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Prominent inflammatory changes on muscle biopsy in patients with Miyoshi myopathy
Neuromuscular Disorders 9 (1999) 417±420
Short case report
www.elsevier.com/locate/nmd
Prominent in¯ammatory changes on muscle biopsy in patients with Miyoshi myopathy Julie Rowin a,*, Matthew N. Meriggioli a, Elizabeth J. Cochran b, Donald B. Sanders c a
Section of Neuromuscular Disease, Department of Neurological Sciences, Rush University, Rush-Presbyterian-St. Luke's, Medical Center, Chicago, IL, USA b Department of Pathology and Neurological Sciences, Rush University, Rush-Presbyterian-St. Luke's, Medical Center, Chicago, IL, USA c Division of Neurology, Duke University Medical Center, Durham, NC, USA Received 24 February 1999; received in revised form 25 March 1999; accepted 7 April 1999
Abstract Miyoshi myopathy is a rare autosomal recessive distal myopathy characterized by early and prominent involvement of the posterior compartment of the legs. We describe two patients with the clinical diagnosis of Miyoshi myopathy who demonstrated marked in¯ammatory changes on muscle biopsy of clinically less affected muscles. This report illustrates the importance of recognizing the marked variability in histopathology of Miyoshi myopathy which may include an in¯ammatory in®ltrate on muscle biopsy which mimics the histopathologic picture of an in¯ammatory myopathy. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Distal myopathy; Hereditary myopathy; In¯ammatory myopathy; Miyoshi myopathy; Myopathy
1. Introduction Type II early adult onset distal myopathy or Miyoshi myopathy (MM) is a rare distal myopathy inherited in an autosomal recessive fashion. This myopathy is characterized by weakness and atrophy that begins in the posterior compartment muscles of the legs. The onset of symptoms is in young adulthood and often begins with the inability to toe walk. Miyoshi myopathy is associated with markedly elevated creatine kinase levels (.10 times normal) and dystrophic changes on muscle histopathology. The gene has been recently mapped to chromosome 2p13, which codes for the `dysferlin' protein [1]. Mutations in the dysferlin gene have also been implicated in limb-girdle muscular dystrophy and distal myopathy with anterior tibial onset [1]. Reported muscle biopsy ®ndings in MM range from mild myopathic features to extensive ®brosis and fatty replacement. Perivascular and perimysial chronic in¯ammation, a critical ®nding in in¯ammatory myopathy [2], is not typically present in MM. There is one reported case of a 14year-old girl with MM whose muscle biopsy showed minimal ®brosis and marked perivascular in¯ammatory in®ltrates [3]. We report two patients in whom clinical and investigative * Corresponding author.
studies were consistent with the diagnosis of MM and whose muscle biopsies exhibited prominent chronic in¯ammation mimicking an in¯ammatory myopathy.
2. Case 1 A 25-year-old Pakistani man was evaluated for a 1.5 year history of progressive atrophy of both calves associated with `limping'. He denied any involvement of the upper extremities. He denied any family history of neuromuscular weakness, but was the product of a consanguineous marriage. On neurological examination, marked atrophy of the posterior compartment muscles of both lower extremities was found. Both extensor digitorum brevis muscles were hypertrophied. His thigh muscles were thin, but not clearly atrophic. Strength was 41/5 (MRC scale) in the left quadriceps, 4/5 in both hamstrings, 2/5 plantar ¯exion bilaterally, 52/5 in dorsi¯exion bilaterally, 42/5 in foot eversion and 41/5 in foot inversion bilaterally. Muscle stretch re¯exes were 11 and symmetrical throughout, with the exception of absent ankle jerks. He was able to rise from a seated position with assistance from his upper extremities. He was able to walk on his heels, but was unable to toe walk. His serum creatine kinase (CK) was 12 599 units/l. Nerve conduction studies were normal. Electromyography demon-
0960-8966/99/$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0960-896 6(99)00041-3
418
J. Rowin et al. / Neuromuscular Disorders 9 (1999) 417±420
Fig. 1. Paraf®n-embedded cross section of the left calf muscle (case 1) stained with hematoxylin and eosin. Note the variability in ®ber size, the degenerating muscle ®ber and slight ®brosis. (Scale bar, 100 m).
strated abnormal spontaneous activity including ®brillation potentials and positive waves, polyphasic motor unit action potentials of low amplitude and short duration and early recruitment in a diffuse pattern with predominant involvement of the lower extremities particularly the gastrocnemius muscles. Biopsy of the tibialis anterior muscle (Fig. 1), performed elsewhere, showed only a subtle increase in endomysial connective tissue. Therefore a second biopsy of the biceps femoris muscle was performed (Fig. 2A,B) which demonstrated scattered degenerating and regenerating ®bers and lymphocytes around degenerating ®bers and in the perimysium. No ®brosis was seen. This biopsy was
felt to be most consistent with an in¯ammatory myopathy. A third muscle biopsy of the medial gastrocnemius muscle was performed. It demonstrated marked perimysial and endomysial ®brosis and fat replacement, with only a few muscle ®bers remaining. Rounded atrophy and hypertrophy of the muscle ®bers was present. No in¯ammation was seen (Fig. 3).
3. Case 2 A 29-year-old woman was evaluated for progressive dif®-
Fig. 2. (A) Paraf®n-embedded longitudinal section of the left biceps femoris muscle (case 1) stained with hematoxylin and eoxin. A degenerating ®ber is in®ltrated and surrounded by lymphocytes. (Scale bar, 60 m). (B) Paraf®n-embedded section of left biceps femoris muscle showing perimysial mononuclear cell in®ltrate (case 1) immunostained with antibody to leukocyte common antigen. (Scale bar, 120 m).
J. Rowin et al. / Neuromuscular Disorders 9 (1999) 417±420
419
Fig. 3. Cryostat cross-section of left gastrocnemius muscle (case 1) stained with hematoxylin and eosin. Severe ®brosis and a cluster of hypertrophic and atrophic ®bers are seen. (Scale bar, 90 m).
culty walking, particularly in high-heeled shoes. Symptoms began at the age of 18 and progressed to include dif®culty walking up stairs and stumbling over her feet. There was no family history of neuromuscular disease. On examination, abnormal ®ndings included bilateral atrophy of the anterior and posterior compartment muscles. There was mild wasting of the thigh muscles. There was mild weakness of hip ¯exors and adductors. Hip abductors were strong. There was moderate weakness in the hamstrings and knee extensors bilaterally. In the distal lower extremities, inversion and plantar ¯exors were slightly stronger than evertors and dorsi¯exors, which were essentially 0±1/5. Both deltoids were also mildly weak. Muscle stretch re¯exes were trace in the upper extremities and trace at the right knee, but otherwise absent in the lower extremities. Her initial CK level was 2313 units/l. Nerve conduction studies were normal and electromyography was consistent with myopathy with small, polyphasic motor units and an early recruitment pattern seen predominantly in the medial gastrocnemius, biceps femoris and deltoid muscles. The tibialis anterior and rectus femoris muscles showed less prominent myopathic changes. Her initial muscle biopsy, of the medial gastrocnemius muscle, was interpreted as an end-stage muscle, and a repeat muscle biopsy of the vastus lateralis muscle revealed extensive perivascular and endomysial lymphocytic in®ltrates along with random mild variation in ®ber size and endomysial ®brosis. This biopsy was felt to be consistent with polymyositis. Neither of the biopsies showed vacuoles. She received a trial of high dose steroids without bene®t.
4. Discussion The muscle histopathology of MM has been reported to
be highly variable depending on the particular muscle that is biopsied [2,4,5]. Our ®rst patient had biopsies of the tibialis anterior, gastrocnemius and biceps femoris muscles in the same limb over an 18-month period. Each biopsy demonstrated quite striking differences. There was minimal ®brosis seen in the tibialis anterior muscle, while the gastrocnemius muscle demonstrated end-stage muscle. In addition, most interestingly, the biceps femoris muscle showed perivascular and perimysial in¯ammation suf®cient to mimic a primary in¯ammatory myopathy. This marked variability in histopathology of muscles from the same limb has been previously reported in MM [5,6]. Reported histologic features of the quadriceps muscle biopsies include slight increases in the variability of ®ber size, rare atrophic ®bers and slight increases in connective tissue. This has previously been found to be co-existent with severe dystrophic ®ndings in the gastrocnemius muscle, i.e. severe replacement of muscle tissue with connective tissue, fat cell in®ltration, marked variation in ®ber size, abundant central nuclei and ®ber splitting. Intermediate changes have been demonstrated in the biceps femoris muscle [5]. There has been one previously reported case of a patient with MM in which muscle biopsy showed marked in¯ammatory changes [3]. As in our cases, these in¯ammatory changes were seen in a clinically less affected muscle. This suggests that in®ltration by in¯ammatory cells may be a relatively early histopathologic feature in some patients with MM, prior to the development of signi®cant dystrophic changes. These ®ndings may easily be misinterpreted as being indicative of a primary in¯ammatory myopathy, as occurred in our cases. The presence of in¯ammatory cells in muscle biopsies from patients with muscular dystrophies has been described, particularly in patients with fascioscapulohumeral muscular
420
J. Rowin et al. / Neuromuscular Disorders 9 (1999) 417±420
dystrophy (FSHD) [7], but also in patients with limb girdle muscular dystrophy (LGMD) [8]. In FSHD, prominent changes indistinguishable from those seen in active polymyositis (widespread ®ber necrosis, regeneration and perivascular in¯ammation) have been reported [9]. The pathophysiology of MM is believed to be gradual breakdown and loss of muscle ®bers with replacement by ®brous and fatty connective tissue similar to other forms of dystrophy such as LGMD and FSHD. As is the case for these other forms of muscular dystrophy, the explanation for the occasional ®nding of prominent in¯ammatory changes on muscle biopsy in patients with MM remains to be elucidated. These two cases illustrate the importance of recognizing that biopsies of patients with MM may show in¯ammatory in®ltrates in the less severely involved muscles, mimicking the histopathologic picture of an in¯ammatory myopathy. Awareness of the possible variability of the histological ®ndings in muscle biopsy of MM patients may obviate unnecessary treatment with steroids or other immunotherapies and their associated adverse side effects.
References [1] Liu J, Aoke M, Illa I, et al. Dysferlin, a novel skeletal muscle gene is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 1998;20:31±36. [2] Barohn RJ. Distal myopathies and dystrophies. Semin Neurol 1993;13:247±255. [3] Austin SG, Pappolia MA, Dimachkie M, Vriesendorp FJ. A confusing case of Miyoshi distal myopathy. Muscle Nerve 1995;18:922±923. [4] Galassi G, Rowland LP, Hays AP, Hopkins LC, Dimauro S. High serum levels of creatine kinase: asymptomatic prelude to distal myopathy. Muscle Nerve 1987;10:346±350. [5] Barohn RJ, Miller RG, Griggs RC. Autosomal recessive distal dystrophy. Neurol 1991;41:1365±1370. [6] Flachenecker P, Kiefer R, Naumann M, Handwerker M, Reichmann H. Distal muscular dystrophy of Miyoshi type: report of two cases and review of the literature. J Neurol 1997;244:23±29. [7] Arahata K, Ishihara T, Fukunaga H, et al. In¯ammatory response in fascioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses. Muscle Nerve 1995;2:S56±S66. [8] Van der Dooi AJ, Ginjaar HB, Busch HF, Wokke JH, Barth PG, de Visser M. Limb girdle muscular dystrophy: a pathological and immunohistochemical reevaluation. Muscle Nerve 1998;21:584±590. [9] Munsat TL, Piper D, Cancill P, Mednick J. In¯ammatory myopathy with fascioscapulohumeral dystrophy. Neurology 1972;22:335.
Short case report
www.elsevier.com/locate/nmd
Prominent in¯ammatory changes on muscle biopsy in patients with Miyoshi myopathy Julie Rowin a,*, Matthew N. Meriggioli a, Elizabeth J. Cochran b, Donald B. Sanders c a
Section of Neuromuscular Disease, Department of Neurological Sciences, Rush University, Rush-Presbyterian-St. Luke's, Medical Center, Chicago, IL, USA b Department of Pathology and Neurological Sciences, Rush University, Rush-Presbyterian-St. Luke's, Medical Center, Chicago, IL, USA c Division of Neurology, Duke University Medical Center, Durham, NC, USA Received 24 February 1999; received in revised form 25 March 1999; accepted 7 April 1999
Abstract Miyoshi myopathy is a rare autosomal recessive distal myopathy characterized by early and prominent involvement of the posterior compartment of the legs. We describe two patients with the clinical diagnosis of Miyoshi myopathy who demonstrated marked in¯ammatory changes on muscle biopsy of clinically less affected muscles. This report illustrates the importance of recognizing the marked variability in histopathology of Miyoshi myopathy which may include an in¯ammatory in®ltrate on muscle biopsy which mimics the histopathologic picture of an in¯ammatory myopathy. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Distal myopathy; Hereditary myopathy; In¯ammatory myopathy; Miyoshi myopathy; Myopathy
1. Introduction Type II early adult onset distal myopathy or Miyoshi myopathy (MM) is a rare distal myopathy inherited in an autosomal recessive fashion. This myopathy is characterized by weakness and atrophy that begins in the posterior compartment muscles of the legs. The onset of symptoms is in young adulthood and often begins with the inability to toe walk. Miyoshi myopathy is associated with markedly elevated creatine kinase levels (.10 times normal) and dystrophic changes on muscle histopathology. The gene has been recently mapped to chromosome 2p13, which codes for the `dysferlin' protein [1]. Mutations in the dysferlin gene have also been implicated in limb-girdle muscular dystrophy and distal myopathy with anterior tibial onset [1]. Reported muscle biopsy ®ndings in MM range from mild myopathic features to extensive ®brosis and fatty replacement. Perivascular and perimysial chronic in¯ammation, a critical ®nding in in¯ammatory myopathy [2], is not typically present in MM. There is one reported case of a 14year-old girl with MM whose muscle biopsy showed minimal ®brosis and marked perivascular in¯ammatory in®ltrates [3]. We report two patients in whom clinical and investigative * Corresponding author.
studies were consistent with the diagnosis of MM and whose muscle biopsies exhibited prominent chronic in¯ammation mimicking an in¯ammatory myopathy.
2. Case 1 A 25-year-old Pakistani man was evaluated for a 1.5 year history of progressive atrophy of both calves associated with `limping'. He denied any involvement of the upper extremities. He denied any family history of neuromuscular weakness, but was the product of a consanguineous marriage. On neurological examination, marked atrophy of the posterior compartment muscles of both lower extremities was found. Both extensor digitorum brevis muscles were hypertrophied. His thigh muscles were thin, but not clearly atrophic. Strength was 41/5 (MRC scale) in the left quadriceps, 4/5 in both hamstrings, 2/5 plantar ¯exion bilaterally, 52/5 in dorsi¯exion bilaterally, 42/5 in foot eversion and 41/5 in foot inversion bilaterally. Muscle stretch re¯exes were 11 and symmetrical throughout, with the exception of absent ankle jerks. He was able to rise from a seated position with assistance from his upper extremities. He was able to walk on his heels, but was unable to toe walk. His serum creatine kinase (CK) was 12 599 units/l. Nerve conduction studies were normal. Electromyography demon-
0960-8966/99/$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0960-896 6(99)00041-3
418
J. Rowin et al. / Neuromuscular Disorders 9 (1999) 417±420
Fig. 1. Paraf®n-embedded cross section of the left calf muscle (case 1) stained with hematoxylin and eosin. Note the variability in ®ber size, the degenerating muscle ®ber and slight ®brosis. (Scale bar, 100 m).
strated abnormal spontaneous activity including ®brillation potentials and positive waves, polyphasic motor unit action potentials of low amplitude and short duration and early recruitment in a diffuse pattern with predominant involvement of the lower extremities particularly the gastrocnemius muscles. Biopsy of the tibialis anterior muscle (Fig. 1), performed elsewhere, showed only a subtle increase in endomysial connective tissue. Therefore a second biopsy of the biceps femoris muscle was performed (Fig. 2A,B) which demonstrated scattered degenerating and regenerating ®bers and lymphocytes around degenerating ®bers and in the perimysium. No ®brosis was seen. This biopsy was
felt to be most consistent with an in¯ammatory myopathy. A third muscle biopsy of the medial gastrocnemius muscle was performed. It demonstrated marked perimysial and endomysial ®brosis and fat replacement, with only a few muscle ®bers remaining. Rounded atrophy and hypertrophy of the muscle ®bers was present. No in¯ammation was seen (Fig. 3).
3. Case 2 A 29-year-old woman was evaluated for progressive dif®-
Fig. 2. (A) Paraf®n-embedded longitudinal section of the left biceps femoris muscle (case 1) stained with hematoxylin and eoxin. A degenerating ®ber is in®ltrated and surrounded by lymphocytes. (Scale bar, 60 m). (B) Paraf®n-embedded section of left biceps femoris muscle showing perimysial mononuclear cell in®ltrate (case 1) immunostained with antibody to leukocyte common antigen. (Scale bar, 120 m).
J. Rowin et al. / Neuromuscular Disorders 9 (1999) 417±420
419
Fig. 3. Cryostat cross-section of left gastrocnemius muscle (case 1) stained with hematoxylin and eosin. Severe ®brosis and a cluster of hypertrophic and atrophic ®bers are seen. (Scale bar, 90 m).
culty walking, particularly in high-heeled shoes. Symptoms began at the age of 18 and progressed to include dif®culty walking up stairs and stumbling over her feet. There was no family history of neuromuscular disease. On examination, abnormal ®ndings included bilateral atrophy of the anterior and posterior compartment muscles. There was mild wasting of the thigh muscles. There was mild weakness of hip ¯exors and adductors. Hip abductors were strong. There was moderate weakness in the hamstrings and knee extensors bilaterally. In the distal lower extremities, inversion and plantar ¯exors were slightly stronger than evertors and dorsi¯exors, which were essentially 0±1/5. Both deltoids were also mildly weak. Muscle stretch re¯exes were trace in the upper extremities and trace at the right knee, but otherwise absent in the lower extremities. Her initial CK level was 2313 units/l. Nerve conduction studies were normal and electromyography was consistent with myopathy with small, polyphasic motor units and an early recruitment pattern seen predominantly in the medial gastrocnemius, biceps femoris and deltoid muscles. The tibialis anterior and rectus femoris muscles showed less prominent myopathic changes. Her initial muscle biopsy, of the medial gastrocnemius muscle, was interpreted as an end-stage muscle, and a repeat muscle biopsy of the vastus lateralis muscle revealed extensive perivascular and endomysial lymphocytic in®ltrates along with random mild variation in ®ber size and endomysial ®brosis. This biopsy was felt to be consistent with polymyositis. Neither of the biopsies showed vacuoles. She received a trial of high dose steroids without bene®t.
4. Discussion The muscle histopathology of MM has been reported to
be highly variable depending on the particular muscle that is biopsied [2,4,5]. Our ®rst patient had biopsies of the tibialis anterior, gastrocnemius and biceps femoris muscles in the same limb over an 18-month period. Each biopsy demonstrated quite striking differences. There was minimal ®brosis seen in the tibialis anterior muscle, while the gastrocnemius muscle demonstrated end-stage muscle. In addition, most interestingly, the biceps femoris muscle showed perivascular and perimysial in¯ammation suf®cient to mimic a primary in¯ammatory myopathy. This marked variability in histopathology of muscles from the same limb has been previously reported in MM [5,6]. Reported histologic features of the quadriceps muscle biopsies include slight increases in the variability of ®ber size, rare atrophic ®bers and slight increases in connective tissue. This has previously been found to be co-existent with severe dystrophic ®ndings in the gastrocnemius muscle, i.e. severe replacement of muscle tissue with connective tissue, fat cell in®ltration, marked variation in ®ber size, abundant central nuclei and ®ber splitting. Intermediate changes have been demonstrated in the biceps femoris muscle [5]. There has been one previously reported case of a patient with MM in which muscle biopsy showed marked in¯ammatory changes [3]. As in our cases, these in¯ammatory changes were seen in a clinically less affected muscle. This suggests that in®ltration by in¯ammatory cells may be a relatively early histopathologic feature in some patients with MM, prior to the development of signi®cant dystrophic changes. These ®ndings may easily be misinterpreted as being indicative of a primary in¯ammatory myopathy, as occurred in our cases. The presence of in¯ammatory cells in muscle biopsies from patients with muscular dystrophies has been described, particularly in patients with fascioscapulohumeral muscular
420
J. Rowin et al. / Neuromuscular Disorders 9 (1999) 417±420
dystrophy (FSHD) [7], but also in patients with limb girdle muscular dystrophy (LGMD) [8]. In FSHD, prominent changes indistinguishable from those seen in active polymyositis (widespread ®ber necrosis, regeneration and perivascular in¯ammation) have been reported [9]. The pathophysiology of MM is believed to be gradual breakdown and loss of muscle ®bers with replacement by ®brous and fatty connective tissue similar to other forms of dystrophy such as LGMD and FSHD. As is the case for these other forms of muscular dystrophy, the explanation for the occasional ®nding of prominent in¯ammatory changes on muscle biopsy in patients with MM remains to be elucidated. These two cases illustrate the importance of recognizing that biopsies of patients with MM may show in¯ammatory in®ltrates in the less severely involved muscles, mimicking the histopathologic picture of an in¯ammatory myopathy. Awareness of the possible variability of the histological ®ndings in muscle biopsy of MM patients may obviate unnecessary treatment with steroids or other immunotherapies and their associated adverse side effects.
References [1] Liu J, Aoke M, Illa I, et al. Dysferlin, a novel skeletal muscle gene is mutated in Miyoshi myopathy and limb girdle muscular dystrophy. Nat Genet 1998;20:31±36. [2] Barohn RJ. Distal myopathies and dystrophies. Semin Neurol 1993;13:247±255. [3] Austin SG, Pappolia MA, Dimachkie M, Vriesendorp FJ. A confusing case of Miyoshi distal myopathy. Muscle Nerve 1995;18:922±923. [4] Galassi G, Rowland LP, Hays AP, Hopkins LC, Dimauro S. High serum levels of creatine kinase: asymptomatic prelude to distal myopathy. Muscle Nerve 1987;10:346±350. [5] Barohn RJ, Miller RG, Griggs RC. Autosomal recessive distal dystrophy. Neurol 1991;41:1365±1370. [6] Flachenecker P, Kiefer R, Naumann M, Handwerker M, Reichmann H. Distal muscular dystrophy of Miyoshi type: report of two cases and review of the literature. J Neurol 1997;244:23±29. [7] Arahata K, Ishihara T, Fukunaga H, et al. In¯ammatory response in fascioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses. Muscle Nerve 1995;2:S56±S66. [8] Van der Dooi AJ, Ginjaar HB, Busch HF, Wokke JH, Barth PG, de Visser M. Limb girdle muscular dystrophy: a pathological and immunohistochemical reevaluation. Muscle Nerve 1998;21:584±590. [9] Munsat TL, Piper D, Cancill P, Mednick J. In¯ammatory myopathy with fascioscapulohumeral dystrophy. Neurology 1972;22:335.