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Infantile polymyositis: A case report
Infantile Polymyositis: A Case Report Toshiro Nagai, MD, Tomonobu Hasegawa, MD, Masamine Saito, MD, Shuuhei Hayashi, MD and Ikuya Nonaka, MD
A 10-month-old Japanese boy developed progressive muscle weakness and hypotonia at 3 months of age. Because of striking inflammatory cellular infiltration in his muscle biopsy, he was diagnosed as having infantile polymyositis and was placed on steroid and immunosuppressive medication when he was 10-month-old. His physical condition was not significantly altered, though serum creatine kinase (CK) level was normalized (1,500 iu/l ~ 90 iu/l). These findings contrast with previous reports documenting improvement with steroid administration. Key words: Infantile polymyositis, congenital muscular dystrophy, nuclear change. Nagai T, Hasegawa T, Saito M, Hayashi S, Nonaka I. Infantile polymyositis: a case report. Brain Dev 1992;14: 167-9
Infantile polymyositis, an inflammatory myopathy manifesting with muscle weakness starting in infancy younger than 12 months of age, is a poorly defined muscle disorder with only a limited number of patients are described in the literature [1-5]. The affected infants may be diagnosed as having congenital muscular dystrophy if there is no definite inflammatory cellular infIltration in their biopsies because both diseases share similar clinical and morphological features. Carpenter et al [1] emphasized that responsiveness to corticosteroid and abnormal nuclei of muscle fibers were crucial findings for this disease. In this communication, we describe a Japanese boy with infantile polymyositis showing his muscle weakness from 3-month-old and no responsiveness to corticosteroid, 6mercaptopurine, or cyclosporine administration. CASE REPORT This male infant was born normally after 37 weeks' gestation as the 3rd child to a 33-year-old mother. Fetal movements were normal and Apgar score was 9 at 5 minutes. Birth weight was 2,690 gm and body length was 45 .6 cm.
From the Department of Neurology, Tokyo Metropolitan Kiyose Children's Hospital (TN, TH, SH); Department of Pediatrics, Keio University School of Medicine (TN, MS); and Division of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (TN, IN), Tokyo. Received for publication : November 6, 1991. Accepted for publication: March 5, 1992. Correspondence address: Dr. Toshiro Nagai, Department of Neurology, Tokyo Metropolitan Kiyose Children's Hospital, 1-3-1 Umezono, Kiyose, Tokyo 204, Japan.
Neither sucking nor swallowing difficulties were observed. He developed normally until 3 months of age when his gross motor development began to deteriorate. At 10 months of age, he was noticed to have high serum CK levels above 1,000 iu/l (normal, < 110) and was referred to our hospital for evaluation. On admission, he measured 74 cm (50th percentile) and weighed 7.9 kg (1 Oth percentile). His cognitive ability was considered as normal for age. Muscle weakness and atrophy were prominent in the neck, shoulders and proximal upper extremities. Muscle strength of hip and lower extremities were relatively well preserved. He could sit with support for a while, but could not hold his head straight up. Neither facial muscle involvement nor joint contracture was observed. Skin rash was not noted. All deep tendon reflexes were absent. Laboratory data were as follows: WBC 9,800/ul, ESR lO/hr, CRP 0 mg/dl, serum CK 1,487 iu/l, SGOT 103 iu/l (normal, <35), SGPT 68 iu/l (normal, <32), serum LDH 337 iu/l (normal, <380), and blood lactate 7.6 mg/dl (normal, < 11.6). Viral antibody titers, including influenza A, B, Coxsackie A and B were not elevated. Cranial CT was normal. EMG revealed brief-duration, small amplitude polyphasic motor units. In the biopsied biceps brachii muscle, there were numerous necrotic and regenerating ·fibers. Mononuclear cellular infIltration around small vessels was prominent (Fig 1). Atrophic fibers with pyknotic nuclear clumps were scattered throughout. No nuclear inclusions bodies were seen. The pathologic findings differed from fascicle to fascicle, ranging from almost normal to those showing severe involvement with numerous necrotic fibers. Dystrophin was stained normally in all fibers. On electron microscopy, in addition
to inflammatory mononuclear cellular infiltration around vessels, two of 20 fibers examined had pyknotic bizzare nuclei with marked nuclear membrane indentation, but with no filamentous or viral particle inclusions (Fig 2). This was compatible with infantile polymyositis. He was placed on oral prednisolone, 2 mg/kg/day, which normalized serum CK level in 5 months (1 ,500 ~ 90 iu/l). However, no clinical improvement occurred. Four months after corticosteroid treatment, it was gradually tapered off within 12 months. This resulted in increase of CK levels up to 440 iu/l and cyclosporine (8 mg/kg) administration was started, decreasing CK level down to 118 iu/l but with no clinical beneficial effect. This administration was off in 10 months. At the age of 6 years, he was mentally normal though severely delayed in motor development. He could not sit up from supine position by himself, raise his head in supine position, or move his arms against gravity. Muscle atrophy was still noticeable especially around the neck. There was no apparent facial muscle weakness or nasal voice. Serum CK levels remained within normal limits since 5 years of age when all medications were withdrawn.
Fig 1 In the muscle biopsy, there is a moderate fiber size varia-
tion with scattered necrotic and regenerating fibers. Striking inflammatory cellular infiltration around vessels is seen. Hematoxylin and eosin, x 500.
DISCUSSION There is little doubt that the present patient had infantile polymyositis from clinical and morphological features; muscle weakness and hypotOnia from 3 months of age with preferential neck muscle involvement commonly seen in this disorder [2,4] and moderate to severe inflammatory reaction with nuclear abnormality in his muscle biopsy. Although serum CK level was normalized after corticosteroid therapy, muscle strength remained unchanged even with subsequent supplementary administration of cyclosporine. Infantile polymyositis is a poorly defined clinical entity. It may be difficult to differentiate from congenital muscular dystrophy since both entities are likely to be heterogenous in etiology and share common clinical and morphological features such as delayed motor developmental milestones, high serum CK level, and muscle fiber necrosis and regeneration. Focal inflammatory cellular infiltration may be seen in muscle biopsies from patients with various muscular dystrophies, including Fukuyama type congenital muscular dystrophy (FCMD) [6-8], as a probable reactive response to fiber necrosis [9]. In FCMD, several abnormal findings on brain CT scan were known, such as periventricular hypodensity and lissencephaly [8, 10]. Although only rarely, there are a few cases of phenotypical FCMD in which dystrophin abnormality was demonstrated [11]. And another clues to make a diagnosis of infantile polymyositis is, therefore, to confirm evidence of an inflammatory process in their muscle biopsies. In the present patient, there were no
168 Brain & Development, Vol 14, No 3, 1992
Fig 2 On electron microscopy, bizzare nuclei with markedly indented nuclear membranes are recognized in some scattered fibers. The fibers with such abnormal nuclei have focal degenerated myofibrils (arrow), x 2,000.
findings suggesting Fukuyama type congenital muscular dystrophy. The lesion of inflammatory cellular infiltration was perivascular and the severity of inflammatory reaction was far more prominent than that of reactive response to muscle fiber degeneration, indicating an inflammatory process in muscle. Nuclear changes of filamentous, tubular or lamellar inclusions, excess dense chromatin, and protrusion of nucleoplasm in muscle fibers described by Carpenter et al may be merely supportive findings for polymyositis [1, 3] because they are commonly seen in inclusion body myositis [12]. Such nuclear changes, however, are not specific abnormalities to the inflammatory muscle diseases, because they are frequently seen in a hereditary myopathy with rimmed vacuole formation [13,14]. The nuclear
Table I Reported and present cases of infantile polymyositis Patient
Onset (months)
2 3 4 5 6
Prenatal 2 2 2 12 12
Our case
3
CK
After
Main symptoms
Outcome
Reference no
Normal
M
15 x 40 x 20-120 x 40x lOx 10 x
10 x
Hypotonia Hypotonia Proximal muscle weakness As above As above As above
SI improved Improved but PSL-dependent Slimproved Improved but PSL-dependent Not described Improved
(4) (4) (4) [i) (3) (3)
M
25 x
Normal
Neck muscle weakness
No improvement
Sex
Before
F M F M
8-40 x Normal
F: female, M: male, CK: serum creatine kinase level, Before: before therapy, After: after therapy, x: fold, PSL: prednisolone, SI: slight.
changes seen in the present patient are, therefore, not specific to a certain neuromuscular disease but can be seen in various neuromuscular disorders including even myotonic dystrophy [15]. Recently Shevell et al reported 3 patients who showed antenatal or neonatal muscle weakness and inflammatory reaction on biopsied muscle [16]. They were treated with steroid resulting in some motor improvement. The inflammatory changes in the muscle were commonly seen in both patients, but they were clinically distinct in the sense that the onset of symptoms was antenatal or neonatal in Shevell's patients whereas it was 3 months of age in our patient. Effectiveness of corticosteroid therapy is an additional supportive evidence of an inflammatory process in muscle [1-4] (Table 1). Serum CK reduction by steroid treatment has been observed with various inflammatory diseases including muscular dystrophy, but was not necessarily accompanied with clinical improvement [6,7]. In 3 patients with infantile polymyositis described by Thompson et aI, serum CK was easily normalized by steroid treatment with some clinical improvement, but their muscle strength did not show complete recovery [4]. Although the present patient had striking inflammatory cellular infiltration in his muscle biopsy, and serum CK level was normalized after steroid administration, there still remains a little possibility of congenital muscular dystrophy, because he had no other evidence of inflammatory process other than muscle pathology and no apparent clinical improvement to corticosteroid and immunosuppressant therapies. ACKNOWLEDGMENTS The authors would like to thank Dr. Nobutake Matsuo, Professor of Pediatrics, Keio University School of Medicine, for his critical reading of the manuscript.
REFERENCES 1. Carpenter S, Karpati G. Pathology of skeletal muscles. New York: Churchill Livingstone, 1984:581-90. 2. Thompson CEo Polymyositis in children. Qin Pediatr 1968; 7:24-8. 3. Carpenter S, Karpati G, Keene 0, Andermann F. Infantile inflammatory myopathy with sick myonuclei. Neurology 1979;29:613. 4. Thompson CEo Infantile polymyositis. Develop Med Child NeuroI1982;24:307-13. 5. Cape CA, Johnson WW, Pitner SE. Nema1ine structures in polymyositis. A nonspecific pathological reaction of skeletal muscles. Neurology 1970;2:494-502. 6. Olney RK, Miller RG. Inflammatory infIltration in Fukuyama type congenital muscular dystrophy. Muscle Nerve 1983;6:75-6. 7. Kinoshita M, Iwasaki Y, Wada F, Segawa M. A case of congenital polymyositis: a possible pathogenesis of Fukuyama type congenital muscular dystrophy (in Japanese). Rinsho Shinkeigaku (Tokyo) 1980;20:911-6. 8. Mori H, Oguni H, Osawa M, Suzuki H, Fukuyama Y. Fukuyama type congenital muscular dystrophy with unusual features (in Japanese) . No To Hattatsu (Tokyo) 1980;12: 544-53. 9. Dubowitz V. Muscle biopsy. A practical approach. 2nd ed. London: Bailliere Tindall, 1985. 10. Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of Fukuyama type - clinical, genetic and pathological consideration. Brain Dev (Tokyo) 1981 ;3: 1-29. 11. Arikawa E, Ishihara T, Nonaka I, et al. Immunocytochemical analysis of dystrophin in congenital muscular dystrophy. J Neurol Sci 1991 ;105: 79-87. 12. Carpenter S, Karpati G, Heller I, Eisen A. Inclusion body myositis: a distinct variety of idiopathic inflammatory myopathy. Neurology 1978;28:8-17. 13. Tome FMS, Fardeau M. Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuropathol 1980;49:85-7. 14. Mizusawa H, Kurisaki H, Takatsu M, et al. Rimmed vacuolar distal myopathy: an ultrastructural study. J Neurol 1987; 234: 137-45. 15. Tome FMS, Fardeau M. Nuclear changes in muscle disorders. Methods Achiev Exp Pathol 1986;12:261-96. 16. Shevell M, Rosenblatt B, Silver K, Carpenter S, Karpati G. Congenital inflammatory myopathy. Neurology 1990;40: 1111-4.
Nagai et al: Infantile polymyositis 169
A 10-month-old Japanese boy developed progressive muscle weakness and hypotonia at 3 months of age. Because of striking inflammatory cellular infiltration in his muscle biopsy, he was diagnosed as having infantile polymyositis and was placed on steroid and immunosuppressive medication when he was 10-month-old. His physical condition was not significantly altered, though serum creatine kinase (CK) level was normalized (1,500 iu/l ~ 90 iu/l). These findings contrast with previous reports documenting improvement with steroid administration. Key words: Infantile polymyositis, congenital muscular dystrophy, nuclear change. Nagai T, Hasegawa T, Saito M, Hayashi S, Nonaka I. Infantile polymyositis: a case report. Brain Dev 1992;14: 167-9
Infantile polymyositis, an inflammatory myopathy manifesting with muscle weakness starting in infancy younger than 12 months of age, is a poorly defined muscle disorder with only a limited number of patients are described in the literature [1-5]. The affected infants may be diagnosed as having congenital muscular dystrophy if there is no definite inflammatory cellular infIltration in their biopsies because both diseases share similar clinical and morphological features. Carpenter et al [1] emphasized that responsiveness to corticosteroid and abnormal nuclei of muscle fibers were crucial findings for this disease. In this communication, we describe a Japanese boy with infantile polymyositis showing his muscle weakness from 3-month-old and no responsiveness to corticosteroid, 6mercaptopurine, or cyclosporine administration. CASE REPORT This male infant was born normally after 37 weeks' gestation as the 3rd child to a 33-year-old mother. Fetal movements were normal and Apgar score was 9 at 5 minutes. Birth weight was 2,690 gm and body length was 45 .6 cm.
From the Department of Neurology, Tokyo Metropolitan Kiyose Children's Hospital (TN, TH, SH); Department of Pediatrics, Keio University School of Medicine (TN, MS); and Division of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (TN, IN), Tokyo. Received for publication : November 6, 1991. Accepted for publication: March 5, 1992. Correspondence address: Dr. Toshiro Nagai, Department of Neurology, Tokyo Metropolitan Kiyose Children's Hospital, 1-3-1 Umezono, Kiyose, Tokyo 204, Japan.
Neither sucking nor swallowing difficulties were observed. He developed normally until 3 months of age when his gross motor development began to deteriorate. At 10 months of age, he was noticed to have high serum CK levels above 1,000 iu/l (normal, < 110) and was referred to our hospital for evaluation. On admission, he measured 74 cm (50th percentile) and weighed 7.9 kg (1 Oth percentile). His cognitive ability was considered as normal for age. Muscle weakness and atrophy were prominent in the neck, shoulders and proximal upper extremities. Muscle strength of hip and lower extremities were relatively well preserved. He could sit with support for a while, but could not hold his head straight up. Neither facial muscle involvement nor joint contracture was observed. Skin rash was not noted. All deep tendon reflexes were absent. Laboratory data were as follows: WBC 9,800/ul, ESR lO/hr, CRP 0 mg/dl, serum CK 1,487 iu/l, SGOT 103 iu/l (normal, <35), SGPT 68 iu/l (normal, <32), serum LDH 337 iu/l (normal, <380), and blood lactate 7.6 mg/dl (normal, < 11.6). Viral antibody titers, including influenza A, B, Coxsackie A and B were not elevated. Cranial CT was normal. EMG revealed brief-duration, small amplitude polyphasic motor units. In the biopsied biceps brachii muscle, there were numerous necrotic and regenerating ·fibers. Mononuclear cellular infIltration around small vessels was prominent (Fig 1). Atrophic fibers with pyknotic nuclear clumps were scattered throughout. No nuclear inclusions bodies were seen. The pathologic findings differed from fascicle to fascicle, ranging from almost normal to those showing severe involvement with numerous necrotic fibers. Dystrophin was stained normally in all fibers. On electron microscopy, in addition
to inflammatory mononuclear cellular infiltration around vessels, two of 20 fibers examined had pyknotic bizzare nuclei with marked nuclear membrane indentation, but with no filamentous or viral particle inclusions (Fig 2). This was compatible with infantile polymyositis. He was placed on oral prednisolone, 2 mg/kg/day, which normalized serum CK level in 5 months (1 ,500 ~ 90 iu/l). However, no clinical improvement occurred. Four months after corticosteroid treatment, it was gradually tapered off within 12 months. This resulted in increase of CK levels up to 440 iu/l and cyclosporine (8 mg/kg) administration was started, decreasing CK level down to 118 iu/l but with no clinical beneficial effect. This administration was off in 10 months. At the age of 6 years, he was mentally normal though severely delayed in motor development. He could not sit up from supine position by himself, raise his head in supine position, or move his arms against gravity. Muscle atrophy was still noticeable especially around the neck. There was no apparent facial muscle weakness or nasal voice. Serum CK levels remained within normal limits since 5 years of age when all medications were withdrawn.
Fig 1 In the muscle biopsy, there is a moderate fiber size varia-
tion with scattered necrotic and regenerating fibers. Striking inflammatory cellular infiltration around vessels is seen. Hematoxylin and eosin, x 500.
DISCUSSION There is little doubt that the present patient had infantile polymyositis from clinical and morphological features; muscle weakness and hypotOnia from 3 months of age with preferential neck muscle involvement commonly seen in this disorder [2,4] and moderate to severe inflammatory reaction with nuclear abnormality in his muscle biopsy. Although serum CK level was normalized after corticosteroid therapy, muscle strength remained unchanged even with subsequent supplementary administration of cyclosporine. Infantile polymyositis is a poorly defined clinical entity. It may be difficult to differentiate from congenital muscular dystrophy since both entities are likely to be heterogenous in etiology and share common clinical and morphological features such as delayed motor developmental milestones, high serum CK level, and muscle fiber necrosis and regeneration. Focal inflammatory cellular infiltration may be seen in muscle biopsies from patients with various muscular dystrophies, including Fukuyama type congenital muscular dystrophy (FCMD) [6-8], as a probable reactive response to fiber necrosis [9]. In FCMD, several abnormal findings on brain CT scan were known, such as periventricular hypodensity and lissencephaly [8, 10]. Although only rarely, there are a few cases of phenotypical FCMD in which dystrophin abnormality was demonstrated [11]. And another clues to make a diagnosis of infantile polymyositis is, therefore, to confirm evidence of an inflammatory process in their muscle biopsies. In the present patient, there were no
168 Brain & Development, Vol 14, No 3, 1992
Fig 2 On electron microscopy, bizzare nuclei with markedly indented nuclear membranes are recognized in some scattered fibers. The fibers with such abnormal nuclei have focal degenerated myofibrils (arrow), x 2,000.
findings suggesting Fukuyama type congenital muscular dystrophy. The lesion of inflammatory cellular infiltration was perivascular and the severity of inflammatory reaction was far more prominent than that of reactive response to muscle fiber degeneration, indicating an inflammatory process in muscle. Nuclear changes of filamentous, tubular or lamellar inclusions, excess dense chromatin, and protrusion of nucleoplasm in muscle fibers described by Carpenter et al may be merely supportive findings for polymyositis [1, 3] because they are commonly seen in inclusion body myositis [12]. Such nuclear changes, however, are not specific abnormalities to the inflammatory muscle diseases, because they are frequently seen in a hereditary myopathy with rimmed vacuole formation [13,14]. The nuclear
Table I Reported and present cases of infantile polymyositis Patient
Onset (months)
2 3 4 5 6
Prenatal 2 2 2 12 12
Our case
3
CK
After
Main symptoms
Outcome
Reference no
Normal
M
15 x 40 x 20-120 x 40x lOx 10 x
10 x
Hypotonia Hypotonia Proximal muscle weakness As above As above As above
SI improved Improved but PSL-dependent Slimproved Improved but PSL-dependent Not described Improved
(4) (4) (4) [i) (3) (3)
M
25 x
Normal
Neck muscle weakness
No improvement
Sex
Before
F M F M
8-40 x Normal
F: female, M: male, CK: serum creatine kinase level, Before: before therapy, After: after therapy, x: fold, PSL: prednisolone, SI: slight.
changes seen in the present patient are, therefore, not specific to a certain neuromuscular disease but can be seen in various neuromuscular disorders including even myotonic dystrophy [15]. Recently Shevell et al reported 3 patients who showed antenatal or neonatal muscle weakness and inflammatory reaction on biopsied muscle [16]. They were treated with steroid resulting in some motor improvement. The inflammatory changes in the muscle were commonly seen in both patients, but they were clinically distinct in the sense that the onset of symptoms was antenatal or neonatal in Shevell's patients whereas it was 3 months of age in our patient. Effectiveness of corticosteroid therapy is an additional supportive evidence of an inflammatory process in muscle [1-4] (Table 1). Serum CK reduction by steroid treatment has been observed with various inflammatory diseases including muscular dystrophy, but was not necessarily accompanied with clinical improvement [6,7]. In 3 patients with infantile polymyositis described by Thompson et aI, serum CK was easily normalized by steroid treatment with some clinical improvement, but their muscle strength did not show complete recovery [4]. Although the present patient had striking inflammatory cellular infiltration in his muscle biopsy, and serum CK level was normalized after steroid administration, there still remains a little possibility of congenital muscular dystrophy, because he had no other evidence of inflammatory process other than muscle pathology and no apparent clinical improvement to corticosteroid and immunosuppressant therapies. ACKNOWLEDGMENTS The authors would like to thank Dr. Nobutake Matsuo, Professor of Pediatrics, Keio University School of Medicine, for his critical reading of the manuscript.
REFERENCES 1. Carpenter S, Karpati G. Pathology of skeletal muscles. New York: Churchill Livingstone, 1984:581-90. 2. Thompson CEo Polymyositis in children. Qin Pediatr 1968; 7:24-8. 3. Carpenter S, Karpati G, Keene 0, Andermann F. Infantile inflammatory myopathy with sick myonuclei. Neurology 1979;29:613. 4. Thompson CEo Infantile polymyositis. Develop Med Child NeuroI1982;24:307-13. 5. Cape CA, Johnson WW, Pitner SE. Nema1ine structures in polymyositis. A nonspecific pathological reaction of skeletal muscles. Neurology 1970;2:494-502. 6. Olney RK, Miller RG. Inflammatory infIltration in Fukuyama type congenital muscular dystrophy. Muscle Nerve 1983;6:75-6. 7. Kinoshita M, Iwasaki Y, Wada F, Segawa M. A case of congenital polymyositis: a possible pathogenesis of Fukuyama type congenital muscular dystrophy (in Japanese). Rinsho Shinkeigaku (Tokyo) 1980;20:911-6. 8. Mori H, Oguni H, Osawa M, Suzuki H, Fukuyama Y. Fukuyama type congenital muscular dystrophy with unusual features (in Japanese) . No To Hattatsu (Tokyo) 1980;12: 544-53. 9. Dubowitz V. Muscle biopsy. A practical approach. 2nd ed. London: Bailliere Tindall, 1985. 10. Fukuyama Y, Osawa M, Suzuki H. Congenital progressive muscular dystrophy of Fukuyama type - clinical, genetic and pathological consideration. Brain Dev (Tokyo) 1981 ;3: 1-29. 11. Arikawa E, Ishihara T, Nonaka I, et al. Immunocytochemical analysis of dystrophin in congenital muscular dystrophy. J Neurol Sci 1991 ;105: 79-87. 12. Carpenter S, Karpati G, Heller I, Eisen A. Inclusion body myositis: a distinct variety of idiopathic inflammatory myopathy. Neurology 1978;28:8-17. 13. Tome FMS, Fardeau M. Nuclear inclusions in oculopharyngeal dystrophy. Acta Neuropathol 1980;49:85-7. 14. Mizusawa H, Kurisaki H, Takatsu M, et al. Rimmed vacuolar distal myopathy: an ultrastructural study. J Neurol 1987; 234: 137-45. 15. Tome FMS, Fardeau M. Nuclear changes in muscle disorders. Methods Achiev Exp Pathol 1986;12:261-96. 16. Shevell M, Rosenblatt B, Silver K, Carpenter S, Karpati G. Congenital inflammatory myopathy. Neurology 1990;40: 1111-4.
Nagai et al: Infantile polymyositis 169