ARTHRITIS ROUNDS Vacuolar Myopathy in a Patient with Positive LE Cell Preparations By DYRC F. SIBRANSAND HOWARD L. HOLLEY R we have had the opportunity to study a patient with progressive muscle weakness and positive lupus erythematosus cell preparations. A muscle biopsy was obtained which showed a vacuolar myopathy. This was a sufficiently rare finding to warrant further investigation. Pearsonl first described such a relationship in 1958. Microscopic muscle lesions are observed not uncommonly in systemic lupus erythematosus (SLE). Several different types of changes are noted, none of which are felt to be specific for SLE. The types previously classified as myopathy of SLE are: (1) interstitial polymyositis, very similar to that seen in rheumatoid arthritis and acute rheumatic fever; (2) acute hyaline necrosis or waxy degeneration of parts of single muscle fibers, a frequent finding in biopsies from patients with polymyositis; ( 3 ) a focal arteritis or vasculitis; ( 4 ) fibrinoid changes in the connective tissue surrounding muscle.2 A review of the subject of vacuolar myopathy was undertaken to evaluate the possibility that the above mentioned finding might be specific for SLE. ECENTLY CASEREPORT H. G., a 29 year old white female, was admitted to the University Hospital on April 20, 1965, complaining of profound muscle weaknesg From the Division of Rheumatic Diseases, Departnient of Medicine, University of Alabama Medical Center, Birmingham, Alabama. DYRCF. SIBRANS,M.D.: Assistant Resident in Medicine. HOWARDL. HOLLEY.M.D.: Professor of Medicine and Director, Division of Rheumatology. This inoestigation was supported by Public Health Service Grant T1 AM 5000 from the of the extremities and associated difficulty in swallowing. She had been in good health until the summer of 1962, when she noted a pigmented maciilar rash on the malar eminences which spread rapidly to the chin, neck, and anterior chest. The rash persisted throughout the summer and faded spontaneously during the following winter months. At that time her only other complaint was persistent nausea. I n January, 1963, she became lethargic and noted the onset of an insidious bnt progressive muscular weakness. The muscle weakness was initially confined to the arms but iater appeared also in the legs. Her hair began to thin and an erythematous macular rash developed in a butterfly distribution over her face. She denied any joint symptoms, pleurisy, easy bruisibility, or urinary symptoms. The muscle weakness progressed, and two months later she could no longer elevate her arms above her head and dress herself. She was hospitalized elsewhere and on the basis of repeated positive L.E. cell preparations a diagnosis of SLE was made and a daily dose of 40 mg. prednisone was inrtituted.* She was subseqnently maintained on a daily dose of 10 mg. prednisone. The muscle weakness was only moderatelv improved, but she was able to return to work. In December 1964 the patient experienced an acute exacerbation of muscle weakness which was again accompanied by a facial skin rash. The prednisone was increased to a daily dose of 30 mg. with improvement in the rash, but the muscle weakness persisted. At that time she complained of difficulty and pain on swallowing. There was no weight loss. National Institute of Arthritis and Metabolic Diseases and Merck Sharp and Dohme, West Point, Pennsylvania. *Several of these L.E. cell preparations were re-examined in the Division of Rheumatic Disease Laboratory, University of Alabama Medical Center, Birmingham, Alabama. 141 142 SIBRANS A h D HOLLE1 Fig. l.-Biopsy of deltoid muscle. Skeletal muscle fibers c u t in cross section and obliquely. The vacuoles vary in size and number. In some of the muscle cells they have replaced sarcoplasm almost completely. The sarcolemmal nuclei tend to be central in location and are not increased in number. Inflammatory cellular infiltration is not present. (Hematoxylin Eosin) ( x 880). The patient became progressively weaker and was confined to bed for the three weeks prior to admission. Physical Examination: On admission there appeared a chronically ill cushingoid young woman with a weak voice, butterfly rash over her face, with obvious generalized muscle weakness. She had prominent striae of the breasts, abdomen, hips, and thighs. The vital signs were B.P. 140/90, pulse 76, resp., 16, temperature 98 F. There was no lymphadenopathy or hepatosplenomegaly. The lung fields were clear. A grade II/VI systolic ejection murmur was heard in the pulmonic area. There was no apparent muscle atrophy and muscle tone appeared normal, but marked weakness of flexors and extensors of arms, legs, and trunk was observed. The cranial nerves were intact. The biceps, triceps, patellar, and Achilles deep tendon reflexes were absent bilaterally. No sensory disturbances were noted. Laboratory Work: Hct. 41, WBC 7,000, segs. 74. Iynphs. 12, monos. 9, eosim;. 5, platelets adequate. Corrected sedimentation rate was 42 ( Wintrobe). Urinalysis revealed 4 white blood cells and 5 red blood cells per high power field and 3-t acetone, but negative for sugar and protein. Serum chemistries included Na 135. K 3.9. C1 100, CO, 26 mEq/L., total protein 6.85 Gm., albumin 2.97, alpha-1 0.32, alpha-2 0.70, beta 1.45, gamma 1.41 Gm. per cent; LE cell preparations negative x3; anti-nuclear factor negative; AS0 titer-250 Todd units; P B 1 4 . 8 pg per cent; and a stool guaiac test was positive. The serum creatine phosphokinase was 1.3 units (normal values 0.3 to 3 units), while the BSP, creatinine clearance, blood glucose, BUN, bleeding and clotting times, VDRL, and urinary coproporphyrins and uroporphyrins were normal. The SGOT was 35, 29, 43, and 25 units. The normal values for SGOT in this laboratory are 5 to 25 units. After admission the patient was given 40 mg. of prednisone daily. Potassium chloride was added to the regimen dne to the initial finding of .I 143 VACUOLAR MYOPATHY Fig. B.--Skeletal muscle fibers c u t longitudinally. Note spotty distribution of t h e vacuolar change. No increase in adipose or fibrous connective tissue is noted. (Hematoxylin Eosin) ( X 880). low serum potassium. and a peptic ulcer regimen was begun. The patient was initially considered to be suffering from polymyositis. A therapeutic trial of neostigmine failed to improve muscle strength. A biopsy was obtained from the deltoid muscle. Microscopic examination revealed considerable vacuolization of groups of muscle cells (Figs. 1, 2 ) . Decrease in size and loss of fine architectural detail was noted in the affected cells. The vacuoles varied markedly in size. In some cells, multiple small vacuoles imparted a honeycomb appearance. In other muscle cells, large vacuoles appeared to replace most of the sarcoplasm. The sarcolemmal nuclei tended to be central in location, and in a few instances were within vacuoles. These nuclei appeared prominent and reactive, but were not increased in number. Muscle weakness continued and the Prednisone dosage was increased to 60 mg. daily. An electromyogram (EMG) was performed. Localized areas of irritability of muscle were demonstrated. These were characterized by a decrease in amplitude of motor unit potentials after voluntary contractures. At rest, fibrillation potentials were present in tested areas of muscle. Conduction velocity in the ulnar nerve was normal. On the 15th hospital day the patient had an acute gastrointestinal hemorrhage which was treated with whole blood transfusions and nazogastric suction. An emergency upper GI series was reported as normal. Because of the hemorrhage the prednisone dosage was gradually reduced. She was given depo-testosterone in an attempt to establish a positive nitrogen balance after discovery of the vacuolar myopathy. The patient went home on the 37th hospital day with little or no improvement in muscle strength. She was discharged on a daily dose of 20 mg. Prednisone, together with supplemental potassium salts. A recent follow-up examination on 10/24/66 revealed improvement. Her muscle strength has increased gradually and she has been able to resume most of her household chores. The patient still fatigues easily; she has been taking 10 mg. prednisone daily. The follow-up laboratory work revealed a negative LE cell preparation, negative antinuclear antibody; the SCOT was normal; the hematocrit was 34 and the corrected sedimentation rate (Wintrohe) was 30 mni. 144 EIBRAXS A S D HOLLEI. frequently in the past two years. The musDISCUSSION A review of the literature revealed that cle wasting and weakness appear to be nine cases of vacuolar myopathy have been reversible, however, and improvement bereported associated with systemic lupus gins within a short time after withdrawal erythematosus. These have been based on of the drug. The toxicity appears to be the microscopic criteria initially described dose and time related. Unfortunately, few by Pearson and Yamazaki in their original muscle histologic studies have been carried case rep0rt.l Their patient had a pruritic out to confirm the clinical observations. skin rash, fatigue, and generalized malaise. EMG studies performed on patients with LE preparations were originally negative, chloroquine myopathy have been interbut later became positive. Muscle weak- preted as consistent with a myopathy or ness was not demonstrated. Markedly ele- a neuropathy. Whisnant’ has shown in his review of vated SGOTs prompted a muscle biopsy. chloroquine neuromyopathy that a vacuoThey described the plump, swollen, sarlar myopathy may develop after prolonged colemmal nuclei with prominent nuclei or high dosage of the drug. It is difficult, more centrally located in the muscle fiber if not impossible, to differentiate clinically and often found within a vacuole. They and histologically these changes from the felt that this finding differentiated the vacuolar myopathy reported by Pearson vacuolar myopathy associated with SLE occurring in SLE. from other types of vacuolar myopathy. A myopathy occurring during steroid Pearson suggests that the vacuolar myopathy of SLE is a diffuse disease which therapy has been recognized for some time may occur with or without muscle weakness and there have been frequent reports in or serum enzyme changes3 Three addi- the literature. Clinically, this is evident in tional cases have been described, and primary Cushing’s disease with marked the histologic lesion is now considered proximal muscle weakness and wasting. In the iatrogenic form, however, the ocspecific for vacuolar myopathy in SLE.4 Vacuolar myopathy has been reported currence of myopathy does not appear to to occur with hypokalemia, periodic pa- be dose-related. Apparently the majority of ralysis, thyrotoxic myopathy, polymyositis, the patients have had symptoms of muscle dermatomyositis, muscle damage after weakness within three weeks of initiation burns or secondary to ischemia, and in of therapy. Several cases of vacuolar myoppatients under treatment with steroids and athy have been reported occurring during chloroquine. The vacuolar myopathy seen steroid therapy,lozll especially triamcinoduring steroid and chloroquine therapy, lone.12l4 However, apparently all of the however, has almost invariably been asso- 17-hydroxycorticosteroids are capable of ciated with muscle wasting and accom- producing this phenomenon.15-17 Again, panied in some cases with mildly elevated the muscle weakness and wasting appears SGOT’s. Documented incidences of myop- to begin in the proximal muscles of the athy secondary to chloroquine have only legs. Perkoff et a1.,l5 in a review of myoprecently been reported, but isolated cases athy associated with steroid5, stated that the most consistent histologic feature was of muscle weakness have been noted.5 Muscle weakness and atrophy confined the presence of large empty vacuoles and primarily to the extensors of the proximal an increase in the number of sarcolemmal muscles of the lower extremities during nuclei. No mention was made of their shape chloroquine therapy have been reported or position in the muscle fiber. This myop- 145 VACUOLAR MYOPATHY Table 1.-Review of Case Reports of Vacuolar Myopathy Occurring in Patients with Systemic Lupus Erythematosus Number of Cases - Pearsonl 1 Positive LE Preps Yes Muscle Weakness Priorto Therapy No Duration of Therapy Prior to Biopsies Steroids Chloroquine Decreased Muscle Weakness on Therapy 3-4 Weeks 0 Yes Decreased Muscle Weakness when Therapy Stopped or Changed ( Prednisone) No information given Pearson? 3 Humphrey22 1 Yes No Lang24 1 Yes No 5 Years ( Prednisone) ( Celestonen ) Jagerl9 1 No Yes (4mo.) 5 Days (Decadron' ) 12-16 mg. 5 Yrs. (500 mg. ) No Yes (On Prednisone) (Chloroquine stopped ) 5 Yrs. (dose not given) NO Yes (Both drugs stopped) Prednisone started 0 Died Died Levy20 1 No Yes 0 0 Yes (on Prednisone) Erbsloe21 1 No Yes 0 0 Yes (on Prednisone) Sibrans 1 Yes Yes ( 3 mo.) 0 Transiently initially "Decadron - 2.5 Years (Prednisone) 15-60 mg. No Dexamethasone, Merck Sharp & Ilohme. athy appears to be reversible when the steroid is discontinued or in some instances when the type of steroid is changed. EMG studies performed on patients with Cushings disease and on patients being treated with steroids have shown the characteristic pattern of a primary myopathy.1°J7Js Both steroids and chloroquine have been used in the treatment of SLE, as well as other diseases from which the majority of the information on their myopathic-producing qualities has been obtained. It would seem safe to assume that a similarity between the vacuolar myopathy associated with SLE and that of other vacuolar myopathies does exist and must be considered in the evaluation of the specificity of this muscular lesion in SLE. A review of the reported cases (Table 1) shows that only three19-21had a history of muscle weakness prior to treatment with steroids and/or chloroquine, However, steroids had been given to Jager's patient before the muscle biopsy was taken. Humphrey's22 patient had had 500 mg. chloroquine per day for three years before the onset of muscle weakness and wasting and five years before biopsy. The muscle biopsy showed a vacuolar myopathy indistinguishable from that described by Pearson. In a review of the same case with electron microscopic studies the possibiIity of chloroquine toxicity was raised.23Langs patient ? ( had had both steroid, prednisone 146 SIBRANS A N D HOLLEY initially, then Celestone,* and chloroquine treatment for 4 years prior to the onset of muscle weakness and 5 years prior to biopsy. When steroids were decreased and chloroquine was discontinued, the patient had almost complete return of previous muscle strength. Jager’s patient revealed a profound muscle weakness, rapidly progressive over a four-month period, and was preceded by a facial rash. The muscle weakness involved even the respiratory inuscles. No L.E. cell preparations were obtained. This patient was on steroid therapy for about five days prior to the muscle biopsy. Histologically, the vacuolization was found to be severe and involved every muscle biopsied, including cardiac muscle. The diagnosis of SLE was made on history of rash and fever, the presence of leukopenia and thrombopenia, and the autopsy findings of “onion skin” lesions in splenic arterioles and “wire loop” changes in the renal glomeruli. Pearson’s patient had no evidence of muscle weakness but did have clinical and ECG evidence of carditis. The patient had been taking prednisone for only 3-4 weeks prior to the muscle biopsy. A facial rash and progressive muscle weakness had begun ten months prior to the time a diagnosis of SLE was made. He was started on prednisone in large doses with initial improvement in general status but the muscle weakness continued. It appears, therefore, that the etiology of vacuolar myopathy found in SLE is still in a state of limbo, and Pearson, himself, describes it as a “bizarre manifestation of a multisystem disease, or, indeed, as a result of our treatment of the disease.” Denny Brownz5 feels that the plump, sarcolemmal nuclei are a manifestation of a regeneration of muscle fibers or a reactive change to chronic inflammation. He classifies vacuolar myopathy as a chronic progressive polymyositis. The apparent ability of steroids and chloroquine to produce a myopathy with vacuolization clouds the issue considerably. The lack of evidence of vacuolization of muscle in SLE before the institution of these modes of therapy is an argument in favor of an iatrogenic production of this phenomenon. Yet the history of profound muscle weakness before steroid therapy in some cases cannot be ignored. The possibility that this is another of the overlap syndrome between SLE and polymyositis must also be considered. The elucidation of the specificity of this lesion for SLE remains in doubt, particularly since a strikingly similar lesion can be produced by drugs frequently used in the treatment of this disease; more work is needed on the mode of action of chloroquine and steroids on muscles as well as on the muscle changes in untreated SLE. It is only from such studies that the true nature of the vacuolar myopathy will bc determined. ACKNOWLEDGMENT We wish to thank Dr. L. H. Robinson, Professor of Pathology, Department of Pathology, Universit! of Alabama Medical Center, for reviewing the microscopic material presented in this paper, and Dr. Ellis Sparks, Huntsville, Alabama, for hi\ help in obtaining a followup examination of thk patient. *Celestone - betamethasone, Schering Corp. SUMMARY A case report is presented of a patient with muscle weakness, positive LE cell preparations and a diffuse vacuolar myopathy. A review of the causes of vacuolar myopathy is given, with special emphasis an chloroquine and corticosteroids, since these two drugs are frequently used in the therapy of systemic lupus erythematosus (SLE). Our patient, together with other reported cases, is discussed in terms of whether this myopathy is due to the disease process or is secondar!- to therapy. 147 VACUOLAR MYOPATHY SUMMARIO IN INTERLINGUA Es reportate le caso de un patiente con asthenia muscular, positive preparatos d e cellulas LE, e un diffuse myopathia vacuolar. Es presentate un revista del causas de myopathia vacuolar, con referentias special a chloroquina e le corticosteroides, viste que iste duo pharmacos es usate frequentemente in le therapia de disseminate lupus erythematose. Le caso de nostre patinte-insimul con alteres a b le litteraturaes commentate in relation a1 question de si iste myopathia es un effect0 del process0 morbide o un disveloppamento secundnri a1 the rapia. REFERENCES 1. Pearson, C. XI., and Yamazaki, J. N.: Vacuolar myopathy in systemic lupus erythematosus. Am. J. Clin. Path. 29:455, 1958. 2. Adams, R. D., Denny-Brown, D., and Pearson, C. Xf.: Disease of Muscle; A Study in Pathology, ed. 2. New York, Harper and Row, 1962, p. 444. 3 . Pearson, C. M.: Personal Communication. 4. Adams, R. D., Eaton, L. M., and Shy, G. M. (Eds.): Neuromuscular Disorders. Association for Research in Nervous and Mental Diseases. Proceedings. 38:472, 1960. 5. Begg, T. B., and Simpson J. A.: Chloroquine neuromyopathy. Brit. Med. J. 1:770, 1964. 6. Editorial: Chloroquine neuromyopathy. Brit. Med. J. 1:452, 1964. 7. Whisnant, J. P., et al.: Chloroquine neuromyopathy. Proc. Mayo Clin. 38:501, 1963. 8. Loftus, L. R.: Peripheral neuropathy following chloroquine therapy. Canad. M. A. J. 89:917, 1963. 9. Blom, S., and Lundberg, P. 0.: Reversible myopathy in chloroquine treatment. Acta Med. Scand. 177:685,1965. 10. Golding, D. N., and Begg, T. B.: Dexamethasone myopathy. Brit. Med. J. 2:1129, 1960. 11. Harman, J. B.: Muscular wasting and corticosteroid therapy. Lancet i:887, 1959. 12. Williams, R. S.: Triamcinolone myopathy. Lancet i:698, 1959. 13. Strandberg, B.: The frequency of myopathy in patients with rheumatoid arthritis treated with triamcinolone. Acta Rheum. Scand. 8:31, 1962. 14. MacLean, K., and Schurr, P. H.: Reversible amyotrophy complicating treatment with fludrocortisone.Lancet i:701, 1959. 15. Perkoff, G. T., et al.: Studies in disorders of muscle. XII. Myopathy due to the administration of therapeutic amounts of 17hydrocorticosteroids. Amer. J. Med. 26:891, 1959. 16. Barbhaiya, H. C.: Steroids and myopathy. Lancet i:1161, 1964. 17. Hagstrom, J. W. C., et al.: Debilitating muscular weakness and steroid therapy. Arch. Neurol. 5530, 1961. 18. Muller, R., and Kugelberg, E.: Myopathy in Cushing’s sydnrome. J. Neurol., Neurosurg., Psychiat. 22:314, 1959. 19. Jager, w. A., and B&t, S. &I.: Vacuolar myopathy. Psychiat. Neurol. h’eurochir. 67: 469, 1964. 20. Levy, J, A.: Miopathia vacuolar de lupus erithematoso. Arq. Neuropsiquiat. 20:142, 1962. 21. Erbsloe, F., and Baedecker, W. D.: Lupus Myopathie, eine klinische, elektromyographische und bioptisch-histoloquische Studie. Deutsch. Med. Wschr. 87:2464, 1962. 22. Humphrey, J. G., and Rewcastle, N. B.: Vacuolar myopathy. A clinical and electron microscopic study. Trans. Amer. Neurol. A. 88:225, 1963. 23. Rewcastle, N. B., and Humphrey, J. G.: Vacuolar myopathy. Arch. Neurol. 12:570, 1965. 24. Lang, P, A., et al.: Vacuolar myopathy in lupus erythematosus. J.A.M.A. 191:49, 1965. 25. Denny-Brown, D.: The nature of polymyositis and related muscular diseases. Tr. Coll. Physicians 28:14, 1960. Discussion THE STATUS OF “vacuolar myopathy” as clinical entity, or indeed even as a clinical syndrome, is still considerably in doubt, as has been alluded to by Drs. Sibrans and Holley. In fact, the finding of ;L significant vacuolation in striated muscle is usually an unexpected histopathologic curiosity and often engenders reevaluation of the patient’s clinical status from various available approaches, inchding careful 14s tabulation of the therapeutic menu, past and present, and estimation of muscular strength, serum enzyme measurements, EMGs and almost invariably at least a clinical pathological conference or, as in the present instance, a case report. Thus, even up to the present time it is a pathologic oddity of uncertain heritage and perhaps dubious specificity, unless more refined tools such as electron microscopy and intrafibcr or even intravacuole electrical potential recordings can eventually be brought to bear on the nature of, or differentiation between, the various causes of muscle fiber vacuolation. When I first reported a case of diffuse vacuolation of striated muscle in a young (age 15) male with unequivocal SLE, only 3 to 4 weeks of prednisone therapy and no antimalarial treatment whatsoever, it struck all of us as a most peculiar finding since there was no demonstrable muscular weakness (none has developed in the subsequent 8 years) and the biopsy was taken from the sternocleidomastoid muscle only incidental to a cervical lymph node biopsy. The elevated serum enzymes had been previously explained as a consequence of an extremely active ‘‘lupus’’ myocarditis, although in retrospect the latter may have been only one contributor to these laboratory abnormalities. Several months after prednisone therapy had been given to this boy, nearly all clinical features of SLE subsided and the serum enzymes had returned to normal; yet a repeat biopsy of the same muscle again showed vacuolation, although only about 20 per cent as extensive as had been noted before. Sitbsequently we have done a rather random sampling of one or more striated muscles in 20 persons with acute or subacute SLli and have noted the following: ( a ) rare (nonspecific) fiber degeneration and interstitial myositis (inflammatory infiltrates) in 10 patients ( 8 taking pred- SIBRASS A S D HOLLEY nisone and 2 of the 8 also taking hydroxychloroquine); ( b ) no changes in 3 patients (all taking prednisone); ( c ) 7 persons with minor or significant muscle fiber vacuolation ( 3 taking prednisone alone, 1 in addition on hydroxychloroquine and 1 from nnother hospital on triamcinolone and Iargc doses of a combination of 3 antimalarials chloroquine, atabrine and camoquine). Thus, although this lesion usually is found, by therapeutic necessity, in SLE with steroid treatment, it need not be so since two persons had no such treatment of any sort (aside from aspirin, which to my knowledge, does not produce these lesions) prior to positive muscle biopsy. We have been impressed in the muscle biopsies that we have studied, that the vacuolar lesions are: ( a ) variable in extent and degree, sometimes being focal and scanty and on other occasions appearing to be widespread and quite extensive in individual fibers; ( b ) almost always accompanicd by “alert” or prominent sarcolemma1 nuclei, usually in the confines of the vacuoles as though some type of nuclear activity or perinuclear reaction was responsible for the initiation and perpetuation of the individual lesion; ( c ) that the histologic vacuolar lesions are not correlatable in any meaningful way with serum enzyme levels or the rough clinical measurements of strength; and ( d ) that antecedent corticosteroid or antimalarial therapy need not have been givcn for development of the vacuolar lesions, although there is no denying that either or both drugs may have intensified a preexisting fiber vacuolation. The vacuolar lesions in one moderately weakened patient (who had also been on massive daily doses of antimalarials) also contained large collections of an unidentified pigmentary material, possibly pyknotic nuclear debris. In the case under discussion I am moderately perplexed about two features which DISCUSSION I have not previously encountered in any of my positive cases, namely ( a ) the absence of LE cells or antinuclear factors, at least one of which was always found in my patients at the time of biopsy, and ( b ) the relative lack of nuclear plumpness or “activation,” at least in the illustrations as shown. As mentioned by Dr. Sibrans and Holley, vacuolation of muscle can be found in a number of conditions in addition to drug (steroid and antimalarial) intake. The most common conditions in which this is found are periodic paralyses of long duration (either hypokalemic or hyperkalemic’ 2, and polymyositis.3 In the latter, the vacuolation is only one element of a spectrum of pathologic changes, but the vacuolation with nuclear prominence resembles that seen in the lesion in lupus. In periodic paralysis, the vacuoles may reach huge dimensions and thus actually compress the adjacent muscle sarcoplasm and myofibrils. However, the muscle nuclei are atrophic, pyknotic and not especially associated with the vacuoles, thus separating this vacuolar lesion from that noted in lupus. By what process or processes does vacuolation occur in muscle? As noted a few years ago, all striated muscle fibers possess an elaborate network of ultramicroscopic canals or channels4 These are called the sarcotubular system and this system is usually separated into three components: ( a ) the transverse tubular system, ( b ) the triads or clusters of 3 tubules adjacent to the Z-disc, and ( c ) the longitudinal tubular system which courses between myofibrils. The membranes of some of these canals apparently are metabolically active and conduct electrical or action potentials into the fiber substance from the outer membrane of the fiber, whereas others seem to have the ability to reversibly chelate and release calcium, thus affecting contraction or relaxation of the contractile protei? actqmyosin and perhaps other contractile pro- 141) teins. The channels contain water, some eleotrolytes and perhaps variable solutes. One would envision that various disease states could disrupt the delicate balance which is normally maintained by these membranes, thus leading to accumulation of a watery mixture of electrolytes, other solutes and glycogen. Moreover, since the perinuclear region is especially rich in tubular structures, these could be maximally affected in SLE, possibly by the localization of “antinuclear” antibodies in these zones with consequent disruptive changes leading to vacuolization. There are other possible explanations for vacuolization in muscle, including ( a ) excessive release of hydrolytic lysosomal enzymes, ( b ) degeneration of sarcoplasm and myofibrils due to unknown primary factors, and ( c ) others. Careful electron microscopic assessment of the early as well as the more fully developed lesions in SLE will tend to clarify which of these factors is most prevalent. Preliminary evidence suggests that it is the sarcotubular system which is principally affected in nearly all of the previously mentioned conditions, and the same would also apply to certain druginduced vacuolar lesions. In summary the following points can be made: (1) Vacuolar myopathy in SLE is not especially rare but its actual incidence has not been systematically surveyed. ( 2 ) Clinically evident muscular weakness need not be prominent or even present at all and is not correlatable (at least within certain limits) with the degree of vacuolation. ( 3 ) The lesion can be found in SLE whether or not certain “vacuole-inducing” drugs are given. ( 4 ) The level of serum enzymes is not a good guide to the presence or absence of vacuoles. ( 5 ) The muscle fiber lesion is diffuse and relatively nonspecific, except if the vacuoles contain within their confines large plump sarcolemma1 nuclei; then the associated cIinicaI disease is most IikeIy to be SLE, or less com- 150 SIBHAKS A N D IIOLLEY monly polymyositis. ( 6 ) The actual vacuolar lesion seems to be brought about by an inbibition of water and solutes within the intramuscular tubular systems from an as vet uncertain cause. CARLM. PEARSON, M.D. Los Angeles, Calif. REFERENCES I . Pearsori. C. M.: The periodic paralyses: Differential features and pathological observations in permanent myopathic weakness. Brain 87:341, 1964. 2. Howes. E. L., Price, H. M., Pearson, C. M.. Hlumberg, J . M.: Hypokalemic periodic paralyses; electron microscopic changes in sarcoplasni. Neurolcgy 16:242, 1966. 3. Denny-Brown, D.: The nature of polymyositis and related muscular diseases. Trans. Coll. Physicians 28:14, 1960. 4. Porter, K. R.: The sarcoplasinic reticulum. Its recent history and present status. J. Biophys. Biochem. Cytol. 10:219, 1961. Dr. Pearson’s excellent discussion reemphasizes the importance of a more definitive study of muscle in SLE, indeed in the whole spectrum of rheumatic diseases. Obviously “vacnolar myopathy” is a much more common lesion than has been previously appreciated. It is only through such a study that a more meaningful explanation of these muscle fiber changes can be made. HOWARD L. HOLLEY,,M.D.