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Late-onset rod myopathy associated with monoclonal gammopathy
Neuromusc. Disord., Vol. 3, No. 5/6, pp. 557
560, 1993 Copyright© 1994ElsevierScienceLtd Printed in Great Britain. All rightsreserved 096~8966/93 $6.00+ .00
Pergamon
LATE-ONSET ROD MYOPATHY ASSOCIATED WITH MONOCLONAL GAMMOPATHY B. EYMARD,* J. C. BROUET,t H . COLL1N,* M . CHEVALLAY,* A. BUSSEL~ a n d M . FARDEAU* * I N S E R M U. 153, C N R S ERS 064, 17 rue du Fer ~. Moulin, F-75005 Paris; t Service d'H6matologie, H6pital Saint Louis, l Avenue C. Vellefaux, 75475 Paris; :]:Unit6 de Plasmaph6r/:ses, H6pital Saint Louis, l Avenue C. Vellefaux, 75475 Paris, France
Abstract--A 31-yr-old woman presented with a severe and rapidly progressive myopathy affecting proximal limbs, neck flexors and respiratory muscles. Muscle biopsy revealed numerous atrophic fibres with marked structural alterations, without inflammatory infiltrate. By electron microscopy, atrophic fibres displayed many rods. A benign monoclonal gammopathy (IgG, lambda chain) was evident in serum. A sarcolemmal deposit of IgG, lambda chain was found by immunostaining. Plasmapheresis and immunosuppressive therapies produced a decrease in paraproteinemia and a partial clinical improvement. This observation is the third to associate monoclonal gammopathy with "late-onset rod myopathy". The pathogenetic role of paraproteinemia remains unclear. Key words: Rod myopathy, monoclonal gammopathy.
INTRODUCTION
CASE REPORT
Three forms o f nemaline myopathy are classically individualized: a severe, neonatal myopathy; a mild congenital, non or slowly progressive myopathy; and an adult-onset form [1, 2]. In 1966, W. K. Engel and Resnick [3] on one side, and A. G. Engel [4] on the other, reported two unrelated observations of subacute myopathies with the presence of numerous rods in atrophic fibres which they named "adult-onset rod myopathies" (AORM). Rare cases [5-8] presented with clinical features close to the three first reported cases, with a subacute proximal and distal weakness occurring in adulthood without any preceding symptom and in the absence of any family history; the disease was severe with a progressive m o t o r deterioration and a poor prognosis. The pathophysiology of these later cases remained obscure. Clinical and pathological differences between congenital and these "late-onset" forms suggested that the latter may represent a different nosological entity. We report here a new case of AORM, associated with a monoclonal gammopathy. It is worthwhile to note that a similar association was already present in two previous cases [4, 7]. Furthermore, we suggest that the paraproteinemia is involved in the pathogenesis of the disease.
A 31-yr-old French woman without past personal or family medical history presented, in February 1989, weakness and wasting of the proximal left upper limb and neck flexors. Three months later, the right upper limb was also involved. In May 1989, the patient complained of difficulties in climbing stairs and running. Dyspnea, mild chewing, swallowing and phonation difficulties developed during the next 3 months. During the same period, lower limb weakness progressed rapidly and walking became difficult. In December 1989, the patient needed assistance in rising from a chair and walking a few metres. When referred to our clinic (March 1990), physical examination revealed a severe, symmetric weakness and atrophy of girdle, neck and trunk muscles. Neck muscles were markedly involved with the head falling on the chest. Mild swallowing difficulties were found. Facial and extraocular muscles were normal. The only symptom associated with muscle weakness was a 10 lb weight loss: pain, skin rash, arthritis, Raynaud or cardiopulmonary symptoms were absent. LABORATORY INVESTIGATIONS
Spirometry revealed a severe decrease in vital capacity (1.50 1, 46% of normal value). Electromyographic studies showed myopathic changes 557
558
B. EYMARDet al.
consisting of motor unit potentials of short duration and low amplitude. There were fibrillations in several of the muscles examined. Motor and sensory conduction velocities were normal. Erythrocyte sedimentation rate was 16, haemogram and creatine phosphokinase (CK) were normal. HIV and HTLVI, hepatitis serologies, Latex Waaler Rose, antinuclear factors, cryoglobulins were negative. Serum protein electrophoresis revealed total protein 7.8 g dl- ~, gammaglobulins 1.54 g dl-~. IgG was 1790 mg dl-), IgM 60 mg dl ~, IgA 130 mg d1-1. Serum immunoelectrophoresis (IEP) disclosed an IgG lambda paraprotein. There was a mild decrease of polyclonal IgG. Urine was negative for BenceJones protein. Bone marrow aspirate and biopsy evidenced 5% mature plasma cells. Blood creatinine and calcium were normal. Radiologic studies were normal except for lacunar aspects in cortical humeral bone without malignancy at biopsy. Muscle biopsy data are presented below.
specimens were fixed in glutaraldehyde, postfixed in osmium tetroxide, and embedded in Epon for electron microscopy. Direct and indirect immunostaining were performed on serial 5 /.tm frozen sections of muscle, fixed in cold acetone. The following reagents were used: rabbit antisera to human IgG, IgA, IgM, kappa and lambda chain, mouse monoclonai antibodies to HLA class I and DR antigens (Dako Corporation). Specific binding was revealed using a peroxidase two step assay (Dako LSAB kit). For indirect immunostaining procedures, a 33% ammonium sulphate precipitated fraction from the patient and from a control (dilution 1.75-7 g 1-~) was overlaid for 112 h on normal muscle. Subsequently immunoglobulin binding was detected as shown above. RESULTS
Histopathology CLINICAL OUTCOME
From June 1990 to February 1991, 32 plasma exchanges were performed, allowing a steady removal of the monoclonal protein with gammaglobulin level at about 0.7 g dl- ~. Swallowing difficulties disappeared and neck weakness improved, no changes were observed in other muscles and in respiratory function. Between March and May 1991, no therapy was administered and the paraproteinemia level increased (gammaglobulin: 1.9 g dl-~). Respiratory capacity deteriorated (vital capacity: 1.36 1). An immunosuppressive therapy was instituted in June 1991: prednisone 80 mg daily for a month, then progressively lowered to 15 mg, and cyclophosphamide 100 mg daily. The gammaglobulin concentration fell to about 0.6 g dlwith a marked decrease in the IgG spike. In February 1993, a 40% improvement in vital capacity (I .901) had occurred and the strength of the quadriceps femoris was significantly increased. Displacement capacities were increased threefold. However, the patient remained very disabled, needing help to stand up from the chair, and using a wheelchair. METHODS
The left deltoid muscle was biopsied. Histological and histochemical stains were used to study 10-/ma-thick frozen sections by standard techniques [9]. Portions of the muscle biopsy
In sections stained with H and E and Gomori trichrome, marked variation in fibre size was found with the presence of many atrophic scattered angulated fibres. Numerous reddish granules were shown by the Gomori trichrome stain (Fig. 1A). Centrally located nuclei were moderately increased. There was no inflammation and necrotic or regenerating fibres were not seen. Atrophic fibres were generally dark with N A D H - T R . There was a type I fibre predominance, and many atrophic fibres lacked staining with myofibrillar ATPase staining (Fig. 1B). By electron microscopy, numerous rods were evident (Fig. 1C), with their characteristic lattice pattern. They were present in structurally modified areas with the loss of thick filaments. Accumulations of rods were mainly seen in atrophic fibres but also occurred at the periphery of some fibres of normal diameter. It took place in the whole fibre when it was very atrophic, or in the periphery of less altered fibres. Small numbers of morphologically normal mitochondria were found.
Immunolabelling By direct immunostaining, muscle biopsy showed positive linear staining for IgG and lambda light chain along the sarcolemmal basement membrane (Fig. l D). Stains for kappa light chain, IgA, IgM, HLA class I, DR antigens were negative. Indirect immunostaining with the patient's globulins revealed no staining.
Late-onset Rod Myopathy
559
~)
Fig. 1. (A) Cryostat section, Gomori trichrome; presence of many atrophic angulated fibres filled with reddish granules, x 160. (B) Cryostat section, myofibrillar ATPase (pH 9.4); type I predominance; spotty absence of staining in a number of atrophic fibres, x 160. (C) Electron micrograph; myofibrillar disorganization and accumulation of numerous rods at the periphery of a muscle fibre, x 15,000. (D) Cryostat section, immunostaining with anti-lambda light chain antibody: thin and uniform deposit at the periphery of the muscle fibre, x 160. (E) Cryostat section, control muscle for immunostaining with anti-lambda antibody: no labelling, x 160.
560
B. EYMARDet al. DISCUSSION
Our observation closely resembles other A O R M cases [3-8]. However, age at onset (31 yr) is lower. As in previous cases, the clinical condition was severe. In contrast with these cases, a partial response to immunosuppressive therapies was obtained. In our case an I g G lambda chain monoclonal paraprotein was present in the serum. In two previous cases o f A O R M , a similar association was reported [4, 7]. G a m m o p a t h y has been described in only one case [7]: the patient had an lgG lambda light chain protein in the serum and C S F with a moderate increase o f plasma ceils in bone m a r r o w biopsy. In contrast with our case, there were no deposits in the muscle by direct immunostaining. Besides the relative frequency o f monoclonal g a m m o p a t h y in A O R M , the involvement o f paraproteinemia in the pathophysiology o f this disease was suggested by two findings: (1) the presence o f deposits o f the same category o f i m m u n o g l o b u l i n (IgG lambda) in the sarcolemma o f the patient's muscle; (2) the favourable clinical response induced by therapies lowering the level o f the monoclonal IgG. These treatments (plasmapheresis, cyclophosphamide, steroids) stopped the severe initial evolution, allowing a moderate gain o f pelvic girdle weakness and a significant improvement o f respiratory capacity. A deterioration in muscle strength shortly followed the interruption o f plasmapheresis, in parallel with an increased a m o u n t o f paraproteinemia. However, the clinical recovery was partial, with the persistence o f a severe weakness of the girdle muscles. The mechanism(s) o f m o n o c l o n a l protein involvement in the pathogenesis o f the disease remain to be demonstrated. In this case, indirect immunostaining procedures failed to show any
binding o f patient's globulins to normal muscle. Furthermore, in contrast with potymyositis, no expression of histocompatibility antigens were found on the muscle sarcolemma. As Dalakas described a subacute m y o p a t h y with numerous rods in H I V patients [10], there is a probable multiplicity o f pathogenic mechanisms, including viral diseases, which m a y lead to A O R M . The potential pathogenic role ofdysproteinemia, even if still unexplained, favours the use in late A O R M o f immunosuppressive therapies including plasma exchanges.
REFERENCES
1. Fardeau M. Congenital myopathies. In: Mastaglia F L, Walton J, eds. Skeletal Muscle Pathology, 2nd Edn, Edinburgh: Churchill Livingstone, 1992: 237-281. 2. Banker B Q. The congenital myopathies. In: Engel A G, Banker B Q, eds. Myology. New York: McGraw-Hill, 1986: 1527-1581. 3. EngelW K, Resnick J S. Late rod myopathy: a newly recognized acquired and progressivedisease. Neurology 1966; 16:308 309. 4. EngelA G. Late onset rod myopathy. Mayo Clin Proc 1966; 41:713 741. 5. Heffernan L P, Rewcastle N B, Humphrey J G. The spectrum of rod myopathies. Arch Neurol 1968; 18:529 542. 6. Kamieniecka A. Late onset myopathy with rod-like particles. Acta Neurol Stand 1973; 49: 547-551. 7. EngelW K, Oberc M A. Abundant nuclear rods in adult onset rod disease. J Neuropathol Exp Neurol 1975; 34: 119 132, 8. Brownell A K W, Gilbert J J, Shaw D T, Garcia B, Wenkebach G F, Lam A K S. Adult onset nemaline myopathy. Neurology 1978; 2,8: 1306-1309. 9. Fardeau M. Caract~ristiques cyotchimiques et ultrastructurales des diff+rents types de fibres musculaires squelettiques extrafusales (cbez rhomme et quelques mammif6res). Ann Anat Pathol 1973; 18:7 34. 10. Dalakas M C, Pezeshkpour G H, Flaherthy M. Progressive nemaline (rod) myopathy associated with HIV infection. N Engl J Med 1987; 317:1602 1603.
560, 1993 Copyright© 1994ElsevierScienceLtd Printed in Great Britain. All rightsreserved 096~8966/93 $6.00+ .00
Pergamon
LATE-ONSET ROD MYOPATHY ASSOCIATED WITH MONOCLONAL GAMMOPATHY B. EYMARD,* J. C. BROUET,t H . COLL1N,* M . CHEVALLAY,* A. BUSSEL~ a n d M . FARDEAU* * I N S E R M U. 153, C N R S ERS 064, 17 rue du Fer ~. Moulin, F-75005 Paris; t Service d'H6matologie, H6pital Saint Louis, l Avenue C. Vellefaux, 75475 Paris; :]:Unit6 de Plasmaph6r/:ses, H6pital Saint Louis, l Avenue C. Vellefaux, 75475 Paris, France
Abstract--A 31-yr-old woman presented with a severe and rapidly progressive myopathy affecting proximal limbs, neck flexors and respiratory muscles. Muscle biopsy revealed numerous atrophic fibres with marked structural alterations, without inflammatory infiltrate. By electron microscopy, atrophic fibres displayed many rods. A benign monoclonal gammopathy (IgG, lambda chain) was evident in serum. A sarcolemmal deposit of IgG, lambda chain was found by immunostaining. Plasmapheresis and immunosuppressive therapies produced a decrease in paraproteinemia and a partial clinical improvement. This observation is the third to associate monoclonal gammopathy with "late-onset rod myopathy". The pathogenetic role of paraproteinemia remains unclear. Key words: Rod myopathy, monoclonal gammopathy.
INTRODUCTION
CASE REPORT
Three forms o f nemaline myopathy are classically individualized: a severe, neonatal myopathy; a mild congenital, non or slowly progressive myopathy; and an adult-onset form [1, 2]. In 1966, W. K. Engel and Resnick [3] on one side, and A. G. Engel [4] on the other, reported two unrelated observations of subacute myopathies with the presence of numerous rods in atrophic fibres which they named "adult-onset rod myopathies" (AORM). Rare cases [5-8] presented with clinical features close to the three first reported cases, with a subacute proximal and distal weakness occurring in adulthood without any preceding symptom and in the absence of any family history; the disease was severe with a progressive m o t o r deterioration and a poor prognosis. The pathophysiology of these later cases remained obscure. Clinical and pathological differences between congenital and these "late-onset" forms suggested that the latter may represent a different nosological entity. We report here a new case of AORM, associated with a monoclonal gammopathy. It is worthwhile to note that a similar association was already present in two previous cases [4, 7]. Furthermore, we suggest that the paraproteinemia is involved in the pathogenesis of the disease.
A 31-yr-old French woman without past personal or family medical history presented, in February 1989, weakness and wasting of the proximal left upper limb and neck flexors. Three months later, the right upper limb was also involved. In May 1989, the patient complained of difficulties in climbing stairs and running. Dyspnea, mild chewing, swallowing and phonation difficulties developed during the next 3 months. During the same period, lower limb weakness progressed rapidly and walking became difficult. In December 1989, the patient needed assistance in rising from a chair and walking a few metres. When referred to our clinic (March 1990), physical examination revealed a severe, symmetric weakness and atrophy of girdle, neck and trunk muscles. Neck muscles were markedly involved with the head falling on the chest. Mild swallowing difficulties were found. Facial and extraocular muscles were normal. The only symptom associated with muscle weakness was a 10 lb weight loss: pain, skin rash, arthritis, Raynaud or cardiopulmonary symptoms were absent. LABORATORY INVESTIGATIONS
Spirometry revealed a severe decrease in vital capacity (1.50 1, 46% of normal value). Electromyographic studies showed myopathic changes 557
558
B. EYMARDet al.
consisting of motor unit potentials of short duration and low amplitude. There were fibrillations in several of the muscles examined. Motor and sensory conduction velocities were normal. Erythrocyte sedimentation rate was 16, haemogram and creatine phosphokinase (CK) were normal. HIV and HTLVI, hepatitis serologies, Latex Waaler Rose, antinuclear factors, cryoglobulins were negative. Serum protein electrophoresis revealed total protein 7.8 g dl- ~, gammaglobulins 1.54 g dl-~. IgG was 1790 mg dl-), IgM 60 mg dl ~, IgA 130 mg d1-1. Serum immunoelectrophoresis (IEP) disclosed an IgG lambda paraprotein. There was a mild decrease of polyclonal IgG. Urine was negative for BenceJones protein. Bone marrow aspirate and biopsy evidenced 5% mature plasma cells. Blood creatinine and calcium were normal. Radiologic studies were normal except for lacunar aspects in cortical humeral bone without malignancy at biopsy. Muscle biopsy data are presented below.
specimens were fixed in glutaraldehyde, postfixed in osmium tetroxide, and embedded in Epon for electron microscopy. Direct and indirect immunostaining were performed on serial 5 /.tm frozen sections of muscle, fixed in cold acetone. The following reagents were used: rabbit antisera to human IgG, IgA, IgM, kappa and lambda chain, mouse monoclonai antibodies to HLA class I and DR antigens (Dako Corporation). Specific binding was revealed using a peroxidase two step assay (Dako LSAB kit). For indirect immunostaining procedures, a 33% ammonium sulphate precipitated fraction from the patient and from a control (dilution 1.75-7 g 1-~) was overlaid for 112 h on normal muscle. Subsequently immunoglobulin binding was detected as shown above. RESULTS
Histopathology CLINICAL OUTCOME
From June 1990 to February 1991, 32 plasma exchanges were performed, allowing a steady removal of the monoclonal protein with gammaglobulin level at about 0.7 g dl- ~. Swallowing difficulties disappeared and neck weakness improved, no changes were observed in other muscles and in respiratory function. Between March and May 1991, no therapy was administered and the paraproteinemia level increased (gammaglobulin: 1.9 g dl-~). Respiratory capacity deteriorated (vital capacity: 1.36 1). An immunosuppressive therapy was instituted in June 1991: prednisone 80 mg daily for a month, then progressively lowered to 15 mg, and cyclophosphamide 100 mg daily. The gammaglobulin concentration fell to about 0.6 g dlwith a marked decrease in the IgG spike. In February 1993, a 40% improvement in vital capacity (I .901) had occurred and the strength of the quadriceps femoris was significantly increased. Displacement capacities were increased threefold. However, the patient remained very disabled, needing help to stand up from the chair, and using a wheelchair. METHODS
The left deltoid muscle was biopsied. Histological and histochemical stains were used to study 10-/ma-thick frozen sections by standard techniques [9]. Portions of the muscle biopsy
In sections stained with H and E and Gomori trichrome, marked variation in fibre size was found with the presence of many atrophic scattered angulated fibres. Numerous reddish granules were shown by the Gomori trichrome stain (Fig. 1A). Centrally located nuclei were moderately increased. There was no inflammation and necrotic or regenerating fibres were not seen. Atrophic fibres were generally dark with N A D H - T R . There was a type I fibre predominance, and many atrophic fibres lacked staining with myofibrillar ATPase staining (Fig. 1B). By electron microscopy, numerous rods were evident (Fig. 1C), with their characteristic lattice pattern. They were present in structurally modified areas with the loss of thick filaments. Accumulations of rods were mainly seen in atrophic fibres but also occurred at the periphery of some fibres of normal diameter. It took place in the whole fibre when it was very atrophic, or in the periphery of less altered fibres. Small numbers of morphologically normal mitochondria were found.
Immunolabelling By direct immunostaining, muscle biopsy showed positive linear staining for IgG and lambda light chain along the sarcolemmal basement membrane (Fig. l D). Stains for kappa light chain, IgA, IgM, HLA class I, DR antigens were negative. Indirect immunostaining with the patient's globulins revealed no staining.
Late-onset Rod Myopathy
559
~)
Fig. 1. (A) Cryostat section, Gomori trichrome; presence of many atrophic angulated fibres filled with reddish granules, x 160. (B) Cryostat section, myofibrillar ATPase (pH 9.4); type I predominance; spotty absence of staining in a number of atrophic fibres, x 160. (C) Electron micrograph; myofibrillar disorganization and accumulation of numerous rods at the periphery of a muscle fibre, x 15,000. (D) Cryostat section, immunostaining with anti-lambda light chain antibody: thin and uniform deposit at the periphery of the muscle fibre, x 160. (E) Cryostat section, control muscle for immunostaining with anti-lambda antibody: no labelling, x 160.
560
B. EYMARDet al. DISCUSSION
Our observation closely resembles other A O R M cases [3-8]. However, age at onset (31 yr) is lower. As in previous cases, the clinical condition was severe. In contrast with these cases, a partial response to immunosuppressive therapies was obtained. In our case an I g G lambda chain monoclonal paraprotein was present in the serum. In two previous cases o f A O R M , a similar association was reported [4, 7]. G a m m o p a t h y has been described in only one case [7]: the patient had an lgG lambda light chain protein in the serum and C S F with a moderate increase o f plasma ceils in bone m a r r o w biopsy. In contrast with our case, there were no deposits in the muscle by direct immunostaining. Besides the relative frequency o f monoclonal g a m m o p a t h y in A O R M , the involvement o f paraproteinemia in the pathophysiology o f this disease was suggested by two findings: (1) the presence o f deposits o f the same category o f i m m u n o g l o b u l i n (IgG lambda) in the sarcolemma o f the patient's muscle; (2) the favourable clinical response induced by therapies lowering the level o f the monoclonal IgG. These treatments (plasmapheresis, cyclophosphamide, steroids) stopped the severe initial evolution, allowing a moderate gain o f pelvic girdle weakness and a significant improvement o f respiratory capacity. A deterioration in muscle strength shortly followed the interruption o f plasmapheresis, in parallel with an increased a m o u n t o f paraproteinemia. However, the clinical recovery was partial, with the persistence o f a severe weakness of the girdle muscles. The mechanism(s) o f m o n o c l o n a l protein involvement in the pathogenesis o f the disease remain to be demonstrated. In this case, indirect immunostaining procedures failed to show any
binding o f patient's globulins to normal muscle. Furthermore, in contrast with potymyositis, no expression of histocompatibility antigens were found on the muscle sarcolemma. As Dalakas described a subacute m y o p a t h y with numerous rods in H I V patients [10], there is a probable multiplicity o f pathogenic mechanisms, including viral diseases, which m a y lead to A O R M . The potential pathogenic role ofdysproteinemia, even if still unexplained, favours the use in late A O R M o f immunosuppressive therapies including plasma exchanges.
REFERENCES
1. Fardeau M. Congenital myopathies. In: Mastaglia F L, Walton J, eds. Skeletal Muscle Pathology, 2nd Edn, Edinburgh: Churchill Livingstone, 1992: 237-281. 2. Banker B Q. The congenital myopathies. In: Engel A G, Banker B Q, eds. Myology. New York: McGraw-Hill, 1986: 1527-1581. 3. EngelW K, Resnick J S. Late rod myopathy: a newly recognized acquired and progressivedisease. Neurology 1966; 16:308 309. 4. EngelA G. Late onset rod myopathy. Mayo Clin Proc 1966; 41:713 741. 5. Heffernan L P, Rewcastle N B, Humphrey J G. The spectrum of rod myopathies. Arch Neurol 1968; 18:529 542. 6. Kamieniecka A. Late onset myopathy with rod-like particles. Acta Neurol Stand 1973; 49: 547-551. 7. EngelW K, Oberc M A. Abundant nuclear rods in adult onset rod disease. J Neuropathol Exp Neurol 1975; 34: 119 132, 8. Brownell A K W, Gilbert J J, Shaw D T, Garcia B, Wenkebach G F, Lam A K S. Adult onset nemaline myopathy. Neurology 1978; 2,8: 1306-1309. 9. Fardeau M. Caract~ristiques cyotchimiques et ultrastructurales des diff+rents types de fibres musculaires squelettiques extrafusales (cbez rhomme et quelques mammif6res). Ann Anat Pathol 1973; 18:7 34. 10. Dalakas M C, Pezeshkpour G H, Flaherthy M. Progressive nemaline (rod) myopathy associated with HIV infection. N Engl J Med 1987; 317:1602 1603.