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Distal inflammatory myopathy: Unusual presentation of polymyositis or new entity?
Neuromuscular Disorders 18 (2008) 493–500 www.elsevier.com/locate/nmd
Distal inflammatory myopathy: Unusual presentation of polymyositis or new entity? Dalia Dimitri a, Odile Dubourg b,c,*, Thierry Maisonobe c,d, Emmanuel Fournier b,d, Brigitte Ranque e, Pascal Laforeˆt b, Jean-Marie Mussini f, Christian Pagnoux g, Anthony Be´hin b, Thomas Papo e, Olivier Benveniste b,h, Bruno Eymard b, Serge Herson b,h a
Centre de Re´fe´rence des Maladies Neuromusculaires ‘‘Garches-Necker-Mondor-Hendaye”, APHP, INSERM U841, CHU Henri Mondor, 51 boulevard du Mare´chal de Lattre de Tassigny, 94010 Cre´teil, France b Centre de Re´fe´rence des Maladies Neuromusculaires ‘‘Paris-Est”, APHP, CHU Pitie´-Salpeˆtrie`re, 47 Bd de l’hoˆpital, 75651 Paris Cedex 13, France c Laboratoire de Neuropathologie, CHU Pitie´-Salpeˆtrie`re, 47 Bd de l’hoˆpital, 75651 Paris Cedex 13, France d Fe´de´ration de Neurophysiologie clinique, CHU Pitie´-Salpeˆtrie`re, 47 Bd de l’hoˆpital, 75651 Paris Cedex 13, France e Service de Me´decine Interne, Groupe Hospitalier Bichat–Claude-Bernard, 46, rue Henri-Huchard, 75877 Paris Cedex 18, France f Centre de Re´fe´rence des Maladies Neuromusculaires Nantes-Angers, CHU Nantes, Hoˆtel Dieu, 1 Place Alexis-Ricordeau, 44093 Nantes Cedex 1, France g Service de Me´decine Interne, CHU Cochin-Port-Royal, APHP, 27, rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France h Service de Me´decine Interne, CHU Pitie´-Salpeˆtrie`re, 47 Bd de l’hoˆpital, 75651 Paris Cedex 13, France Received 13 December 2007; received in revised form 19 February 2008; accepted 14 April 2008
Abstract New classification of idiopathic inflammatory myopathy (IIM) defined three major entities, polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (s-IBM). We report the clinical, electrophysiological and pathological characteristics of three patients with a rare form of IIM not fulfilling the diagnostic criteria for any of these three major entities. The three patients presented with a subacute, distal asymmetrical weakness in upper limbs. Muscle biopsy showed an active myositis, with necrosis and regeneration, T cell infiltrates with invasion of non-necrotic fibers, without rimmed vacuoles, and diffuse major histocompatibility complex-I (MHC-I) immunostaining in muscle fibers. All patients responded to immunosuppressive agents. Seven others cases were identified in the literature. It is important to recognize this atypical presentation as it seems to respond to immunosuppressive agents. Ó 2008 Elsevier B.V. All rights reserved. Keywords: Inflammatory myopathy; Distal myopathy; Polymyositis; Inclusion body myositis; Malignant thymoma
1. Introduction Idiopathic inflammatory myopathies (IIM) are divided into three major diseases: polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (s-IBM) [1,2]. In more recent classifications, other categories have been added (non-specific myositis, immune-mediated nec* Corresponding author. Address: Laboratoire de Neuropathologie, Hoˆpital Pitie´-Salpeˆtrie`re, 47 Bd de l’hoˆpital, 75013 Paris, France. Tel.: +33 (1) 42 16 18 84; fax: +33 (1) 42 16 18 99. E-mail address: [email protected] (O. Dubourg).
0960-8966/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2008.04.015
rotizing myopathy, and overlap myositis) [3,4]. Distal muscle involvement is typical of s-IBM, but only occurs in more advanced cases in PM and DM, in association with proximal weakness. However, rare forms of IIM essentially involving distal muscles and different from s-IBM have been reported [5–11]. We report three patients with a distal inflammatory myopathy involving the upper limbs with a misleading presentation suggesting motor neuropathy or s-IBM. We describe the clinical, pathological and electrophysiological features of our three patients and discuss the nosology of this distal myositis in the light of other reported cases and of the diagnostic criteria of IIM [1–4].
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As immunosuppressive therapy produced improvement in all three cases, recognizing and treating this type of myositis with distal presentation is particularly important. 2. Patients and methods 2.1. Patients From January 2000 to March 2004, we identified three patients with an atypical distal presentation of myositis. Clinical data were obtained from clinical examination and a review of the patients’ case notes. Strength was evaluated with the MRC (Medical Research Council) grading scale. All patients were screened for a malignancy with chest and abdominal CT, gynecologic examination and mammography or prostate evaluation. Electromyography (EMG) was performed in the three patients. Serum CK, liver enzymes, complete blood cells count, erythrocyte sedimentation rate, C reactive protein and assays for antinuclear antibodies (ANA), anti-ENA (anti-extractable nuclear antigens), anti-double-stranded-DNA, anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor were performed. 2.2. Muscle pathology All muscle biopsies described above were obtained before treatment with corticosteroids. All three patients had at least two biopsies. Muscle samples were conventionally processed for light microscopy using standard procedures. Frozen and paraffin-embedded sections were stained using hematoxylin–eosin (H&E), Masson and modified Gomori trichrome, Sudan black, periodic acid-Schiff (PAS), and histoenzymatic reactions including NADH-tetrazolium reductase, succinate dehydrogenase, cytochrome C oxidase. Expressions of major histocompatibility complex (MHC)-1, membrane attack complex (MAC)/C5b-9, CD3, CD4, CD8, CD20, CD68 (Dakocytomation, Glostrup, Denmark), dystrophin, sarcoglycans, and dysferlin (Novocastra, Newcastle Upon Tyne, UK) were evaluated by immunoperoxidase assay performed on frozen sections by using an automated immunostainer (VentanaÒ, Tucson, Az). Electron microscopy was performed for the three patients. 3. Results 3.1. Clinical features and laboratory data We reviewed data from our three patients and the seven other cases with distal muscular involvement identified from our literature search [5–11]. Data are shown in Table 1. 3.2. Patient 1 A 65-year-old man was admitted in February 2000 for a progressive asymmetrical weakness in hands. He had a his-
tory of mild, non-erosive rheumatoid arthritis diagnosed in 1990 and treated for over 3 years with prednisone (6 mg/ day), which was stopped a few days before the onset. In June 1999, he developed progressive weakness in wrist and finger extension in the right hand, then in the left one. Examination showed asymmetrical weakness in wrist and hand muscles, predominating in extensors (extension of fingers graded at 2 to 3/5) in the right hand, without atrophy. Lower limb muscles, tendon reflexes, sensory and skin examination were normal. Serum CK was 468 IU/L (normal <160 IU/L). ANA was positive (1:2560) and anti-DNA antibody was negative. Both rheumatoid factor and anti-CCP antibodies (278 U/ml, normal <50 IU/L) were positive. EMG showed reduced-duration small-amplitude motor unit potentials (so-called ‘‘myopathic changes”) in distal upper limbs with mild spontaneous activity. Biopsy of right brachioradialis showed an active inflammatory myopathy without rimmed vacuoles. The patient was given 1200 mg of IV methylprednisolone (IVMP), followed by prednisone 10 mg/day. He remained stable and CK varied between 276 and 796 IU/L. In September 2003, the weakness in the hands worsened and a severe weakness in deltoid and biceps muscles (graded at 2/5) with marked atrophy appeared. CK increased to 1000 IU/L. EMG showed an extension of myopathic changes in proximal upper limbs with active fibrillation. A deltoid biopsy showed an active inflammatory myopathy. He was treated with IVMP (1 g daily for 3 days) followed by prednisone (80 mg/day) and methotrexate (20 mg/week). He improved markedly in the following month (distal muscles graded at 4 to 5/5, left biceps muscle at 3/5, right biceps and deltoid muscles at 5/5). CK normalized. In 2004, prostatectomy was performed because of an adenocarcinoma. In 2005, while on prednisone 15 mg/day and methotrexate 20 mg/week, muscle strength was graded at 4 to 5/5. 3.3. Patient 2 A 37-year-old man presented in December 2001 with subacute weakness in the hands. He had a history of lympho-epithelial thymoma with pericardic invasion, treated with thymectomy and radiotherapy in November 2000 and an euthyroid multinodular goitre. He was considered in complete remission of thymoma, when in April 2001, he developed left shoulder pain, followed by weakness in the left hand in June. One month later, weakness developed in the right hand. Examination showed asymmetrical weakness in wrist and finger extensors (graded at 2 to 3/5 in the left and 3 to 4/5 in the right), and milder weakness in wrist and finger flexors, interossei and proximal muscles (left brachioradialis graded at 3/5, biceps and triceps muscles graded at 4/5). Atrophy in the hand and forearm muscles, predominating in the left was noted (Fig. 1). Lower limb muscles, tendon reflexes, sensory and skin examination were normal. EMG showed myopathic changes in distal muscles of the upper limbs with mild fibrillation and
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Table 1 Clinical, laboratory and electrophysiological features Eaton [5]
Hollinrake [6]
Bates [7]
Stark [8]
Age of onset (years)/ sex
45/F
59/F
60/M
45/F
Disease duration when diagnosed (biopsy)
3 yrs
6 yrs
2 yrs
6 yrs
Weakness distribution at onset UL/LL LL Distal/proximal D Asymmetrical/ ND symmetrical
UL D A
LL P ND
UL D A
Weakness distribution at peak severity UL/LL LL UL: distal > proximal LL: distal > proximal D P Axial/facial /+ Time to maximum ND severity
UL+LL D P D P / 6 yrs
UL+LL P+D P+D +/+ 2 yrs
UL+LL D P / 6 yrs
+ +
+
+ +
ACTH, pred (improvement) 9 mo Mild distal weakness in four limbs
Pred (improvement) Several mo improved
Pred (arrest of the process) 5 yrs 1 relapse steady
Muscle pain Atrophy Dysphagia DM-like rash Dyspnoea Treatment Follow-up Outcome Auto-immune disease Cancer Creatine kinase (maximum) (IU/L) Autoantibodies ESR/CRP EMG Muscle biopsy
+ + ND Cortisone ND ND ND ND ND
Psoriasis 620 (10N)
4690 (?)
456 (5N)
ND 27 Myopathic ‘‘Interstitial myositis” without details
AAN 1:40 rheumatoid factor 24 Myopathic Tibialis anterior, triceps; extensive endomysial mononuclear infiltrates
AAN 85 Myopathic Deltoid; perivascular infiltrates; perimysial and endomysial fibrosis
ND 2 Myopathic Biceps brachii; endomysial and perivascular florid mononuclear infiltrates
Van Kasteren [9]
Sundaram [10]
Marconi [11]
Case 1
Case 2
Case 3
49/F 6 yrs LL D A UL+LL D P D +/ 6 yrs + +
50/F 7 yrs LL D A LL
64/ M 9 mo UL D A UL D P
+
+
+
37/ M 7 mo UL D A UL+LL D P D / 11 mo + +
41/ F 2 yrs UL D A UL D P
P+D / 7 yrs
20/M 1 mo LL D A UL+LL P+D P+D / 8 yrs
Corticoid, aza (arrest of the process) 7 yrs steady
Pred (improvement) 8 yrs 1 relapse, steady
Pred, mtx (improvement) 5 yrs 1 relapse, strength near to normal Rheumatoid arthritis
Pred, IVIg (resistance), mtx, aza (improvement) 6 yrs 1 relapse, strength near normal
Pred, IVIg (improvement) 6 yrs Severe weakness
Pred (improvement) 1 yr Strength near normal
/ 8 mo
/ 2 yrs +
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D. Dimitri et al. / Neuromuscular Disorders 18 (2008) 493–500 (continued on next page)
Table 1 (continued) Van Kasteren [9]
Sundaram [10]
Marconi [11]
166 (2.5N) AAN, Rheumatoid factor
558 (4.5N) ?
2632 (53N) Rheumatoid factor+
5 Myopathic
20 Myopathic
Tibialis anterior and quadriceps; interstitial and perivascular infiltrates mainly T lymphocyte and rare macrophages
Quadriceps; scattered lymphocytes and macrophages interstitial infiltrates
35 Myopathic and neurogenic Quadriceps and deltoid; inflammatory perivascular infiltrates
Case 1
Case 2
Prostate
Thymoma Thyroid 400 (2.5N)
1000 (2.5N) Rheumatoid factor+ 40/ N Myopathic Brachioradialis, deltoid; see Table 2
Case 3
N Anti-CCP Ab+
ND/ N Myopathic
17/ N Myopathic
2 Brachioradialis; see Table 2
Deltoid; 2 brachioradialis; see Table 2
3.4. Patient 3
Fig. 1. Patient 2: This photograph of the arms demonstrates the asymmetrical atrophy of hand and forearm muscles.
neuromuscular junction study was normal. Serum CK was 400 IU/L. Antibodies to Ach receptor were slightly positive (3.7 nmol/L; normal <2 nmol/L). Muscle biopsy of the left brachioradialis showed an inflammatory myopathy. Prednisone (0.7 mg/kg/day) was started with mild improvement and CK normalization. Four months later, thyroidectomy of his multinodular goitre was performed. Pathological examination revealed a papillary unifocal carcinoma. In March 2000, prednisone was tapered to 0.3 mg/kg/day because of a central serous chorioretinopathy and methotrexate (30 mg/week) and IVIg (2 g/kg) were started. A few days later, he worsened with muscle pain, increased weakness in distal upper limb muscles and new asymmetrical weakness in foot dorsiflexion (graded at 2 to 3). CK was normal. IVMP at 500 mg daily for 3 days was followed by prednisone 1 mg/kg/day and azathioprine 100 mg/day. Progressive improvement began 7 months after starting treatment. In 2004, immunosuppressive agents were stopped and he had mild residual weakness and hand atrophy (wrist extensors graded at 3 to 4/5). In April 2005, a pleural localization of the thymoma was diagnosed without any muscular aggravation. He was still in remission of his myopathy in 2007.
A 43-year-old woman was admitted to the hospital in November 2003 for a progressive weakness in the hands. She had a history of treated hypothyroidism. In 2000, she developed progressive weakness in wrist and finger extensors of the left hand followed by the right. In 2001, she experienced muscle pain and fatigue in lower limbs. She stopped working as cleaning woman. Her first deltoid biopsy in 2003 showed an active inflammatory myopathy. Examination showed severe bilateral weakness in finger extensors (1 to 2/5) and wrist extensors (2/5) predominating in the left hand (Fig. 2), milder weakness in the wrist and finger flexors and in the right biceps muscle (3/5). Lower limbs strength, tendon reflexes, sensory and skin examination were normal. EMG showed myopathic changes in the upper limbs, particularly in wrist extensors, without fibrillation. Neuromuscular junction study was normal. CK and thyroid testing were normal. ANA (1:160) and anti-CCP (100 U/mL) were positive without rheumatoid factor. Antibodies to Ach receptor were negative. Thoracic CT showed interstitial infiltrates in basal fields and pulmonary functional tests showed mild reduction of diffusion capacity. Brachioradialis muscle biopsy showed necrosis and regeneration with inflammation. She
Fig. 2. Patient 3: This photograph of the arms demonstrates the weakness of wrist extensors.
D. Dimitri et al. / Neuromuscular Disorders 18 (2008) 493–500
was treated with a tapering dose of oral prednisone, beginning at 80 mg/day in August 2004. One month later, IVIg 2 g/kg/course, was added because of the inefficacy and side effects of prednisone. In October 2005, after 13 IVIg infusions, prednisone was stopped. The patient partially improved (finger extensors (2 to 3/5), wrist extensors (3/ 5), wrist and finger flexors and right biceps muscle (4/5)), but she could start again with her work. In May 2006, she was stable. A third brachioradialis muscle biopsy was performed in November 2006, still showing an active myositis without rimmed vacuoles. 3.5. Electromyography Motor and sensory nerve conduction studies including median, ulnar and radial nerves showed neither conduction slowing nor conduction block in all three patients. Neuromuscular transmission was studied by 3 Hz repetitive nerve stimulation (RNS) in deltoid, anconeus, extensor digitorum communis (ECD) and abductor digiti minimi (ADM) muscles. RNS was repeated every minute over 4 min after a 1 min exercise. During the disease course, results showed neither decrement with 3 Hz RNS nor post-exercise exhaustation nor post-exercise compound
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action potential (CMAP) increment in all three patients, including patient 2 who had a thymoma. CMAP recorded in radial, median and ulnar nerve territories were reduced in amplitude in patient 2. Needle EMG revealed reducedduration small-amplitude motor unit potentials (so-called ‘‘myopathic changes”) in distal muscles of the upper limbs. In all three patients, myopathic pattern reflected the clinical topography of deficits, with a predilection for the forearm muscles (in particular, brachioradialis, extensor carpi radialis, extensor digitorum communis, and flexor carpi radialis muscles), contrasting with the sparing of the lower limbs. There was no neurogenic pattern. In patient 1, the extension of myopathic changes to the proximal muscles of upper limbs occurred according to clinical aggravation. Abnormal spontaneous activity, with fibrillation, sharp wave positive potentials and pseudo-myotonic discharges, was minute at presentation (patients 1 and 2), and became more obvious with clinical aggravation (patient 1). 3.6. Pathology Muscle biopsy showed in all three patients inflammatory infiltrates in perimysial, endomysial and perivascular regions, focal invasion of non-necrotic fibers and diffuse fiber
Table 2 Muscle pathology in patients with distal myositis Case 1
Case 2
Case 3
Time from disease onset to biopsy (months)
7
10
36
Muscles
Brachioradialis
Brachioradialis
Brachioradialis
Pathological features Lymphocytic inflammation Perimysial Endomysial Perivascular In non-necrotic muscle fibers
+ + + +
+ + + +
+ + + +
+ + +
+ + +
+
+ +
+ +
+ +
+
+
+
+
+
Muscle fiber size Atrophy Hypertrophy Grouped small round fibers Perifascicular atrophy Muscle fiber pathology Necrosis Scattered Regional (large groups) Regeneration Rimmed vacuoles COX negative fibers Increased endomysial connective tissue Immunohistochemistry MHC-1 Diffuse Perifascicular Scattered C5b-9 deposition Muscle fibers Capillaries Lymphocytes type CD3/CD20 CD4/CD8 a
Confined to necrotic and inflammatory area.
+
+
+
+a +
+
CD3 > CD20 CD4 > CD8
CD3 > CD20 CD4 = CD8
CD3 > CD20 CD4 = CD8
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atrophy, regeneration and necrosis (Table 2 and Figs. 3 and 4). Inflammatory infiltrates consisted mainly of T lymphocytes. The proportion of CD4+ T lymphocytes was equivalent to CD8+ in patients 2 and 3 and greater in patient 1. MHC-I molecules immunostaining in muscle fibers was diffuse in patients 1 and 3 and scattered in patient 2. Perifascicular atrophy and rimmed vacuoles were absent. Endomysial connective tissue was moderately increased in patients 1 and 2. Capillary pathology, including deposition of the terminal components of complement was absent. All three patients had normal dysferlin immunostaining. Electron microscopic examination did not find 15–18 nm intranuclear or intracytoplasmic tubulofilamentous inclusions. 4. Discussion We describe three patients with an inflammatory myopathy presenting with distal and asymmetrical weakness of upper limb muscles, who responded to immunosuppressive
therapy. The initial presentation in our patients was misleading, since the deficit involved predominantly finger and wrist extensors, mimicking radial palsy. However, a thorough examination revealed that weakness was not confined to a single nerve territory and was not associated with a sensory deficit. ALS or motor neuropathy with conduction blocks could be suspected, but fasciculations and cramps were absent, and, with respect to ALS, signs of upper motor neuron involvement were lacking. CK was normal or moderately raised. EMG showed reduced-duration small-amplitude motor unit potentials (so-called ‘‘myopathic changes”), mainly involving the clinically affected muscles, and confirmed the absence of motor neuropathy (neither conduction block nor large-amplitude motor unit potentials). No patient had DM- like rash. Some clinical features, as response to immunosuppressive therapy, association with cancer and with auto-antibodies, and interstitial lung disease (patient 3) were in accordance with usual clinical fea-
Fig. 3. Cryostat sections stained with hematoxylin–eosin showing signs of inflammatory myopathy with endomysial (A, patient 1; C, patient 3) and perivascular (D, patient 2) infiltrates, focal invasion of non-necrotic fibers (E, patient 1; F, patient 2), necrotic fibers (B, patient 2) and variation in fiber size (A–F).
D. Dimitri et al. / Neuromuscular Disorders 18 (2008) 493–500
tures of PM or overlap myositis, but so did not the distal distribution of weakness [4,12]. Indeed, although a late distal involvement may occur in severe cases, diagnostic criteria for PM require symmetric and proximal pattern of muscle involvement, which was absent in our patients [1,3]. Conversely, distal muscle involvement and asymmetry are common features in s-IBM. However, initial weakness rarely involves distal muscles and upper limbs [2,13]. At the time of diagnosis, distal weakness occurs in about 50% of patients with s-IBM, but is greater than proximal weakness in 35% and initial weakness involves upper limbs in 10% only [13]. No patient fulfills the clinical requirements for a diagnostic of s-IBM, neither at onset nor after at least five years of disease course [2]. Actually, the pattern of distal upper limbs involvement was different from sIBM, since weakness was more severe in wrist and finger extensors than in flexors. Moreover, s-IBM usually responds poorly to immunosuppressive treatments. Rare cases of granulomatous inflammatory myopathies with distal presentation have been described [14,15]. Granuloma and multinucleated giant cells were not seen in our cases. Moreover, some cases of myositis in the context of myasthenia gravis and thymoma have been described [16]. It could have been discussed in patient 2, who had a thymoma, but study of the neuromuscular junction was normal in upper limb distal muscles. Finally, distal muscle involvement may occur in some muscular dystrophies, like dysferlinopathy, in which inflammation can occasionally be seen [17,18]. However, the upper limb muscular involvement, the good response to immunosuppressive treatments
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and the normal immunostaining for dysferlin exclude this diagnosis in our patients. Seven other patients with distal myositis and response to immunosuppressive treatments were identified (Table 1) [5– 11]. Two patients presented with distal upper limbs weakness and atrophy [6,8]. Extension to lower limbs occurred in the disease course. In the five remaining cases, lower limbs were involved with extension to upper limbs in 3, and marked atrophy in all [5,7,9–11]. Muscle biopsies in our three patients showed necrosis and regeneration, T cell infiltrates with invasion of nonnecrotic fibers, and MHC-I molecules expression in muscle fibers (Table 2). Pathological features thus fulfill the criteria for PM [3]. In PM (and s-IBM), there seems to be an MHC-I restricted cytotoxicity mediated by cytotoxic CD8+ T cells, which are the prominent type of lymphocytes in muscle biopsy [12]. However, the CD4/CD8 proportion may vary in PM, and prominence of CD4+ was reported in PM associated with HTLV1 [19]. In our patients, the proportion of CD4+ T lymphocytes was equivalent to CD8+ in 2 patients and greater in 1. The absence of rimmed vacuoles at light microscopy and tubulofilamentous inclusions in electron microscopy make the diagnosis of s-IBM highly improbable. The diagnosis of DM was excluded because there were neither deposits of C5b9 in capillaries nor perifascicular atrophy [3]. None of our patients fulfills the clinical diagnostic criteria for IIM, but morphological findings were in accordance with those of PM [1–3]. Recognizing this unusual presentation may be of importance, to avoid an erroneous diagnosis
Fig. 4. Immunohistochemistry on cryostat sections showing diffuse MHC-I immunoreactivity (A, patient 1), CD8+ lymphocytes perivascular infiltrate (B, patient 2), CD3+ (C, patient 2) and CD8+ (D, patient 1) lymphocytes invading non-necrotic fibers.
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of s-IBM which may lead to exclude patients from effective treatments. Nevertheless, because of the small number of reported cases, it remains unclear whether distal myositis represents a new disease entity or a particular presentation of PM. Acknowledgements This work was supported by the Association Francßaise contre les Myopathies (AFM), by the Assistance Publique des Hoˆpitaux de Paris (APHP), the Universite´ Pierre et Marie Curie, the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM). References [1] Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344–7. [2] Griggs RC, Askanas V, DiMauro S, et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705–13. [3] Hoogendijk JE, Amato AA, Lecky BR, et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10–12 October 2003, Naarden, The Netherlands. Neuromuscul Disord 2004;14:337–45. [4] Troyanov Y, Targoff IN, Tremblay JL, et al. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine (Baltimore) 2005;84:231–49. [5] Eaton LM. The perspective of neurology in regard to polymyositis; a study of 41 cases. Neurology 1954;4:245–63.
[6] Hollinrake K. Polymyositis presenting as distal muscle weakness. A case report. J Neurol Sci 1969;8:479–84. [7] Bates D, Stevens JC, Hudgson P. ‘‘Polymyositis” with involvement of facial and distal musculature. One form of the fascioscapulohumeral syndrome? J Neurol Sci 1973;19:105–8. [8] Stark RJ. Polymyositis presenting with severe weakness involving only one arm. Aust N Z J Med 1978;8:544–6. [9] Van Kasteren BJ. Polymyositis presenting with chronic progressive distal muscular weakness. J Neurol Sci 1979;41:307–10. [10] Sundaram MB, Ashenhurst EM. Polymyositis presenting with distal and asymmetrical weakness. Can J Neurol Sci 1981;8:147–9. [11] Marconi G, Ronchi O, Taiuti R. Polymyositis with severe distal muscular involvement. Acta Neurol (Napoli) 1982;4:340–6. [12] Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003;362:971–82. [13] Lotz BP, Engel AG, Nishino H, Stevens JC, Litchy WJ. Inclusion body myositis. Observations in 40 patients. Brain 1989;112:727–47. [14] Robberecht W, Theys P, Lammens M, Leenders J. Distal myopathy as the presenting manifestation of sarcoidosis. J Neurol Neurosurg Psychiatry 1995;59:642–3. [15] Roux KL, Streichenberger N, Vial C, et al. Granulomatous myositis: a clinical study of thirteen cases. Muscle Nerve 2007;35:171–7. [16] Raschilas F, Mouthon L, Andre MH, et al. Concomitant polymyositis and myasthenia gravis reveal malignant thymoma. A case report and review of the literature. Ann Med Intern (Paris). 1999;150(Sep.):370–3. [17] Gallardo E, Rojas-Garcia R, de Luna N, et al. Inflammation in dysferlin myopathy: immunohistochemical characterization of 13 patients. Neurology 2001;57:2136–8. [18] Mastaglia FL, Lamont PJ, Laing NG. Distal myopathies. Curr Opin Neurol 2005;18:504–10. [19] Saito M, Higuchi I, Saito A, et al. Molecular analysis of T cell clonotypes in muscle-infiltrating lymphocytes from patients with human T lymphotropic virus type 1 polymyositis. J Infect Dis 2002;186:1231–41.
Distal inflammatory myopathy: Unusual presentation of polymyositis or new entity? Dalia Dimitri a, Odile Dubourg b,c,*, Thierry Maisonobe c,d, Emmanuel Fournier b,d, Brigitte Ranque e, Pascal Laforeˆt b, Jean-Marie Mussini f, Christian Pagnoux g, Anthony Be´hin b, Thomas Papo e, Olivier Benveniste b,h, Bruno Eymard b, Serge Herson b,h a
Centre de Re´fe´rence des Maladies Neuromusculaires ‘‘Garches-Necker-Mondor-Hendaye”, APHP, INSERM U841, CHU Henri Mondor, 51 boulevard du Mare´chal de Lattre de Tassigny, 94010 Cre´teil, France b Centre de Re´fe´rence des Maladies Neuromusculaires ‘‘Paris-Est”, APHP, CHU Pitie´-Salpeˆtrie`re, 47 Bd de l’hoˆpital, 75651 Paris Cedex 13, France c Laboratoire de Neuropathologie, CHU Pitie´-Salpeˆtrie`re, 47 Bd de l’hoˆpital, 75651 Paris Cedex 13, France d Fe´de´ration de Neurophysiologie clinique, CHU Pitie´-Salpeˆtrie`re, 47 Bd de l’hoˆpital, 75651 Paris Cedex 13, France e Service de Me´decine Interne, Groupe Hospitalier Bichat–Claude-Bernard, 46, rue Henri-Huchard, 75877 Paris Cedex 18, France f Centre de Re´fe´rence des Maladies Neuromusculaires Nantes-Angers, CHU Nantes, Hoˆtel Dieu, 1 Place Alexis-Ricordeau, 44093 Nantes Cedex 1, France g Service de Me´decine Interne, CHU Cochin-Port-Royal, APHP, 27, rue du Faubourg Saint-Jacques, 75679 Paris Cedex 14, France h Service de Me´decine Interne, CHU Pitie´-Salpeˆtrie`re, 47 Bd de l’hoˆpital, 75651 Paris Cedex 13, France Received 13 December 2007; received in revised form 19 February 2008; accepted 14 April 2008
Abstract New classification of idiopathic inflammatory myopathy (IIM) defined three major entities, polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (s-IBM). We report the clinical, electrophysiological and pathological characteristics of three patients with a rare form of IIM not fulfilling the diagnostic criteria for any of these three major entities. The three patients presented with a subacute, distal asymmetrical weakness in upper limbs. Muscle biopsy showed an active myositis, with necrosis and regeneration, T cell infiltrates with invasion of non-necrotic fibers, without rimmed vacuoles, and diffuse major histocompatibility complex-I (MHC-I) immunostaining in muscle fibers. All patients responded to immunosuppressive agents. Seven others cases were identified in the literature. It is important to recognize this atypical presentation as it seems to respond to immunosuppressive agents. Ó 2008 Elsevier B.V. All rights reserved. Keywords: Inflammatory myopathy; Distal myopathy; Polymyositis; Inclusion body myositis; Malignant thymoma
1. Introduction Idiopathic inflammatory myopathies (IIM) are divided into three major diseases: polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (s-IBM) [1,2]. In more recent classifications, other categories have been added (non-specific myositis, immune-mediated nec* Corresponding author. Address: Laboratoire de Neuropathologie, Hoˆpital Pitie´-Salpeˆtrie`re, 47 Bd de l’hoˆpital, 75013 Paris, France. Tel.: +33 (1) 42 16 18 84; fax: +33 (1) 42 16 18 99. E-mail address: [email protected] (O. Dubourg).
0960-8966/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.nmd.2008.04.015
rotizing myopathy, and overlap myositis) [3,4]. Distal muscle involvement is typical of s-IBM, but only occurs in more advanced cases in PM and DM, in association with proximal weakness. However, rare forms of IIM essentially involving distal muscles and different from s-IBM have been reported [5–11]. We report three patients with a distal inflammatory myopathy involving the upper limbs with a misleading presentation suggesting motor neuropathy or s-IBM. We describe the clinical, pathological and electrophysiological features of our three patients and discuss the nosology of this distal myositis in the light of other reported cases and of the diagnostic criteria of IIM [1–4].
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As immunosuppressive therapy produced improvement in all three cases, recognizing and treating this type of myositis with distal presentation is particularly important. 2. Patients and methods 2.1. Patients From January 2000 to March 2004, we identified three patients with an atypical distal presentation of myositis. Clinical data were obtained from clinical examination and a review of the patients’ case notes. Strength was evaluated with the MRC (Medical Research Council) grading scale. All patients were screened for a malignancy with chest and abdominal CT, gynecologic examination and mammography or prostate evaluation. Electromyography (EMG) was performed in the three patients. Serum CK, liver enzymes, complete blood cells count, erythrocyte sedimentation rate, C reactive protein and assays for antinuclear antibodies (ANA), anti-ENA (anti-extractable nuclear antigens), anti-double-stranded-DNA, anti-cyclic citrullinated peptide (CCP) antibodies and rheumatoid factor were performed. 2.2. Muscle pathology All muscle biopsies described above were obtained before treatment with corticosteroids. All three patients had at least two biopsies. Muscle samples were conventionally processed for light microscopy using standard procedures. Frozen and paraffin-embedded sections were stained using hematoxylin–eosin (H&E), Masson and modified Gomori trichrome, Sudan black, periodic acid-Schiff (PAS), and histoenzymatic reactions including NADH-tetrazolium reductase, succinate dehydrogenase, cytochrome C oxidase. Expressions of major histocompatibility complex (MHC)-1, membrane attack complex (MAC)/C5b-9, CD3, CD4, CD8, CD20, CD68 (Dakocytomation, Glostrup, Denmark), dystrophin, sarcoglycans, and dysferlin (Novocastra, Newcastle Upon Tyne, UK) were evaluated by immunoperoxidase assay performed on frozen sections by using an automated immunostainer (VentanaÒ, Tucson, Az). Electron microscopy was performed for the three patients. 3. Results 3.1. Clinical features and laboratory data We reviewed data from our three patients and the seven other cases with distal muscular involvement identified from our literature search [5–11]. Data are shown in Table 1. 3.2. Patient 1 A 65-year-old man was admitted in February 2000 for a progressive asymmetrical weakness in hands. He had a his-
tory of mild, non-erosive rheumatoid arthritis diagnosed in 1990 and treated for over 3 years with prednisone (6 mg/ day), which was stopped a few days before the onset. In June 1999, he developed progressive weakness in wrist and finger extension in the right hand, then in the left one. Examination showed asymmetrical weakness in wrist and hand muscles, predominating in extensors (extension of fingers graded at 2 to 3/5) in the right hand, without atrophy. Lower limb muscles, tendon reflexes, sensory and skin examination were normal. Serum CK was 468 IU/L (normal <160 IU/L). ANA was positive (1:2560) and anti-DNA antibody was negative. Both rheumatoid factor and anti-CCP antibodies (278 U/ml, normal <50 IU/L) were positive. EMG showed reduced-duration small-amplitude motor unit potentials (so-called ‘‘myopathic changes”) in distal upper limbs with mild spontaneous activity. Biopsy of right brachioradialis showed an active inflammatory myopathy without rimmed vacuoles. The patient was given 1200 mg of IV methylprednisolone (IVMP), followed by prednisone 10 mg/day. He remained stable and CK varied between 276 and 796 IU/L. In September 2003, the weakness in the hands worsened and a severe weakness in deltoid and biceps muscles (graded at 2/5) with marked atrophy appeared. CK increased to 1000 IU/L. EMG showed an extension of myopathic changes in proximal upper limbs with active fibrillation. A deltoid biopsy showed an active inflammatory myopathy. He was treated with IVMP (1 g daily for 3 days) followed by prednisone (80 mg/day) and methotrexate (20 mg/week). He improved markedly in the following month (distal muscles graded at 4 to 5/5, left biceps muscle at 3/5, right biceps and deltoid muscles at 5/5). CK normalized. In 2004, prostatectomy was performed because of an adenocarcinoma. In 2005, while on prednisone 15 mg/day and methotrexate 20 mg/week, muscle strength was graded at 4 to 5/5. 3.3. Patient 2 A 37-year-old man presented in December 2001 with subacute weakness in the hands. He had a history of lympho-epithelial thymoma with pericardic invasion, treated with thymectomy and radiotherapy in November 2000 and an euthyroid multinodular goitre. He was considered in complete remission of thymoma, when in April 2001, he developed left shoulder pain, followed by weakness in the left hand in June. One month later, weakness developed in the right hand. Examination showed asymmetrical weakness in wrist and finger extensors (graded at 2 to 3/5 in the left and 3 to 4/5 in the right), and milder weakness in wrist and finger flexors, interossei and proximal muscles (left brachioradialis graded at 3/5, biceps and triceps muscles graded at 4/5). Atrophy in the hand and forearm muscles, predominating in the left was noted (Fig. 1). Lower limb muscles, tendon reflexes, sensory and skin examination were normal. EMG showed myopathic changes in distal muscles of the upper limbs with mild fibrillation and
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Table 1 Clinical, laboratory and electrophysiological features Eaton [5]
Hollinrake [6]
Bates [7]
Stark [8]
Age of onset (years)/ sex
45/F
59/F
60/M
45/F
Disease duration when diagnosed (biopsy)
3 yrs
6 yrs
2 yrs
6 yrs
Weakness distribution at onset UL/LL LL Distal/proximal D Asymmetrical/ ND symmetrical
UL D A
LL P ND
UL D A
Weakness distribution at peak severity UL/LL LL UL: distal > proximal LL: distal > proximal D P Axial/facial /+ Time to maximum ND severity
UL+LL D P D P / 6 yrs
UL+LL P+D P+D +/+ 2 yrs
UL+LL D P / 6 yrs
+ +
+
+ +
ACTH, pred (improvement) 9 mo Mild distal weakness in four limbs
Pred (improvement) Several mo improved
Pred (arrest of the process) 5 yrs 1 relapse steady
Muscle pain Atrophy Dysphagia DM-like rash Dyspnoea Treatment Follow-up Outcome Auto-immune disease Cancer Creatine kinase (maximum) (IU/L) Autoantibodies ESR/CRP EMG Muscle biopsy
+ + ND Cortisone ND ND ND ND ND
Psoriasis 620 (10N)
4690 (?)
456 (5N)
ND 27 Myopathic ‘‘Interstitial myositis” without details
AAN 1:40 rheumatoid factor 24 Myopathic Tibialis anterior, triceps; extensive endomysial mononuclear infiltrates
AAN 85 Myopathic Deltoid; perivascular infiltrates; perimysial and endomysial fibrosis
ND 2 Myopathic Biceps brachii; endomysial and perivascular florid mononuclear infiltrates
Van Kasteren [9]
Sundaram [10]
Marconi [11]
Case 1
Case 2
Case 3
49/F 6 yrs LL D A UL+LL D P D +/ 6 yrs + +
50/F 7 yrs LL D A LL
64/ M 9 mo UL D A UL D P
+
+
+
37/ M 7 mo UL D A UL+LL D P D / 11 mo + +
41/ F 2 yrs UL D A UL D P
P+D / 7 yrs
20/M 1 mo LL D A UL+LL P+D P+D / 8 yrs
Corticoid, aza (arrest of the process) 7 yrs steady
Pred (improvement) 8 yrs 1 relapse, steady
Pred, mtx (improvement) 5 yrs 1 relapse, strength near to normal Rheumatoid arthritis
Pred, IVIg (resistance), mtx, aza (improvement) 6 yrs 1 relapse, strength near normal
Pred, IVIg (improvement) 6 yrs Severe weakness
Pred (improvement) 1 yr Strength near normal
/ 8 mo
/ 2 yrs +
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D. Dimitri et al. / Neuromuscular Disorders 18 (2008) 493–500 (continued on next page)
Table 1 (continued) Van Kasteren [9]
Sundaram [10]
Marconi [11]
166 (2.5N) AAN, Rheumatoid factor
558 (4.5N) ?
2632 (53N) Rheumatoid factor+
5 Myopathic
20 Myopathic
Tibialis anterior and quadriceps; interstitial and perivascular infiltrates mainly T lymphocyte and rare macrophages
Quadriceps; scattered lymphocytes and macrophages interstitial infiltrates
35 Myopathic and neurogenic Quadriceps and deltoid; inflammatory perivascular infiltrates
Case 1
Case 2
Prostate
Thymoma Thyroid 400 (2.5N)
1000 (2.5N) Rheumatoid factor+ 40/ N Myopathic Brachioradialis, deltoid; see Table 2
Case 3
N Anti-CCP Ab+
ND/ N Myopathic
17/ N Myopathic
2 Brachioradialis; see Table 2
Deltoid; 2 brachioradialis; see Table 2
3.4. Patient 3
Fig. 1. Patient 2: This photograph of the arms demonstrates the asymmetrical atrophy of hand and forearm muscles.
neuromuscular junction study was normal. Serum CK was 400 IU/L. Antibodies to Ach receptor were slightly positive (3.7 nmol/L; normal <2 nmol/L). Muscle biopsy of the left brachioradialis showed an inflammatory myopathy. Prednisone (0.7 mg/kg/day) was started with mild improvement and CK normalization. Four months later, thyroidectomy of his multinodular goitre was performed. Pathological examination revealed a papillary unifocal carcinoma. In March 2000, prednisone was tapered to 0.3 mg/kg/day because of a central serous chorioretinopathy and methotrexate (30 mg/week) and IVIg (2 g/kg) were started. A few days later, he worsened with muscle pain, increased weakness in distal upper limb muscles and new asymmetrical weakness in foot dorsiflexion (graded at 2 to 3). CK was normal. IVMP at 500 mg daily for 3 days was followed by prednisone 1 mg/kg/day and azathioprine 100 mg/day. Progressive improvement began 7 months after starting treatment. In 2004, immunosuppressive agents were stopped and he had mild residual weakness and hand atrophy (wrist extensors graded at 3 to 4/5). In April 2005, a pleural localization of the thymoma was diagnosed without any muscular aggravation. He was still in remission of his myopathy in 2007.
A 43-year-old woman was admitted to the hospital in November 2003 for a progressive weakness in the hands. She had a history of treated hypothyroidism. In 2000, she developed progressive weakness in wrist and finger extensors of the left hand followed by the right. In 2001, she experienced muscle pain and fatigue in lower limbs. She stopped working as cleaning woman. Her first deltoid biopsy in 2003 showed an active inflammatory myopathy. Examination showed severe bilateral weakness in finger extensors (1 to 2/5) and wrist extensors (2/5) predominating in the left hand (Fig. 2), milder weakness in the wrist and finger flexors and in the right biceps muscle (3/5). Lower limbs strength, tendon reflexes, sensory and skin examination were normal. EMG showed myopathic changes in the upper limbs, particularly in wrist extensors, without fibrillation. Neuromuscular junction study was normal. CK and thyroid testing were normal. ANA (1:160) and anti-CCP (100 U/mL) were positive without rheumatoid factor. Antibodies to Ach receptor were negative. Thoracic CT showed interstitial infiltrates in basal fields and pulmonary functional tests showed mild reduction of diffusion capacity. Brachioradialis muscle biopsy showed necrosis and regeneration with inflammation. She
Fig. 2. Patient 3: This photograph of the arms demonstrates the weakness of wrist extensors.
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was treated with a tapering dose of oral prednisone, beginning at 80 mg/day in August 2004. One month later, IVIg 2 g/kg/course, was added because of the inefficacy and side effects of prednisone. In October 2005, after 13 IVIg infusions, prednisone was stopped. The patient partially improved (finger extensors (2 to 3/5), wrist extensors (3/ 5), wrist and finger flexors and right biceps muscle (4/5)), but she could start again with her work. In May 2006, she was stable. A third brachioradialis muscle biopsy was performed in November 2006, still showing an active myositis without rimmed vacuoles. 3.5. Electromyography Motor and sensory nerve conduction studies including median, ulnar and radial nerves showed neither conduction slowing nor conduction block in all three patients. Neuromuscular transmission was studied by 3 Hz repetitive nerve stimulation (RNS) in deltoid, anconeus, extensor digitorum communis (ECD) and abductor digiti minimi (ADM) muscles. RNS was repeated every minute over 4 min after a 1 min exercise. During the disease course, results showed neither decrement with 3 Hz RNS nor post-exercise exhaustation nor post-exercise compound
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action potential (CMAP) increment in all three patients, including patient 2 who had a thymoma. CMAP recorded in radial, median and ulnar nerve territories were reduced in amplitude in patient 2. Needle EMG revealed reducedduration small-amplitude motor unit potentials (so-called ‘‘myopathic changes”) in distal muscles of the upper limbs. In all three patients, myopathic pattern reflected the clinical topography of deficits, with a predilection for the forearm muscles (in particular, brachioradialis, extensor carpi radialis, extensor digitorum communis, and flexor carpi radialis muscles), contrasting with the sparing of the lower limbs. There was no neurogenic pattern. In patient 1, the extension of myopathic changes to the proximal muscles of upper limbs occurred according to clinical aggravation. Abnormal spontaneous activity, with fibrillation, sharp wave positive potentials and pseudo-myotonic discharges, was minute at presentation (patients 1 and 2), and became more obvious with clinical aggravation (patient 1). 3.6. Pathology Muscle biopsy showed in all three patients inflammatory infiltrates in perimysial, endomysial and perivascular regions, focal invasion of non-necrotic fibers and diffuse fiber
Table 2 Muscle pathology in patients with distal myositis Case 1
Case 2
Case 3
Time from disease onset to biopsy (months)
7
10
36
Muscles
Brachioradialis
Brachioradialis
Brachioradialis
Pathological features Lymphocytic inflammation Perimysial Endomysial Perivascular In non-necrotic muscle fibers
+ + + +
+ + + +
+ + + +
+ + +
+ + +
+
+ +
+ +
+ +
+
+
+
+
+
Muscle fiber size Atrophy Hypertrophy Grouped small round fibers Perifascicular atrophy Muscle fiber pathology Necrosis Scattered Regional (large groups) Regeneration Rimmed vacuoles COX negative fibers Increased endomysial connective tissue Immunohistochemistry MHC-1 Diffuse Perifascicular Scattered C5b-9 deposition Muscle fibers Capillaries Lymphocytes type CD3/CD20 CD4/CD8 a
Confined to necrotic and inflammatory area.
+
+
+
+a +
+
CD3 > CD20 CD4 > CD8
CD3 > CD20 CD4 = CD8
CD3 > CD20 CD4 = CD8
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atrophy, regeneration and necrosis (Table 2 and Figs. 3 and 4). Inflammatory infiltrates consisted mainly of T lymphocytes. The proportion of CD4+ T lymphocytes was equivalent to CD8+ in patients 2 and 3 and greater in patient 1. MHC-I molecules immunostaining in muscle fibers was diffuse in patients 1 and 3 and scattered in patient 2. Perifascicular atrophy and rimmed vacuoles were absent. Endomysial connective tissue was moderately increased in patients 1 and 2. Capillary pathology, including deposition of the terminal components of complement was absent. All three patients had normal dysferlin immunostaining. Electron microscopic examination did not find 15–18 nm intranuclear or intracytoplasmic tubulofilamentous inclusions. 4. Discussion We describe three patients with an inflammatory myopathy presenting with distal and asymmetrical weakness of upper limb muscles, who responded to immunosuppressive
therapy. The initial presentation in our patients was misleading, since the deficit involved predominantly finger and wrist extensors, mimicking radial palsy. However, a thorough examination revealed that weakness was not confined to a single nerve territory and was not associated with a sensory deficit. ALS or motor neuropathy with conduction blocks could be suspected, but fasciculations and cramps were absent, and, with respect to ALS, signs of upper motor neuron involvement were lacking. CK was normal or moderately raised. EMG showed reduced-duration small-amplitude motor unit potentials (so-called ‘‘myopathic changes”), mainly involving the clinically affected muscles, and confirmed the absence of motor neuropathy (neither conduction block nor large-amplitude motor unit potentials). No patient had DM- like rash. Some clinical features, as response to immunosuppressive therapy, association with cancer and with auto-antibodies, and interstitial lung disease (patient 3) were in accordance with usual clinical fea-
Fig. 3. Cryostat sections stained with hematoxylin–eosin showing signs of inflammatory myopathy with endomysial (A, patient 1; C, patient 3) and perivascular (D, patient 2) infiltrates, focal invasion of non-necrotic fibers (E, patient 1; F, patient 2), necrotic fibers (B, patient 2) and variation in fiber size (A–F).
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tures of PM or overlap myositis, but so did not the distal distribution of weakness [4,12]. Indeed, although a late distal involvement may occur in severe cases, diagnostic criteria for PM require symmetric and proximal pattern of muscle involvement, which was absent in our patients [1,3]. Conversely, distal muscle involvement and asymmetry are common features in s-IBM. However, initial weakness rarely involves distal muscles and upper limbs [2,13]. At the time of diagnosis, distal weakness occurs in about 50% of patients with s-IBM, but is greater than proximal weakness in 35% and initial weakness involves upper limbs in 10% only [13]. No patient fulfills the clinical requirements for a diagnostic of s-IBM, neither at onset nor after at least five years of disease course [2]. Actually, the pattern of distal upper limbs involvement was different from sIBM, since weakness was more severe in wrist and finger extensors than in flexors. Moreover, s-IBM usually responds poorly to immunosuppressive treatments. Rare cases of granulomatous inflammatory myopathies with distal presentation have been described [14,15]. Granuloma and multinucleated giant cells were not seen in our cases. Moreover, some cases of myositis in the context of myasthenia gravis and thymoma have been described [16]. It could have been discussed in patient 2, who had a thymoma, but study of the neuromuscular junction was normal in upper limb distal muscles. Finally, distal muscle involvement may occur in some muscular dystrophies, like dysferlinopathy, in which inflammation can occasionally be seen [17,18]. However, the upper limb muscular involvement, the good response to immunosuppressive treatments
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and the normal immunostaining for dysferlin exclude this diagnosis in our patients. Seven other patients with distal myositis and response to immunosuppressive treatments were identified (Table 1) [5– 11]. Two patients presented with distal upper limbs weakness and atrophy [6,8]. Extension to lower limbs occurred in the disease course. In the five remaining cases, lower limbs were involved with extension to upper limbs in 3, and marked atrophy in all [5,7,9–11]. Muscle biopsies in our three patients showed necrosis and regeneration, T cell infiltrates with invasion of nonnecrotic fibers, and MHC-I molecules expression in muscle fibers (Table 2). Pathological features thus fulfill the criteria for PM [3]. In PM (and s-IBM), there seems to be an MHC-I restricted cytotoxicity mediated by cytotoxic CD8+ T cells, which are the prominent type of lymphocytes in muscle biopsy [12]. However, the CD4/CD8 proportion may vary in PM, and prominence of CD4+ was reported in PM associated with HTLV1 [19]. In our patients, the proportion of CD4+ T lymphocytes was equivalent to CD8+ in 2 patients and greater in 1. The absence of rimmed vacuoles at light microscopy and tubulofilamentous inclusions in electron microscopy make the diagnosis of s-IBM highly improbable. The diagnosis of DM was excluded because there were neither deposits of C5b9 in capillaries nor perifascicular atrophy [3]. None of our patients fulfills the clinical diagnostic criteria for IIM, but morphological findings were in accordance with those of PM [1–3]. Recognizing this unusual presentation may be of importance, to avoid an erroneous diagnosis
Fig. 4. Immunohistochemistry on cryostat sections showing diffuse MHC-I immunoreactivity (A, patient 1), CD8+ lymphocytes perivascular infiltrate (B, patient 2), CD3+ (C, patient 2) and CD8+ (D, patient 1) lymphocytes invading non-necrotic fibers.
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of s-IBM which may lead to exclude patients from effective treatments. Nevertheless, because of the small number of reported cases, it remains unclear whether distal myositis represents a new disease entity or a particular presentation of PM. Acknowledgements This work was supported by the Association Francßaise contre les Myopathies (AFM), by the Assistance Publique des Hoˆpitaux de Paris (APHP), the Universite´ Pierre et Marie Curie, the Institut National de la Sante´ et de la Recherche Me´dicale (INSERM). References [1] Bohan A, Peter JB. Polymyositis and dermatomyositis (first of two parts). N Engl J Med 1975;292:344–7. [2] Griggs RC, Askanas V, DiMauro S, et al. Inclusion body myositis and myopathies. Ann Neurol 1995;38:705–13. [3] Hoogendijk JE, Amato AA, Lecky BR, et al. 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10–12 October 2003, Naarden, The Netherlands. Neuromuscul Disord 2004;14:337–45. [4] Troyanov Y, Targoff IN, Tremblay JL, et al. Novel classification of idiopathic inflammatory myopathies based on overlap syndrome features and autoantibodies: analysis of 100 French Canadian patients. Medicine (Baltimore) 2005;84:231–49. [5] Eaton LM. The perspective of neurology in regard to polymyositis; a study of 41 cases. Neurology 1954;4:245–63.
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