. T., Silber, R., Tyler, F. H., Cartwright, G. E., Wintrobe, M.M. (1959) Amer. J. Med. 26, 891. Poskanzer, D. C., Kerr, D. N. S. (1961a) Lancet, ii, 511. (1961b) Amer. J. Med. 31, 328. Rooke, E. D., Eaton, L. M., Lambert, E. H., Hodgson, C. H. (1960) Med. Clin. N. Amer. 44, 977. Ross, K. F. A. (1963). Unpublished observations. Schmid, R., Hammaker, L. (1961) New Engl. J. Med. 264, 223. Mahler, R. (1959) J. clin. Invest. 38, 2044. Shy, G. M. (1962) World Neurology, 3, 149. Engel, W. K., Somers, J. E., Wanko, T. (1963) Brain, 86, 793. Magee, K. R. (1956) ibid. 79, 610. Wanko, T., Rowley, P. T., Engel, A. G. (1961) Exper. Neurol. 3, 53. Sibley, J. A., Lehninger, A. L. (1949) J. nat. Cancer Inst. 9, 303. Simpson, J. A. (1960) Scot. med. J. 5, 419. (1964) in Disorders of Voluntary Muscle (edited by J. N. Walton); -
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—
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Prospect of Advance .
These are only a few of the disorders of muscle. I have said nothing about many of the metabolic forms of myopathy, including the disorders associated with myoglobinuria and such rarities as amyloid myopathy. I have not so much as touched on the various forms of congenital dismyopathy, including those manifold and obscure orders causing infantile hypotonia and a " floppy " infant. Even within this group, new discoveries are being made from year to year, and the description of " central core disease " by Shy and Magee (1956) has now been succeeded by the recognition of a curious congenital myopathy with rod-shaped bodies (Shy et al. 1963). No doubt in the coming years additional specific biochemical or histological subvarieties of congenital myopathy will be recognised. As our knowledge has grown, more and more entities have been identified and clarified, and in some of them effective treatment has become possible. The myopathic disorders are by no means as hopeless as has been supposed. REFERENCES
Abbott, B. C., Creutzfeldt, O. D., Fowler, B., Pearson, C. M. (1962) Fed Proc. 21, 318. Aebi, U., Richterich, R., Colombo, J. P., Rossi, E. (1962) Enzymol. biol. clin. 1, 61. Anderson, H. J., Churchill-Davidson, H. C., Richardson, A. T. (1953) Lancet, ii, 1291. Asbøe-Hansen, G., Iversen, K., Wicaman, R. (1952) Acta endocr., Kbh. 11, 376.
L. (1953) Ann. rheum. Dis. 12, 98. Barwick, D. D. (1963). Research in Muscular Dystrophy; p. 10. London. — Newell, D. J., Walton, J. N. (1963) Neurology, Minneapolis, 13, 12. — Walton, J. N. (1963) Amer. J. Med. 35, 646. Becker, P. E., Kiener, F. (1955) Z. Neurol. 193, 427. Bickerstaff, E. R., Woolf, A. L. (1960) Brain, 83, 10. Blyth, H., Pugh, R. J. (1959) Ann. hum. Genet., Lond. 23, 127. Buchthal, F., Engbaek, L., Gamstorp, I. (1958) Neurology, Minneapolis, 8, 347. Burnet, F. M. (1962) Brit. med. J. ii, 807. Chung, C. S., Morton, N. E., Peters, H. A. (1960) Amer. J. hum. Genet. 12, 52. Churchill-Davidson, H. C., Richardson, A. T. (1952) J. Neurol. Psychiat. 15, 129. Cöers, C., Desmedt, J. E. (1959) Acta. neurol. belg. 59, 539. Conn, J. W. (1955) J. Lab. clin. Med. 45, 661. Streeten, D. H. P. (1960) The Metabolic Basis of Inherited Disease (edited by J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson);
Bagratuni,
—
p. 867. New York.
Creutzfeldt, O. D. (1961) Fortschr. Neurol. Psychiat. 29, 529. Denny-Brown, D. (1960) Trans. Coll. Phycns Philad. 28, 14. Dowben, R. M. (1959) Nature, Lond. 184, 1966. (1963) New Engl. J. Med. 268, 912. Drager, G. A., Hammill, J. F., Shy, G. M. (1958) Arch. Neurol. Psychiat. 80, 1. Dreyfus, J. C., Schapira, G., Schapira, F., Demos, J. (1956) Clin. Chim. Acta, 1, 434. (1961). Proceedings of 2nd International Congress of Human Genetics, Rome; p. 80. Dubowitz, V. (1960) Brain, 83, 432. (1963) J. Neurol. Psychiat. 26, 322. Ebashi, S., Toyokura, Y., Momoi, H., Sugita, H. (1959) J. Biochem., Tokyo, 46, 103. Emery, A. E. H. (1963) Lancet, i, 1126. Ferguson, F. R., Hutchinson, E. C., Liversedge, L. A. (1955) ibid. ii, 636. Gamstorp, I. (1956) Acta pœdiat., Uppsala, 45, suppl. 108, p. 1. (1962) Acta neurol. scand. 38, 3. Geiger, R. S., Garvin, J. S. (1957) J. Neuropath, exp. Neurol. 16, 532. Gordon, I. (1960) Quart. J. Med. 116, 473. Gottlieb, B., Laurent, L. P. E. (1961) Lancet, ii, 528. Gresham, G. A., Cruickshank, J. G. (1960). J. Neuropath. exp. Neurol. 19,
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chap. 13. London. Somers, J. E., Irwin, R. L., Shy, G. 543.
—
—
(1963) Neurology, Minneapolis, 13,
Stevenson, A. C. (1953) Ann. Eugenics, 18, 50. Strauss, A. J. L., Seegal, B. C., Hsu, K. C., Burkholder, P. M., Nastuk, W. L., Osserman, K. E. (1960) Proc. Soc. exp. Biol. Med. 105, 184. Swinyard, C. A., Deaver, G. G., Greenspan, L. (1957) Arch. phys. Med. 38, 574.
Thomson, W. H. S., Guest, K. E. (1963) J. Neurol. Psychiat. 26, 111. — Leyburn, P., Walton, J. N. (1960) Brit. med. J. ii, 1276. Todd, J. W. (1961) Lancet, ii, 1111. Tyler, F. H., Stephens, F. E., Gunn, F. D., Perkoff, G. T. (1951) J. clin. Invest. 30, 492. van den Bosch, J. (1963) Research in Muscular Dystrophy; p. 23. London. van’t Hoff, W. (1962) Quart. J. Med. 31, 385. Walton, J. N. (1955) Ann. hum. Genet. 20, 1. (1956) ibid. 21, 40. (1961) Res. Publ. Ass. nerv. ment. Dis. 38, 378. (1963) Muscular Dystrophy in Man and Animals (edited by G. H. Bourne and M. N. Golarz); chap. 7. Basle. Adams, R. D. (1958) Polymyositis. Edinburgh. Nattrass, F. J. (1954) Brain, 77, 164. Phillips, U., Smith, C. A. B. (1956) Ann. hum. Genet. 21, 155. Warrick, C. K. (1954) Brit. J. Radiol. 27, 1. Wise, R. P., MacDermot, V. (1962) J. Neurol. Psychiat. 25, 31. Zierler, K. L., Andres, R. (1957) J. clin. Invest. 36, 730. -
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AN IMMUNOLOGICAL METHOD OF INCREASING THE SENSITIVITY OF PRIMARY SARCOMAS TO LOCAL IRRADIATION WITH X RAYS
-
—
M.
ALEXANDER HADDOW M.D., D.Sc. Edin., F.R.S. DIRECTOR
PETER ALEXANDER Ph.D., D.Sc. Lond.
—
-
HEAD,
RADIOBIOLOGY DEPARTMENT
CHESTER BEATTY RESEARCH
INSTITUTE, RESEARCH, ROYAL CANCER HOSPITAL, LONDON, S.W.3
INSTITUTE OF CANCER
—
342.
Grob, D., Liljestrand, A., Johns, R. J. (1957) Amer. J. Med. 23, 356. Harvey, A. M., Johns, R. J. (1961) ibid. 32, 1. Hughes, B. P. (1963) Research in Muscular Dystrophy. London. Jackson, C. E., Carey, J. N. (1961) Pediatrics, 28, 77. Kloepfer, H. W., Talley, C. (1958) Ann. hum. Genet., Lond. 22, 138. Lamy, M., de Grouchy, J. (1954) J. Genet. hum., Geneva 3, 219. Leyburn, P., Thomson, W. H. S., Walton, J. N. (1960) Ann. hum. Genet., Lond. 25, 41.
HOST factors are known to play a part in clinical radiotherapy (Glucksman 1960), and indirect factors have best shown
influence the radiation response of tumours in experimental animals (Hollcroft et al. 1950). In this paper, experiments will be reported which show that in rats the effectiveness of a single dose of 2000r of X rays in retarding the growth of a primary fibrosarcoma can be enhanced by an autograft of the tumour, obtained by to
SOME DISEASES OF MUSCLE *
JOHN N. WALTON M.D.
Durh., F.R.C.P.
NEUROLOGIST, REGIONAL NEUROLOGICAL CENTRE, NEWCASTLE GENERAL HOSPITAL; PHYSICIAN IN NEUROLOGY, ROYAL VICTORIA INFIRMARY, NEWCASTLE UPON TYNE " " and " muscular dysSINCE the terms myopathy trophy " have different meanings for different people, I must begin by explaining how I apply them. In my " " view, the term myopathy may justifiably be used to describe any disorder of muscular structure or function in which the primary abnormality-structural, electrical, or biochemical-is in the muscle-fibre or its membrane or myoneural junction, or in the connective tissue within the muscle itself. Muscular dystrophy ", on the other hand, should be reserved for those forms of progressive muscularweakness and wasting which fall into the category of genetically determined, primary, degenerative "
myopathy (Walton 1961). Progressive Muscular Dystrophy
Though modifications have become necessary (Walton 1961, 1963), the classification of progressive muscular dystrophy proposed by Professor Nattrass and myself (Walton and Nattrass 1954) now seems generally acceptable. If one excludes cases with myotonia, and the relatively uncommon distal and ocular forms of dystrophy, most of the remaining cases fall into three groupsnamely, the Duchenne (pseudohypertrophic), limb-girdle, and facioscapulohumeral varieties. I shall here confine myself to the Duchenne type. This is, of course, the most severe form of the disease. Unlike so many other neurological disorders in childhood (e.g., cerebral palsy) which either remain static or tend to improve, muscular dystrophy is an insidious process of progressive deterioration. Beginning with a tendency to fall frequently and to waddle, with difficulty in climbing stairs and in rising from the floor, the child has increasing difficulty in walking, is confined to a wheelchair at about the age of 10, goes on to develop progressive skeletal distortion and atrophy (Walton and Warrick 1954), and usually dies before the age of 20. It is now apparent that in over 90% of families this form of the disease is inherited by a sex-linked recessive mechanism: it is manifest in males and transmitted by females. Support for this view comes not only from a study of affected pedigrees (Stevenson 1953, Walton 1955, 1956, Morton and Chung 1959) but also from the fact that the disease has been described in children born of the same mother but by different fathers. Final confirmation is given by the description of the disease in a female " who was found to be suffering from Turner’s syndrome (ovarian agenesis) and who had an XOchromosome constitution (Walton 1956), and from the *From the Savill memorial lecture delivered at the West End Hospital for Nervous Diseases, London, on Oct. 17, 1963. 7331
29
February 1964
fact that in one family crossing-over with the gene for red-green colour-blindness has been described (Walton et al. 1956). Attempts to demonstrate linkage or crossing-over between the gene responsible for this form of muscular dystrophy and the genes responsible for other sex-linked recessive traits have so far been unsuccessful. Recent work suggests, however, that not all cases are inherited by a sex-linked recessive mechanism; even within the sex-linked recessive variety, Becker and Kiener (1955) and Gresham and Cruickshank (1960) identify a sub-variety which is clinically milder, often of later onset, and in many respects more benign. Also it seems that in up to 10% of families the Duchenne-type muscular dystrophy may be inherited by an autosomal recessive mechanism (Lamy and de Grouchy 1954, Kloepfer and Talley 1958, Blyth and Pugh 1959, Dubowitz 1960, Jackson and Carey 1961). This form of inheritance unquestionably accounts for the great majority of cases in girls, and this subvariety is also more benign than the sex-linked recessive form.
Serum-enzyme Studies. In 1949 Sibley and Lehninger pointed out that the serum-aldolase level was raised in patients who had muscular dystrophy. While the normal activity of this enzyme is usually less than 10 Bruns units per millilitre, figures over 100 are frequently encountered in muscular dystrophy (Thomson et al. 1960), declining as the disease progresses. Pearson (1957) showed that in the preclinical stage of the disease the serum-aldolase may be much above normal. In 1959 Ebashi et al. found a pronounced increase in creatine-kinase activity in the serum of such cases, and it is now apparent that this enzyme is the most sensitive indicator of muscular dystrophy of the Duchenne type. While the average normal level is about 2 units per ml., with an upper level of 3-5 (Pearce et al. 1964b), values of up to several hundred units have been found in early cases. The highest serum-creatine-kinase value (1060 units) yet encountered by us was in a clinically normal younger brother of an affected boy; and we now believe it possible to identify, shortly after birth, those males who will later develop the clinical features of this disease. Pearson (1962) has shown that in preclinical cases the changes in serum-enzyme levels are associated with recognisable pathological change in muscle biopsy
specimens. Detection of Carriers In genetic counselling it is clearly important to be able to identify female carriers of the sex-linked recessive gene responsible for muscular dystrophy of the Duchenne type. Chung et al. (1960) and Dreyfus et al. (1956) found the serum-aldolase to be elevated in a small portion of carriers. Later Dreyfus et al. (1961) detected 23 out of 26 carrier females using serum-enzyme determinations and measurements of circulation-time, while Aebi et al. (1962) found a raised serum-creatine-kinase activity in
448 8 of 9 carriers. Leyburn et al. (1960) reported no significant rise in creatine output or in serum-aldolase in a series of carriers, but Hughes (1963) and Pearce et al. (1964c) say that 70-80% of female carriers can be accur-
identified by creatine-kinase estimation. In a proportion of carriers, slight but probably significant electromyographic (E.M.G.) abnormalities have been discovered (van den Bosch 1963, Barwick 1963). These findings can be correlated with the observations of Dubowitz (1963), of Pearson (1963), and of Pearce, Pearce, and Walton (1964), all of whom have shown that, in a proportion of known female carriers, slight histological abnormalities compatible with early dystrophic change can be discerned in muscle-biopsy specimens. These observations give modest support to the Lyon hypothesis (Lyon 1961) which suggests that in a proportion of female cells one X-chromosome may be inactivated. This may mean that in the cells in question the X-chromosome carrying the gene responsible for the Duchenne-type dystrophy has a phenotypic effect; and this is why biochemical, electrical, and pathological evidence of patchy muscle-fibre degeneration can be detected by the tests referred to. The proportion of cells in which these changes occur is small; and this is why clinical evidence of muscular weakness is usually lacking in these female carriers, even though minor clinical abnormalities have been reported in a small proportion of them (Chung et al. 1960, Emery 1963).
ately
Treatment When one considers treatment, it is difficult not to be despondent. Among the many forms tried and found wanting one can include glycine, vitamin E and its analogues, polyvitamin therapy, ’mixed aminoacids, and many others. Recently, Dowben (1963) has recommended anabolic steroid drugs with digitoxin. He had previously found (Dowben 1959) that these prolonged the lives of dystrophic mice of the Bar Harbor strain. Using similar anabolic steroid drugs in 40 cases, Barwick et al. (1963), in a double-blind trial, found no improvement in the disease and no evidence of arrest. Yet more recently, a mixture of nucleotides and nucleosides known commercially as ’Lasvadosin’ has been said to improve a proportion of patients with muscular dystrophy of the Duchenne type and to arrest of the disease in others (Thomson and Guest 1963). As the trial was uncontrolled, this report must be treated with reserve; but the numerous controlled trials of lxvadosin now in progress should determine whether it has any permanent place in treatment. I believe that the discovery of an effective remedy for the disease depends on elucidation of its primary biochemical cause.
Denny-Brown (1960), on the other hand, preferred a pathological classification, and suggested that only cases with histological evidence of inflammation should be called polymyositis. He would recognise as separate entities such disorders as necrotising myopathy, chronic progressive vacuolar myopathy, and progressive granular degeneration of muscle. Neither of these proposals seems to me satisfactoryfirst because the aetiology of the illness often remains obscure despite full investigation, and secondly because a response to steroid therapy (suggesting a relationship with disease of the collagen or connective-tissue group) may be seen in patients who show no clinical sign of disease other than the myopathy and in whom biopsy reveals only a necrotising myopathy or (rarely) a vacuolar myopathy without inflammatory change. Hence I still favour the purely clinical and empirical grouping of cases proposed by Walton and Adams (1958):
..J
Polymyositis with dominant muscular weakness but with some evidence of an associated collagen disease, or dermatomyositis with severe muscular disability and with slight or transient skin changes. III. Polymyositis complicating severe collagen diseasee.g., rheumatoid arthritis, or dermatomyositis with florid skin changes and minor muscle weakness. iv. Polymyositis complicating malignant disease (including carcinomatous myopathy and dermatomyositis in patients with malignant disease). Ill.
I would agree that
some
of the
cases
here classified
arbitrarilyand particularly some of the acute cases with myoglobinuria, the progressive cases of late onset, and indolent cases associated with carcinoma-may be due to metabolic abnormalities unrelated astiologically to the collagen or connective-tissue disorders to which most cases of polymyositis belong. And here I should mention the concept of carcinomatous myopathy. I believe that many patients presenting with a myopathic syndrome in relation to carcinoma are in fact suffering from polymyositis. I would, however, exclude the characteristic myasthenicmyopathic syndrome described particularly in relation to bronchogenic carcinoma, in which there are certain relatively specific clinical and electrophysiological abnormalities (Rooke et al. 1960, Wise and MacDermot 1962), A series of 52 cases of polymyositis seen in the Newcastle area between 1958 and 1962 has recently been reported TABLE I—CLASSIFICATION OF
52 CASES
OF POLYMYOSITIS
(Newcastle series 1958-1962, from Barwick and Walton 1963)
Current Trends in Research In this country, techniques being used to study the disease process include electron microscopy (Pearce 1963, Mair 1963), tissue culture and interference microscopy (Geiger and Garvin 1957, Pearce 1963, Ross 1963), histochemistry (Pearse 1963), phospholipid studies of the fibre membrane (McArdle 1963), and muscle-enzyme studies
(Pennington 1961, 1964). Polymyositis Classification of polymyositis remains somewhat controversial. Shy (1962) proposed that the late-life myopathies should simply be called polymyopathies, and should be identified separately by specifying the astiological factors known to operate in the particular case.
*These figures in the right-hand column indicate the number of case; c: carcinomatous myopathy which would fall into each of the first ihK: groups if the presence of malignancy was ignored or overlooked.
449 TABLE II AGE AT ONSET IN 432 CASES OF POLYMYOSITIS
(From Barwick and Walton 1963)
the remainder improved. The results were most satisfactory in group-n cases (i.e., polymyositis with very little evidence of other collagen disease, or polymyositis with dermatomyositis in which skin changes were slight); but they were only a little less good in patients in group I (" pure " polymyositis) and group ill (florid dermatomyositis or diffuse collagen disease with polymyositis as a
with Dr. Barwick (Barwick and Walton 1963). Table i arranges them according to our clinical classification, and in table n I give the age-incidence of 432 reported cases. In table in I have listed the signs and symptoms reported in 152 cases including the present series. Muscular pain and tenderness is noted in only about half, as is dysphagia. Two-thirds show cutaneous manifestations and a third a Raynaud phenomenon, while " rheumatic features " occur in less than a third. Muscular weakness involves the proximal limb muscles in almost all cases and the distal muscles in under a third, whereas two-thirds of the patients have weakness of neck muscles, and a third develop contractures at some stage of the illness. The erythrocyte-sedimentation rate was raised in less than half of the cases and comparatively few showed any increase in serum gamma-globulin. The serum transaminase (S.G.O.T.) and aldolase were raised in about half the cases in our series, and less than a quarter showed electrocardiographic abnormalities. In half the patients, however, there were electromyographic abnormalities which, by the criteria of Walton and Adams (1958), were strongly suggestive of polymyositis, whereas in several more the appearances were those of a non-specific myopathy. It is interesting that the electromyogram was normal or only slightly abnormal in 10 of the 52. Muscle
biopsy, too, may give relatively non-specific findings. In half the cases subjected to a single biopsy the changes TABLE III-SIGNS AND SYMPTOMS IN 152 CASES OF POLYMYOSITIS
(From Barwick
and Walton
1963)
secondary effect). The period of follow-up
is now between 9 months and five years. I agree with Pearson (1964) that the response to treatment is on the whole better in patients whose symptoms are of comparatively short duration. I would also stress that many patients require high dosage of prednisone, which must be given, irrespective of side-effects, until a response is obtained. Several of our patients TABLE IV-CLINICAL RESPONSE TO ADRENAL STEROIDS IN 52 PATIENTS WITH POLYMYOSITIS ACCORDING TO INITIAL CLINICAL GROUPING
(From Barwick and Walton 1963)
received 60 mg. of prednisone daily for weeks before improving. In 2 there was no clinical improvement with prednisone, but a satisfactory response was obtained with corticotrophin 80 units daily. We have not found any of the newer steroids (e.g., betamethasone and dexamethasone) superior to prednisone; and indeed, compared to prednisone and prednisolone, they are more likely to cause steroid myopathy. In several of our patients it has been possible to withdraw treatment without relapse after eighteen months to three years; but in several others a small maintenance dose is being continued for more than three years after the onset. One patient has been under treatment for over four years and relapses whenever an attempt is made to withdraw the drug. Nevertheless, the outlook for patients has been immeasurably improved since steroid treatment was introduced.
Polymyalgia Rheumatica Polymyalgia rheumatica (Bagratuni 1953, Gordon 1960, Todd 1961) must often have been overlooked in the
characteristic of polymyositis, and in were those of a myopathy, not characteristic of though polymyositis. In 14 of 32 cases so examined, however, the muscle biopsy gave completely normal findings. In assessing the results of treatment we used a classification of disability in which seven grades of muscular weakness are recognised (Swinyard et al. 1957). All 52 patients were treated with steroid drugs and all but 1 received prednisone or prednisolone. Table IV shows that, if one excludes patients with malignant disease, the results are much more satisfactory than is generally supposed. They do not depend entirely on the clinical category. Only 5 (11%) of the 46 patients who did not have malignant disease died as a direct result of the polymyositis ; more than half recovered completely, while most of were
regarded
as
3 others the appearances
past; for I have seen no fewer than 7 cases in the past year. All the patients were elderly and their principal complaint was of widespread muscular pain, often with local tenderness, minor constitutional upset, and general malaise. No muscular weakness was demonstrable, though movement was often restricted by the pain. None showed any evidence of cranial arteritis (Paulley and Hughes 1960) of joint involvement, and electromyography gave normal findings in all. Muscle biopsy was done in several, again with negative results. The serum enzymes were normal in all, but in every patient the erythrocytesedimentation rate was raised, usually to more than 50 mm. in the first hour, and the response to steroid therapy was immediate and dramatic. In many patients, steroids have been withdrawn, after three to six months’ treatment, without relapse. I regard this condition as a disorder of the intramuscular connective tissue, not involving the muscle-fibres. It is likely to be confused with polymyositis, but the absence of clinical, biochemical, electrical, and pathological evior
450
dence of muscle-fibre degeneration, combined with the finding of a high E.S.R., is sufficient to establish the clinical diagnosis when the pattern is otherwise characteristic. Myasthenia Gravis
aetiology In 1960
Simpson suggested that myasthenia gravis was autoimmune disorder and that the thymus probably might produce an antibody against muscle end-plate protein. In the same year Strauss et al. (1960) demonstrated a muscle-binding globulin in myasthenic serum, and further evidence supporting this concept has accumulated since (Harvey and Johns 1961, Burnet 1962). Also of importance are the observations of Coers and Desmedt (1959), Bickerstaff and Woolf (1960), and MacDermot (1960) upon the intramuscular nerve-endings in this disease : definite pathological changes are seen in terminal arborisations of nerve-fibres, and it has been suggested that the primary abnormality may be in the nerve-fibres themselves. Despite the constancy of these findings, it seems more likely that they are secondary to the antigenantibody reaction taking place at or near the motor end-plate. Relationship with Carcinoma A second point of interest is the relation between true myasthenia gravis and the myasthenic syndrome occurring in patients with bronchogenic carcinoma (Anderson et al. 1953) and occasionally in those with carcinoma elsewhere. In this syndrome the changes in the motor end-plate are quite different from those in true myasthenia gravis (Wise and MacDermot 1962). Furthermore, there are distinctive clinical and electrophysiological differences. For instance, the tendon reflexes are generally diminished in the carcinomatous syndrome but are often normal or even increased in true myasthenia (Simpson 1960). Again, patients with the carcinomatous myasthenic-myopathic syndrome show a poor response to treatment with neostigmine and are abnormally sensitive to decamethonium, whereas patients with myasthenia are resistant to this drug (Churchill-Davidson and Richardson 1952). In addition, Rooke et al. (1960) have demonstrated that after an initial period of muscular fatigue following exercise, patients with the disorder related to malignant disease may show a progressive potentiation in muscular strength. Electrically this is mirrored by a post-tetanic increment in the amplitude of the evoked action potentials produced by electrical stimulation of the motor nerve at rates of more than 50 per second (Rooke et al. 1960). Simpson (1964), however, has observed a similar phenomenon occurring occasionally in patients with true myasthenia; so it is not completely specific. Clearly, in patients found to have a myasthenic syndrome different from myasthenia gravis and showing the positive features described, thorough search for a bronchogenic neoplasm is advisable. Treatment and Prognosis I agree with Ferguson et al. (1955) when they say that myasthenia sometimes remains limited to the external ocular muscles and never spreads to involve the bulbar muscles and limbs. I agree also with Simpson’s view that an
the disease tends to burn itself out, or at least to reach a static phase, within five years of the onset (Simpson 1960). Two points about the management are not sufficiently recognised. The first is that different muscles and muscle groups within the same person may be differentially responsive to neostigmine. Thus while certain muscles
remain clinically weak and require more of the drug, others may be so sensitive to it that any increase in dose will increase the weakness by depolarisation block. In one patient, for example, the limb muscles remained weak on a small dose of neostigmine, but, if this was increased, the diaphragm became paralysed and respiratory embarrassment ensued. Secondly, in many patients with longstanding myasthenia, permanent muscular weakness and wasting supervenes. This is particularly true in the external ocular muscles; after several years of responsiveness to neostigmine these muscles may become totally resistant, with permanent partial paralysis. In the upper limbs it is the triceps especially which is affected (Simpson 1960), and the pattern of muscular wasting is usually quite different from that of progressive muscular dystrophy, though the irreversible changes in the muscles are not dissimilar, both electrically and pathologically, from those of muscular dystrophy. Simpson (1964) has found that most patients prefer pyridostigmine to neostigmine, because of its longer effect and comparative freedom from side-effects. However, many miss the quick boost experienced with neostigmine, and most patients seem to be satisfactorily stabilised on a combination of the two remedies. Ambenonium chloride (’ Mytelase ’) seems to be little, if at all, superior to neostigmine; and aldosterone inhibitors, which have been tried by Gottlieb and Laurent (1961), seem at present unlikely to be of lasting value. On the other hand, the new remedy lycoramine (Somers et al, 1963) may well prove useful. As regards thymectomy, I can only agree with Simpson that it may sometimes have to be performed in desperation, and even as an emergency, in patients failing to respond to medical treatment-particularly those requiring assisted respiration. As an elective operation, its results seem to be best by far in young women whose disease is severe and of comparatively short duration. Metabolic
Myopathies
Under this heading I shall say something about some recent advances in our understanding of the various forms of periodic paralysis. In passing, I may mention that the uncommon form which sometimes complicates hyperthyroidism and which seems to be particularly common in Japan (Okinaka et al. 1957), and chronic thyrotoxic myopathy, are disorders which invariably improve when the hyperthyroidism is treated. (In 1952 Asboe-Hansen et al, reported a pathological change which they regard as specific for chronic thyrotoxic myopathy-namely, crescent-shaped areas within muscle-fibres. But I have not yet seen it in pathological material.) Another form of metabolic myopathy is the generalised muscular weakness of Addison’s disease and hypopituitarism; but the changes in the muscle-fibres have yet to be elucidated.
Cushing’s Syndrome and Steroid Myopathy In 1959 Miiller and Kugelberg described 6 patients with Cushing’s syndrome, of whom 5 had weakness of the muscles of the pelvic girdle and thighs. Electromyography demonstrated myopathic changes but histological abnormalities in the muscle were few. In the same year Perkoff et al. reported similar muscular weakness in patients under treatment with steroids. Since then both naturally occurring myopathy and the iatrogenic disorder have been frequently reported; and it seems that the latter is most often caused by steroids with a fluorine atom in the 9-alpha position. Triamcinolone is particularly
451
likely to have this effect and should in my view no longer be used. In patients with steroid myopathy due to dexamethasone or betamethasone, the weakness has resolved when prednisone was substituted. .lfcArdle’s Syndrome In 1951 McArdle described the case of a man of 30 with increasing muscular pain and stiffness during slight exertion. McArdle showed that the blood lactate and pyruvate failed to rise after exercise, and he suggested that the disorder was due to a defect of glucose utilisation. In 1959 two additional cases were reported (Schmid and Mahler 1959, Mommaerts et al. 1959). In at least one of these cases there was also myoglobinuria; in both, muscle glycogen was increased and myophosphorylase activity was absent. Recently another case has been described by Mellick et al. (1962) in which there was some permanent muscular weakness indicating that a limb-girdle type of myopathy was developing. Schmid and Hammaker (1961) described three cases in a single family; they thought the disorder might be due to an autosomal recessive gene. Probably some patients previously described as having myotonia paradoxa were suffering from this syndrome. Although rare, it is noteworthy as the first clinical form of muscle disease in which a single enzyme defect has been conclusively demonstrated. No curative treatment is possible, but many patients can be improved by taking glucose, or preferably 50-100 mg. of fructose, before exertion. We must hope that many other obscure myopathies may eventually be shown to be due to a specific enzyme defect which can be ameliorated by an
appropriate remedy. Periodic Paralysis Syndromes The classical or hypokalaemic variety of periodic paralysis is well known. It gives rise to attacks of flaccid weakness of the voluntary muscles, usually sparing those of speech, swallowing, and respiration. As a rule, they begin in the second decade and are most frequent in early adult life; usually they last for several hours, and commonly they come on early in the morning on waking, or after a period of rest following exertion, or after a heavy carbohydrate meal. During the attacks the plasmapotassium is usually found to be low-i.e., less than 3 mEq. per litre. There is positive balance of potassome or all of the retained potassium passes into the muscle cell (Grob et al. 1957, Zierler and Andres 1957). Recent work (Shy et al. 1961) has shown that the resting membrane potential is normal during an attack of paralysis, but electron microscopy of muscle specimens has revealed that the vacuoles which can be seen in the muscle cell with the light microscope are due to dilatation of the sarcoplasmic reticulum. The normal resting membrane potential during an attack, even when potassium has moved into the cell, is probably due to a concomitant inward movement of water. Recently, Conn and Streeten (1960) suggested that this hypokalaemic form of periodic paralysis might be due to intermittent aldosteronism. Increased aldosterone excre-
sium, and it seems that
tion, however, is seen in comparatively few cases (Shy et al. 1961); and, although patients with primary aldosteronism due to aldosterone-secreting tumours of the adrenal (Conn 1955) do have attacks of muscular weakness, the role of aldosterone in the xtiology of periodic paralysis has probably been exaggerated. Patients with true aldosteronism generally have polyuria and polydipsia in addition, and can be cured by removal of the tumour. For an attack of this form of periodic paralysis the
appropriate treatment is administration of chloride, though it does not often seem to shorten an attack significantly. When attacks are frequent, it may be useful to give maintenance does of potassium; and, if these do not prevent the attacks, a possible alternative is spironolactone, which has been found to reduce their frequency and severity (Poskanzer and Kerr 1963a). However, the condition does improve spontaneously with age, and one of my patients who is a policeman now has only occasional mild attacks; he has managed a satisfactory career in the Police Force without the authorities ever knowing that he has the disease. The fact that
potassium is often given to these patients brought light a group of cases in which the serumpotassium does not fall during the attacks and in which the condition is actually made worse by potassium chloride (Tyler et al. 1951). Gamstorp (1956) studied two to a
families with this form of the disorder and gave it the name of adynamia episodica hereditaria (hyperkalsemic periodic paralysis might be more appropriate). It is closely related to paramyotonia; for some of the patients show definite myotonia (Drager et al. 1958), though in others the myotonia seems curiously limited to the muscles around the eye (van’t Hoff 1962). The typical attack usually occurs immediately after exercise, and it is usually shorter than those of the hypokalaemic variety, lasting on an average thirty to forty minutes and seldom more than one to two hours. Gamstorp (1962) and McArdle (1962) have shown that as a rule the attacks are associated with a rise in the serum-potassium, though some patients have severe weakness when the serumpotassium is no higher than 4 mEq. per litre:certainly weakness is usually severe when the level reaches 5 mEq., whereas in normal people a serum-potassium of 8 mEq. is needed before weakness develops. Electromyography in such cases often shows slight myopathic changes during the attacks as well as hyperirritability of myotonic type (Buchthal et al. 1958, Creutzfeldt 1961, Gamstorp 1962). Recently Abbott et al. (1962) have shown that the musclefibre membrane potential is lowered during attacks. The attacks themselves are rarely long enough to require treatment, though they can be shortened by intravenous calcium gluconate. Acetazolamide and hydrochlorothiazide have both been used successfully for prophylaxis; and, in the hands of McArdle (1964), the dichlorphenamide (50-100 mg. daily) has been even more successful. It will be interesting to see whether, by preventing attacks of paralysis, such maintenance treatment will prevent the development of the mild but irreversible muscular weakness or myopathy which supervenes eventually in most cases.
A third type of periodic paralysis is described by Poskanzer and Kerr (1961b). It bears in many respects a close resemblance to the hyperkalsemic variety, but the attacks commonly lasted for days or even weeks and often occurred at night. Even in severe attacks the serumpotassium remained normal and there was a positive potassium balance. However, paralysis was made worse or precipitated by giving potassium, and was always improved by large doses of sodium chloride. In these cases 9-fx-nuorohydrocortisone (0-1 mg. daily), when combined with acetazolamide, prevented attacks. Though these disorders are not common, it is important to recognise the different varieties and to bear in mind that a form of hypokalaemic periodic paralysis may complicate thyrotoxicosis and can be cured by the treatment
452 of the thyroid disorder. Careful investigation of every such case is necessary, because effective treatment depends on accurate diagnosis. Clearly the abnormalities in potassium metabolism are but one facet of a disease process whose nature we do not yet understand. Attempts to demonstrate a primary enzyme defect or a specific disorder of carbohydrate metabolism have so far been unsuccessful. For the present, changes in the serumpotassium remain one of the most reliable indices to diagnosis and treatment.
Lyon, M. (1961) Nature, Lond. 190, 372. Mair, W. (1963) Research in Muscular Dystrophy. London. McArdle, B. (1951) Clin. Sci. 10, 13. (1962) Brain, 85, 121. (1963a) Research in Muscular Dystrophy. London. (1964) in Disorders of Voluntary Muscle (edited by J. N. Walton); chap. 15. London. MacDermot, V. (1960) Brain, 83, 24. Mellick, R. S., Mahler, R. F., Hughes, B. P. (1962) Lancet, i, 1045. Mommaerts, W. F. H. M., Illingworth, B., Pearson, C. M., Guillory, R. J., Seraydarian, K. (1959) Proc. nat. Acad. Sci. 45, 791. Morton, N. E., Chung, C. S. (1959) Amer. J. hum. Genet. 11, 360. Müller, R., Kugelberg, E. (1959) J. Neurol. Psychiat. 22, 314. Okinaka, S., Shizume, K., Iino, S., Watanabe, A., Irie, M., Noguchi, A., Kuma, S., Kuma, K., Ito, T. (1957) J. clin. Endocrin. 17, 1454. Paulley, J. W., Hughes, J. P. (1960) Brit. med. J. ii, 1562. Pearce, G. W. (1963) Research in Muscular Dystrophy. London. Pearce, J. M. S., Walton, J. N. (1964) In preparation. Pennington, R. J., Walton, J. N. (1964a) J. Neurol. Psychiat. (in the press). (1964b) ibid. (in the press). (1964c) ibid. (in the press). Pearse, A. G. E. (1963) Research in Muscular Dystrophy; p. 189. London. Pearson, C. M. (1957) New Engl. J. Med. 256, 1069. (1962) Brain, 85, 109. (1963a) Rev. canad. Biol. 21, 533. (1964) in Disorders of Voluntary Muscle (edited by J. N. Walton); chap. 12. London. Pennington, R. J. (1961) Nature, Lond. 192, 884. (1964) in Disorders of Voluntary Muscle (edited by J. N. Walton); chap. 10. London. Perkoff, G. T., Silber, R., Tyler, F. H., Cartwright, G. E., Wintrobe, M.M. (1959) Amer. J. Med. 26, 891. Poskanzer, D. C., Kerr, D. N. S. (1961a) Lancet, ii, 511. (1961b) Amer. J. Med. 31, 328. Rooke, E. D., Eaton, L. M., Lambert, E. H., Hodgson, C. H. (1960) Med. Clin. N. Amer. 44, 977. Ross, K. F. A. (1963). Unpublished observations. Schmid, R., Hammaker, L. (1961) New Engl. J. Med. 264, 223. Mahler, R. (1959) J. clin. Invest. 38, 2044. Shy, G. M. (1962) World Neurology, 3, 149. Engel, W. K., Somers, J. E., Wanko, T. (1963) Brain, 86, 793. Magee, K. R. (1956) ibid. 79, 610. Wanko, T., Rowley, P. T., Engel, A. G. (1961) Exper. Neurol. 3, 53. Sibley, J. A., Lehninger, A. L. (1949) J. nat. Cancer Inst. 9, 303. Simpson, J. A. (1960) Scot. med. J. 5, 419. (1964) in Disorders of Voluntary Muscle (edited by J. N. Walton); -
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Prospect of Advance .
These are only a few of the disorders of muscle. I have said nothing about many of the metabolic forms of myopathy, including the disorders associated with myoglobinuria and such rarities as amyloid myopathy. I have not so much as touched on the various forms of congenital dismyopathy, including those manifold and obscure orders causing infantile hypotonia and a " floppy " infant. Even within this group, new discoveries are being made from year to year, and the description of " central core disease " by Shy and Magee (1956) has now been succeeded by the recognition of a curious congenital myopathy with rod-shaped bodies (Shy et al. 1963). No doubt in the coming years additional specific biochemical or histological subvarieties of congenital myopathy will be recognised. As our knowledge has grown, more and more entities have been identified and clarified, and in some of them effective treatment has become possible. The myopathic disorders are by no means as hopeless as has been supposed. REFERENCES
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AN IMMUNOLOGICAL METHOD OF INCREASING THE SENSITIVITY OF PRIMARY SARCOMAS TO LOCAL IRRADIATION WITH X RAYS
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M.
ALEXANDER HADDOW M.D., D.Sc. Edin., F.R.S. DIRECTOR
PETER ALEXANDER Ph.D., D.Sc. Lond.
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HEAD,
RADIOBIOLOGY DEPARTMENT
CHESTER BEATTY RESEARCH
INSTITUTE, RESEARCH, ROYAL CANCER HOSPITAL, LONDON, S.W.3
INSTITUTE OF CANCER
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342.
Grob, D., Liljestrand, A., Johns, R. J. (1957) Amer. J. Med. 23, 356. Harvey, A. M., Johns, R. J. (1961) ibid. 32, 1. Hughes, B. P. (1963) Research in Muscular Dystrophy. London. Jackson, C. E., Carey, J. N. (1961) Pediatrics, 28, 77. Kloepfer, H. W., Talley, C. (1958) Ann. hum. Genet., Lond. 22, 138. Lamy, M., de Grouchy, J. (1954) J. Genet. hum., Geneva 3, 219. Leyburn, P., Thomson, W. H. S., Walton, J. N. (1960) Ann. hum. Genet., Lond. 25, 41.
HOST factors are known to play a part in clinical radiotherapy (Glucksman 1960), and indirect factors have best shown
influence the radiation response of tumours in experimental animals (Hollcroft et al. 1950). In this paper, experiments will be reported which show that in rats the effectiveness of a single dose of 2000r of X rays in retarding the growth of a primary fibrosarcoma can be enhanced by an autograft of the tumour, obtained by to