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Granulomatous polymyositis
Journal of the neurological Sciences, 18 (1973) 1-9
1
~ ElsevierScientific Publishing Company,Amsterdam - Printed in The Netherlands
Granulomatous Polymyositis P. G. L Y N C H AND D. V. BANSAL
The Neuropathology Department, Manchester University and Ancoats Hospital, Manchester (Great Britain)
(Received 14 June, 1972)
INTRODUCTION Granulomatous lesions composed of epithelioid cells, multinucleated giant cells, fibroblasts and lymphocytes have been found in sarcoidosis (Wallace, Latte, Malia and Ragan 1958), in myasthenia gravis (Mendelow and Genkins 1954), in a case of myocarditis complicated by a thymoma (Waller, Shapiro and Paltauf 1957), in rheumatoid arthritis (Maurice 1955), in miliary tuberculosis (Reverdin 1891; Lanz and Dequervain 1893; Kaiser 1905; Plummer, Sanes and Smith 1934), in tertiary syphilis (Skobel 1965), in toxoplasmosis (Adams, Denny-Brown and Pearson 1962a) and in carcinoma (Shy 1962). Similar lesions have been described in a rare form of slowly progressive polymyositis which may involve the pectoral and pelvic girdles and the proximal and distal regions of the upper and lower extremities. The first report of this disorder was that of Devic, Masson and Bonnefoy (1955). Since then 23 new cases have been added to the literature. No clinical or radiological evidence of any systemic disease process which might have accounted for the muscle lesions has so far been found in these patients. Analysis of the cases shows that there were 4 affected males and 19 affected females; the age of the youngest patient was 27 years and that of the oldest 76 years. The duration of symptoms ranged from 3 weeks to 25 years and treatment with steroids has led to a slight improvement in some instances. The position of this disorder in any classification of muscle disease must remain uncertain until the results of full autopsy studies are available. In the only fully-studied case cited by Nevin (1960) no lesions were found at autopsy outside the skeletal muscles. The clinical and pathological findings in a further case of granulomatous polymyositis occurring in a 56-year-old woman are described and discussed in this paper together with a brief review of the literature. Cases in which granulomatous lesions were found outside voluntary muscle either in life or at autopsy have been excluded from the discussion. For details of such cases, the reader is referred to the excellent account by CoErs and Carbone (1966). CASE REPORT A 56-year-oldhousewifewas first seen in July 1969complaining of weakness in the upper and lower limbs.
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P. G. LYNCH, D. V. BANSAL
Symptoms began in 196l when her legs suddenly gave way while walking. Weakness in the lower limbs gradually became more severe, so that the patient found difficulty first in climbing stairs, then in walking on level ground. In 1965, the patient noticed the onset of weakness in the proximal regions Of both upper limbs, An aching sensation, but never severe pain, was noted occasionally in the affected muscles. There were no complaints of visual, swallowing or speech difficulties. There was no family history of iacuromuscu!ar disease. On examination the patient weighed 70 kg; blood pressure 220/110 mm Hg. There were no abnormalities in the cardiovascular, alimentary or respiratory systems. Examination of the central ne~ vous system showed that reflexes were present and equal in the upper limbs. The ankle and knee jerks were absent bilaterally, the plantar responses flexor. There were no sensory disorders. Examination of the musculature revealed weakness of the upper and lower limbs which was more marked proximally. The fiice and neck muscles were unaffected. There was no evidence of muscle wasting nor of muscle tenderness. Tone was not impaired. Investigations showed a normal haemoglobin level and blood film; ESR (Wintrobe) 14 mm/l hr no abnormalities found in urine or faeces; serum electrolytes including calcium and phosphorus were normal; serum albumin 3.5 g/100 ml: serum globulin 4.6 g l00 ml: electrophoresis o! serum showed slightly increased levels of ~2- and 7-globulins; serum alkaline phosphatase, LDH, SGOT, aldola~ and C P K were normal; liver biopsy was normal: WR, THA and R P C F tests for syphilis negative. Brucella agglutinins not detected; Mantoux test 1/100--negative: muscle biopsy findings are described under the heading of pathological features; chest X-ray showed elevation of the right diaphragm : eleclrocardiography was not performed ; nerve conduction studies performed in the left upper limb showed no abnormalities : an E M G performed on the right and left deltoid muscles showed a complete pattern with m~ny myopathic units. The patient was treated with prednisolone 20 mg t.d.s, but there was only a slight improvement after 4 weeks of therapy. After discharge from hospital the patient failed to attend for follow-up studies. MATERIALS AND METHODS Specimens were carefully excised under general anaesthesia from the left deltoid and left peroneus brevis muscles. Thin strips of the peroneus brevis muscle, from its origin to insertion, were injected immediately after excision with 0.015 ~u methylene blue solution (Boots Pure Drug Co. Ltd.) using a fine hypodermic needle. The injected strips of muscle were oxygenated for 1 hr and then placed in freshly filtered ice-cold 8 i'~, ammonium molybdate solution for 24 hr. After fixation, the specimens were thoroughly rinsed in distilled water and squash preparations were made by the technique of Dastur (1956). The resulting preparations were dehydrated in alcohol, cleared in xylol and mounted in Xam. Cryostat sections of deltoid muscle rapidly frozen in liquid nitrogen were used for enzyme histochemical studies. Sections were stained for phosphorylase using the method of Takeuchi and K uriaki (1955), and for lactic dehydrogenase using the method of Hess, Scarpelli and Pearse (1958). The remaining tissue was fixed in 10 ° / f o r m o l calcium. Part of this material was embedded in paraffin and part was kept for frozen section work. Paraffin sections were stained by the following methods; Weigert's haematoxylin and eosin ; a!cian blue; periodic acid-Schiff (PAS); Mallory's trichrome; phosphotungstic acid haematoxylin; methasol fast blue; haematoxylin and Van Gieson ; Von Kossa for calcium ; Gordon and Sweet's reticulin stain ; Zieht-Neetsen stain for tubercle bacilli; Gram; Gomori's methenamine silver stain for fungi. Longitudinal and transverse sections of formol calcium-fixed material were cut at 151~ on a freezing microtome. These frozen sections were stained with Sudan IV and Nile blue sulphate to demonstrate neutral fat and phospholipids. RESULTS
Muscle patholoyy Lej~ deltoid muscle. There is an apparent loss of muscle fibres with fatty infiltration and endomysial fibrosis. In the perimysium and endomysium there are several well-circumscribed nodular and fusiform collections of cells composed of histiOcytes, fibroblasts, epithelioid cells and multinucleated giant cells of the Langhan's variety (Fig. 1). The granulomas are separated from adjacent muscle fibres by thin zones of collagen or reticulin. In the outer region there are a few lymphocytes. Reticulin and collagen fibres interlace the granulomas in a network pattern (Fig. 2). There is no evidence of caseation and the cytoplasm o f many of the giant cells contains an acid mucopolysaccharide which stains strongly with alcian blue at p H 4.5. No Schaumann bodies or asteroid inclusions can be seen in the lesions and special stains fail to reveal the presence of acid-fast bacilli, other bacteria, fungi or parasites. Many of the epithelioid and giant cells contain occasional cytoplasmic granules measuring 1/~ or less in size. These granules which stain positively with PAS before and after treatment with diastase, also give a dark blue colour with Nile blue sulphate. The granules do not give a reaction with alcian blue, methenamine silver, Sudan IV or the Ziehl Neelsen stain. Several intramuscular arterioles show deposits of calcium in their walls. The vessels are otherwise unremarkable. There is atrophy of occasional muscle fibres in the vicinity of the granulomas but these fibres show
GRANULOMATOUS POLYMYOSITIS
3
Fig. 1. Left deltoid muscle showing details of granulomatous infiltrate. H.-E., x 100.
Fig. 2. Left deltoid muscle showing reticulin network in granulomatous infiltrate. Reticulin, x 200.
preservation of cross striations and no sarcoplasmic abnormalities. Muscle fibres remote from the lesions show no structural changes and no abnormal cellular infiltrates in the sarcoplasm. Enzyme histochemical studies utilising the phosphorylase and lactic dehydrogenase reactions reveal a characteristic chequerboard pattern of Type 1 and Type 2 fibres adjacent to and remote from the granulomas. Frozen sections of
4
P . G . LYNCH, D. V. BANSAL
Fig. 3. Left peroneus brevis muscle. Large spherical swelling oll axon of intramuscular nerve lihtc. Methylene blue 400.
Fig. 4. Left peroneus brevis muscle. Branching of subterminal axon with formation of three end-plates supplying different muscle fibres. Methylene blue, x 300.
GRANULOMATOUS POLYMYOSITIS
5
Fig. 5. Left peroneus brevis muscle. Ultraterminal sprouting from a single end-plate. Methylene blue, × 200.
muscle stained with Sudan IV and Nile blue sulphate show no increased a m o u n t s of intrasarcoplasmic lipid in both fibre types. Left peroneus brevis muscle. The light microscope appearances are similar to those described in the left deltoid muscle, but there is a more pronounced degree of endomysial fibrosis. The vitally stained methylene blue preparations reveal several changes. Many of the axons in the intramuscular nerve bundles carry one or more large, almost spherical swellings at points along their length (Fig. 3). Many subterminal axons well outside the granulomatous foci show evidence of collateral sprouting with one axon giving rise to three or more end-plates on different muscle fibres (Fig. 4). An occasional example of ultraterminal sprouting can be found (Fig. 5) and occasional end-plates show fusion of the terminal axonic expansions. Beaded axons can be seen in the intramuscular nerve bundles and amongst the subterminal axons.
DISCUSSION
The present case showed no clinical or radiological evidence of sarcoidosis, active tuberculosis, rheumatoid arthritis or cardiomyopathy. Laboratory investigations revealed no abnormalities of calcium metabolism. Serum electrophoresis showed slightly raised levels of ~2- and y-globulins. The ESR was not increased. The Kveim test was not performed because the patient was treated with steroids as soon as the muscle biopsy findings were available. Liver biopsy was negative. Analysis of cases in the literature (Devic et al. 1955 ;Ammitzboll 1956 ; Bammer 1958; Garcin and Lapresle 1958; McConkey 1958; Harvey 1959; Kryger and Ronnov-Jessen 1959; Erbsl6h and Dietel 1959; Nevin 1960; Brun 1961 ; Talbot 1967; Schimrigk and Uldall 1968; Co~rs and Carbone 1966; Crompton and MacDermott 1961; Lebacq 1964; Hinterbuchner and Hinterbuchner 1964; Castaigne, Cambier, Escourolle and Brunet 1965; Meyer
6
P, (i. [,YNCH, I). V. BANSAL
and Regli 1965) reveals that the Kveim test was only performed in the case described by Talbot (1967). In this instance, the test was reported as negative. Most of the recorded cases have presented with weakness and atrophy of the proxy mal limb muscles. Involvement of distal limb muscles was also a feature of the cases of Schimrigk and U ldall (19681 and of t of the cases of Meyer and Regli (1965J. I)ysphagia was noted in 4 cases. In the cases described by Schimrigk and Utdall (19681 and by C ~ r s and Carbone (1966), dysphagia was a presenting symptom. The facial muscles were involved in 2 patients and in one-third of the cases muscle pain preceded the onset of muscular weakness. Pseudohypertrophy of the calf muscles was noted in I of the cases described by Erbsl6h and Dietel (19591. Tendon reflexes were found to disappear with increasing severity of muscular atrophy. The clinical course ~s that of a chronic and progressive muscular disorder. Complete spontaneous remissions have not yet been recorded. Electromyography shows the picture of a myopathy with brief and polyphasic action potentials reduced in amplitude. In some instances (Bammer 1958: Hinterbuchner and Hinterbuchner 1964; Meyer and Regli 1965: CoiSrs and Carbone 1966) etectromyography has shown evidence of myopathic, myotonic and neurogenic processes. The light microscope appearances of the muscle biopsy specimens in the present case correspond with the description of "'muscle sarcoid" given by Adams. Denny-Brown and Pearson (1962b) and by Pearson and Rose (1961 ). The muscle changes were similar to those found in previously recorded cases. Earlier authors have. however, also described degenerative changes in the muscle fibres adjacent to and remote from the granulomatous loci (Crompton and MacDermott 1961 ; CoOrs and ('arbone 19661. The basic problem as to whether these muscle fibre changes are primary or secondary in origin remains to be resolved. Crompton and MacDermott (1961) go further and suggest that this condition may be a type of sarcoidosis occurring in muscles already affected by another disease process. The 3 cases studied in some detail by CoOrs and Carbone (1966) tend further support to this hypothesis. Regarding the histology of the lesions, care must be taken to distinguish between myogenous giant cells and multinucleated giant cells of the Langhans variety. Schaumann bodies and asteroid inclusion bodies are not a feature of the lesions and have only been described in the case of Erbsl6h and Dietel (1959). The absence of such bodies does not of course rule out the diagnosis of sarcoidosis for it should be noted that Langhans type giant cells without inclusions may be seen in scalene lymph nodes in some patients who develop sarcoidosis in association with bronchogenic carcinoma. There are few previous studies of the intramuscular nerve endings in granulomatous polymyositis. In 3 cases (Co&s 1962, 1965) there was evidence of denervation and reinnervation in the muscles examined. This was typified by collateral axonal branching with the formation of multiple motor end-plates. These changes were thought to be due to direct involvement of some of the intramuscular nerve fibres by the disease process. Non-specific changes were also seen remote from the granulomatous foci. These consisted of fine, ramifying beaded axons and abnormal variation in the size and shape of motor end-plates. Within the granulomatous loci there were irregular thickenings of subterminal axons and fusion of the terminal expansions. In the present case there was evidence of collateral axonal branching, beaded axons, degenerate
GRANULOMATOUS POLYMYOSITIS
7
motor end-plates and large spherical axonal swellings. All these changes were found outside the granulomatous foci. The significance of the large spherical axonal swellings is obscure. They occur in a variety of neuromuscular disorders and are seldom seen in muscles taken from patients less than 40 years of age. Woolf (1969) noted that the swellings occurred most frequently in the peroneus brevis muscle and thought that they were an age-dependent phenomenon affecting some of the longest neurones in the body. Another possible explanation is that the swellings are in some way related to repeated minor injuries to the legs with partial damage to the musculocutaneous nerve. Why the swellings are seldom found at any age in distal upper limb muscles is a mystery. In a personal study (unpublished) of the intramuscular nerves of the hand lumbrical muscles taken from patients over 40 years of age who were suffering from a variety of non-neurological and neurological diseases, argyrophilic axon swellings were seldom found. No previously published reports of the histochemical examination of muscle in granulomatous polymyositis can be found in the literature. Histochemical studies in the present case were incomplete and although there was preservation of Type 1 and Type 2 muscle fibres adjacent to and remote from the granulomatous foci, nothing was learned about the histochemical characteristics of those cells constituting the granulomas. Glycogen and lipid content was within the normal range for the two fibre types. Some doubt exists as to whether this and the previously reported cases are instances of isolated muscle sarcoidosis as distinct from affection of muscle by generalised sarcoidosis. Only complete post-mortem studies can establish for certain that the pathological changes are limited to the muscles as in the cases described by Nevin (1960). It is becoming widely recognised that sarcoidosis embraces several distinct disease entities which are united only in exciting a similar non-specific tissue reaction to their various antigens. Scadding (1950) suggested that sarcoidosis should be classified as far as possible on an aetiological basis and spoke, for example, of tuberculous sarcoidosis and beryllium sarcoidosis. Amongst other bacterial infections, brucellosis was cited as a cause of granulomatous lesions in a variety of tissues. Tuberculosis, berylliosis and brucellosis were excluded in the present case. It is quite probable that other, as yet undetermined, agents can elicit the sarcoid reaction. The aetiological agent in the present case remains to be determined. ACKNOWLEDGEMENTS
Our thanks are due to Professor W. B. Matthews and to Dr. Rhys T. Williams for supplying clinical details of the patient, to Professor P. O. Yates for his interest and advice, to Miss P. Farnworth and Mrs. C. Evans for typing the manuscript, to Mrs. G. M. Worsley for technical assistance and to Mr. G. Humberstone for preparing the photomicrographs. SUMMARY
An account is given of a pathological condition, more common in women, which presents clinically as a slowly progressive muscular disorder of adult life.
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P . G . LYNCH, 1). V. BANSAL
The essential histological lesion is an infiltration of the connective tissue sheaths of voluntary muscle by non-specific granulomas composed of epithelioid cells, histiocytes, multinucleated giant cells and lymphocytes. The granulomas are non-caseating and show an outer zone of fibrosis and an inner fine reticulin network. Special stains have failed to detect bacterial, parasitic or fungal agents. Twenty-four cases of chronic granulomatous polymyositis have been previously reported in the literature. Post-mortem findings have, so far, been described in only 1 of these cases. The clinical, electromyographic and pathological findings in a further case are presented. Light-microscopic observations revealed granulomatous lesions in biopsy specimens of deltoid and peroneus brevis muscles. The cytoplasm of many of the multinucleated giant cells in the granulomas contained large amounts of acid mucopolysaccharide. Although there was atrophy of muscle fibres in the vicinity of the lesions, the structure of the fibres was preserved and there was no evidence of abnormal cellular infiltrates in the sarcoplasm. Muscle fibres remote from the lesions showed no abnormalities. The intramuscular nerves showed branching of the subterminal axons, beaded axons, occasional degenerate motor end-plates and large numbers of spherical axonal swellings in the intramuscular nerve bundles. Histochemical studies were incomplete, but there was an apparently normal distribution of glycogen, lipid, lactic dehydrogenase and phosphorylase activity in Type 1 and Type II fibres. Because of incomplete pathological data, the nosology of this condition, for the time being must remain uncertain. Some workers consider that it is a form of sarcoidosis restricted to voluntary muscle.
REFERENCES
ADAMS, R. D., D. DENNY-BROWN AND C. M. PEARSON (1962a) Inflammatory diseases (myositis). In: Diseases of Muscle. A study in Pathology, Hoeber, New York, 2nd ed., pp. 408-41 I. ADAMS, R. D., D. D~NNv-BROWN AND C. M. PEARSON (1962b) Inflammatory diseases (myositis). ln: Diseases of Muscle. A Study in Pathology, Hoeber, New York, 2nd ed., pp. 455-457. AMMITZBOLL, F. (1956) A case of Boeck's sarcoid with isolated localisation in the musculature. Acta rheum, scand., 2:3 1-10. BAMMER,H. 0958) Ein Fall yon sarkoid der Skelettmusculatur unter dem Bilde einer progressiver Muskeldystrophie, Nervenarzt, 29 : 422-425. BRUN, A. (1961) Chronic polymyositis on the basis ofsarcoidosis, Actapsychiat. neurol, scand, 36~ 515-523. CASTA1GNE, P., J. CAMBIER, R. ESCOUROLLEAND P. BRUNET (1965) Sarcoidose musculaire a forme pseudomyopathique, Rev. neurol., 113 : 43-45. COi~RS, C. (1962) Analyse critique et essai &interpretation des anomalies morphologiques de la junction neuromusculaire en pathologie humaine, Mere. Acad. roy. Med. Belg., 4: 71-148. CoORs, C. (1965) Histology of the myoneural junction in myopathies. In: P. M. PAUL,E- E; DANIEL, C. M. KAY AND G. MONCKTON (Eds.), Muscle, Pergamon Press, London, pp. 453-478. COERS, C. AND F. CARBONE(1966) La myopathie granulomateuse, Acta neurot, belg, 66: 353--381. CROMPTON, M. R. AND MACDERMO'fT (1961) Sarcoidosis associated with progressive muscular wasting and weakness, Brain, 84:62 74. DASTUR, D. K. 0956) The motor unit in leprous neuritis. A clinicopathological study, Bull. neuroL Soc. India, 4: 1--27. DEVlC, M., R. MASSON AND J. BONNEFOY (1955) A p r o p o s d'une observation de myosite a nodules de Besnier-Boeck-Schaumann, Rev. neurol., 92: 563-567. ERBSL6~, F. AND W. DiETEL (1959) [3ber exogene Spatmyopathien. I, Die Polymyositis granulomatosa Boeck, Arch. Psychiat. Nervenkr., 199: 215-234.
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GARCIN, R. AND J. LAPRESLE(1958) Sur un cas de sarcoidosis ayant simul8 une polymyosite, Rev. neurol., 99:322 326. HARVEY, J. C. (1959) A myopathy of Boeck's sarcoid, Amer. J. Med., 27: 356-363. HESS, R., D. G. SCARPELLIAND A. G. E. PEARSE(1958) Cytochemical localisation of pyridine nucleotide linked dehydrogenases, Nature (Lond.), 181:1531-1532. HINTERBUCHNER, C. N. AND L. P. HINTERBUCHNER(1964) Myopathic syndrome in muscular sarcoidosis, Brain, 87: 355-366. KAISER, F. (1905) Zur Kenntniss der prim~iren Muskeltuberculose, Arch. klin. Chir., 77: 1033-1072. K RYGER,J. AND V. RONNOV-JESSEN(1959) Myopathy in Boeck's sarcoid, A cta rheum, scand., 5: 314-322. LANZ, O. AND F. DEQUERVAIN(1893) ~)ber Hematogens Muskeltuberculose, Arch. klin. Chir., 46:97 138. LEBACQ, E. (1964) La Sarcoidose de Besnier-Boeck-Schaumann, Arscia, Brussels, pp. 205 211. MCCONKEY, }3. (1958) Muscular dystrophy in sarcoidosis, Arch. int. Med., 102: 443-446. MAURJCE, P. A. (1955) La participation de la musculature/t la maladie de Besnier-Boeck-Schaumann, Heir. med. Acta, 22: 1642. MENDELOW, H. AND G. GENK1NS(1954) Studies in myasthenia gravis. Cardiac and associated pathology, J. Mt. Sinai Hosp., 21 : 218-225. MEYER, H. J. AND F. REGLI (1965) 121berdie Beziehungen der Polymyositis granulomatosa Boeck zur late onset myopathy, Dtsch. Z. Nervenheilk., 186: 547-570. NEVm, S. (1960) Value of muscle biopsy, Proc. roy. Soc. Med., 53: 828-832. PEARSON, C. M. AND A. S. ROSE(1961) Myositis, the inflammatory disorders of muscle, Res. Publ. Ass. Herr. merit. Dis., 38: 422-478. PLUMMER, W. W., S. SANESAND W. S. SMITH (1934) Haematogenous tuberculosis of skeletal muscle: report of a case with involvement of the gastrocnemius muscle, J. Bone It. Sur9., 16: 631-639. REVERD1N,J. L. (1891) Note sur un cas de tuberculose musculaire primitive, Conyresfrancais de Chirurqie, 5 : 560-568. SCADDING, J. G. (1950) Sarcoidosis with special reference to lung changes, Brit. med. J., 1 : 745-753. SCHIMRIGK, K. AND B. ULDALL(1968) The disease of Besnier-Boeck-Schaumann granulomatous polymyositis, Europ. Neurol. (Basel), l: 137 159. SHY, G. M. (1962) The late onset myopathy. World Neurol., 3: 149-158. SKOBEL,P. (1965) Diskussionbeitrag. In: R. HoPPE (Ed.), Sarkoidose, Schatauer, Stuttgart, p. 113. TAKEUCHI, T. AND H. KURIAKI (1955) Histochemical detection of phosphorylase in animal tissues. J. Histochem. Cytochem., 3:153 160. TALBOT, P. S. (1967) Sarcoid myopathy, Brit. med. J., 4: 465-466. WALLACE, S. C., R. LATTE, J. P. MALIA AND C. RAGAN (1958) Muscle involvement in Boeck's sarcoid, Ann. intern. Med., 48:497-511. WALLER, J. V., M. SHAPIROAND R. PALTAUF(1957) Congestive heart failure in post-menopausal muscular dystrophy, Amer. Heart J., 53: 479-484. WOOLF, A. L. (1969) Pathological anatomy of the intramuscular nerve endings. In: J. N. WALTON (Ed.), Disorders of Voluntary Muscle, 2nd ed., Churchill, London, pp. 208 209.
1
~ ElsevierScientific Publishing Company,Amsterdam - Printed in The Netherlands
Granulomatous Polymyositis P. G. L Y N C H AND D. V. BANSAL
The Neuropathology Department, Manchester University and Ancoats Hospital, Manchester (Great Britain)
(Received 14 June, 1972)
INTRODUCTION Granulomatous lesions composed of epithelioid cells, multinucleated giant cells, fibroblasts and lymphocytes have been found in sarcoidosis (Wallace, Latte, Malia and Ragan 1958), in myasthenia gravis (Mendelow and Genkins 1954), in a case of myocarditis complicated by a thymoma (Waller, Shapiro and Paltauf 1957), in rheumatoid arthritis (Maurice 1955), in miliary tuberculosis (Reverdin 1891; Lanz and Dequervain 1893; Kaiser 1905; Plummer, Sanes and Smith 1934), in tertiary syphilis (Skobel 1965), in toxoplasmosis (Adams, Denny-Brown and Pearson 1962a) and in carcinoma (Shy 1962). Similar lesions have been described in a rare form of slowly progressive polymyositis which may involve the pectoral and pelvic girdles and the proximal and distal regions of the upper and lower extremities. The first report of this disorder was that of Devic, Masson and Bonnefoy (1955). Since then 23 new cases have been added to the literature. No clinical or radiological evidence of any systemic disease process which might have accounted for the muscle lesions has so far been found in these patients. Analysis of the cases shows that there were 4 affected males and 19 affected females; the age of the youngest patient was 27 years and that of the oldest 76 years. The duration of symptoms ranged from 3 weeks to 25 years and treatment with steroids has led to a slight improvement in some instances. The position of this disorder in any classification of muscle disease must remain uncertain until the results of full autopsy studies are available. In the only fully-studied case cited by Nevin (1960) no lesions were found at autopsy outside the skeletal muscles. The clinical and pathological findings in a further case of granulomatous polymyositis occurring in a 56-year-old woman are described and discussed in this paper together with a brief review of the literature. Cases in which granulomatous lesions were found outside voluntary muscle either in life or at autopsy have been excluded from the discussion. For details of such cases, the reader is referred to the excellent account by CoErs and Carbone (1966). CASE REPORT A 56-year-oldhousewifewas first seen in July 1969complaining of weakness in the upper and lower limbs.
2
P. G. LYNCH, D. V. BANSAL
Symptoms began in 196l when her legs suddenly gave way while walking. Weakness in the lower limbs gradually became more severe, so that the patient found difficulty first in climbing stairs, then in walking on level ground. In 1965, the patient noticed the onset of weakness in the proximal regions Of both upper limbs, An aching sensation, but never severe pain, was noted occasionally in the affected muscles. There were no complaints of visual, swallowing or speech difficulties. There was no family history of iacuromuscu!ar disease. On examination the patient weighed 70 kg; blood pressure 220/110 mm Hg. There were no abnormalities in the cardiovascular, alimentary or respiratory systems. Examination of the central ne~ vous system showed that reflexes were present and equal in the upper limbs. The ankle and knee jerks were absent bilaterally, the plantar responses flexor. There were no sensory disorders. Examination of the musculature revealed weakness of the upper and lower limbs which was more marked proximally. The fiice and neck muscles were unaffected. There was no evidence of muscle wasting nor of muscle tenderness. Tone was not impaired. Investigations showed a normal haemoglobin level and blood film; ESR (Wintrobe) 14 mm/l hr no abnormalities found in urine or faeces; serum electrolytes including calcium and phosphorus were normal; serum albumin 3.5 g/100 ml: serum globulin 4.6 g l00 ml: electrophoresis o! serum showed slightly increased levels of ~2- and 7-globulins; serum alkaline phosphatase, LDH, SGOT, aldola~ and C P K were normal; liver biopsy was normal: WR, THA and R P C F tests for syphilis negative. Brucella agglutinins not detected; Mantoux test 1/100--negative: muscle biopsy findings are described under the heading of pathological features; chest X-ray showed elevation of the right diaphragm : eleclrocardiography was not performed ; nerve conduction studies performed in the left upper limb showed no abnormalities : an E M G performed on the right and left deltoid muscles showed a complete pattern with m~ny myopathic units. The patient was treated with prednisolone 20 mg t.d.s, but there was only a slight improvement after 4 weeks of therapy. After discharge from hospital the patient failed to attend for follow-up studies. MATERIALS AND METHODS Specimens were carefully excised under general anaesthesia from the left deltoid and left peroneus brevis muscles. Thin strips of the peroneus brevis muscle, from its origin to insertion, were injected immediately after excision with 0.015 ~u methylene blue solution (Boots Pure Drug Co. Ltd.) using a fine hypodermic needle. The injected strips of muscle were oxygenated for 1 hr and then placed in freshly filtered ice-cold 8 i'~, ammonium molybdate solution for 24 hr. After fixation, the specimens were thoroughly rinsed in distilled water and squash preparations were made by the technique of Dastur (1956). The resulting preparations were dehydrated in alcohol, cleared in xylol and mounted in Xam. Cryostat sections of deltoid muscle rapidly frozen in liquid nitrogen were used for enzyme histochemical studies. Sections were stained for phosphorylase using the method of Takeuchi and K uriaki (1955), and for lactic dehydrogenase using the method of Hess, Scarpelli and Pearse (1958). The remaining tissue was fixed in 10 ° / f o r m o l calcium. Part of this material was embedded in paraffin and part was kept for frozen section work. Paraffin sections were stained by the following methods; Weigert's haematoxylin and eosin ; a!cian blue; periodic acid-Schiff (PAS); Mallory's trichrome; phosphotungstic acid haematoxylin; methasol fast blue; haematoxylin and Van Gieson ; Von Kossa for calcium ; Gordon and Sweet's reticulin stain ; Zieht-Neetsen stain for tubercle bacilli; Gram; Gomori's methenamine silver stain for fungi. Longitudinal and transverse sections of formol calcium-fixed material were cut at 151~ on a freezing microtome. These frozen sections were stained with Sudan IV and Nile blue sulphate to demonstrate neutral fat and phospholipids. RESULTS
Muscle patholoyy Lej~ deltoid muscle. There is an apparent loss of muscle fibres with fatty infiltration and endomysial fibrosis. In the perimysium and endomysium there are several well-circumscribed nodular and fusiform collections of cells composed of histiOcytes, fibroblasts, epithelioid cells and multinucleated giant cells of the Langhan's variety (Fig. 1). The granulomas are separated from adjacent muscle fibres by thin zones of collagen or reticulin. In the outer region there are a few lymphocytes. Reticulin and collagen fibres interlace the granulomas in a network pattern (Fig. 2). There is no evidence of caseation and the cytoplasm o f many of the giant cells contains an acid mucopolysaccharide which stains strongly with alcian blue at p H 4.5. No Schaumann bodies or asteroid inclusions can be seen in the lesions and special stains fail to reveal the presence of acid-fast bacilli, other bacteria, fungi or parasites. Many of the epithelioid and giant cells contain occasional cytoplasmic granules measuring 1/~ or less in size. These granules which stain positively with PAS before and after treatment with diastase, also give a dark blue colour with Nile blue sulphate. The granules do not give a reaction with alcian blue, methenamine silver, Sudan IV or the Ziehl Neelsen stain. Several intramuscular arterioles show deposits of calcium in their walls. The vessels are otherwise unremarkable. There is atrophy of occasional muscle fibres in the vicinity of the granulomas but these fibres show
GRANULOMATOUS POLYMYOSITIS
3
Fig. 1. Left deltoid muscle showing details of granulomatous infiltrate. H.-E., x 100.
Fig. 2. Left deltoid muscle showing reticulin network in granulomatous infiltrate. Reticulin, x 200.
preservation of cross striations and no sarcoplasmic abnormalities. Muscle fibres remote from the lesions show no structural changes and no abnormal cellular infiltrates in the sarcoplasm. Enzyme histochemical studies utilising the phosphorylase and lactic dehydrogenase reactions reveal a characteristic chequerboard pattern of Type 1 and Type 2 fibres adjacent to and remote from the granulomas. Frozen sections of
4
P . G . LYNCH, D. V. BANSAL
Fig. 3. Left peroneus brevis muscle. Large spherical swelling oll axon of intramuscular nerve lihtc. Methylene blue 400.
Fig. 4. Left peroneus brevis muscle. Branching of subterminal axon with formation of three end-plates supplying different muscle fibres. Methylene blue, x 300.
GRANULOMATOUS POLYMYOSITIS
5
Fig. 5. Left peroneus brevis muscle. Ultraterminal sprouting from a single end-plate. Methylene blue, × 200.
muscle stained with Sudan IV and Nile blue sulphate show no increased a m o u n t s of intrasarcoplasmic lipid in both fibre types. Left peroneus brevis muscle. The light microscope appearances are similar to those described in the left deltoid muscle, but there is a more pronounced degree of endomysial fibrosis. The vitally stained methylene blue preparations reveal several changes. Many of the axons in the intramuscular nerve bundles carry one or more large, almost spherical swellings at points along their length (Fig. 3). Many subterminal axons well outside the granulomatous foci show evidence of collateral sprouting with one axon giving rise to three or more end-plates on different muscle fibres (Fig. 4). An occasional example of ultraterminal sprouting can be found (Fig. 5) and occasional end-plates show fusion of the terminal axonic expansions. Beaded axons can be seen in the intramuscular nerve bundles and amongst the subterminal axons.
DISCUSSION
The present case showed no clinical or radiological evidence of sarcoidosis, active tuberculosis, rheumatoid arthritis or cardiomyopathy. Laboratory investigations revealed no abnormalities of calcium metabolism. Serum electrophoresis showed slightly raised levels of ~2- and y-globulins. The ESR was not increased. The Kveim test was not performed because the patient was treated with steroids as soon as the muscle biopsy findings were available. Liver biopsy was negative. Analysis of cases in the literature (Devic et al. 1955 ;Ammitzboll 1956 ; Bammer 1958; Garcin and Lapresle 1958; McConkey 1958; Harvey 1959; Kryger and Ronnov-Jessen 1959; Erbsl6h and Dietel 1959; Nevin 1960; Brun 1961 ; Talbot 1967; Schimrigk and Uldall 1968; Co~rs and Carbone 1966; Crompton and MacDermott 1961; Lebacq 1964; Hinterbuchner and Hinterbuchner 1964; Castaigne, Cambier, Escourolle and Brunet 1965; Meyer
6
P, (i. [,YNCH, I). V. BANSAL
and Regli 1965) reveals that the Kveim test was only performed in the case described by Talbot (1967). In this instance, the test was reported as negative. Most of the recorded cases have presented with weakness and atrophy of the proxy mal limb muscles. Involvement of distal limb muscles was also a feature of the cases of Schimrigk and U ldall (19681 and of t of the cases of Meyer and Regli (1965J. I)ysphagia was noted in 4 cases. In the cases described by Schimrigk and Utdall (19681 and by C ~ r s and Carbone (1966), dysphagia was a presenting symptom. The facial muscles were involved in 2 patients and in one-third of the cases muscle pain preceded the onset of muscular weakness. Pseudohypertrophy of the calf muscles was noted in I of the cases described by Erbsl6h and Dietel (19591. Tendon reflexes were found to disappear with increasing severity of muscular atrophy. The clinical course ~s that of a chronic and progressive muscular disorder. Complete spontaneous remissions have not yet been recorded. Electromyography shows the picture of a myopathy with brief and polyphasic action potentials reduced in amplitude. In some instances (Bammer 1958: Hinterbuchner and Hinterbuchner 1964; Meyer and Regli 1965: CoiSrs and Carbone 1966) etectromyography has shown evidence of myopathic, myotonic and neurogenic processes. The light microscope appearances of the muscle biopsy specimens in the present case correspond with the description of "'muscle sarcoid" given by Adams. Denny-Brown and Pearson (1962b) and by Pearson and Rose (1961 ). The muscle changes were similar to those found in previously recorded cases. Earlier authors have. however, also described degenerative changes in the muscle fibres adjacent to and remote from the granulomatous loci (Crompton and MacDermott 1961 ; CoOrs and ('arbone 19661. The basic problem as to whether these muscle fibre changes are primary or secondary in origin remains to be resolved. Crompton and MacDermott (1961) go further and suggest that this condition may be a type of sarcoidosis occurring in muscles already affected by another disease process. The 3 cases studied in some detail by CoOrs and Carbone (1966) tend further support to this hypothesis. Regarding the histology of the lesions, care must be taken to distinguish between myogenous giant cells and multinucleated giant cells of the Langhans variety. Schaumann bodies and asteroid inclusion bodies are not a feature of the lesions and have only been described in the case of Erbsl6h and Dietel (1959). The absence of such bodies does not of course rule out the diagnosis of sarcoidosis for it should be noted that Langhans type giant cells without inclusions may be seen in scalene lymph nodes in some patients who develop sarcoidosis in association with bronchogenic carcinoma. There are few previous studies of the intramuscular nerve endings in granulomatous polymyositis. In 3 cases (Co&s 1962, 1965) there was evidence of denervation and reinnervation in the muscles examined. This was typified by collateral axonal branching with the formation of multiple motor end-plates. These changes were thought to be due to direct involvement of some of the intramuscular nerve fibres by the disease process. Non-specific changes were also seen remote from the granulomatous foci. These consisted of fine, ramifying beaded axons and abnormal variation in the size and shape of motor end-plates. Within the granulomatous loci there were irregular thickenings of subterminal axons and fusion of the terminal expansions. In the present case there was evidence of collateral axonal branching, beaded axons, degenerate
GRANULOMATOUS POLYMYOSITIS
7
motor end-plates and large spherical axonal swellings. All these changes were found outside the granulomatous foci. The significance of the large spherical axonal swellings is obscure. They occur in a variety of neuromuscular disorders and are seldom seen in muscles taken from patients less than 40 years of age. Woolf (1969) noted that the swellings occurred most frequently in the peroneus brevis muscle and thought that they were an age-dependent phenomenon affecting some of the longest neurones in the body. Another possible explanation is that the swellings are in some way related to repeated minor injuries to the legs with partial damage to the musculocutaneous nerve. Why the swellings are seldom found at any age in distal upper limb muscles is a mystery. In a personal study (unpublished) of the intramuscular nerves of the hand lumbrical muscles taken from patients over 40 years of age who were suffering from a variety of non-neurological and neurological diseases, argyrophilic axon swellings were seldom found. No previously published reports of the histochemical examination of muscle in granulomatous polymyositis can be found in the literature. Histochemical studies in the present case were incomplete and although there was preservation of Type 1 and Type 2 muscle fibres adjacent to and remote from the granulomatous foci, nothing was learned about the histochemical characteristics of those cells constituting the granulomas. Glycogen and lipid content was within the normal range for the two fibre types. Some doubt exists as to whether this and the previously reported cases are instances of isolated muscle sarcoidosis as distinct from affection of muscle by generalised sarcoidosis. Only complete post-mortem studies can establish for certain that the pathological changes are limited to the muscles as in the cases described by Nevin (1960). It is becoming widely recognised that sarcoidosis embraces several distinct disease entities which are united only in exciting a similar non-specific tissue reaction to their various antigens. Scadding (1950) suggested that sarcoidosis should be classified as far as possible on an aetiological basis and spoke, for example, of tuberculous sarcoidosis and beryllium sarcoidosis. Amongst other bacterial infections, brucellosis was cited as a cause of granulomatous lesions in a variety of tissues. Tuberculosis, berylliosis and brucellosis were excluded in the present case. It is quite probable that other, as yet undetermined, agents can elicit the sarcoid reaction. The aetiological agent in the present case remains to be determined. ACKNOWLEDGEMENTS
Our thanks are due to Professor W. B. Matthews and to Dr. Rhys T. Williams for supplying clinical details of the patient, to Professor P. O. Yates for his interest and advice, to Miss P. Farnworth and Mrs. C. Evans for typing the manuscript, to Mrs. G. M. Worsley for technical assistance and to Mr. G. Humberstone for preparing the photomicrographs. SUMMARY
An account is given of a pathological condition, more common in women, which presents clinically as a slowly progressive muscular disorder of adult life.
8
P . G . LYNCH, 1). V. BANSAL
The essential histological lesion is an infiltration of the connective tissue sheaths of voluntary muscle by non-specific granulomas composed of epithelioid cells, histiocytes, multinucleated giant cells and lymphocytes. The granulomas are non-caseating and show an outer zone of fibrosis and an inner fine reticulin network. Special stains have failed to detect bacterial, parasitic or fungal agents. Twenty-four cases of chronic granulomatous polymyositis have been previously reported in the literature. Post-mortem findings have, so far, been described in only 1 of these cases. The clinical, electromyographic and pathological findings in a further case are presented. Light-microscopic observations revealed granulomatous lesions in biopsy specimens of deltoid and peroneus brevis muscles. The cytoplasm of many of the multinucleated giant cells in the granulomas contained large amounts of acid mucopolysaccharide. Although there was atrophy of muscle fibres in the vicinity of the lesions, the structure of the fibres was preserved and there was no evidence of abnormal cellular infiltrates in the sarcoplasm. Muscle fibres remote from the lesions showed no abnormalities. The intramuscular nerves showed branching of the subterminal axons, beaded axons, occasional degenerate motor end-plates and large numbers of spherical axonal swellings in the intramuscular nerve bundles. Histochemical studies were incomplete, but there was an apparently normal distribution of glycogen, lipid, lactic dehydrogenase and phosphorylase activity in Type 1 and Type II fibres. Because of incomplete pathological data, the nosology of this condition, for the time being must remain uncertain. Some workers consider that it is a form of sarcoidosis restricted to voluntary muscle.
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