Medical Mycology September 2009, 47, 648652 Case Reports Madura leg due to Exophiala jeanselmei successfully treated with surgery and itraconazole therapy Med Mycol Downloaded from informahealthcare.com by McMaster University For personal use only. JAFFAR A. AL-TAWFIQ*$ & SAMIR S. AMR$ *Internal Medicine Services Division, and $Pathology Services Division, Dhahran Health Center, Saudi Aramco Medical Services Organization, Saudi Aramco, Dhahran, Saudi Arabia Exophiala jeanselmei, also known as Phialophora jeanselmei, is a dematiaceous fungus widely distributed in nature. The organism can cause cutaneous, subcutaneous or systemic infections. An uncommon clinical presentation is eumycetoma, i.e., a subcutaneous infection associated with draining sinuses releasing clumps or granules of the fungus. We describe a case of a long standing mycetoma with several draining sinuses involving the left lower leg of a 47-year-old Saudi Arab male. The disease required extensive surgical excision coupled with intense antifungal chemotherapy to achieve cure. Keywords Exophiala jeanselmei, Madura leg, eumycetoma, dematiaceous fungi Introduction Exophiala jeanselmei is a pigmented (dematiaceous) fungus that is widely distributed in the environment, especially associated with soil, wood, polluted water and sewage [1]. E. jeanselmei usually causes superficial, cutaneous, or subcutaneous infections but may be the etiologic agent of systemic infections [1,2]. Recently, the organism was implicated as the cause of fungemia in 19 patients [3]. However, E. jeanselmei is infrequently responsible for eumycetoma [46]. Here, we describe a patient with prolonged history of eumycetoma caused by this mold which involved his left leg. In addition, we review the available literature on this subject. Case report A 39-year-old Saudi male with diabetes mellitus initially presented in 1991 for evaluation of a mass on his left leg. About 20 years earlier, the patient sustained Received 6 September 2008; Received in final revised form 2 November 2008; Accepted 6 December 2008 Correspondence: Jaffar A. Al-Tawfiq, PO Box 76, Room A-420, Building 61, Dhahran Health Center, Saudi Aramco, Dhahran 31311, Saudi Arabia. Tel: 9663 877 3524; fax: 9663 877 3790; E-mail: jaffar.tawfiq@aramco.com; jaltawfi@yahoo.com – 2009 ISHAM minor trauma related to a wood splinter involving the left lower leg area. He sustained his injury while living in the eastern province of Saudi Arabia and had not traveled outside the region. Subsequently, the patient developed a painless mass that slowly increased in size over the following years. Initial examination in 1991 showed a mass that measured 10 4 cm situated over the anterolateral aspect of the lower third of the left leg. The mass was irregular with nodular protuberance and ill defined margins. Computed axial tomography (CT scan) showed a complex mass, measuring 10 4.0 3.0 cm, of the soft tissue with involvement of the muscles and tendons but with no obvious extension to the bone. There was involvement of segments of the anterior lateral muscle group, as well as the tissues deep to these muscles at certain levels. The considered etiologies were complex lipoma or angiolipoma. In addition, low grade inflammatory processes due to tuberculosis or fungal infections, could not be excluded completely. An excisional biopsy revealed multiple abscesses harboring clumps of fungal hyphae surrounded by neutrophils. The inflammatory process was diagnosed as euomycytoma. He was treated for mycetoma but the details of his treatment are not well documented. The patient reported healing of the lesion site. Eight years later, the patient returned with a recurrent left lower leg mass, which measured 63 cm, with DOI: 10.1080/13693780802669194 Med Mycol Downloaded from informahealthcare.com by McMaster University For personal use only. Successful treatment of Madura leg due to Exophiala jeanselmei multiple sinuses. The lesion had been increasing in size over the previous months. A magnetic resonance imaging (MRI) of the left leg showed a lobular lesion involving the entire anterior compartment and extended superiorly. The mass had heterogeneous signal intensity in both T1- and T2-weighted images with foci of hyperintense signal in T1-weighted images representing mucinous material (Fig. 1). The signal intensity of the underlying bony structures was preserved, as well as the posterior and lateral compartmental muscular structures. The images of the mass enhanced heterogeneously after the introduction of contrast material and the areas of low signal in both the T1- and T2weighted images may represent fibrous tissues or calcifications. He underwent radical excision of the chronic mycetomatous mass with reconstruction of the extensor tendon. Histopathological examination revealed fibrous and aponeurotic connective tissue with adjacent skeletal muscle fibers and fatty tissue. There were areas of abscess formation surrounded by granulomatous type inflammatory reaction with lymphocytes, plasma Fig. 1 A magnetic resonance imaging (MRI) of the left leg showing a lobular lesion involving the entire anterior compartment and extending superiorly. – 2009 ISHAM, Medical Mycology, 47, 648652 649 Fig. 2 Photomicrograph featuring a large clump of fungal hyphae covered by eosinophilic proteinaceous deposit (Splendore-Hoeppli phenomenon), surrounded by neutrophils and adjacent granulomatous inflammation (H&E100). cells, histiocytes and multinucleated giant cells. The abscesses showed numerous neutrophils surrounding irregular granules, which were composed of numerous fungal hyphae clumped together and covered by thick eosinophilic proteinaceous deposits, the so-called Splendore-Hoeppli phenomenon (Fig. 2). Examination of PAS and Gomori’s silver methenamine stained sections revealed tangles and clumps of fungal hyphae, some with bulbous forms, surrounded by proteinaceous deposits and neutrophils (Fig. 3). Clumps of fungal granules were extracted from the submitted tissue and sent to the microbiology lab for mycological evaluation. Cultures inoculated with these granules yielded Exophiala jeanselmei. The organism was also identified at the Laboratory of the Medicine and Pathology Department of the Mayo Clinic, Rochester (USA) but Fig. 3 High power photomicrograph of clumps demonstrating fungal hyphae, some with bulbous forms (PAS stain400). 650 Al-Tawfiq & Amr molecular techniques were not available at that time. The patient then received itraconazole therapy (200 mg orally twice daily) for one year with resolution of symptoms. A repeat MRI showed previous surgical resection of the anterior compartment of the left leg with loss of the muscular volume. There were scattered enhanced scar tissues but no evidence of recurrence of the previously described lesion, with no evidence of bone marrow edema or periosteal reaction (Fig. 4). He was followed up for an additional six years and had no relapse. Med Mycol Downloaded from informahealthcare.com by McMaster University For personal use only. Discussion The term mycetoma was created by Carter in 1861 to distinguish this condition from other types of tumors [7]. The name Madura foot is derived from a district in India where it was first described. Mycetoma is a localized, chronic infection of skin and subcutaneous tissues. The disease is characterized by the development of abscesses, draining sinuses, and the formation of fistulae discharging granules. The grains contain aggregates of the causative organisms that may be discharged onto the skin surface through multiple sinuses. Eumycetoma is associated with fungi in contrast to the actinomycetoma that are caused by filamentous bacteria. Of the total cases of mycetoma, 60% are actinomycetomas and 40% are eumycetoma. Fig. 4 A repeat MRI showing previous surgical resection of the anterior compartment of the left leg with loss of the muscular volume. There were scattered enhanced scar tissues but no evidence of recurrence of the previously described lesion. The causative organisms are found in the soils and plants of tropical and subtropical regions [8]. Mycetoma infection occurs at the site of organism’s inoculation which is frequently caused by penetrating trauma on the foot. The disease develops gradually and is usually painless. Bone involvement is an ultimate feature that may be localized or extensive in nature. In a study of 29 patients from Saudi Arabia, bone destruction was observed in 37.5% [9]. However, as in the current case, the tendons and nerves are usually not involved in the disease [9]. There might be difference in the rate of bone involvement depending on the causative organism as reported in cases due to the Pseudallescheria complex [10]. Mycotic infections of skin and subcutaneous tissues caused by black fungi are divided into different clinical entities, i.e., subcutaneous phaeohyphomycosis, phaeomycotic cysts and mycetoma. Phaeohyphomycosis and mycotic cysts are distinguished from mycetoma by the absence of grain formation. In a study of 21 mycotic cysts from Saudi Arabia, including eight phaeomycotic cysts, trauma due to wood splinters were identified in 11 cases [11]. There are over 30 different fungal species that have been reported associated with eumycetoma in humans, with the most common etiologic agent being members of the genus Madurella [8]. In a study of 31 cases of mycetoma in Saudi Arabia, 18 (58%) were due to Streptomyces somaliensis, 10 (32%) to Madurella mycetomatis, and one each to Actinomadura madurae, Nocardia asteroides, and an unidentified species of Cladosporium [12]. In another study of 21 mycetoma Saudi Arabia cases, none were due to E. jeanselmei [13]. This is not surprising since while E. jeanselmei is the most important agent of subcutaneous phaeohyphomycosis, it is an infrequent cause of mycetoma [46]. A review of the literature revealed 18 cases of eumycetoma due to E. jeanselmei (Table 1) affecting various anatomical sites [46,1428] and 14 of the cases were summarized previously by Severo et al. [25]. Of the total cases, 16 (84.2%) were reported in males and the mean age (9SD) was 46.4915.8 years. The male predominance is probably related to the involvement of males in farming and gardening. Almost all patients had lower extremity involvement [46,14,15,1721, 2328] except one patient who had involvement of the right hand [16] and a second in which the left index finger was the site of infection [20]. Similar to the current case, most of the patients had no underlying immune deficiency [4,6], but one case involving E. jeanselmei developed in a 73-year-old man with idiopathic CD4  T-cell lymphocytopenia [26]. Radiographic imaging may delineate the extent of tissue involvement in mycetoma. In the present case, – 2009 ISHAM, Medical Mycology, 47, 648652 Successful treatment of Madura leg due to Exophiala jeanselmei Med Mycol Downloaded from informahealthcare.com by McMaster University For personal use only. Table 1 651 Summary of data from cases of Eumycetoma due to Exophiala jeanselmei infection Reference Country Gender Age (yrs) Body Site Duration (yrs) [4] [5] [6] [14,15] [16] [17] [18] [19] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] Current case India Bangladesh Trinidad Martinique USA Korea Pakistan India India Philippines Paraguay Thailand Jamaica Brazil Brazil Germany USA/Panamanian India Saudi Arabia M M M M M M M M M M F F M M M M F M M 35 65 44 49 67 35 Middle age 49 28 35 39 19 53 49 74 73 36 8 39 Left foot Right foot Right foot Right foot Right hand Right ankle Right ankle Right foot Left thigh Right foot Right foot Left index finger Right ankle Left foot Right foot Right leg Right leg Left foot Left leg 8 15 20 3 2 8 30 NA NA 1 5 5 10 NA 50 NA 37 1 15 NAnot available. the MRI showed heterogeneous signal intensity in both T1- and T2-weighted images with foci of hyperintense signal in T1-weighted images, as described previously [29,30]. In another report, it was difficult to distinguish through the T2-weighted image between the edema in the subcutaneous tissues and muscles [31]. Other investigators described the ‘dot-in-circle’ sign on the MRI which represents a collection of small highintensity lesions surrounded by low-intensity matrix on T2-weighted or T1-weighted post-gadolinium images [32]. Histological examination of the current case revealed the presence of the Splendore-Hoeppli phenomenon surrounding clumps of fungi. This phenomenon refers to radiating or annular amorphous eosinophilic deposits of host-derived materials and possibly of parasite antigens. It is usually formed around fungi, helminths or their ova, or bacterial colonies and, on rare occasions, suture material in tissues. It is usually surrounded by inflammatory cells including eosinophils, neutrophils, histiocytes, lymphocytes and multinucleated giant cells. The infiltrate varies from one case to another. Immunohistochemical studies reveal the presence of immunoglobulin deposition or deposits of eosinophilic major basic protein [33]. It was initially described in Brazil by Splendore in 1908, who thought that it was a new species of Sporotrichum. The phenomenon had been reported most commonly in association with cases of botryomycosis. The latter represents a conglomerate of – 2009 ISHAM, Medical Mycology, 47, 648652 bacteria rather than a fungal infection [34]. In addition, various other infectious processes have been associated with this phenomenon including actinomycosis [35], aspergillosis [36] and zygomycosis, particularly basidiomycosis [37]. The treatment of eumycetoma usually requires surgical excision of the lesions. However, a combination of medical and surgical intervention is required to prevent recurrence of the disease [27]. Current recommendations are 1 to 2 months of antifungal therapy, surgical excision, and another 6 to 12 months of antifungal therapy [38]. In vitro susceptibility testing showed that E. jeanselmei is susceptible to itraconazole [39] and promising results were obtained with this antifungal in cases of phaeohyphomycosis caused by this organism [40]. In addition, triazoles have emerged as promising therapeutic options for eumycetoma [41]. In conclusion, E. jeanselmei is a rare cause of eumycetoma. The clinical presentation is not specific and radiographic evaluation with an MRI may help in the examination of the extent of the disease. The treatment usually requires both a medical and a surgical approach. Acknowledgment The authors wish to acknowledge the use of Saudi Aramco Medical Services Organization (SAMSO) facilities for the data and study, which resulted in this paper. Opinions expressed in this article are those of the author and not necessarily of SAMSO. 652 Al-Tawfiq & Amr Declaration of interest: The authors report no conflicts of interest. 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