We report a man with an acute myalgidcramp syndrome and tubular aggregates on his muscle biopsy. He was placed on prednisone and was found to be exquisitely sensitive to the drug, with changes of only 5 mg precipitating recurrence of symptoms. He was eventually tapered off all steroids, without symptoms, and repeat biopsy showed no tubular aggregates. We recommend similar patients be given a trial of high-dose steroids. Key words: tubular aggregates myopathy steroid-response myalgias sarcoplasmic reticulum MUSCLE & NERVE 14:233-236 1991
STEROID=RESPONSIVE TUBULAR AGGREGATE MYOPATHY JAMES M. GILCHRIST, MD, MARY AMBLER, MD, and PAUL AGATIELLO, MD
Tubular aggregates are uncommon but not rare findings on muscle biopsy. 'w' They are distinctive in structure but nonspecific in occurrence, being present in a wide variety of disorders, but most commonly in the periodic paralyses.' Four syndromes have been described with tubular aggregates as the distinguishing feature: a myasthenic ~ y n d r o m e , ' ~ an autosomal dominant myopathy withI8 or without pain,20223 an autosoma1 recessive m y ~ p a t h y ,and ~ a myalgia/cramp syndrome.~--".~O,~ 1,14,16,17,21,25 We report a patient with the latter syndrome whose disease was remarkably sensitive to prednisone. CASE REPORT
The patient was a 57-year-old male firefighter in good health except for mild hypertension until mid-June 1987, when he developed soreness of his hips and shoulders. This progressed over 2 weeks such that every movement hurt and he was unable to do such tasks as comb his hair, climb stairs, or get out of chairs. When first seen in late July 1987, his muscle exam was limited by pain with mild if any proximal weakness. He was begun on prednisone 60 mg per day for a presumptive
diagnosis of polymyositis. Four days later an EMG was normal and 1 day post-EMG a right quadriceps muscle biopsy was obtained (see Pathology section and Fig. 1). His CPK, aldolase, SMA-20 and sedimentation rate were all normal. The patient had a dramatic improvement and within 5 days of starting the prednisone had virtually no pain. Three weeks after starting treatment he was begun on a tapering regime (Fig. 2) but when he reached 60 mg every other day, he had a recrudescence of his symptoms. His pain rapidly abated when his prednisone was changed back to every day, 40 mg alternating with 20 mg. He again had an exacerbation when his prednisone was dropped from 30 mg alternating with 20 mg to 20 mg every day, which resolved upon resumption of the higher dose. Slower tapering over several months was well tolerated, though he had another worsening of his myalgias when he dropped from 10 mg alternating with 5 mg to 5 mg every day. Eventually, 16 months after starting prednisone, it was discontinued and the patient remained without symptoms and with a normal exam. A left quadriceps muscle biopsy was done 4 months after cessation of steroids (see Pathology, Fig. 3). PATHOLOGY
From the Departments of Neurology, Pathology, and Internal Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island. Address reprint requests to Dr James Gilchrist, 110 Lockwood Street, Providence, RI 02903. Accepted February 8, 1990
CCC 0148-639X/91/030233-04
$04.00
0 1991 John Wiley & Sons, Inc.
Steroid-Responsive Tubular Aggregate Myopathy
Biopsy # 1 (8/3/87): Cross-sectional fibers showed minor variation in size with angular, atrophic fibers and occasional central nuclei. There was no fiber necrosis. Mosaic fiber typing was preserved. The modified trichrome and the NADH stains revealed superficial and central purple compact de-
MUSCLE & NERVE
March 1991
233
FIGURE 1. Biopsy #1 (813187). (A) Abnormally large and dense subsarcolemmal and interfibrillary deposits are in the pale, presumptive type II, muscle cells. NADH stain, original magnification ( x 250). (B) Electron photomicrograph. A perinuclear collection of closely packed cross and obliquely sectioned tubules is (C) separated from the underlying normal myofibrils (~9,220). Electron photomicrograph. At higher magnification the aggregates of tubules demonstrate predominantly double walls with variable electron density in the inner lumina (~70,150).
234
Steroid-Responsive Tubular Aggregate Myopathy
MUSCLE & NERVE
March 1991
70
5 6(r 0
1
0
n
30
5
YES
-
2
n
FIGURE 2. Patient's pain as a response to changes in prednisone dose over time.
posits most prominent in type 2 fibers (Fig. 1A). The deposits were not detected by H&E, PAS, OilRed 0, or ATPase stains. Electron microscopy demonstrated tubular aggregates in either parallel or chaotic orientation. (Fig. lB) In cross-section the tubules were closely packed and most often double-lumened (Fig. 1C). Dilated membrane-
FIGURE 3. Biopsy #2 (3/17/89). A diffuse reticular pattern of enzyme is seen in both the light and dark fibers. NADH stain (original magnification ~ 2 5 0 ) .
Steroid-Responsive Tubular Aggregate Myopathy
bound vacuoles containing diffuse granular material of moderate electron density were sometimes trapped within the aggregates. Normal triads with minimally enlarged terminal cisternae were also noted both adjacent to the tubular aggregates and in unaffected fibers. The cell membranes overlying subsarcolemma tubular aggregates were generally maintained. Intramuscular nerves and myoneural junctions were normal. Biopsy #2 (3117189): Scattered atrophy with nuclear knots and foci of endomysial fibrosis were noted with light microscopy. N o cytoplasmic inclusions were identified by trichrome or NADH stains (Fig. 3 ) . Fiber typing demonstrated a normal pattern. Electron microscopy revealed perinuclear glycogen deposits and a mild increase in lipid droplets as suggested by PAS and Oil-Red 0 stains, respectively. The triads, terimnal sacs, and sarcoplasmic reticulum were normal and no tubular aggregates were identified by electron microsCOPY. DISCUSSION
Myopathy with tubular aggregates has been seen in inherited and s oradic cases of pain and cramp syndromes~-6,1()- 14.16- 18,y 1,25 but has not been
g,
shown to respond to medication prior to our report. No treatment was mentioned in a number of reports,:3-5, 1 1,14,16,17,2 125 but in the autosoinal dominantly inherited cases reported by PierobonBormioli et al.," acetazolamide was of no benefit in 2 patients. Lazaro et al.'" tried muscle relaxants, corticosteroids, phenytoin, carbamazepine, and probenecid and allopurinol with no improvement in their patient's symptoms. It is possible that our patient represents a different disorder with a similar pathologic finding but this is unlikely given the similarity of his symptoms, signs, and muscle biopsy. The dose or type of steroids given to the patient of Lazaro, et a1.I' was not reported and given the exquisite sensitivity of our patient, where a change of 5 mg would cause exacerbation, it is possible the dosage of corticosteroid was not high enough. Tubular aggregates are currently felt to derive from sarcoplasmic r e t i c u ~ u m . " Salviati, ~~ et a1." found that tubular aggregates, in muscle from an autosomal dominantly inherited myopathy, accumulated calcium oxalate. They concluded that tubular aggregates were equivalent to hypertrophied sarcoplasmic reticulum and theorized that tubular aggregates may be a reactive rather than degenerative change in response to increased calcium influx to prevent calcium accumulation lead-
MUSCLE & NERVE
March 1991
235
ing to irreversible contraction and myonecrosis. Why prednisone would cause such a dramatic improvement is not clear. Polymyalgia rheurnatica is another disorder characterized by myalgias, sensitive to even low doses of steroids, but those patients invariably have elevated sedimentation rates and do not have muscle biopsy abnormalities.2 The cause of polymyalgia rheumatica is not known. Other disorders with pain and/or cramping are associated with disorders of the sarcoplasmic reticulum, ie, Brody’s syndrome* and verapamil-responsive myalgia syndrome^."^^ The patient’s rapid improvement precluded a trial of calcium-channel blockers. Unlike the patients with Brody’s syndrome, he never had abnormal relaxation of his muscles, even when his symptoms were in exacerbation. Both Brody’s syndrome
and the verapamil-responsive myalgias appear to be related to deficiencies in sarcoplasmic reticulum Ca2f-ATPase,8r26 an enzyme which controls reuptake of Ca2+ into the sarcoplasmic reticulum. Prednisone is a drug with wide-ranging effects in multiple organ systems and is of benefit in some diseases for unknown reasons, eg, Duchenne muscular dystrophy.13 Hypothetical reasons why prednisone may have benefited our patient include membrane ~tabilization,~~ enzymatic modulation, l 3 changes in substrate availability, and an effect on nuclear genetic regulation. l9 This report suggests that any patient with muscle pain or cramps associated with tubular aggregates of muscle should be given a trial of high-dose corticosteroids.
REFERENCES
1. Banker BQ: The congenital myopathies, in Engel AG, Banker BQ (eds): Myology. New York, McGraw-Hill, 1986, vol. 2, pp 1554- 1555. 2. Banker BQ: Other inflammatory myopathies, in Engel A
STEROID=RESPONSIVE TUBULAR AGGREGATE MYOPATHY JAMES M. GILCHRIST, MD, MARY AMBLER, MD, and PAUL AGATIELLO, MD
Tubular aggregates are uncommon but not rare findings on muscle biopsy. 'w' They are distinctive in structure but nonspecific in occurrence, being present in a wide variety of disorders, but most commonly in the periodic paralyses.' Four syndromes have been described with tubular aggregates as the distinguishing feature: a myasthenic ~ y n d r o m e , ' ~ an autosomal dominant myopathy withI8 or without pain,20223 an autosoma1 recessive m y ~ p a t h y ,and ~ a myalgia/cramp syndrome.~--".~O,~ 1,14,16,17,21,25 We report a patient with the latter syndrome whose disease was remarkably sensitive to prednisone. CASE REPORT
The patient was a 57-year-old male firefighter in good health except for mild hypertension until mid-June 1987, when he developed soreness of his hips and shoulders. This progressed over 2 weeks such that every movement hurt and he was unable to do such tasks as comb his hair, climb stairs, or get out of chairs. When first seen in late July 1987, his muscle exam was limited by pain with mild if any proximal weakness. He was begun on prednisone 60 mg per day for a presumptive
diagnosis of polymyositis. Four days later an EMG was normal and 1 day post-EMG a right quadriceps muscle biopsy was obtained (see Pathology section and Fig. 1). His CPK, aldolase, SMA-20 and sedimentation rate were all normal. The patient had a dramatic improvement and within 5 days of starting the prednisone had virtually no pain. Three weeks after starting treatment he was begun on a tapering regime (Fig. 2) but when he reached 60 mg every other day, he had a recrudescence of his symptoms. His pain rapidly abated when his prednisone was changed back to every day, 40 mg alternating with 20 mg. He again had an exacerbation when his prednisone was dropped from 30 mg alternating with 20 mg to 20 mg every day, which resolved upon resumption of the higher dose. Slower tapering over several months was well tolerated, though he had another worsening of his myalgias when he dropped from 10 mg alternating with 5 mg to 5 mg every day. Eventually, 16 months after starting prednisone, it was discontinued and the patient remained without symptoms and with a normal exam. A left quadriceps muscle biopsy was done 4 months after cessation of steroids (see Pathology, Fig. 3). PATHOLOGY
From the Departments of Neurology, Pathology, and Internal Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island. Address reprint requests to Dr James Gilchrist, 110 Lockwood Street, Providence, RI 02903. Accepted February 8, 1990
CCC 0148-639X/91/030233-04
$04.00
0 1991 John Wiley & Sons, Inc.
Steroid-Responsive Tubular Aggregate Myopathy
Biopsy # 1 (8/3/87): Cross-sectional fibers showed minor variation in size with angular, atrophic fibers and occasional central nuclei. There was no fiber necrosis. Mosaic fiber typing was preserved. The modified trichrome and the NADH stains revealed superficial and central purple compact de-
MUSCLE & NERVE
March 1991
233
FIGURE 1. Biopsy #1 (813187). (A) Abnormally large and dense subsarcolemmal and interfibrillary deposits are in the pale, presumptive type II, muscle cells. NADH stain, original magnification ( x 250). (B) Electron photomicrograph. A perinuclear collection of closely packed cross and obliquely sectioned tubules is (C) separated from the underlying normal myofibrils (~9,220). Electron photomicrograph. At higher magnification the aggregates of tubules demonstrate predominantly double walls with variable electron density in the inner lumina (~70,150).
234
Steroid-Responsive Tubular Aggregate Myopathy
MUSCLE & NERVE
March 1991
70
5 6(r 0
1
0
n
30
5
YES
-
2
n
FIGURE 2. Patient's pain as a response to changes in prednisone dose over time.
posits most prominent in type 2 fibers (Fig. 1A). The deposits were not detected by H&E, PAS, OilRed 0, or ATPase stains. Electron microscopy demonstrated tubular aggregates in either parallel or chaotic orientation. (Fig. lB) In cross-section the tubules were closely packed and most often double-lumened (Fig. 1C). Dilated membrane-
FIGURE 3. Biopsy #2 (3/17/89). A diffuse reticular pattern of enzyme is seen in both the light and dark fibers. NADH stain (original magnification ~ 2 5 0 ) .
Steroid-Responsive Tubular Aggregate Myopathy
bound vacuoles containing diffuse granular material of moderate electron density were sometimes trapped within the aggregates. Normal triads with minimally enlarged terminal cisternae were also noted both adjacent to the tubular aggregates and in unaffected fibers. The cell membranes overlying subsarcolemma tubular aggregates were generally maintained. Intramuscular nerves and myoneural junctions were normal. Biopsy #2 (3117189): Scattered atrophy with nuclear knots and foci of endomysial fibrosis were noted with light microscopy. N o cytoplasmic inclusions were identified by trichrome or NADH stains (Fig. 3 ) . Fiber typing demonstrated a normal pattern. Electron microscopy revealed perinuclear glycogen deposits and a mild increase in lipid droplets as suggested by PAS and Oil-Red 0 stains, respectively. The triads, terimnal sacs, and sarcoplasmic reticulum were normal and no tubular aggregates were identified by electron microsCOPY. DISCUSSION
Myopathy with tubular aggregates has been seen in inherited and s oradic cases of pain and cramp syndromes~-6,1()- 14.16- 18,y 1,25 but has not been
g,
shown to respond to medication prior to our report. No treatment was mentioned in a number of reports,:3-5, 1 1,14,16,17,2 125 but in the autosoinal dominantly inherited cases reported by PierobonBormioli et al.," acetazolamide was of no benefit in 2 patients. Lazaro et al.'" tried muscle relaxants, corticosteroids, phenytoin, carbamazepine, and probenecid and allopurinol with no improvement in their patient's symptoms. It is possible that our patient represents a different disorder with a similar pathologic finding but this is unlikely given the similarity of his symptoms, signs, and muscle biopsy. The dose or type of steroids given to the patient of Lazaro, et a1.I' was not reported and given the exquisite sensitivity of our patient, where a change of 5 mg would cause exacerbation, it is possible the dosage of corticosteroid was not high enough. Tubular aggregates are currently felt to derive from sarcoplasmic r e t i c u ~ u m . " Salviati, ~~ et a1." found that tubular aggregates, in muscle from an autosomal dominantly inherited myopathy, accumulated calcium oxalate. They concluded that tubular aggregates were equivalent to hypertrophied sarcoplasmic reticulum and theorized that tubular aggregates may be a reactive rather than degenerative change in response to increased calcium influx to prevent calcium accumulation lead-
MUSCLE & NERVE
March 1991
235
ing to irreversible contraction and myonecrosis. Why prednisone would cause such a dramatic improvement is not clear. Polymyalgia rheurnatica is another disorder characterized by myalgias, sensitive to even low doses of steroids, but those patients invariably have elevated sedimentation rates and do not have muscle biopsy abnormalities.2 The cause of polymyalgia rheumatica is not known. Other disorders with pain and/or cramping are associated with disorders of the sarcoplasmic reticulum, ie, Brody’s syndrome* and verapamil-responsive myalgia syndrome^."^^ The patient’s rapid improvement precluded a trial of calcium-channel blockers. Unlike the patients with Brody’s syndrome, he never had abnormal relaxation of his muscles, even when his symptoms were in exacerbation. Both Brody’s syndrome
and the verapamil-responsive myalgias appear to be related to deficiencies in sarcoplasmic reticulum Ca2f-ATPase,8r26 an enzyme which controls reuptake of Ca2+ into the sarcoplasmic reticulum. Prednisone is a drug with wide-ranging effects in multiple organ systems and is of benefit in some diseases for unknown reasons, eg, Duchenne muscular dystrophy.13 Hypothetical reasons why prednisone may have benefited our patient include membrane ~tabilization,~~ enzymatic modulation, l 3 changes in substrate availability, and an effect on nuclear genetic regulation. l9 This report suggests that any patient with muscle pain or cramps associated with tubular aggregates of muscle should be given a trial of high-dose corticosteroids.
REFERENCES
1. Banker BQ: The congenital myopathies, in Engel AG, Banker BQ (eds): Myology. New York, McGraw-Hill, 1986, vol. 2, pp 1554- 1555. 2. Banker BQ: Other inflammatory myopathies, in Engel A
