Polymyositis

Polymyositis* DAVID D. BARWICK, M.B., M.R.C.P.E. and JOHN N. WALTON, M.D., F.R.C.P. Newcastle ufion Tyne, England THIS communication we endeavor to describe briefly the main clinical features of the polymyositis syndrome, to describe some of the more important laboratory findings in patients affected by this disorder, and to indicate its natural history and its response to treatment. The information is based upon a review of the literature, upon the experience of one of us (.I. N. W.) with forty-one cases of polymyositis seen in Newcastle upon Tyne and in Boston [7], and upon our more recent experience with fifty-two cases seen in Newcastle upon Tyne since 1958. These latter cases form part of a group of patients presently being studied by one of us (D. D. B.) in a follow-up investigation of all cases of polymyositis encountered in this area.

I

N

CLASSIFICATION

Classification of cases of polymyositis remains and controversial. There are unsatisfactory considerable difhculties in deciding which conditions should be included under the heading of polymyositis, especially since a considerable number of recently described nonhereditary myopathies, some of which are associated with other well established clinical disorders, have tended to obscure the picture [2]. W’hen the acquired myopathy, such as that complicatin,g thyrotoxicosis, is clearly related to an underlying disease, and when treatment of the primary disorder results in resolution of the myopathy, its place as a separate and distinct entity appears secure. However, when the primary disease is itself of uncertain etiology (e.g., Sjiigren’s syndrome, sarcoidosis) the nosologic position of the myopathy which is occasionally associated is even more uncertain. Indeed, Shy [3] proposes that the myopathies which occur late in life should simply be referred to as polymyopathies and should be identified as separate entities by specifying when possible

the etiologic factors known to be operative in any particular case. Denny-Brown [d], on the other hand, prefers a classification which is essentially pathologic, and suggests that only cases in which there is evidence of inflammation should be called polymyositis: he identifies as separate entities necrotizing myopathy (with or without myoglobinuria), chronic progressive vacuolar myopathy and progressive granular degeneration of muscle. We do not consider either of these suggestions satisfactory, first because the etiology of many such cases remains despite full investigation; secondly obscure because a response to steroid therapy, suggesting a possible relationship to the diseases of the “collagen” or “connective tissue” group, occurs in some patients in whom no clinical evidence of disease other than the myopathy is to be found and in whom muscle biopsy findings indicate only a necrotizing myopathy or, rarely, a vacuolar myopathy without inflammatory changes. While agreeing, therefore, that no classification yet proposed is entirely satisfactory, we follow here the purely clinical and empiric grouping of cases proposed by Walton and Adams [7] which divided cases of polymyositis into the following groups: Acute,

Group I: Polymyositis

with myoglobinuria

/ \

-in

childhood

-in

middle

\ or

Group II: Polymyositis with dominant muscular weakness but with some evidence of an associated collagen disease or dermatomyositis with severe muscular disability and with minimal or transient skin changes.

* From the Regional Neurological Centre, Newcastle General Hospital, Newcastle upon Tyne, England. study was aided by research grants from the Muscular Dystrophy Associations of America, Inc., the Muscular trophy Association of Canada, and the Muscular Dystrophy Group of Great Britain.

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Polymyositis-Barwick, TABLE CLASSIFICATION

OF FIFTY-TWO

(Newcastle

I CASES

TABLE OF

POLYMYOSITIS

AGE

Grouping

AT

ONSET

Series 1958-1962) Age

Clinical

Walton

of Cases

Group I Polymyositis with clinical evidence suggesting a purely muscular affliction Acute with myoglobinuria, Subacute in childhood. Of in early adult life. Chronic I in middle or late life

No. of Cases *

Range

(yr.)

.~~___..___~_ O-15

0 3 3

11

Polymyositis with some skin manifestations or with some features of associated “collagen” disorder,

16-30 31.-45 46 -60 6lGover

IN

432

II

CASES OF POLYMYOSITIS*

No. of Cases

I

,1Per Cent of ‘I’otal

__m___~lL

~_.__ ~~_ 16's

69

56 108 157 42

* From Eaton 1954, Christianson and Adams 1958, Pearson 1963, series.

i /

1572, 24 :I;, .‘r6“4,

I

0 ‘7;,

I et al. 1956, Walton and the Newcastle

Table I shows the distribution of our present series of cases according to these clinical criteria. INCIDENCE

I;lorid dcrmatomyositis or scverc collagen disease with less striking muscatlar manifestations.

14

Grou?IL’ “Carcinomatom myopathy” and dermatomyositis or poiymyositis in association with malignant disease.

6

* The figures in the right-hand column indicate the number of cases of carcinomatous myopathy which would fall into each of the first three groups if the presence of malignancy was ignored or overlooked. Gro7L@ Ill: Polymyositis complicating severe collegen disease, e.g., rheumatoid arthritis, or dermatomyositis with florid skin changes and minor muscle weakness. Groujh IV. Polymyositis complicating malignant disease (including carcinomatous myopathy and dermatomyositis occurring in patients with malignant disease). \Ye appreciate that, as Shy [.3] and IlennyBrown [-!I have suggested, some of the cases which we have classified arbitrarily in these and particularly some acute cases groups, associated with myoglobinuria, progressive cases of late onset and indolent cases in association with carcinoma, may be due to metabolic abnormalities which are totally unrelated etiologically to the group of “collagen” or “connective tissue” disorders in which most cases of polymyositis rightfully belong. However, we wish to make the point that neither the finding of Inyoglobinuria nor any single pathologic abnormality is sufficient to identify cases which are nosologically different. Hence we believe that a clinical classification is still appropriate. VOL.

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1963

A valid estimate of the geographic or social incidence of polymyositis is not yet possible. Cases have, however, been reported from South .4merica [5,S] and in the African Segro [7] as well as large numbers from Europe and Sorth America. The disease may begin at virtually any age from infancy to late adult life ( I$‘]. The range of ages at onset in our current Newcastle series of cases was from four to sr\:cnty-eight years. Pearson 1.91 lists the age at onset in 380 cases of polymyositis, made up of his own cases and those reported by Eaton [/o], Walton and Adams [.I], and Christianson et al. L/1]. Table II shows the age incidence in 432 cases, including the Newcastle series in addition to those mentioned. The sex distribution in 152 cases, including those of Pearson 191 and the present series, was fifty-three males (33 per cent) and ninety-nine females (67 per cent). The frequency of polymyositis compared with other diseases is not known accurately. In our own experience, we find that polymyositis is considerably more common in adult life than progressive muscular dystrophy, but it is much less common than the latter in childhood. Pearson [9] estimates that he sees new cases of polymyositis about half as frequently as new cases of gout. POSSIB1.E

PRECIPITATING

F-ZCTC)RS

Many factors have been suggested as possible precipitants in isolated cases of polymyositis. Among these are an antecedent febrile illness [I_‘], various infections and trauma j I,?], acute exanthemas [Y&76], pneumonitis [17] and numerous other infective disorders IS]. None

Polymyositis--Barwick,

648

TABLE SIGNS

AND

-

SYMPTOMS

I_

Clinical Features

IN

WuZton

III

152

CASES

OF

POLYMYOSITIS

No. of Cases

Eaton

~-

-

Walton,

Pearson, Rose

Adams

Barwick,

Walton

Total

-SjWlfbT?lS Muscular

pain or tenderness

.......

Dysphagia....................... Cutaneous manifestations. ........ Raynaud’s phenomenon. ........ Rheumatic features. ............. Muscular Weakness Proximal muscles. ................ Distal muscles. ................... Neck muscles. ................... Facial muscle-s. ..................

Contractures..................... -

18 22 22 10 10

16 21 23 10 10

14 14 16 2 10

40 20 33 21 8

88 77 94 43 38

38 24 14 5 11

40 14 33 5 8

19 6 15 1 14

52 6 40 6 16

149 50 102 17 49

-

-

of these, however, appears to be of major importance when large series of cases are studied. Physical agents appear to be of little significance although exposure to sunlight certainly precipitates the cutaneous eruption in some cases of dermatomyositis [8,78], and photosensitivity is common at all stages of the condition. Therapy with sulfonamides has been implicated as an initiating or aggravating factor by various investigators [18-Z]. In the present series, we have not found any such instances. The relationship of the onset of polymyositis with the menopause, occurring either naturally or after hysterectomy, has been remarked upon by many workers [21,22]. There is, however, no strong evidence that hormonal factors are of major etiologic importance. Christianson et al. [irl] suggested that the relationship between polymyositis and malignant disease is fortuitous, being simply due to the age group mainly involved. However, it is now clear that the association with malignancy occurs far more frequently than can be accounted for by chance, particularly in patients with florid dermatomyositis [23-24. In this connection, it is of interest that Grace and Dao [26] found that a woman with dermatomyositis and cancer of the breast was hypersensitive to an extract of her own tumor, showing an immediate skin reaction as well as a positive passive transfer test. Similar findings were described by Curtis et al. [27] in another

with dermatomyositis and lung cancer, suggesting the possibility that polymyositis in such patients may represent an autosensitivity to malignancy. In our own series, six patients had malignant disease. There seems to be general agreement that the relationship to malignancy does not hold in childhood cases. There were forty-six adult cases in our series, which gives an incidence of malignancy of 13 per cent. woman

CLINICAL

MANIFESTATIONS

The over-all clinical manifestations in 152 cases of polymyositis are analyzed in Table III. Detailed descriptions of the clinical picture in the main clinical groups, as previously outlined, follow. Group I. Acute cases: There are no acute cases associated with myoglobinuria in the present series. The following description is based on the previous experience of one of us (I. N. W.) and upon reports in the world literature [7,28-301. A frequent antecedent to the development of the fully developed clinical picture is the presence of constitutional upset. Thus fever, malaise, dysphagia and tenderness are often present, together with painful and swollen joints. Dark urine containing myoglobin is passed at some stage, usually at the onset. Florid skin changes are absent, but transient edema of the limbs or face, particularly in the periorbital regions, is frequent. Severe global weakness of the proximal limb muscles and of the AMERICAN

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Polymyositis-Barwick, muscles of the neck, with little or no atrophy, is usual. Less frequently the muscles of the face and ja\v ma)- be involved. Usually all the involved muscles are tender. Rapid and marked weight loss, hepatosplenomegaly and lymphadenopathy are sometimes present. Eviclence of cardiac involvement is usually slight and is confined to electrocardiographic rather than clinical changes, but renal involvement is con~mon and is often a major hazard. In the prcsc~cc of massive myoglobinuria, renal tubular I)lock with anuria and death from renal failure may occur. Subaczrte and chronic cases: Constitutional s)rmptams are relatively rare in this group of patients, in contrast to those with the acute form of the disease. It is the evidence of muscular weakness that predominates. Initially, Lvcakness of the pelvic qircllc muscles is usually obser\.ed, causing diAiculty in climbing stairs or in getting out of a low chair (IJ,?l\. Initial weakness of the shoulclcr girdle and neck muscles is much less common and occurred in only one patient in the present series. Usually the muscles of the upper lunbs and neck are affected sotne time after those of the lower limbs, giving rise to symptoms such as ditliculty in dressing the hair or in lifting objects. Facial weakness is usual11 slight or absent. Dysphagia is often present and is normally due to involvement of pharyngeal muscles in the disease process. In some cases (t1z.o in the present series) myasthenic features ma)- be striking, with a history of marked muscular fatigability; often there is a rapid response to the intravenous administration of Tcnsilon@ (edrophonium) and improvement on oral treatment with neostigmine and related preparations. This improvement is usually less striking and more cphemcral than that seen in true’ m),asthcnia gratis. ;\lthough in progressive cases the distal muscles lnay e\rentually become involved, the predominant lvcakness is usually proximal. This was so in all the Newcastle cases. However, Eaton [10] described a case in which there was striking distal muscular weakness and l)ennyBrown 111 has also emphasized the existence of a chronic distal form of polymyositis. A41though weakness is almost always bilateral and symbe predominantly it may rarrly mc.trical, unilateral as in a case described by van cler l,uqt !.3_?]. One of our own patients, a woman aqcd fifty-one, presented with weakness, wasting and local pain in one quadriceps muscle. The VOL. 35,

NOVEMBER 1963

Walton

diagnosis was in considerable doubt but she showed a good response to a short course of treatment with prednisone. Shortly after treatment was stopped there was a marked exacerbation, with weakness and pain in the girdle muscles of both upper and lower liml,s, raised erythrocyte sedimentation rate, abnormal serum enzyme activity and widespread electromyographic changes. She responded DYA~to a second course of steroid therapy but still needed a small maintenance dose eighteen months later. Muscular wastinS is variable, but is usually mild and surprisingly out of proportion to the degree of weakness present. Pscudohypertrophy, especially of the calf muscles, ma)- occur but it not common, occurring in only one case in the present series. The global weakness of proximal muscles in polymyositis has alread) been stressed, and this is in contrast to the selective mvolvement seen in hereditary muscular dystrophy. However, in rare instances polymyositis may be remarkably selective, and in another case in our present series we made an initial diagnosis of limb girdle dystrophy because of the very selective nature of the muscle involvement. The unequivocal inflammatory changes revealed by lnuscle biopsy and the improvement produced by strroid therapy showed clearly that we were in fact dealing \2-ith a case of polymyositis. Muscle tenderness is variable and not ahvays associated with pain: it is often associated itith other e\idrxncc of activity of the disease process, either at the onset of the condition or in relapse. Contracture formation is a feature of some cases and tends to occur, in our experience, especially in the subacute childhood cases and in some of the chronic adult cases in lvhich there is u idespread muscle involvement. In these latter casts, bony atrophy with decalcification of shafts of long bones may be seen. Subcutaneous and intramuscular calcification may occur in this group, but is uncommon. Reflex changes are curiousl) variable, the deep tendon reflexes being either depressed, normal or brisk; brisk reflexes in a case of myopathy suggest a diagnosis of polymyositis rather than muscular dystrophy. The course of the untreated disease in these casrs is extraordinarily variable and appears to bear little relationship to the mode of onset. Among possible modes of progression, the followiIl(: are frequently met with: a fluctuating course with exacerbations and remissions; progressi\le deterioration, more or less ra.pid, with

650

Polymyositis-Barwick,

either fatal termination or arrest; or slow insidious progression over many years. The latter is most often found in middle-aged or elderly females [21,33]. The outlook is probably best in children and young adults, in whom prolonged and more or less permanent remissions may occur [34]. Against this background the assessment of the results of treatment is difficult. Group II. Separate description of the clinical manifestations of muscular involvement in these cases is unnecessary since they so closely resemble those of group I. The feature which distinguishes these cases, and makes diagnosis easier, is the presence at some time in the course of the illness of cutaneous involvement or of minimal evidence of some other “collagen” disease. The most frequently observed dermal manifestation is an erythematous rash, often over the face in distribution, but sometimes in“butterfly” volving the trunk or limbs at the same time. The rash is characteristically of a “violaceous” hue and may be moist and shiny or scaly and dry. These manifestations may precede the onset of the muscular weakness or may appear transiently during the course of the illness; when persistent, the changes are usually mild and are easily overlooked. Associated dermal changes may include the Iiaynaud phenomenon with thinning and reddening of the skin of the hands, particularly at the base of the nails, where it may become tight, losing its elasticity. Over exposed areas such as the heels, elbows and knuckles, ulceration of the skin may occur and the ulcerated areas may extrude calcium. Minor joint changes, resembling clinically those of early rheumatoid arthritis, may occur; in the present series of cases such manifestations have tended to appear most often in the later stages of the disease, and have sometimes followed the withdrawal of steroids. Groufi ZZZ. In these cases it is the dermal manifestations which are dominant. These consist of a heliotrope erythema, usually involving the face in butterfly distribution, but also extending on to the trunk and limbs. Often the lesions are photosensitive and may have a raised discoid appearance, closely resembling the dermal manifestations of lupus erythematosus. However, many different varieties of skin lesion may be present and may resemble those of a variety of conditions, e.g., seborrheic dermatitis, exfoliative dermatitis, poikiloderma or’ lichen planus. Hypertrichosis, alopecia and

Walton

patchy hyperpigmentation and vitiligo may become evident in chronic cases. Hemorrhagic subcutaneous lesions of the hands and feet are not uncommon and ulcerated lesions with extensive secondary infection may be difhcult to treat. The range of dermal changes has been reviewed by Domzalski and Morgan [,?5]. Muller et al. [36] have reported a detailed study of calcinosis in dermatomyositis. This is a complication which is particularly liable to develop in children, especially those surviving two or three years after the initial manifestations of the disease. The calcinosis tends to involve proximal limb muscles, as does the weakness, and is associated with a good prognosis so far as survival is concerned but indicates the likelihood of only poor functional recovery. In our own experience, this seems to be the case; usually, when cutaneous involvement is severe and there is extensive ulceration of the skin, it is these dermal manifestations which remain the most striking and disabling despite corticosteroid treatment, which may nevertheless bring about considerable recovery of muscular power. Other complications occurring rarely in this group of cases, but not seen in the present series, are retinal in\rolvement with macular and peripapillary floccular exudates or hemorrhages, sometimes associated with papilledema 18,371. Polster [38] reports bilateral optic atrophy following optic neuritis associated with dermatomyositis in a child, but this must be very rare. Esophageal ulceration and hematemesis [ 181, epistaxis and intestinal hemorrhage purpura, [
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Polymyositis-Barwick, ship between the clinical course of the tumor and that of the myopathy is variable. Usually the myopathy, whether or not it shows an initial response to steroid therapy, eventuall! becomes progressive and the patient may die from the effects of the muscle disease rather than from the neoplasm. Table I shows the number of cases in group IV in the present series and also indicates into which clinical category the cases would have been classified had no neoplasm been present. Most of the cases described by Henson ct al. [~I333 M-ould he designated as group I cases in our classification. Although dermatomy-ositis in association \vith malignant disease is probably more frequent numerically, the presence of a “pure” poll.myositis, particularly in a man over fifty years old, is likely to be associated with malignant disease. The relationship of the specific myasthenic-myopathic syndrome which mav complicate bronchogenic carcinoma [&] to polymyositis is at present obscure. Rowland [45] reported that 10.7 per cent of 382 patients with derrnatomyositis were found to have cancer. He also listed 117 cases in the literature in which the tumor site was recorded. These were in descending order of frequency, breast, stomach, lun:r, ovary, rcticuloendothelial system, uterus and vagina, unknown primary, gallbladder, rectum, colon, kidney, prostate, sarcoma, csophagus and pancreas. He also reported isolated associations with myeloma and with malignant growths of the parotid, thyroid, pyriform sinus and larynx. It is of interest that in our present series there were three cases of comparatively uncommon associated neoplasms, namely, prostate, pancreas and esophagus. INVESTIGATIONS In Table IV we list some of the more important results of investigations carried out in the Newcastle cases. Erythrocyte Sedimentation Rate. L2:e have not found the crythrocyte sedimentation rate to be of much value in the diagnosis of this condition or as a guide to therapy. In over half of the patients it was normal throughout the course of the disease and was slightly increased in only one of the patients with malignant disease, until a very late stage in the illness. The highest values were recorded in those cases of dermatomyositis which were florid and \vere often associated with troublesome skin changes. The erythrocyte sedimentation rate was often normal

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TABLE IV SOME IMPORTANT INVESTIGATIONS

IN

FIFTY-TWO

CASES

OF POLYMYOSITIS

No. of

Investigation

C:aSeS

_ /

Erythrocyte Sedimmtntion Rat? (52) Increased Normal. ._~__

2I ~

.S~rzrmElectrophoretic Pattern (42) Abnormal (increase in 012 or camma lin). _. _. Normal

El‘lcctrocardioLqram(46) Abnormal (mainly changes) Normal. .

_______~

Elertromyogram (50) Findings suggesting Findings indicating Normal or minimal

nonspecific

I ;

globlt.’

Abnormal (more than 40 units/ml.) Normal (less than 40 units/ml.) :lldolase (20) :Ibnormal (more than 9.6 units/ml. Normal (Icss than 9.6 units/ml.)

‘I‘

31

0 33

.

1

19 16

I.

/

15

5 wa\~

~~~~_ ~.. ~~ ~~ polymyositis. only “myopathy” abnormality.

1

::(

:2 25 15

IO

.Ilucle k?iop,psy i.72) Indicating polymyositis Indicating only “myopathy”. Normal or non-specific changes. NOTE: Figures patients examined.

in

parentheses

15

3 14 indicate

number

of

when the disease, by clinical and biochemical criteria, was in an “active” phase. Serum Proteins. LVe have found the serum proteins of little help also. There were abnormalities in only nine of forty-two patients examined. These varied from markedly elevated gamma glohulin levels to minor elevations of yamma or alpha2 globulin evident upon electrophoresis. Patients showing these changes were usually those with severe disease or with manifestations of “collagen” disease elsewhere (such as disseminated lupus erythematosus). Serum lkymes. LVe have found estimations of the level of activity of certain serum enzymes to be of great help in the diagnosis of polymyositis and in assessing the activity- of the disease. At the present time, serum glutamic oxalacetic transaminase (SGOT) and serum

652

Polymyositis-Barwick,

aldolase appear to us to be most helpful. Serum glutamic pyruvic transaminase (SGPT) seems to be a less sensitive index of muscle destruction. We have had only limited experience with estimations of creatine kinase in such cases but our present experience [46] suggests that, in contrast to the findings in muscular dystrophy, the activity of this enzyme shows less striking deviations from the normal. The normal readings for aldolase and SGOT have been found, with only one exception, in samples taken from patients whose disease at the time was judged clinically to be inactive or in remission. We can, therefore, confirm the view of Pearson [9] that serial estimations of enzymes such as aldolase, which is probably the most sensitive, and SGOT, provide the best guide to the course of the illness and are of great help in diagnosis, and particularly in differentiating myopathy from weakness and wasting of muscles due to primary neurologic disease. Immunological Studies. Our attempts, admittedly not very vigorous, to demonstrate the presence of circulating antibodies against muscle and connective tissue, using such technics as the tanned red cell agglutination method have been uniformly unsuccessful to date. Electrocardiography. In our present series of cases we have found that electrocardiographic abnormalities are often absent and are rarely striking. One of our patients had a myocardial infarction, which was clearly evident electrocardiographically during the course of his muscle disease, but we have no reason to suppose that this was directly related to his myopathy. Nor can we be certain in two of our other patients, one of whom showed atrioventricular dissociation and the other atria1 fibrillation, that these abnormalities were due to myocardial involvement by the disease, although this was certainly possible. More frequent changes included nonspecific T wave abnormalities and, occasionally, low voltage QRS complexes. Electromyography. The electromyographic changes found in this condition have been reviewed at length elsewhere [ 1,471; briefly the characteristic changes are as follows: (1) The presence at rest of potentials indistinguishable from those of spontaneous fibrillation; as well as occurring at rest, these also follow movement of the exploring needle in the muscle. So-called “saw-tooth” or “injury” potentials may also occur with the muscle at rest.

W&on

(2) Bursts of brief duration potentials repeating rapidly and dying away after a brief initial volley. These potentials resemble the “myotonic associated with the clinical phedischarges” nomenon of myotonia but are much less prolonged and intense. These discharges are initiated by mechanical stimulation (e.g., movement of the needle electrode) but also tend to rather than after, volitional occur during, contraction. (3) On volitional activity, the presence of a complex and polyphasic pattern. Individual motor unit potentials have a reduced mean duration and amplitude. These features also result in a shift to the high frequency end of the histogram of a frequency analyser if this is used in conjunction with the electromyogram [&I. These changes, although not specific for polymyositis, strongly suggest that a nonhereditary myopathy is present. A reduction in mean duration and amplitude of motor unit potentials is seen in any myopathy, including muscular it is the presence of abnormal dystrophy; activity at rest and on movement of the needle electrode which is suggestive of polymyositis. We have occasionally encountered all these changes, however, in cases of thyrotoxic myopathy and in one case of steroid-induced myopathy. Nevertheless, they were present in half the patients in the present series who were examined electromyographically. In another fifteen cases the abnormal “spontaneous” and “insertion” activity was absent and the electromyographic appearances were indistinguishable from those of a hereditary myopathy. In many of these latter instances, however, muscle biopsy revealed the characteristic inflammatory changes of a myositis. Electromyography has certain advantages over muscle biopsy in the diagnosis of polymyositis in that it is easy to examine many areas of several different muscles and thus to obtain some indication of the extent, and perhaps also of the severity of the muscle disease. However, like most electrophysiologic investigations, electromyography only indicates a disorder of function and can rarely be used to identify a specific pathologic process. 1Ve would not agree with Pearson’s view [9] that electromyography should be used routinely as a guide to the site of muscle biopsy. Unless the muscle biopsy is taken immediately following electromyographic exploration, there is, as Woolf [49] has pointed out, a likelihood that the trauma of the needle AMERICAN

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Polymyositis-Barwick, exploration will itself cause an inflammator) reaction in the muscle which may cause difficulty in interpretation when the biopsy specimen is taken. Since muscular involvement is usually symmetrical, it may be convenient to take a biops)- specimen from the corresponding lnuscle of the opposite limb when electromyographic changrs have been demonstrated. f’uthology. In the present series of cases, muscle biopsy specimens were obtained in thirty-two patients and in only eighteen of these were they definitely abnormal; in fifteen there \vt‘re pathologic changes which we regarded as characteristic of polymyositis and in three others the changes were those of a nonspecific myopathy. \l:e believe that the value of a single ~nusclc biopsy in the diagnosis of polymyositis is \‘ery limited. \Vhen positive changes are present the, results are, of course, extremely valuable. However, in several of our cases in which more than one biopsy specimen was eventually taken, normal muscle was obtained on one occasion, or from one muscle, yet a second biopsy revealed drfinitc and characteristic abnormalities. Unfortunately, in our view it is not justifiable to perform multiple biopsies as a routine and hence \ve have accepted a diagnosis of polymyositis in the absence of histologic abnormality when the clinical picture, serum enzyme levels, electrompographic findings and the course of the disease in response to treatment have all seemed to be characteristic. The following findings, occurring with different degrees of prominence, have been common in almost all of our biopsies in which the results were positive: (1) focal or estensi1.e degeneration, sometimes \z.ith vacuolation, of individual muscle fibres; (3) necrosis of a part or the bvhole of a muscle fiber with phagocytosis; (3) marked variations in indi\iclual fiber size; (4) areas of sarcoplasmic basophilia with large vesicular nuclei and prominent nucleoli indicative of attempts at rcg:rncsration; (5) interstitial andi’or perivascular cellular infiltrates consisting of inflammator) cells: and (bj interstitial fibrosis. have been described and These changes illustrated in greater detail elsewhere by Walton and Adams [ 11, and by Adams, Denny-Brown and Pearson [SO]. 12:e would, however, stress the variability of the changes as demonstrated by single or even multiple biopsy. In one clinically subacute case, in which the patient is responding well to steroid therapy, there may be patchy focal necrosis of fibers with little or no inflammavol..

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653 TABLE

L’RHEUMATIC”

VANIFESTATIONS

v IN FIFTY-TWI-1

PhTIENTS

\VITH POLYMYOSITIS

Muscle pains. Joint pains. Joint swellings Recurrent bursitis Joint deformities. Positive Rose-\l’aaler or latex fixation test results (tests in 30 cast-s only),

40 12

8 4 2

’

2

tory cellular reaction; whereas in another cast presenting with similar clinical features, fiber necrosis and inflammatory infiltrates may be surprisingly extensive. Other Investigations. A brief rev&v of some other investigations carried out in our patients may be of interest. In the adult cases and especially in patients showing cutaneous and articular lesions, repeated attempts to obtain positive lupus erythematosus cell preparations have failed in all but one case, in which the subsequent evolution was into clinically typical disseminated lupus et-)-thematosus. Pearson 1511 has reviewed the incidence of “rheumatic” manifestations in a group of patients with polymvositis. In Table v, in which the incidence manifestations in our of various “rheumatic” own series is shown, it will IX seen that the incidence of the \,arious manifestations falls off sharply as the): become increasingly specific. In contrast to Pearson’s finding of posit ivr reactions to latex fixation or S.S.C. (Rose-12:aaler) tests in five or six casts tested, we have, only found two positive results in thirty cases tested. This may, of course, represent a different spectrum of cases, as encountered in a neurologic clinic rather than in the clinic of a general physician interested in rheumatolog)-. The two patients with positive Kose-N’aalcr or latex test results showed all the other rheumatic manifestations listed, and could be regarded clinically as having rheumatoid arthritis with polymyositis. In one instance, the muscle disease hat1 bcen prominent in the early stages but later became of secondary importance as the rheumatoid arthritis increased in severity. DIFFEREN1’I.-\L,

DIAGNOSIS

Problems of differential diagnosis have been discussed recently by a number of investigators

654

Polymyositis-Burwick,

[52-54. The steps in establishing the diagnosis of polymyositis seem to us to be as follows: on clinical suspicion of neuromuscular disease, the presence of a myopathic process is established by means of serum enzyme studies, electromyography and muscle biopsy. Once a disorder of the lower motor neurone and of peripheral nerves has been excluded, polymyositis must be distinguished from the hereditary myopathies and from the other acquired myopathies. U’hen dermatologic findings are striking, clinical suspicion usually becomes a certainty- which can then be confirmed by the appropriate investigations. Acute polymyositis must be distinguished from the paroxysmal, paralytic form of myoglobinuria [55]. This condition takes two forms, one in which the repeated attacks occur in relation to exercise, and another in which the illness is acute and severe and affects mainly children, often after nonspecific infections. It has been suggested that cases of the former type may well be examples of McArdle’s myopathy, due to the absence of muscle phosphorylase. The separation of the latter type from acute polymyositis is somewhat inexact. As Acheson and McAlpine [56] have pointed out, subcutaneous edema and erythema are often seen in these acute attacks and the differential diagnosis from polymyositis may depend upon the presence or absence of inflammatory infiltrates in a muscle biopsy specimen. The infective and fiarasitic myositides are rarely confused with polymyositis as these illnesses are usually acute and painful and often localized to one limb; muscular weakness is absent, and muscle biopsy findings are often diagnostic. The myopathy which may occasionally complicate sarcoidosis is clinically indistinguishable from polymyositis but can be identified by the presence of typical sarcoid granulomatous changes in muscle biopsy specimens. Severe pain situated proximally around the limb girdles, the absence of muscle weakness and wasting, an onset in middle or old age and the presence of a high erythrocyte sedimentation rate are the main features ofpolymyalgia rfleumatica [57], which shows a rapid response to steroid therapy. Normal serum enzyme levels and normal findings on electromyography and muscle biopsy have, in our own experience, served to differentiate these cases, which are not uncommon, from polymyositis. The difficulties in differentiating certain cases of polymyositis from muscular

Walton

dystro_bfly are well known and have already been mentioned. This differentiation is particularly difficult in childhood and in middle age. The variability of the course of polymyositis, its rapidity of progression and occasional remission, and the discovery of minor cutaneous changes are useful clinical aids to diagnosis. In many of the slowly progressive cases, however, the clinical and laboratory findings may be equally compatible with a diagnosis of hereditary myopathy. If characteristic changes are not evident on muscle biopsy, and a striking response to steroid therapy is not obtained, we agree with Rowland [58] and Shy [3] that it may be difficult or impossible to distinguish some such cases of presumed polymyositis from sporadic cases of limb girdle dystrophy. Tfyrotoxic myopatfiy may at times closely resemble polymyositis especially in cases occurring in middle age when the usual signs of thyrotoxicosis may be minimal. Some of these patients may show a myasthenic fatigability and improvement on neostigmine treatment [59]. Gimlette [SO] has reviewed the clinical and electromyographic features of this condition. When a clinical distinction is difficult, diagnosis may depend upon the results of a radioactive iodine uptake test, as pathologic changes in the two conditions can be similar. Of the endocrine myofiathies, that associated with Addison’s disease and also seen in occasional cases of hypopituitarism [67] usually bears little clinical resemblance to polymyositis, and the associated clinical and biochemical disturbances readil) distinguish this condition. Muscular wasting and weakness is common in Gushing’s syndrome [S&63]. The endocrine disturbance is usually evident clinically but in some cases the muscular manifestations, which are identical with those of steroid myopathy (uide infra), may dominate the clinical picture [58,64]. Rowland [58] and Vicale [65] have also drawn attention to the prominence of muscular weakness in some cases of hyperparatfyroidism; these cases, in which rapid weakness develops, involving limb girdle muscles, especially those of the legs, may closely resemble polymyositis. Normal findings on electromyography and muscle biopsy, and the roentgenologic and chemical evidence of metabolic bone disease, served to differentiate this condition. The development of proximal muscle weakness in cases of rheumatoid arthritis and in other collagen diseases in which the patients are receiving steroid therapy presents difficulties; AMERICAN

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Polymyositis-Barwick, these features are sometimes due to an associated poly-myositis, but if they develop after treatment has t)een in progress for some time they are most often due to the drugs. Triamcinolone, betamethasone and dexamethasone most often have this effect: most such patients promptly recover when therapy is discontinued or when an alternate steroid, e.g., prednisone, is used. In long standing cases of myusthenia grnvis, weakness and wasting of proximal limb muscles mav also develop [66]. It is usually possible, ho\ve&r, to distinguish these cases from those of polymyositis in which fatigahility is present because (1) in myasthenic patients the fatigability had been present long before the onset of muscle kveakness and wasting, (2) the triceps muscle is often selectively involved in myasthenia, and (3) the serum enzyme levels are normal [67]. Furthermore, in polymyositis, the response to neostigmine is rarely striking and sustained, and the fatigability and muscular weakness and wasting usually go hand in hand. A syndrome, as yet not fully defined but which must also be considered in differential diagnosis, is diabetic arnyotrojhy [68]. In this condition, recently further delineated by Locke et al. [69], as>,rnmetrical painful wasting and weakness develops in the thighs, usually in middle-aged men ~vho have had diabetes for some time. There is often rvidence of a peripheral neuropathy as lvell. Pathologically, the changes are those of single fiber atroph)-, and are quite unlike those of polym!-ositis. CLINICI\I.

COURSE

AND

RESPONSE

TO

‘I‘REAThlEh’l

‘I‘he clinical course of this disorder is cxtremel) variable and often appears to bear little or no relationship to the severity of the initial clinical features. This makes any attempt to assess the response to various forms of therapy rxtremel) difficult. The condition is sufficiently uncommon to make it unlikely that any single physician would have the opportunity of carrying out a controlled trial of treatment. Further, the disease can bc so serious and disablilig as to raise serious ethical difficulties in withholding possibly efrective therapy from control patients. In our o\rn series, all patients have been treated with some form of steroid therapy but there has been no uniformity of therapy, either in the choice of drug or in the dosage used. A few of the patients described herein, although seen by us at some stage, have been under the care of other physicians in the North East of England. VOL.

35,

NOVEMBER

1963

Tb’alton

Against this background of variabilipj in clinical course it is not surprising that many remedies have been claimed to t)e of therapeutic value. Among other drugs, amino acids, arsenic, antibiotics, calcium chloride, ephedrinr, leukocyte suspensions, mepacrine, para-aminobenzoic acid, prostigmine, pyrotherapy, quinidine, quinine, salic),lates, sulfonamides, corticosterone, th),roxinc, vaccines, vitamin E and other Gtamins, and wheat germ ha\,e all bern used and have been claimed by various investigators to be eff‘ectivc in polymyositis and dermatomyositis. \2:hen the number of remedies recommended is as large as this it is usuall) implied that no single treatment is uniformly successful. Zarafonetis [ 701 claimed that para-aminobenzoic acid had beneficial effects, in particular on the dermatologic aspects. However, most of his patients were suffering from scleroderma or progressive systemic sclerosis. Our aclmittedly limited experience has not demonstrated. that the drug is of any value. The use of prostigmine, mestinon or ephedrine may produce some improvement in patients with polym\ositis who show a “myasthenic” fatigability. Tl;is response is often slight and transient. In two patients in our series who showed such features, these drugs gave no lasting benefit. Published information on the value of I\C:TH, and of cortisone and related steroids, must be gleaned from the experience of a numl)cr of clinicians in \-arious centers all of whom have treated a comparatively small number of cases. Schuermann [23] stated that in dermatomyositis there were some early beneficial cl’t‘ects but concluded that steroid therapy did not affect the ,ultimate course or outcolne of the disease. Everett and (Curtis [7/l and (Carlisle and Good ( 721, who studied childhood cases in particular, cxprcssed smilar views. However, Christianson et al. I? /I expressed the opinion that, in addition to bein? lifesaving in acute progressive cases? steroid therapy also produced considerable benefit in chronic cases, moreover that the myopathp associated lvith malignant disease might also respond strikingly to trcaltulent. From these reports and from the many isolated cases recorded, it seems that patients with dermatomyositis generally show less response to steroid drugs than do children and adults with subacute or chronic polymyositis. In cases of the latter type, considerable improvement in most cases has been reported by man). workers jl,lO,N,_?1]. It is, however, obvious that not all

Walton

Polymyositis-Barwick, TABLE CLINICAL

RESPONSE

TO ADRENAL

STEROID

ACCORDING

Functional Grading Prior to Treatment

Grade Grade Grade Grade Grade Grade Grade

2 3 4 5 6 7 8

No. of Patients

i

11

’

TO INITIAL

-

IN

FIFTY-TWO

FUNCTIONAL

6

23

5

10 51 i

:

\VITH POLYMYOSITIS

No. Unchanged

No. LYorse

,

No. Died1

3 2 0 1 2 0 1 years after onset)

I:2!$

i

-

* Prednisone in forty-five cases; prednisolone in six cases; triamcinolone in one case. t Of the nine patients who died, six showed a moderate or marked improvement initially

dition deteriorated

T

6 13 4 1 0 0 0

&

1

PATIENTS

GRADING

No. Recovered No. Improved (by 1 grade or more) , (grade 1 or normal)

;I

I

VI

THERAPY*

-

but later their con-

gnd they became unresponsive.

patients with subacute or chronic polym)rositis do respond satisfactorily, even when the most rigid clinical and histologic criteria of the condition are satisfied. In our own series of fiftytwo cases, we have paid particular attention to the effect of the drugs upon muscular weakness. We have used a table of ratings of functional ability, modified from that proposed originally by Swinyard et al. [73]. This proposed a grading of eight stages of functional ability to bc used in the assessment of patients with muscular dystrophy. We have used this in its original form in assessing the response to treatment of hereditary myopathy with anabolic steroids [7/i] and found it to be useful. For the purposes of’ the present study the criteria have been modified to read as follows: (1) Ambulates with mild waddling gait and lordosis, elevation activities adequate (can climb a flight of stairs without needing the support of the arms). Cannot run. (2) Ambulates with moderate waddling gait and lordosis. Elevation activities deficient (needs the support of the arms to negotiate a flight of stairs). (3) Ambulates with moderately sc\.cre \vaddling gait and lordosis. Cannot negotiate a flight of stairs without help from another person. Can manage to achieve a correct posture frown a standard height chair without assistance. (4) Ambulates with severe waddling gait and lordosis. Unable to rise from a standard height chair without assistance.

(5) Able to sit in a chair and maintain good posture. Able to stand but unable to walk without assistance. (6) Unable to walk even with assistance. Able to perform some activities of daily living in wheelchair or bed. (7) Confined to bed unable to feed without assistance. (8) Severely paralysed with involvement of respiratory muscles. The virtues of this classification are that it is sufficiently crude to bc applied to the initial condition of the patient as assessed either b>, the clinical findings gi\,en in hospital records or by the recollection of patients not seen at the onset of the illness. It has certain drawbacks in that it takes little or no account of those cases in which there is predominant weakness of muscles around the shoulders and neck, and, of course, it takes no account of the various nonmuscular manifestations of the disorder. With these limitations in mind, we present in Table VI the clinical response of muscle weakness, assessed in this way, to adrenal steroid therap) in our fifty-two patients with polymyositis. In Table VII we analyze the response to treatment shown by patients in the various clinical groups as previously outlined. The drugs used were prednisone in forty-five cases, prednisolone in six cases and triamcinolone in one case. The usual regimen of treatment has been to give 60 mg. of prednisone daily for four to five days, thereafter reducing the dosage to 40 mg. daily AMERICAN

JOURNAL

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MEDICINE

Polymyositis--Barwick, ?rABLE CI.lNI(:.\l.

RESPOKSE

TO .4DREN.4L

STEROID

ACCORDING

Clinical

Groupin?

VI1

THERAPY

TO INITIAL

IN FIFTY-T\YO CI.Ih’IC.41,

No. Improved

of Chsas (by

1 q~~le

657

M~blton PATIENTS

\VITH

POI.\‘M~‘OSITIS

(:ROUPING

No. liecovrred

or morc~)

and rqulatinq tlw subsequent maintenance dusasc accordinq to the clinical response of tlic patient and ‘or, in our more recent cases, accordin? to the swum enz)mr levels. \Vhen prednisolonc or triamcinolone has t)cen used, the dosaac has I wen usually of the same order of therapeutic potency. Cnfortunatcly, however, not all l)atients rcccived the drugs in exact11 the sanrc \\-a>‘.In some, the initial dosage was 1obcr and there has, of course, then great variation in the level of the maintenance treatment. In some’ cases \VYhave found it nccessar) to persist with a large dose, for example SO to 60 III%. of prednisone every day for many days. and occasionally for weeks, before a satisfactoq clinical response has been obtained. Theduration of 111~follow-up period has varied hetbvcen five !.cars and sis months. Although in many of thcw casts pwdnisonc has been givw alone bitt1 a +)od result, man)- patients received various antibiotics and other remedies in addition. It ~vc.~ulclbe impossilAe in the space available hew to detail all the forms of ancillary treatincnt or the complications which may arise,. Iii one cast, respirator). paralysis required intwnittcnt positive pressure respiration for se\.caral months on t\vo separate occasions, but the patient c\wltually died two and a half years after the onset. \Vc stated at the outset that WC did not plan a controlled clinical trial but \ve give here merel) a wcord of cspcriencc. It bill l)e seen from ‘TatlIes V; and VIL that man!’ patients eithrr improwd or rcco\.cred virtually colnplctely, al~lwugh the possibility of further relapse still ysists. ‘T’\\w~ty-four of the fifty-two patients ha\vz rrcowwcl (functional grade, 1 or Iwttcr). This rcfcrs only to functional anal! sis, however, al bilit)- and ignores such phenomena as joint in\.c)l\,c.inc’iit, cl\-sphaqia and thr skin Irsions, all

of \vhich \ve have found to respond ra thw less \vcll than does muscular function. In gcncral. we would agree \vith Pearson [Cl] that the response to treatment is better in patients whose s:Fmptoms \verc of comparatively short duration I.vhcn treatment \vas commenced. It also mmust be pointed out that over half of these patients arc still maintained on steroid therap)-. although at a low level of dosage. Ten additional patients ha\re impro\wl hy one or more grades of functional ability, but are still solne\vhat tlisahlcd by the muscle weakness. Fi\,e patients. are unchanged and thrw are worst despite steroid therapy. Of the nine patients lx-hose illnrss terminated fatally duriq treatnwnt, sis had shown a moderate or lnarkcd improve mcnt initially but later deteriorated, lwcomin;; lmresponsive to treatment. All the fatal cases occurred in adults. Thr immediate cause of death and postmortcrn tindings with regard to the presence or ahscncc of malignant discasc are recorded in Table VIII. Three of the four patients with maliqant disease showed an initial impro\wnent in muscle .wcakncss \vith treatlnent, as did thrcr iI1 whoIn no neoplasm VW clisco\:errd. The paticllt ~vho died of pulmonary cmholism probably had ;I L‘unctional grade df 1 or better at the time of death. In the fi\.e men o\‘cr fifty years of age \vho died, the incidence of cletcctahle neoplastic (disease at postmortem examination was less than 580 per cent. This is in contrast to the suqqestion of Shy [J’] that malignant disease is almost in\,ariat)ly present in male patients with myopathy ‘in this aYe group. In pass@, we should mention that :2rinstrony and Murdoch 175) have reported on the i)eneficial erects of anabolic liorinonc3 in dcrmatom\-ositis. Thcsc drugs have not Iwcn used cxtcnsivcly in the present wric,s but \vc

Polymyositis-Burwz&

658

TABLE CASES

Age at Death

Case NO.

Sex

OF

POLYMYOSITIS

Immediate

TERMINATING

Cause

Walton

VIII FATALLY

-

IN

THE

FOLLOW-UP

Duration of Muscle Disease Prior to Death

of Death

(yr.1

PERIOD

Other Significant Postmortem Findings

(yr. 1 --

2 3 4 6 25 29 32 35 37

50 60 55 57 51 61 41 46

M M M M F M F F

68

F

Bronchogenic carcinoma No evidence of malignancy No evidence of malignancy Bronchogenic carcinoma Carcinoma of pancreas Carcinoma of oesophagus No evidence of malignancy No evidence of malignancy

Bronchopneumonia Bronchopneumonia Staphylococcal pneumonia Bronchopneumonia Bronchopneumonia Bronchopneumonia, rrspiratory paralysis Pulmonary embolism Bronchopneumonia, chronic urinary infection Bronchopneumonia

have given them to patients in whom there has been gross weight loss with marked muscle wasting. It seems to us that these preparations are of particular value in speeding convalescence once a response to the antiinflammatory steroids has occurred. We have not as yet been impressed by their value in other patients who do not show rapid weight loss during their illness. 1Vc have mentioned already that in this series dermatologic manifestations have, in general, responded less well to steroid therapy. Thus, it has been a not uncommon experience to see a patient whose functional ability is normal, or nearly so, but who still shows signs of skin lesions. Further, we have found a tendency for the dermatologic manifestations to “flare-up” when the level of steroid medication is reduced to a level which is still sufficient to control muscular weakness. Of those patients whose functional grade was 1 or normal at the time of follow-up (t\ventyfour cases), sixteen were still receiving steroids and eight were not receiving any treatment at all (these eight patients were adults). Of patients in the other categories, all except the three patients who showed no response to treatment were receiving prednisone at the time of follow-up. We have not been able to formulate any general rule as to the amount or duration of treatment; this seems to us to be still an entirely empiric matter. We would, however, mention that a minimum of one year’s treatment is always necessary and in some patients wc have continued for several years. The best guides seem to us to be first, a general clinical assessment of the patient, and secondly estimations

No evidence

of malignancy

-

-

of serum aldolase or SGOT activity. However, the fact that serum enzyme levels have become normal when the patient has been receiving treatment for many months is not invariably a safe guide. Some patients will have a relapse immediately following the reduction or cessation of treatment, while others may remain in remission for quite long periods but will eventually have a relapse. Although a considerable number of patients may show protracted remissions, we have as yet no means of identifying such cases and such a clinical course can only be verified in retrospect. Acknowledgment: We wish to express our gratitude to the many physicians in the North East of England for referring cases to us and for allowing us access to other patients under their care. REFERENCES

1.

WALTON,

J.

N. and ADAMS, R. and London, 1958.

D. Polymyositis. Edinburgh E. & S. Livingstone, Ltd. 2. SHY, G. M. Some metabolic and endocrinological aspects of disorders of striated muscle. Res. Publ. A. ~Veeru.,Lfeent. Dir.,

38: 274,

1960.

3. SHY, G. M. The late onset of myopathy. IVorld ,\Te~rol., 2: 149, 1962. 4. DENNY-BROWN, D. The nature of polymyositis and related muscular diseases. TY. B Stud. Coil. Physicians Philadelphia, 28: 14, 1960.

5.

MUSSA,

J. J., CRUZ, R.. A., UBILLA, V. Dermatomiositis.

OSSANDON, M.

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R., OLMEDO DIAZ, M. and FERRARIS, I,. Dermatomiositis. A prop6sito de dos observaciones. Rev. FOG. Cirnc. AMld. liniu. Grdoba, 17:

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Polymyositis-Barroick, B. G., KANKIN, A. M. and ROBERTSON, .I. H. Polymyositis. &it. M. J., 2: 5184, 1960. 8. (;.ARCIN. R., LAPRESLE, J., GRUNER, J. and SCHERKIT. J. Les polymyosites. Rev. Xewol., 92: 465,1955. 9. PI-ARSON, C. M. Polymyositis and related disorders. In: Disorders of Voluntary Muscle, London, 1963. .J. & A. Churchill, Ltd. IO. I
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1963

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