Systemic sarcoidosis: the “leopard–man” sign

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Joint Bone Spine 73 (2006) 109–112 http://france.elsevier.com/direct/BONSOI/

Case report

Systemic sarcoidosis: the “leopard–man” sign Fouad Fayad a, Michèle Duet b,c, Philippe Orcel a,c, Frédéric Lioté a,c,* a

Rheumatology Federation, Viggo Petersen Center, Lariboisière Teaching Hospital, Paris (AP-HP), 2, rue Ambroise Paré, 75475 Paris cedex 10, France b Biophysics and Nuclear Medicine Department, Lariboisière Teaching Hospital, Paris, France c Lariboisière-Saint Louis School of Medicine, Paris 7 University, Paris, France Received 2 March 2004; accepted 8 April 2005 Available online 28 September 2005

Abstract Systemic sarcoidosis is often diagnosed late. A 37 year-old man from the Antilles was admitted for evaluation of arthralgia, subcutaneous and cutaneous nodules, multiple enlarged lymph nodes, and an epididymal lump. He had been given a diagnosis of epididymal and nodal tuberculosis but had not responded to antitubercular agents. Gallium-67 scintigraphy showed multiple hot spots in the soft tissues, skin, muscles, mediastinum, and lachrymal glands, producing a diffuse dappled pattern. Magnetic resonance imaging of the thighs confirmed the muscular and subcutaneous involvement. Systemic sarcoidosis was diagnosed. Prednisone therapy was promptly effective. We suggest the term “dappled-body sign” or “leopard-man sign” to designate the heretofore undescribed scintigraphic pattern in our patient. © 2005 Elsevier SAS. All rights reserved. Keywords: Sarcoidosis; Muscle; Scintigraphy; Gallium-67 scintigraphy, MRI

1. Introduction Sarcoidosis is a systemic inflammatory disease of unknown cause characterized by the development of noncaseating epithelioid granulomas within involved organs [1]. Acute sarcoidosis usually presents as Löfgren syndrome (bilateral hilar lymphadenopathy, erythema nodosum, and acute joint disease). Insidious forms, however, are dominated by symptoms related to organ involvement [1]. The clinical manifestations vary widely; among them, genitourinary and cutaneous symptoms usually occur during the course of the disease rather than at presentation. The diagnosis rests on a converging set of clinical features, laboratory test results, pathological findings, and imaging study findings. Atypical presentations and uncommon locations to a single organ may lead to diagnostic challenges. Octreotide or gallium scintigraphy can contribute to the diagnosis, particularly in patients with muscle involvement [2–4]. We report the case of a 37-year-old man in whom the diagnosis was not established until 18 months after symptom onset. Gallium scintigraphy in this patient showed a heretofore undescribed finding, which we called the “leopard-man sign”. * Corresponding author. Tel.: +33 1 49 95 62 91; fax: +33 1 49 95 86 31. E-mail address: [email protected] (F. Lioté). 1297-319X/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.jbspin.2005.04.007

2. Case report A 37-year-old man from the Antilles was admitted to the Rheumatology Department in April 2000 for unclassified polyarthritis, subcutaneous nodules, and a decline in general health. He had a history of atopy. In November 1998, he started experiencing pain in the right scrotal region. A painful lump developed in the right epididymis; it was removed in June 1999 and found to contain numerous epithelioid granulomas, giant cells, and lymphocytes, as well as a few plasma cells, without caseating necrosis. No acid-fast bacteria were seen on the smears, and cultures for pyogenic bacteria and the tubercle bacillus were negative. He had a history of BCG vaccination. Four months later, a biopsy of a right inguinal node showed epithelioid granulomas and giant cells with necrosis. A diagnosis of epididymal and nodal tuberculosis was given. Three-drug antitubercular therapy was started in December 1999 and switched to two-drug therapy in April 2000. In addition, the patient reported joint pain for more than a year involving the knees, ankles, and right wrist. Nonsteroidal antiinflammatory drug therapy given in April 2000 provided no relief. Physical examination showed painless subcutaneous nodules starting around December 1999, polyarthritis, and enlarged submandibular lymph nodes. Sar-

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Fig. 1. Magnetic resonance imaging of the thighs (axial T1-weighted fat-saturation sections after gadolinium injection): multiple, round or oval, high signal nodules throughout the subcutaneous tissue and subfascial region of several muscles. The nodules predominate on the left side.

coidosis was suspected and the patient was admitted in April 2000 for investigations. At admission, the patient reported weight loss of 9 kg over the last year. Polyarthritis of the right wrist, knees, and ankles was found. Multiple painless nodules were felt in the subcutaneous tissue and embedded within the muscles of the thighs and legs; the appearance of the overlying skin was normal. Several lymph nodes less than 1 cm in diameter were felt in the submandibular and right supraclavicular space. Muscle strength, deep tendon reflexes, and cranial nerve function were normal. Findings were normal from physical examination of the heart and lungs. The liver and spleen were normal to palpation, and no abdominal mass was felt. The otorhinolaryngological examination showed bilateral nasal obstruction, which was ascribed to allergic rhinitis. Blood test results were as follows: hemoglobin, 15 g/dl; leukocytes, 6000 per mm3; platelets, 270,000 per mm3; erythrocyte sedimentation rate, 26 mm/h; C-reactive protein, 63 mg/l (N < 5); prothrombin level, 70%; activated partial thromboplastin time ratio, 1.27; calcium, 2.49 mmol/l; creatinine, 75 µmol/l; ASAT, 22 UI/l; ALAT, 10 UI/l; alkaline phosphatase, 73 UI/l; gamma-GT, 38 IU/l; bilirubin, 9 µmol/l; CPK, 114 IU/l (N < 170); LDH, 164 IU/l; aldolase, 4.8 U/l (N < 7.5); serum protein electrophoresis, polyclonal hypergammaglobulinemia (20 g/l); and angiotensin-converting enzyme, 124 U/l (N 35–115). Proteinuria was 0.07 g/24 h and calciuria 15 mmol/24 h (body weight, 84 kg). Synovial fluid from the right knee contained 8500 leukocytes per mm3 with a predominance of macrophages and no microcrystals. Cultures for pyogenic bacteria were negative. A biopsy of a subcutaneous nodule in the left arm showed no evidence of inflammation. Findings were normal from radiographs of the knees, ankles, hands, and sinuses. A chest radiograph, however, disclosed a nodular and micronodular infiltrate of medium profusion predominating in the lower lobes and accompanied with bilateral hilar lymphadenopathy. Computed tomography (CT) of the chest confirmed these findings. Lung function tests evidenced an obstructive pattern that was significantly improved by b-agonist inhalation. The ratio of diffusing capacity of the lung for carbon monoxide over alveolar ventilation was normal. MRI of the muscles and subcutaneous tissue at the thighs disclosed multiple round or oval nodules, sometimes in a rosary-bead arrangement, generating high signal on T1-

weighted fat-saturation postgadolinium images and high signal on STIR sequences. The nodules were disseminated throughout the subcutaneous tissue and in the subfascial muscle tissue of the thighs; they were more numerous on the left side (Figs. 1 and 2). Gallium scintigraphy showed multiple hot spots disseminated throughout the body but predominating in the four limbs. Nodules were seen in the subcutaneous tissue, in both lower lung lobes and the mediastinum, in the lachrymal and parotid glands, and in the nasal mucosa. The result was a dappled appearance of the entire body, for which we suggest the term “leopard-man sign” (Fig. 3). The above-described findings confirmed the diagnosis of systemic sarcoidosis. The history of epididymal and nodal granulomatous disease was ascribed to sarcoidosis. Prednisone was started on May 17, 2000, in a daily dosage of 2/3 mg/kg (50 mg/day). The clinical manifestations improved promptly. Eight months into therapy, the daily dosage was 17.5 mg, the patient was symptom-free without palpable subcutaneous nodules, and laboratory tests were normal. CT showed clearance of the pulmonary nodules. Lung function test results including the diffusing capacity for carbon mon-

Fig. 2. Magnetic resonance imaging of the thighs (coronal STIR section): high signal nodules throughout the muscles and subcutaneous tissue.

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Fig. 3. Gallium-67 muscle scintigraphy: diffuse hot spots in the soft tissues, skin, muscles, mediastinum, and lachrymal glands producing a dappledbody sign in addition to the panda sign visible at the face.

oxide were unchanged. In June 2003, shortly after decreasing the prednisone dosage to less than 5 mg/day, the patient reported recurrent joint pain. Synovitis was found at the wrists, knees, and left ankle, as well as nodules in the thigh and calf muscles. The prednisone dosage was increased to 8 mg/day. In November 2003, the patient was admitted for evaluation of disease control. No nodules were felt in the lower limb muscles. Neurological findings were normal. Serum C-reactive protein was normal (10 mg/l), but muscle enzyme activities were increased (CPK, 451 IU/l and aldolase, 17 IU/l (normal < 7.5). Lung function tests and CT of the chest showed no changes. The daily prednisone dosage was increased to 10 mg. 3. Discussion Involvement of the epididymis followed by spread to the local lymph nodes was inaugural in our patient. This location, together with the histological evidence of giant-cell granuloma and necrosis led to a diagnosis of tuberculosis. The negative cultures and lack of response to antitubercular agents were crucial findings. Later in the course, the presence of lung infiltrates, skin and muscle lesions, and joint manifestations in an individual from the Antilles rapidly suggested systemic sarcoidosis. We will review below the clinical and imaging study features of the muscle manifestations, which were combined in our patient with subcutaneous nodules.

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Asymptomatic muscle involvement is common in systemic sarcoidosis, with about 50–80% of routine muscle biopsies showing abnormalities. Muscle symptoms, in contrast, are found in only 1.4–2.5% of patients [5–7] and are rarely inaugural [8–10]. The earliest description of muscle involvement due to sarcoidosis seems to have been published in 1908. In 1952, Myers emphasized the muscle lesions of systemic sarcoidosis (in Ref. [11]). The first reports in France were published in 1954 (in Ref. [10]). Three clinical patterns are usually distinguished, of which the most common is chronic myopathy (86%) [6]. The typical patient is a postmenopausal woman with known sarcoidiosis [6,8]. The muscle involvement is symmetric, predominates proximally, and usually manifests as muscle weakness and muscle wasting. Patients may report muscle pain. Electrophysiological test results are nonspecific [6]. Little is to be learned from MRI or muscle ultrasonography [3,12]. Gallium67 scintigraphy is the only imaging study that can visualize the muscle lesions and their extent in this form [3]. Muscle biopsy shows epithelioid granulomas without caseating necrosis; muscle fiber atrophy and fibrosis are additional findings [12]. Acute myositis is less common (11%) and occurs in patients younger than 40 years [12,13]. Presenting manifestations consist of marked systemic symptoms and muscle pain, usually with joint manifestations, erythema nodosum, or both [13]. Acute myositis either occurs against a background of chronic myositis or inaugurates the muscle involvement [14]. A symmetric proximal distribution is the rule. Muscle weakness and evidence of inflammation are less common [10]. A case with respiratory muscle involvement has been reported [15]. At the calf, acute myositis may simulate deep venous thrombosis in patients with no other manifestations. Muscle enzyme elevation and electrophysiological abnormalities similar to those seen in polymyositis are common. MRI of the muscles may be normal, as the lesions are small, whereas gallium-67 scintigraphy discloses diffuse hyperactivity [4,16]. Muscle biopsy differentiates sarcoidosis from incipient polymyositis: after immunolabeling, the CD4+/CD8+ ratio if high in sarcoidosis, whereas CD8+ cells predominate in nonnecrotic muscle fibers of patients with polymyositis or inclusion body myositis [17]. A few cases of concomitant sarcoidosis and dermatomyositis have been reported [18]. Nodular or tumor-like myositis is the least common pattern (3% of cases), although it was described first in [6]. The nodules are usually multiple, palpable, and painless. They predominate in the lower limbs, as in our patient. However, myalgia or muscle spasm may be present. Findings are usually normal from muscle strength testing, CPK assays, and electrophysiological testing. Erythema nodosum and subcutaneous sarcoid nodules are clinical differential diagnoses [12]. MRI of the muscles is the best morphological investigation. Axial MRI sections disclose sharply circumscribed oval lesions generating low signal on T1 images and high signal on T2 images compared to the normal adjacent muscle; a central star-shaped region generating low signal on both T1 and

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T2 images denotes fibrosis. Peripheral gadolinium enhancement is seen [3]. MRI has been considered inadequate for differentiating sarcoid nodules from benign or malignant tumors. Thus, combined gallium-67 and dimercaptosuccinic acid (DMSA) Tc (V)99 scintigraphy may be useful to investigate muscle lesions [19]. The panda sign is produced by gallium-67 accumulation in the lachrymal and parotid glands, together with the normal nasopharyngeal uptake, whereas the lambda sign denotes paratracheal and bilateral hilar gallium67 accumulation [20]. We suggest the term “leopard-man sign” to describe the diffuse gallium-67 hot spots due to soft tissue sarcoid lesions in our patient. Histology shows multiple clumps of granulomas with CD4+ cells in the center and CD8+ cells peripherally and in the endomysium [21]. Octreotide scintigraphy may offer greater sensitivity, most notably in patients with chest lesions [2]. Nevertheless, the indications for scintigraphy are limited. They include detection of a silent lesion accessible to biopsy. Scintigraphy has no prognostic value and is not validated for monitoring treatment results. Systemic glucocorticoid therapy in a daily dosage of 0.5– 1 mg is the mainstay of the treatment in patients with muscle sarcoidosis. Myositis and nodular disease usually occur in patients with recent-onset sarcoidosis and respond well to glucocorticoid therapy. In sarcoid myopathy, in contrast, the response is less marked; in addition, glucocorticoid-induced myopathy may develop [22]. Methotrexate has produced promising results [12,23]. Chloroquine or azathioprine has been used in corticoid-resistant or corticoid-dependent forms [24]. Thalidomide and infliximab have been found beneficial in some cases. The effectiveness of these medications seems related to TNF inhibition [25,26].

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