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An unusual pathologic feature associated with dermatomyositis
Neuromuscular Disorders 16 (2006) 391–393 www.elsevier.com/locate/nmd
Case report
An unusual pathologic feature associated with dermatomyositis Jacinda B. Sampson a,*, Steven S. Chin c, Frederic C. Clayton c, Alan Pestronk e, Kathryn J. Swoboda a,b, Kevin M. Flanigan a,b,c,d a
Department of Neurology, University of Utah, Salt Lake City, UT, USA Department of Pediatrics, University of Utah, Salt Lake City, UT, USA c Department of Pathology, University of Utah, Salt Lake City, UT, USA d Department of Human Genetics, University of Utah, Salt Lake City, UT, USA e Department of Neurology, Washington University, St Louis, MO, USA b
Received 31 October 2005; received in revised form 14 March 2006; accepted 16 March 2006
Abstract We present a case of juvenile dermatomyositis with unusual histopathologic findings. The child presented with a course consistent with dermatomyositis, a diagnosis confirmed by finding reticulotubular aggregates in endothelial cells on electron microscopy. However, histopathology of his muscle biopsy revealed a striking pattern of glycogen accumulation, to an extent similar to that seen in glycogen storage diseases; this degree of accumulation could potentially confound histopathologic diagnosis. q 2006 Elsevier B.V. All rights reserved. Keywords: Anasarca; Myositis; Pediatric dermatomyositis; Reticulotubular aggregates; Glycogen
1. Introduction
2. Case report
Juvenile dermatomyositis is an inflammatory process affecting the small vessels of the skin and muscle. The characteristic skin finding is a heliotrope rash, which can precede the muscle weakness, and be ephemeral, subtle, or absent [1]. Prior to the era of steroid treatment, juvenile dermatomyositis was reported as following an acute, chronic, or polycyclic course, and at times had spontaneous recovery, but was often fatal [2]. Diagnosis is typically confirmed by muscle biopsy, and the most sensitive early pathologic feature is an ultrastructural one—reticulotubular aggregates in endothelial cells, detectable early in the course of disease [3]. However, a perifascicular pattern of myofiber atrophy, readily detectable on histopathology, is considered diagnostic, particularly in association with the presence of complement deposition on vessel walls [4].
The patient, a 41⁄2 year old boy, complained of sore throat, headache, fatigue, muscle pain, and weakness. He had been tripping easily, and had difficulty with stairs, standing up from the floor, and raising his arms. His parents noted swelling of his muscles and puffiness of his face and limbs. This progressively worsened over 2 weeks. At age 2, the patient had had a similar episode of weakness and swelling; his parents recall having to hold him in a seated position to bathe him. His mother noticed dryness of his knuckles and darkening of his joints. The weakness lasted 1 month, and was attributed to a viral infection. He recovered fully, and his motor developmental milestones were normal, and review of systems was otherwise unremarkable. Family history was unremarkable. His general exam was notable for excoriations of his forearms due to itching. His neurologic exam was notable for hyporeflexia and generalized weakness. There was tightness of his hamstrings and Achilles tendons. His creatine kinase was 1065 U/L (upper limits of normal: 298 U/L). Alanine aminotransferase was elevated to three times the upper limits of normal, and aspartate aminotransferase was elevated to two times the upper limits of normal,
* Corresponding author. Tel.: C1 801 585 5885; fax: C1 801 581 4192. E-mail address: [email protected] (J.B. Sampson).
0960-8966/$ - see front matter q 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2006.03.013
392
J.B. Sampson et al. / Neuromuscular Disorders 16 (2006) 391–393
but alkaline phosphatase, albumin, and bilirubin were normal. He was anemic with a hematocrit of 31. Renal function was normal. Antinuclear antibody, rheumatoid factor, and thyroid stimulating hormone testing were normal. His electrocardiogram showed sinus rhythm with premature atrial complexes and left axis deviation. He underwent sedated electromyography (EMG) testing, which showed decreased amplitude of peroneal motor nerve response, but normal latency and velocity. Sural sensory responses were normal. Needle EMG showed abnormal insertional activity, fibrillations and sharp waves in both proximal and distal limb muscles. Voluntary motor units were polyphasic. Magnetic resonance imaging of his lower extremities showed diffuse, heterogeneous increased T2 signal in all muscle groups without gadolinium enhancement. A muscle biopsy of the rectus femoris was performed. No necrosis or inflammatory infiltrates were seen. The most striking finding consisted of prominent vacuoles stainable by periodic acid-Schiff (PAS) in myofibers in a perifascicular distribution (see Fig. 1). Diastase digestion
eliminated PAS staining of the vacuolar material. No accumulation of PAS was seen in any other cell types or location. Acid phosphatase staining was unremarkable, showing that the glycogen was not lysosomal. Myophosphorylase staining was normal. Immunostaining for complement membrane attack complex (C5b-9) was positive on capillary endothelium (see Fig. 1), particularly in perifascicular regions. Staining for MHC class I demonstrated upregulation on all myofibers, with a tendency for more staining of cytoplasm in small muscle fibers in perifascicular regions. In addition to confirming the accumulation of non-membrane bound glycogen, electron microscopy demonstrated reticulotubular aggregates in capillary endothelial cells.
3. Discussion Dermatomyositis typically presents with muscle weakness and pain in association with a rash, which is characteristically found in the periorbital region, over the
Fig. 1. Histology of the rectus femorus muscle biopsy. Hematoxylin and eosin staining shows vacuolar changes in the regions of perifascicular atrophy (A: scaleZ50 mm). Periodic acid-Schiff staining shows the vacuoles contain PAS-positive material (B: scaleZ50 mm), which was digested by diastase treatment (not shown). Electron microscopy demonstrated non-membrane bound, homogeneous granular material in the inclusions consistent with glycogen in the subsarcolemmar region of muscle cells (C: scaleZ1 mm) and reticulotubular aggregates (arrow) adjacent to the nuclear membrane in endothelial cells (D: scaleZ1 mm).
J.B. Sampson et al. / Neuromuscular Disorders 16 (2006) 391–393
extensor surfaces of the joints, or over the anterior neck and chest. Anasarca can occur, and is thought to be an indicator of severity [5]. In the case we report, the edema and the characteristic rash were transitory. Consistent with the diagnosis, the patient’s muscle strength improved following treatment with steroids and methotrexate, and 6 months later was back to normal strength. Our patient reported a prior episode of weakness and edema, for which medical care was not sought. Such a prior episode is unusual, although a relapsing/remitting course of dermatomyositis in the absence of steroid treatment has been reported [2]. Complement membrane attack complexes (C5b-9) are seen in the vessels of both juvenile and adult dermatomyositis. The presence of the C5b-9 is thought to be secondary to loss of CD59, which is constitutively present on endothelial cells and prevents assembly of the C5b-9 [4]. Complement membrane attack complexes localized to the muscle fibers, however, are not specific to dermatomyositis or inflammatory myopathies in general. In fact, C5b-9 has been found on non-necrotic fibers in facioscapulohumeral and limb-girdle muscular dystrophies [6]. Electron microscopy detected reticulotubular aggregates in endothelial cells in a perinuclear distribution. Reticulotubular aggregates are associated with autoimmune diseases, viral infections including human immunodeficiency virus, interferon treatment, and dermatomyositis [3]. In this case, the reticulotubular aggregates supported the diagnosis of dermatomyositis. Perifascicular atrophy and glycogen accumulation can be seen in the myopathy associated with scleromyxedema, as can rare C5b-9-positive fibers [6]. While our patient had pruritis, which is common in scleromyxedema, he did not have the nodular skin changes seen in that disorder. Our patient was lost to followup, and did not undergo skin biopsy, nor was he tested for monoclonal gammopathy, which is frequently associated with scleromyxedema. However, previous reports of electron microscopy of muscle biopsies from scleromyxedema patients [7] have not described any vascular endothelial cell changes characteristic of dermatomyositis, as found in our patient. The striking feature of our case is the prominence of PAS staining in perifascicular fibers. Small glycogen accumulations have been reported as a pathological feature of dermatomyositis [8], but the inclusions are typically few and usually noted only upon electron microscopy, and the total amount of glycogen in the muscle is unchanged [9]. Glycogen accumulations appearing like picorna-virus inclusions have rarely been reported in polymyositis [10]. In our case, clinically and ultrastructurally consistent with dermatomyositis, PAS staining was unusually prominent, to a degree that suggested to us a glycogen storage disease. However, since acid phosphatase staining was not increased, and the glycogen was not membrane bound, we
393
concluded that this was not acid maltase deficiency or lysosome-associated membrane protein-2 deficiency (LAMP-2 deficiency, or Danon disease) [11]. His relapsing/remitting course, response to therapy, and otherwise normal motor milestones also argued against a glycogen storage disease. The glycogen was found in a perifascicular distribution atypical for a glycogen storage disease but typical for the atrophy associated with childhood dermatomyositis. We have since seen rare large glycogen accumulations in another case of pediatric dermatomyositis (data not shown), but not to the degree seen in this case. The diagnosis of dermatomyositis should be considered in cases where the predominant feature on muscle biopsy shows marked glycogen accumulation in a perifascicular distribution atypical for glycogen storage disease.
Acknowledgements We thank Dr Andrew Engel for edifying discussions.
References [1] van der Meulen MF, Bronner IM, Hoogendijk JE, et al. Polymyositis: an overdiagnosed entity. Neurology 2003;61(3): 316–21. [2] Bitnum S, Daeschner Jr CW, Travis LB, Dodge WF, Hopps HC. Dermatomyositis. J Pediatr 1964;64:101–31. [3] De Visser M, Emslie-Smith AM, Engel AG. Early ultrastructural alterations in adult dermatomyositis. Capillary abnormalities precede other structural changes in muscle. J Neurol Sci 1989;94(1–3): 181–92. [4] Goncalves FG, Chimelli L, Sallum AM, Marie SK, Kiss MH, Ferriani VP. Immunohistological analysis of CD59 and membrane attack complex of complement in muscle in juvenile dermatomyositis. J Rheumatol 2002;29(6):1301–7. [5] Mitchell JP, Dennis GJ, Rider LG. Juvenile dermatomyositis presenting with anasarca: a possible indicator of severe disease activity. J Pediatr 2001;138(6):942–5. [6] Spuler S, Engel AG. Unexpected sarcolemmal complement membrane attack complex deposits on nonnecrotic muscle fibers in muscular dystrophies. Neurology 1998;50(1):41–6. [7] Verity MA, Toop J, McAdam LP, Pearson CM. Scleromyxedema myopathy. Histochemical and electron microscopic observations. Am J Clin Pathol 1978;69(4):446–51. [8] Engel AG, Hohlfeld R. The polymyositis and dermatomyositis syndromes. In: Engel AG, Franzini-Armstrong C, editors. Myology. 3rd ed. New York: McGraw-Hill, Medical Publishing Division; 2004. p. 1321–67. [9] Hess JW. Phosphorylase activity and glycogen, glucose-6-phosphate, and lactic acid content of human skeletal muscle in various myopathies. J Lab Clin Med 1965;66(3):452–63. [10] Katsuragi S, Miyayama H, Takeuchi T. Picornavirus-like inclusions in polymyositis—aggregation of glycogen particles of the same size. Neurology 1981;31(11):1476–80. [11] Sugie K, Yamamoto A, Murayama K, Oh SJ, Takahashi M, Mora M, et al. Clinicopathological features of genetically confirmed Danon disease. Neurology 2002;58(12):1773–8.
Case report
An unusual pathologic feature associated with dermatomyositis Jacinda B. Sampson a,*, Steven S. Chin c, Frederic C. Clayton c, Alan Pestronk e, Kathryn J. Swoboda a,b, Kevin M. Flanigan a,b,c,d a
Department of Neurology, University of Utah, Salt Lake City, UT, USA Department of Pediatrics, University of Utah, Salt Lake City, UT, USA c Department of Pathology, University of Utah, Salt Lake City, UT, USA d Department of Human Genetics, University of Utah, Salt Lake City, UT, USA e Department of Neurology, Washington University, St Louis, MO, USA b
Received 31 October 2005; received in revised form 14 March 2006; accepted 16 March 2006
Abstract We present a case of juvenile dermatomyositis with unusual histopathologic findings. The child presented with a course consistent with dermatomyositis, a diagnosis confirmed by finding reticulotubular aggregates in endothelial cells on electron microscopy. However, histopathology of his muscle biopsy revealed a striking pattern of glycogen accumulation, to an extent similar to that seen in glycogen storage diseases; this degree of accumulation could potentially confound histopathologic diagnosis. q 2006 Elsevier B.V. All rights reserved. Keywords: Anasarca; Myositis; Pediatric dermatomyositis; Reticulotubular aggregates; Glycogen
1. Introduction
2. Case report
Juvenile dermatomyositis is an inflammatory process affecting the small vessels of the skin and muscle. The characteristic skin finding is a heliotrope rash, which can precede the muscle weakness, and be ephemeral, subtle, or absent [1]. Prior to the era of steroid treatment, juvenile dermatomyositis was reported as following an acute, chronic, or polycyclic course, and at times had spontaneous recovery, but was often fatal [2]. Diagnosis is typically confirmed by muscle biopsy, and the most sensitive early pathologic feature is an ultrastructural one—reticulotubular aggregates in endothelial cells, detectable early in the course of disease [3]. However, a perifascicular pattern of myofiber atrophy, readily detectable on histopathology, is considered diagnostic, particularly in association with the presence of complement deposition on vessel walls [4].
The patient, a 41⁄2 year old boy, complained of sore throat, headache, fatigue, muscle pain, and weakness. He had been tripping easily, and had difficulty with stairs, standing up from the floor, and raising his arms. His parents noted swelling of his muscles and puffiness of his face and limbs. This progressively worsened over 2 weeks. At age 2, the patient had had a similar episode of weakness and swelling; his parents recall having to hold him in a seated position to bathe him. His mother noticed dryness of his knuckles and darkening of his joints. The weakness lasted 1 month, and was attributed to a viral infection. He recovered fully, and his motor developmental milestones were normal, and review of systems was otherwise unremarkable. Family history was unremarkable. His general exam was notable for excoriations of his forearms due to itching. His neurologic exam was notable for hyporeflexia and generalized weakness. There was tightness of his hamstrings and Achilles tendons. His creatine kinase was 1065 U/L (upper limits of normal: 298 U/L). Alanine aminotransferase was elevated to three times the upper limits of normal, and aspartate aminotransferase was elevated to two times the upper limits of normal,
* Corresponding author. Tel.: C1 801 585 5885; fax: C1 801 581 4192. E-mail address: [email protected] (J.B. Sampson).
0960-8966/$ - see front matter q 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2006.03.013
392
J.B. Sampson et al. / Neuromuscular Disorders 16 (2006) 391–393
but alkaline phosphatase, albumin, and bilirubin were normal. He was anemic with a hematocrit of 31. Renal function was normal. Antinuclear antibody, rheumatoid factor, and thyroid stimulating hormone testing were normal. His electrocardiogram showed sinus rhythm with premature atrial complexes and left axis deviation. He underwent sedated electromyography (EMG) testing, which showed decreased amplitude of peroneal motor nerve response, but normal latency and velocity. Sural sensory responses were normal. Needle EMG showed abnormal insertional activity, fibrillations and sharp waves in both proximal and distal limb muscles. Voluntary motor units were polyphasic. Magnetic resonance imaging of his lower extremities showed diffuse, heterogeneous increased T2 signal in all muscle groups without gadolinium enhancement. A muscle biopsy of the rectus femoris was performed. No necrosis or inflammatory infiltrates were seen. The most striking finding consisted of prominent vacuoles stainable by periodic acid-Schiff (PAS) in myofibers in a perifascicular distribution (see Fig. 1). Diastase digestion
eliminated PAS staining of the vacuolar material. No accumulation of PAS was seen in any other cell types or location. Acid phosphatase staining was unremarkable, showing that the glycogen was not lysosomal. Myophosphorylase staining was normal. Immunostaining for complement membrane attack complex (C5b-9) was positive on capillary endothelium (see Fig. 1), particularly in perifascicular regions. Staining for MHC class I demonstrated upregulation on all myofibers, with a tendency for more staining of cytoplasm in small muscle fibers in perifascicular regions. In addition to confirming the accumulation of non-membrane bound glycogen, electron microscopy demonstrated reticulotubular aggregates in capillary endothelial cells.
3. Discussion Dermatomyositis typically presents with muscle weakness and pain in association with a rash, which is characteristically found in the periorbital region, over the
Fig. 1. Histology of the rectus femorus muscle biopsy. Hematoxylin and eosin staining shows vacuolar changes in the regions of perifascicular atrophy (A: scaleZ50 mm). Periodic acid-Schiff staining shows the vacuoles contain PAS-positive material (B: scaleZ50 mm), which was digested by diastase treatment (not shown). Electron microscopy demonstrated non-membrane bound, homogeneous granular material in the inclusions consistent with glycogen in the subsarcolemmar region of muscle cells (C: scaleZ1 mm) and reticulotubular aggregates (arrow) adjacent to the nuclear membrane in endothelial cells (D: scaleZ1 mm).
J.B. Sampson et al. / Neuromuscular Disorders 16 (2006) 391–393
extensor surfaces of the joints, or over the anterior neck and chest. Anasarca can occur, and is thought to be an indicator of severity [5]. In the case we report, the edema and the characteristic rash were transitory. Consistent with the diagnosis, the patient’s muscle strength improved following treatment with steroids and methotrexate, and 6 months later was back to normal strength. Our patient reported a prior episode of weakness and edema, for which medical care was not sought. Such a prior episode is unusual, although a relapsing/remitting course of dermatomyositis in the absence of steroid treatment has been reported [2]. Complement membrane attack complexes (C5b-9) are seen in the vessels of both juvenile and adult dermatomyositis. The presence of the C5b-9 is thought to be secondary to loss of CD59, which is constitutively present on endothelial cells and prevents assembly of the C5b-9 [4]. Complement membrane attack complexes localized to the muscle fibers, however, are not specific to dermatomyositis or inflammatory myopathies in general. In fact, C5b-9 has been found on non-necrotic fibers in facioscapulohumeral and limb-girdle muscular dystrophies [6]. Electron microscopy detected reticulotubular aggregates in endothelial cells in a perinuclear distribution. Reticulotubular aggregates are associated with autoimmune diseases, viral infections including human immunodeficiency virus, interferon treatment, and dermatomyositis [3]. In this case, the reticulotubular aggregates supported the diagnosis of dermatomyositis. Perifascicular atrophy and glycogen accumulation can be seen in the myopathy associated with scleromyxedema, as can rare C5b-9-positive fibers [6]. While our patient had pruritis, which is common in scleromyxedema, he did not have the nodular skin changes seen in that disorder. Our patient was lost to followup, and did not undergo skin biopsy, nor was he tested for monoclonal gammopathy, which is frequently associated with scleromyxedema. However, previous reports of electron microscopy of muscle biopsies from scleromyxedema patients [7] have not described any vascular endothelial cell changes characteristic of dermatomyositis, as found in our patient. The striking feature of our case is the prominence of PAS staining in perifascicular fibers. Small glycogen accumulations have been reported as a pathological feature of dermatomyositis [8], but the inclusions are typically few and usually noted only upon electron microscopy, and the total amount of glycogen in the muscle is unchanged [9]. Glycogen accumulations appearing like picorna-virus inclusions have rarely been reported in polymyositis [10]. In our case, clinically and ultrastructurally consistent with dermatomyositis, PAS staining was unusually prominent, to a degree that suggested to us a glycogen storage disease. However, since acid phosphatase staining was not increased, and the glycogen was not membrane bound, we
393
concluded that this was not acid maltase deficiency or lysosome-associated membrane protein-2 deficiency (LAMP-2 deficiency, or Danon disease) [11]. His relapsing/remitting course, response to therapy, and otherwise normal motor milestones also argued against a glycogen storage disease. The glycogen was found in a perifascicular distribution atypical for a glycogen storage disease but typical for the atrophy associated with childhood dermatomyositis. We have since seen rare large glycogen accumulations in another case of pediatric dermatomyositis (data not shown), but not to the degree seen in this case. The diagnosis of dermatomyositis should be considered in cases where the predominant feature on muscle biopsy shows marked glycogen accumulation in a perifascicular distribution atypical for glycogen storage disease.
Acknowledgements We thank Dr Andrew Engel for edifying discussions.
References [1] van der Meulen MF, Bronner IM, Hoogendijk JE, et al. Polymyositis: an overdiagnosed entity. Neurology 2003;61(3): 316–21. [2] Bitnum S, Daeschner Jr CW, Travis LB, Dodge WF, Hopps HC. Dermatomyositis. J Pediatr 1964;64:101–31. [3] De Visser M, Emslie-Smith AM, Engel AG. Early ultrastructural alterations in adult dermatomyositis. Capillary abnormalities precede other structural changes in muscle. J Neurol Sci 1989;94(1–3): 181–92. [4] Goncalves FG, Chimelli L, Sallum AM, Marie SK, Kiss MH, Ferriani VP. Immunohistological analysis of CD59 and membrane attack complex of complement in muscle in juvenile dermatomyositis. J Rheumatol 2002;29(6):1301–7. [5] Mitchell JP, Dennis GJ, Rider LG. Juvenile dermatomyositis presenting with anasarca: a possible indicator of severe disease activity. J Pediatr 2001;138(6):942–5. [6] Spuler S, Engel AG. Unexpected sarcolemmal complement membrane attack complex deposits on nonnecrotic muscle fibers in muscular dystrophies. Neurology 1998;50(1):41–6. [7] Verity MA, Toop J, McAdam LP, Pearson CM. Scleromyxedema myopathy. Histochemical and electron microscopic observations. Am J Clin Pathol 1978;69(4):446–51. [8] Engel AG, Hohlfeld R. The polymyositis and dermatomyositis syndromes. In: Engel AG, Franzini-Armstrong C, editors. Myology. 3rd ed. New York: McGraw-Hill, Medical Publishing Division; 2004. p. 1321–67. [9] Hess JW. Phosphorylase activity and glycogen, glucose-6-phosphate, and lactic acid content of human skeletal muscle in various myopathies. J Lab Clin Med 1965;66(3):452–63. [10] Katsuragi S, Miyayama H, Takeuchi T. Picornavirus-like inclusions in polymyositis—aggregation of glycogen particles of the same size. Neurology 1981;31(11):1476–80. [11] Sugie K, Yamamoto A, Murayama K, Oh SJ, Takahashi M, Mora M, et al. Clinicopathological features of genetically confirmed Danon disease. Neurology 2002;58(12):1773–8.