Mycetoma: A review

Am J Clin Dermatol 2006; 7 (5): 315-321 1175-0561/06/0005-0315/$39.95/0

REVIEW ARTICLE

 2006 Adis Data Information BV. All rights reserved.

Mycetoma A Review Vanessa Lichon1 and Amor Khachemoune2 1 2

University of Illinois, Chicago, Illinois, USA Department of Dermatology, New York University School of Medicine, New York, New York, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 1. Historical Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 2. Epidemiology and Etiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 3. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 4. Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 5. Differential Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 6. Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 6.1 Type I Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 6.2 Type II Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 6.3 Type III Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 6.4 Other Diagnostic Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 7. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 7.1 Eumycetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318 7.2 Actinomycetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320

Abstract

Mycetoma is a chronic granulomatous infection that is present worldwide and endemic in tropical and subtropical regions. The infection is caused by the traumatic inoculation of a fungus (eumycetoma) or a bacterium (actinomycetoma) and generally remains localized, causing cutaneous and subcutaneous tissue swelling, nodule formation, and drainage through sinus tracts. This review details the history of mycetoma, which may date as far back as the Byzantine period (300–600 AD), the epidemiology of the disease, which is characterized by an endemic region located between the latitudes of 15° south and 30° north, and the clinical presentation and treatment of mycetoma, focusing on the differences between eumycete and actinomycete infections. Diagnosis is established by identifying the type of grains found in the discharge, which guides treatment. Mycetoma caused by bacteria can usually be managed effectively with antibacterial medication alone, while infections with fungi require antifungal medication and surgery. Without proper treatment, mycetoma can lead to deformity, amputation, and death.

Mycetoma, or maduromycosis, is a chronic granulomatous infection that is caused either by a fungus (eumycetoma) or by a bacterium (actinomycetoma).[1-3] Although mycetoma is not endemic in the US, the continual influx of immigrants from areas where the disease is endemic creates a need for increased awareness and education regarding the clinical presentation and treatment of this disease. Mycetoma is not contagious and typically

remains localized, involving cutaneous and subcutaneous tissue, fascia, and bone.[2,3] Clinically, mycetoma is characterized by painless subcutaneous swelling with nodules that develop and drain through sinus tracts.[1,4] The organisms causing mycetoma aggregate into grains or sclerotia and are found in the discharge.[2,3] Without treatment, this disease may lead to severe local tissue destruction, requiring surgical amputation.[1]

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1. Historical Perspective The oldest known case of mycetoma may date as far back as the Byzantine period (300–600 AD), with possible evidence from an adult skeleton suggesting mycetoma based on morphologic changes in the bone.[5] The first written reference to mycetoma is found in the ancient Indian religious book Atharva Veda, where it is mentioned as “pada valmikam,” or “anthill foot.”[6] In the early 18th century, French missionaries recorded the first cases of mycetoma in India.[7] The first description of mycetoma found in the medical literature was by Godfrey in 1846, who referred to the condition as “morbus tuberculosis pedis.”[8] In 1860, Carter[9] used the term ‘mycetoma’ to describe this disease. Mycetoma was divided into two separate categories, based on etiology (actinomycosis or true fungi [eumycetes]), by Pinoy in 1913.[10] 2. Epidemiology and Etiology Although mycetoma is found worldwide, its exact incidence is unknown because of the slow, chronic nature of the disease and late presentation by the majority of individuals with the condition.[11] Mycetoma is endemic in tropical and subtropical areas, and the majority of disease occurs in the ‘mycetoma belt,’ which stretches between the latitudes of 15° south and 30° north.[1,2,4] Within this belt are countries such as Sudan, Somalia, Senegal, India, Yemen, Mexico, Venezuela, Colombia, and Argentina.[1,4] Regions in the mycetoma belt are characterized by short rainy seasons that last for 4–6 months with fairly consistent daily temperatures (30–37°C) and relative humidity of 60–80%, followed by dry seasons of 6–8 months with variable daytime temperatures (45–60°C) and relative humidity of 12–18%.[1] These alternating weather conditions may contribute to the survival of the causative organisms.[1] While most mycetomas are limited to these regions, there have been occasional case reports outside the mycetoma belt, including in the US[12-14] and Europe.[15,16] Mycetoma is more common in individuals who have more frequent and direct contact with the field environment, such as farmers, herdsmen, and other field laborers.[1,4,17] Males are more likely to be affected than females, with the ratio ranging from approximately 3 : 1 to 5 : 1 within the literature.[1,4,18,19] Researchers are unsure of the exact cause of this discrepancy, and one study[20] suggests that progesterone levels in females may inhibit growth of certain causative species. Most infections occur between the ages of 20 and 40 years and are not considered to be transmissible from animals to people or from human to human.[1,4] The most common cause of mycetoma worldwide is eumycetes, particularly Madurella mycetomatis, which causes >70% of cases in certain regions of Central Africa, including Sudan.[1] Mycetoma is especially endemic and severely debilitat 2006 Adis Data Information BV. All rights reserved.

ing in Sudan, where Abbott reported 1231 cases occurring over a 2.5-year period.[21] Other causative organisms (table I) include M. grisea, Leptosphaeria senegalensis, and Scedosporium apiospermum.[1,22] Interestingly, the predominant source also varies by region. For example, in Central America and Mexico, mycetoma is more commonly caused by the actinomycetes Nocardia brasiliensis, Streptomyces somaliensis, Actinomadura madurae, and A. pelletierii.[2,22] In the US, mycetoma is most commonly caused by the fungus Pseudallescheria boydii.[22,23] 3. Pathogenesis Mycetoma is categorized as a subcutaneous infection because it is primarily limited to subcutaneous tissue and dermis with minimal, rare systemic disease.[2,22] All subcutaneous mycoses are caused by fungi or bacteria that enter the skin via a penetrating injury, often a thorn prick or splinter.[1,3] Recently, this route has been disputed because of case reports lacking a history of trauma.[4] The incubation period for the disease is variable and not well defined; some individuals present with symptoms lasting several weeks and others with symptoms lasting years.[14,24,25] Often, the patient’s exact recall of the trauma is not reliable.[18] Furthermore, these details are difficult to investigate because of late presentation by patients (after obvious draining or swelling), lack of accessible healthcare facilities, and fear of amputation.[1,3,14] 4. Clinical Presentation The characteristic clinical triad for mycetoma is swollen tissue (figure 1), draining sinuses, and identification of grains from the discharge.[17] Initially, some individuals may report a feeling of pain or discomfort at the site,[3] while others may not recall any direct trauma.[14] Inoculation is followed by development of a painless subcutaneous nodule that spreads slowly.[1-3] Usually, this nodule is round and firm,[4] but it may also be soft, lobulated or, rarely, cystic.[26] As the nodule increases in size, secondary nodules and papules may develop with accompanying sinuses that drain serous, serosanguineous, or purulent discharge.[1,2,4] Over time, some of the sinuses close and heal, while new ones form.[4] The overlying skin may be shiny with local hyperhidrosis and is usually hyperpigmented but may also be hypopigmented.[4,19,27] Abscesses occur under the surface of the skin and as the disease progresses, the lesions extend into bony tissue, causing small cavities (2–10mm) to develop.[3,4] If untreated, bony involvement can be extensive and devastating, leading to complete bone destruction.[3] Much later and more rarely in the disease, lesions may affect nerves and tendons.[4,28] Local lymphadenopathy is common with small and shotty lymph nodes, and may result from secondary bacterial infection, spread of mycetoma, or immune complex Am J Clin Dermatol 2006; 7 (5)

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Table I. Causative organisms of mycetoma and corresponding appearance of grains[1,2,22,23] Organism

Color of grain

Eumycetes Acremonium falciforme

White

A. kiliense

White

A. recifei

White

Cylindrocarpon cyanescens

White

C. destructans

White

Pseudallescheria boydii

White

Fusarium oxysporum

White

F. solani

White

F. moniliforme

White

Neotestudina rosatii

White

Polycytella hominis

White

Aspergillus nidulans

White

Plenodomus avramii

Black

Corynespora cassiicola

Black

Curvularia geniculata

Black

C. lunata

Black

Leptosphaeria senegalensis

Black

L. thompkinsii

Black

Madurella grisea

Black

Pseudochaetosphaeronema larense

Black

Pyrenochaeta mackinnonii

Black

P. romeroi

Black

M. mycetomatis

Black

Exophiala jeanselmei

Black

Phialophora verrucosa

Black

A. flavus

Green

Actinomycetes Streptomyces somaliensis

Yellow/brown

Actinomadura madurae

White/yellow/pink

A. pellitieri

Red

Actinomyces israelii

White/yellow

Nocardia asteroides

White

N. brasiliensis

White

N. caviae

White/yellow

N. farcinica

White/yellow

N. transvalensis

White

N. dassonvillei

Cream

Throughout active disease, the sinus discharge is composed of organisms that produce distinctively colored grains, or sclerotia, when observed under a microscope.[4,23] These grains, which help to identify the causative organism and guide treatment of the disease, vary in size and consistency and may be black, white, yellow, red, or a mix of colors.[4,23] Mycetoma is typically unilateral, and most often (≈70–80%) the foot is the primary site of infection, followed by the hands (≈12%), legs, and knee joints (table II).[1,4,23] Individuals infected with actinomycetes exhibit a more rapid, progressive clinical disease with increased inflammation, local destruction, and quicker bone invasion compared with those infected with eumycetes (table III), who have well-defined, slower growing lesions that stay encapsulated longer.[4,17,22] 5. Differential Diagnosis The differential diagnosis of mycetoma includes soft tissue tumors such as lipoma, fibroma, fibrolipoma, sarcomas, and malignant melanoma, as well as chronic osteomyelitis.[4,17] Further considerations include tuberculosis, Kaposi sarcoma, and other subcutaneous mycoses such as sporotrichosis and chromoblastomycosis (table IV).[4,17] 6. Diagnosis A variety of modalities exist to diagnose mycetoma, the most definite of which is to obtain a sample of discharge and visualize its grains.[22] This sample can be obtained from any open sinus or by deep surgical biopsy.[1,22] Use of a variety of stains, including 20% potassium hydroxide, acid-Schiff, or Grocott’s methenamine silver, allows visualization of grains and fungal and actinomycete filaments.[22] Actinomycetes are usually observed with granules

deposition as part of the local immune response to infection; continual lymphatic spread is rare (≈1–3% of cases).[2,4,28] Chronic infection may lead to disability, distortion, and deformity, and may be fatal if untreated.[4]  2006 Adis Data Information BV. All rights reserved.

Fig. 1. Characteristic swollen foot with draining sinuses in a patient with mycetoma. Am J Clin Dermatol 2006; 7 (5)

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Table II. Sites of mycetoma infection[1] Occurrence

Site

Common

Feet (≈70–80%) Hands (≈12%) Legs Knee joints

Highly endemic regions

Arm Head/neck

6.3 Type III Reaction

The type III reaction is characterized by a well organized epithelioid granuloma that contains Langerhans’ giant cells.[4] Occasionally, remnants of fungal material can be seen within the center of the granuloma.[4] Other inflammatory and histologic changes are similar to those seen in type I and type II reactions.[4] 6.4 Other Diagnostic Methods

Thighs Perineum Rare

Chest Abdominal wall Facial bones Mandible Paranasal sinuses Eyelid Vulva Orbit Scrotum Old surgical incisions

≈100µm in diameter and delicate, branched filaments about 1µm in diameter; eumycetes are usually seen as a mass of hyphae embedded in intercellular cement with filaments wider than 1µm.[19] Three types of histologic tissue reactions are observed. These are described in sections 7.1, 7.2, and 7.3. 6.1 Type I Reaction

Type I reaction involves grains surrounded by a layer of polymorphonuclear leukocytes, with the innermost neutrophils closely attached to the surface of the grain or sometimes invading the substance of the grain.[4] Outside this layer of cells is granulation tissue with macrophages, lymphocytes, plasma cells, and a few neutrophils.[4] Russell’s bodies and vacuolated cytoplasm, which have a positive reaction to lipid, are seen in many of the macrophages.[4] Layers of fibrin surround capillaries and venules concentrically.[4] Finally, the outermost layer of the lesion contains fibrous tissue.[4]

Another method of diagnosis is to culture the grains on media such as Sabouraud, blood agar, and malt extract agar to isolate fungi or bacteria.[4,17] This is one of the most cumbersome ways to diagnose mycetoma as it is time consuming and easily contaminated.[4] Fine needle aspiration cytology smears enable diagnose of mycetoma through visualization of the characteristic lesion of polymorphous inflammatory cells mixed with grains, neutrophils, lymphocytes, plasma cells, histiocytes, macrophages, and foreign body giant cells.[4] Depending on the stage of infection, radiology can be used to diagnose mycetoma. The early x-ray appearance of the lesion resembles a soft tissue granuloma. With progression, x-rays show bone scalloping with variable periosteal reaction and, finally, multiple cavities.[4] Bone scans or magnetic resonance imaging may detect bone lesions earlier than x-rays and have been shown to be more sensitive and specific diagnostic modalities than plain x-rays.[2,30-32] Ultrasonic imaging is another method for diagnosing mycetoma because the grains, capsule, and granuloma display characteristic echoes on ultrasound.[4] Immunodiagnosis uses stains for CD15 (neutrophils), CD68 (macrophages), and CD3 (T lymphocytes) to diagnose mycetoma, while serodiagnosis evaluates levels of antibodies against the causative agent.[4] Recently, molecular tests have been developed to improve the quality of diagnosis of mycetoma. These include polymerase chain reaction, which identifies species based on amplification of a region of ribosomal gene complex.[1,22,33,34] These tests give hope for better identification and detection of the disease, which will lead to improvements in patient care and facilitate research into the pathogenesis and epidemiology of the disease.[1] 7. Treatment

6.2 Type II Reaction

Management of mycetoma depends on the causative organism. In the type II reaction, most of the neutrophils are replaced by macrophages and multinucleated giant cells that are engulfing grain material, while other inflammatory cells and changes are similar to those seen in type I reactions.[4]  2006 Adis Data Information BV. All rights reserved.

7.1 Eumycetes

Individuals infected with eumycetes require both medical and surgical intervention.[1] First-line medical management recomAm J Clin Dermatol 2006; 7 (5)

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mendations from the Mycetoma Research Center at the University of Khartoum (Khartoum, Sudan) are either ketoconazole 400–800mg daily or itraconazole 400mg daily.[29] Cure rates with ketoconazole seem to be dose dependent, with some individuals requiring treatment for months or years.[35] Use of itraconazole has been associated with good clinical response with low recurrence rates.[29] With both medications, liver function tests should be monitored before and during treatment, as both may be hepatotoxic.[17,29]

wide excision should be performed for early localized lesions and debulking surgery for extensive disease with bony involvement.[36] Chemotherapy must accompany any debulking surgery.[29] Amputation may be necessary in advanced disease or for resistant organisms.[17,29,36] Following completion of surgery, flooding of the wound with iodine is recommended to eliminate any residual fungi.[4]

Medical management of eumycetes is discontinued with clinical, serologic, radiologic, and ultrasonic cure.[17,29] The criteria for cure outlined by the Mycetoma Research Center are as follows: disappearance of the subcutaneous mass with healing of the sinuses and the skin to normal, three consecutive negative counter-immuno-electrophoresis tests 1 month apart, restoration of the normal radiological appearance of bone with remodeling, absence of hyperreflective echoes and cavities on ultrasonic examination, and absence of grains seen on fine needle aspiration.[17,29]

Unlike eumycetes, infections caused by actinomycetes have a better response to medical management with antibacterials and other chemotherapeutics.[1,17] A variety of combinations have been employed to combat actinomycetes infections. In 1976, Mahgoub[37] described the efficacy of trimethoprim/sulfamethoxazole (cotrimoxazole), dapsone, streptomycin, sulfadoxine/ pyrimethamine and rifampin (rifampicin). The most common starting regimen consists of streptomycin (14 mg/kg daily) intramuscularly for 4 weeks, which is then given on alternate days with dapsone (1.5 mg/kg twice daily).[1,17] If this regimen fails, dapsone is replaced by trimethoprim/sulfamethoxazole (14 mg/kg twice daily) or rifampicin (15–20 mg/kg daily).[1,17] Drug resistance among these organisms is high and best combatted with combined

Surgery is often also performed as a first-line treatment for eumycetes.[17] Care must be taken throughout any surgical procedure to prevent contamination and further infection, with emphasis placed on maintaining the integrity of the capsule.[17,29] Aggressive

7.2 Actinomycetes

Table III. Clinical differences between actinomycotic and eumycotic mycetoma[1,4,17,29] Actinomycetes

Eumycetes

Causative organism

Bacteria

Fungi

Clinical lesion

Diffuse with no clear margin

Well encapsulated with well defined margin

Sinuses

Many

Few

Color of grains

Various, but not black

Various, but mostly white or black

Gram stain

Gram-negative centers with Gram-positive, fine, radiating fringes ≈1µm in diameter

Gram-negative septate hyphae embedded in intercellular cement with filaments wider than 1µm

Course of infection

Inflammatory with rapid progression

Slowly progressive

Bony involvement

Rapid

After a long period of time

Cavities in radiograph

Numerous, small in size (except in case of Actinomadura madurae with unclear margins)

Small in number but large in size, with clear margins

Ultrasonic imaging

Grains are less distinct as compared with eumycetes

Numerous, sharp, bright, hyper-reflective echoes (consistent with black grains) Multiple, thick-walled cavities with absent acoustic enhancement

Management of choice

Medical treatment (surgery if advanced)

Medical and surgical intervention required

Drug of choice

Streptomycin (14 mg/kg daily) intramuscularly for 4 weeks, then on alternate days with dapsone (1.5 mg/kg twice daily) Second-line/if no response for a few months: replace dapsone with rifampin (rifampicin) [15–20 mg/kg daily] or trimethoprim/ sulfamethoxazole (cotrimoxazole) [14 mg/kg twice daily]

Ketoconazole (400–800mg daily) or itraconazole (400mg daily)

 2006 Adis Data Information BV. All rights reserved.

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Table IV. Differential diagnosis of subcutaneous mycoses[17,22] Infection

Causative organism

Clinical cutaneous features

Chromoblastomycosis

Cladosporium (Cladophialophora) carrionii, Fonsecaeae compacta, F. pedrosoi, Phialophora verrucosa, Rhinocladiella aquaspera

Verrucous plaques or nodules on feet/legs/arms/upper trunk, which grow into clusters of large hyperkeratotic verrucous plaques with central scarring, ulceration, and cystic areas

Lobomycosis

Lacazia (Loboa) loboi

Usually plaques, verrucous or keloid-like on exposed areas (face, ears, trunk), which enlarge, ulcerate, and become pruritic with secondary nodules

Mycetoma

Actinomycetes, Eumycetes

Firm, painless nodule leading to secondary nodules/papules, draining sinuses, tissue swelling, chronic sinus formation, and subsequent bony involvement

Paracoccidioidomycosis

Paracoccidioides brasiliensis

Varies from crusted papules to ulcers, nodules, plaques, and verrucous lesions (mostly a result of hematogenic dissemination of the fungus from the primary lung infection) Oral lesions are common

Pheohyphomycosis

Bipolaris species, Exophiala jeanselmei, Wangiella dermatitidis

Single inflammatory cyst on proximal limbs that enlarges and limits range of motion of joints

Rhinosporidiosis

Rhinosporidium seeberi

Large, flesh-colored polyps, usually in nose

Sporotrichosis

Sporothrix schenckii

Subcutaneous diseases: lymphangitic infection (usually on hands, feet; dermal nodule leading to ulcer; inflamed, swollen lymphatics) fixed infection (localized lesion, ulcerates)

drug therapy.[4,17,29] The reported cure rate for these infections is 60–90%, with the mean duration of treatment being >1 year.[17,29] Recurrence rates increase if an individual’s treatment course is not completed.[17,29] Other medications that have been used with efficacy against certain actinomycetes include amikacin,[38-40] imipenem,[39,41] and amoxicillin/clavulanic acid.[42] Ramam et al.[43] described the efficacy of a two-step regimen. Patients were initially placed on penicillin, gentamicin, and trimethoprim/sulfamethoxazole, then switched to maintenance treatment with amoxicillin and trimethoprim/sulfamethoxazole. Overall, the response to particular regimens of antibacterials varies among individuals with actinomycotic infection, and a few trials may be necessary to determine the most efficacious combination of medical treatments. Surgery is indicated for individuals whose infections are resistant to medical treatment or bony involvement that will not respond to continual long-term conservative treatment.[17] These procedures require removal of a margin of healthy tissue because actinomycetoma has an ill-defined border.[17,29] 8. Conclusion As case reports of mycetoma continue to emerge throughout the world, the search for the best way to diagnose and treat this disease continues. While mycetoma may not be endemic in the US, the  2006 Adis Data Information BV. All rights reserved.

increasing number of immigrants to this country makes awareness of and education about this disease extremely valuable. With continued research, hope lies in finding earlier means of detecting the disease and preventing its devastating consequences. Acknowledgments The authors have no conflict of interests financially or otherwise with any subject matter discussed in this review. No sources of funding were used in the preparation of this review.

References 1. Ahmed AO, van Leeuwen W, Fahal A, et al. Mycetoma caused by Madurella mycetomatis: a neglected infectious burden. Lancet Infect Dis 2004 Sep; 4 (9): 566-74 2. Hay RJ. Deep fungal infections. In: Freedberg IM, Eisen AZ, Wolff K, et al., editors. Fitzpatrick’s dermatology in general medicine. 5th edition. Vol. 2. New York: McGraw-Hill; 1999: 2372-7 3. McGinnis MR. Mycetoma. Dermatol Clin 1996 Jan; 14 (1): 97-104 4. Fahal AH. Mycetoma: a thorn in the flesh. Trans R Soc Trop Med Hyg 2004 Jan; 98 (1): 3-11 5. Hershkovitz I, Speirs M, Katznelson A, et al. Unusual pathological condition in the lower extremities of a skeleton from ancient Israel. Am J Phys Anthropol 1992 May; 88 (1): 23-6 6. Kwon-Chung KJ, Bennett JE. Mycetoma. In: Cann C, editor. Medical mycology. Malvern (PA): Lea & Febiger; 1992: 560-93 7. Corre A. La maladie de Ballingall (pied du Madur´e). Arch Med Nav 1883; 39 (81): 204-24 8. Godfrey J. Diseases of the foot not hitherto described. Lancet 1846; 1: 593-4 9. Carter HV. On a new striking form of fungus disease principally affecting the foot and prevailing endemically in many parts of India. Trans Med Phys Soc Bombay 1860; 60: 140-2 Am J Clin Dermatol 2006; 7 (5)

Mycetoma

321

10. Pinoy E. Actinomycoses and mycetomas. Bull Inst Past 1913; 11: 929-38

30. Abd Bagi ME, Fahal AH, Sheik HE, et al. Pathological fractures in mycetoma.

11. Fahal AH. Review article [online]. Khartoum: Mycetoma Research Center, 2000. Available from URL: http://www.mycetoma.org/updates.htm [Accessed 2006 Sep 12]

31. Sharif HS, Clark DC, Aabed MY, et al. Mycetoma: comparison of MR imaging

12. Green WO, Adams TE. Mycetoma in the United States. Am J Clin Path 1964 Jul; 42: 75-91

32. Czechowski J, Nork H, Haas D, et al. MR and other imaging methods in the

13. Tight RR, Bartlett MS. Actinomycetoma in the United States. Rev Infect Dis 1981 Nov-Dec; 3 (6): 1139-50 14. Foltz KD, Fallat LM. Madura foot: atypical finding and case presentation. J Foot Ankle Surg 2004 Sep-Oct; 43 (5): 327-31 15. Rigopoulos D, Mavridou M, Nicolaidou E, et al. Mycetoma due to actinomycetes: a rare entity in Europe. Int J Dermatol 2000 Jul; 39 (7): 557-8 16. De Palma L, Marinelli M, Pavan M, et al. A rare European case of Madura foot due to actinomycetes. Joint Bone Spine 2006 May; 73 (3): 321

Trans R Soc Trop Med Hyg 2003 Sep-Oct; 97 (5): 582-4 with CT. Radiology 1991 Mar; 178 (3): 865-70 investigation of mycetomas. Acta Radiol 2001 Jan; 42 (1): 24-6 33. Yera H, Bougnox ME, Jeanrot C, et al. Mycetoma of the foot caused by Fusarium solani: identification of the etiologic agent by DNA sequencing. J Clin Microbiol 2003 Apr; 41 (4): 1805-8 34. Ahmed A, Adelmann D, Fahal A, et al. Environmental occurrence of Madurella mycetomatis, the major agent of human eumycetoma in Sudan. J Clin Microbiol 2002 Mar; 40 (3): 1031-6

17. Lupi O, Tyring SK, McGinnis MR. Tropical dermatology: fungal tropical diseases. J Am Acad Dermatol 2005 Dec; 53 (6): 931-51

35. Mahgoub ES, Gumaa SA. Ketoconazole in the treatment of eumycetoma due to

18. Maiti PK, Ray A, Bandyopadhyay S. Epidemiological aspects of mycetoma from a retrospective study of 264 cases in West Bengal. Trop Med Int Health 2002 Sep; 7 (9): 788-92

36. Aiyenuro O, Nathan S. Mycetoma presenting as a painful ankle monoarthropathy:

19. Welsh O, Vera-Cabrera L, Salinas-Carmona MC. Mycetoma [online]. New York: eMedicine.com, 2005. Available from URL: http://www.emedicine.com/derm/ topic280.htm [Accessed 2006 Sep 12] 20. Khatri ML, Al-Halali HM, Fouad Khalid M. Mycetoma in Yemen: clinicoepidemiologic and histopathologic study. Int J Dermatol 2002 Sep; 41 (9): 586-93

Madurella mycetoma. Trans R Soc Trop Med Hyg 1984; 78 (3): 376-9 a case report. Foot Ankle Surg 2006; 12: 43-6 37. Mahgoub ES. Medical management of mycetoma. Bull World Health Organ 1976; 54 (3): 303-10 38. Welsh O, Sauceda E, Gonzalez J, et al. Amikacin alone and in combination with trimethoprim-sulfamethoxazole in the treatment of actinomycotic mycetoma. J Am Acad Dermatol 1987 Sep; 17 (3): 443-8

21. Abbott P. Mycetoma in the Sudan. Trans R Soc Trop Med Hyg 1956 Jan; 50 (1): 11-30

39. Kashima M, Kano R, Mikami Y, et al. A successfully treated case of mycetoma due

22. Pang KR, Wu JJ, Huang DB. Subcutaneous fungal infections. Dermatol Ther 2004; 17 (6): 523-31

40. Sharma N, Mendiratta V, Sharma RC, et al. Pulse therapy with amikacin and

23. Sobera JO, Elewski BE. Mycetoma. In: Bolognia JL, Jorizzo JL, Rapini RP, et al., editors. Dermatology. Vol. 1. New York: Mosby, 2003: 1187-8 24. Verdolini R, Amerio P, Bugatti L, et al. Madura’s foot: report of a case caused by Madurella mycetomatis. Eur J Dermatol 2000 Dec; 10 (8): 627-9 25. Turner PG. Madura foot or plantar fibromatosis. J Bone Joint Surg Br 1989 May; 71 (3): 531 26. Fahal AH, el Hassan AM, Abdelalla AO, et al. Cystic mycetoma: an unusual clinical presentation of Madurella mycetomatis infection. Trans R Soc Trop Med Hyg 1998 Jan-Feb; 92 (1): 66-7

to Nocardia veterana. Br J Dermatol 2005 Jun; 152 (6): 1349-52 dapsone for the treatment of actinomycotic foot: a case report. J Dermatol 2003 Oct; 30 (10): 742-7 41. Fuentes A, Arenas R, Reyes M, et al. Actinomycetoma and Nocardia sp.: report of five cases treated with imipenem or imipenem plus amikacin [in Spanish]. Gac Med Mex 2006 May-Jun; 142 (3): 247-52 42. Gomez A, Saul A, Bonifaz A, et al. Amoxicillin and clavulanic acid in the treatment of actinomycetes. Int J Dermatol 1993 Mar; 32 (3): 218-20 43. Ramam M, Garg T, D’Souza P, et al. A two-step schedule for the treatment of

27. Richardson MD, Warnock DW. Mycetoma. In: Richardson MD, Warnock DW. Fungal infection diagnosis and management. 2nd ed. Malden (MA): Blackwell Science, Inc., 1997: 204-9

actinomycotic mycetomas. Acta Derm Venereol 2000 Sep-Oct; 80 (5): 378-80

28. Boiron P, Locci R, Goodfellow M, et al. Nocardia, nocardiosis and mycetoma. Med Mycol 1998; 36 Suppl. 1: 26-37

Correspondence and offprints: Dr Amor Khachemoune, Ronald O. Perelman

29. Fahal AH. Evidence based guidelines for mycetoma patients’ management [online]. Khartoum: Mycetoma Research Center, 2000. Available from URL: http:/ /www.mycetoma.org/updates_managment.htm [Accessed 2006 Sep 12]

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Department of Dermatology, New York University School of Medicine, 530 First Avenue, Suite 7R, New York, NY 10016, USA. E-mail: [email protected]

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