 GENERAL ORTHOPAEDICS

The orthopaedic aspects of mycetoma

A. H. Fahal, S. Shaheen, D. H. A. Jones

This article presents an overview of mycetoma and offers guidelines for orthopaedic surgeons who may be involved in the care of patients with this condition.

From The Mycetoma Research Centre, Soba University Hospital, Khartoum, Sudan

Mycetoma is a painless, progressive, disfiguring, destructive and sometimes fatal disease. It spares no tissue and is characterised by subcutaneous chronic granulomata containing grains which, through multiple sinus formation, may reach the skin as a purulent discharge. In general, black grains are more frequently seen in the fungal type of mycetoma and thereby define the condition as eumycetoma, compared with actinomycetoma, which is caused by bacteria and characterised by yellow, white or red grains. However, the clinical triad of a painless subcutaneous mass, sinus formation and grains within a purulent discharge is pathognomonic (Fig. 1). Since 1991, The Mycetoma Research Centre at Soba University Hospital, Khartoum, has accumulated experience in research and the clinical care of over 6600 patients. As the condition affects the limbs in over 80% of patients, treatment may fall within the remit of an orthopaedic surgeon.

 A. H. Fahal, FRCS,, MD, FRCP(London), Professor of Surgery University of Khartoum, The Mycetoma Research Centre and Soba University Hospital, Faculty of Medicine, Department of Surgery, Khartoum, Sudan.  S. Shaheen, MBBS, MD, JMHPE, Associate Professor of Orthopaedic Surgery University of Khartoum, Faculty of Medicine, Department of Surgery, Khartoum, Sudan.  D. H. A. Jones, MB, ChB, FRCS, FRCS Ed(Orth), Honorary Consultant Orthopaedic Surgeon Great Ormond Street Hospital for Children, London WC1N 3JH, UK. Correspondence should be sent to Professor A. H. Fahal; e-mail: [email protected] ©2014 The British Editorial Society of Bone & Joint Surgery doi:10.1302/0301-620X.96B3. 31421 $2.00 Bone Joint J 2014;96-B:420–5. Received 5 December 2012; Accepted after revision 15 November 2013

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Cite this article: Bone Joint J 2014;96-B:420–5.

Epidemiology Mycetoma has major serious medical, social and economic impacts in many tropical and subtropical regions. It has recently been included in the World Health Organization’s list of neglected diseases1 and deserves attention as it can be prevented. The incidence of the condition is not known because it is painless, slowly progressive and, due to lack of health education, most patients present late, with massive infection. Mycetoma is particularly endemic between the latitudes of 15° South and 30° North, in an area of vast forests and savannah. This includes Sudan, Somalia, Senegal, India, Yemen, Mexico and South America. The African continent, particularly Sudan, has the highest prevalence, although the condition has also been reported in many temperate regions.2,3

The geographical distribution of the individual causative organisms shows considerable variation in relation to environmental and climatic factors. For example, actinomycetoma predominates in Mexico, whereas in Africa most cases are eumycetomas, where the organism is commonly Madurella mycetomatis. In actinomycetoma one often finds Streptomyces somaliensis in arid areas, Actinomadura pelletieri with more rainfall and Nocardia species in temperate zones.4 Many aspects of the susceptibility and resistance to the disease and the route of infection remain controversial. Although traumatic inoculation of the causative organism into the subcutaneous tissue is the popular theory, in endemic areas where barefoot travel is common and thorn pricks are plentiful, many patients have no history of trauma at the site of infection. Many authors believe that there is an as yet unidentified intermediate host.4 The incubation period in mycetoma is unknown due to the difficulty in establishing the time of initial infection. The disease is not contagious between humans or from animal to human.4 Males are predominately affected, with a ratio of 3.5:1. This is a genuine difference and not related to outdoor work; in endemic areas, females are equally committed to these activities. No age is spared, but mycetoma commonly affects adults between 20 and 40 years of age who come into contact with the land including young students, farmers and herdsmen. In endemic regions, children and the elderly may also be affected, along with people in other occupations.

Clinical features The parts of the body which come into contact with soil during daily activities are usually affected – the lower limb in 82% of patients and the hand in 7%.3 The arm, head and neck and THE BONE & JOINT JOURNAL

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Fig. 1 Photograph showing eumycetoma of the ankle, with multiple sinuses, discharge and typical black grains.

perineum may be involved less frequently in endemic areas. Rarer sites include the abdominal wall, facial bones, mandible, testes, paranasal sinuses, oral cavity and eye.5-8 It usually presents as an enlarging subcutaneous mass, which is generally firm and rounded but can be soft and lobulated or rarely cystic. Secondary nodules may develop and suppurate and drain through interconnecting sinus tracts. These may close transiently after discharge during the active phase of disease. The sinuses connect deep-seated abscesses to the surface. The discharge is usually purulent and often contains grains, the colour of which depends on the causative organism (Fig. 1). Mycetoma is usually painless and it is suggested that the lesion produces substances with an anaesthetic action; pain is usually due to secondary bacterial infection.2,3,9,10 As the granuloma enlarges, the overlying skin is tethered and stretched, becoming smooth, pigmented and shiny with areas of hyperhidrosis, which may be due to sympathetic nerve over-stimulation or increased temperature from highly vascular chronic inflammation.8,11 The deep structures are eventually invaded. This process is usually gradual and delayed in eumycetoma and earlier, and more extensive in actinomycetoma. The tendons and nerves are curiously spared until late in the disease2,4,7 and this feature, along with a good blood supply, may explain the scarcity of neurological and trophic changes, even with long-standing disease.11 The regional lymph nodes are commonly enlarged, which may be due to lymphatic spread, more common in actinomycetoma, secondary bacterial infection or local immune responses.2,3,5,10 Blood-borne spread has also been reported.9,11 As mycetoma is a localised infection, constitutional disturbances are rare but when present are generally due to secondary bacterial infection. In late cases, cachexia and anaemia are common and usually due to malnutrition, sepsis and depression.2,5,8 Mycetoma produces disability and deformity and can be fatal, especially in cranial cases. The clinical features are not always reliable indicators of the extent of involvement, as small lesions with few sinuses may have a deep, extensive network of sinus tracts. This VOL. 96-B, No. 3, MARCH 2014

Fig. 2a

Fig. 2b

Radiograph of mycetoma, with a) eumycetoma of the lower tibia showing a soft-tissue mass, scalloping, periosteal reaction and bone cavities, and b) extensive actinomycetoma of the hand. The cavities are smaller than in eumycetoma and there is extensive bone destruction with the sun-ray appearance of an osteosarcoma.

explains why surgery under local anaesthesia is contraindicated2,3,5,10 and moreover, lymphatic spread is provoked by repeated inadequate excision.

Investigations Radiography. A soft-tissue granuloma is an early feature, shown as a dense shadow or several scattered shadows. Calcification and obliteration of the fascial planes may occasionally be seen.12 With progression of the disease, the cortex may be compressed by the granuloma, leading to scalloping, which is followed by a variable amount of periosteal reaction. Eventually, many punched-out cavities appear. In eumycetoma, these are large, and with welldefined margins (Fig. 2a), whereas in actinomycetoma they are usually smaller, more numerous and have poorlydefined margins. Later, periosteal new bone spicules are laid down at right angles to the cortex to create a sun-ray appearance that may be indistinguishable from primary osteosarcoma (Fig. 2b).12 The cavities are usually filled with solid masses of grains and fibrous tissue, which provide mechanical support and may explain the rarity of pathological fractures.13,14 The bony changes in the skull are unique; they are purely sclerotic with dense bone formation and loss of trabeculation, the cause of which is unclear.9 Osteoporosis at and distal to the affected part is well recognised; this may be due to disuse atrophy. With successful chemotherapy, radiological improvement through absorption of sclerotic bone and remodelling can be seen.2,8,10 Ultrasound. The grains and accompanying granuloma have specific ultrasonic appearances, which can differentiate between eumycetoma and actinomycetoma, as well as

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Fig. 3 Ultrasound image of a eumycetoma of the knee (under the patella tendon (PT)) showing grains within the granuloma. In actinomycetoma, the grains are smaller and less distinct.

other conditions. In eumycetoma, the grains produce numerous sharp bright hyper-reflective echoes, which probably originate from the cement substance associated with the grains (Fig. 3). Also, there are many thick-walled nonechogenic cavities. In actinomycetoma, the findings are similar but the grains are less distinct. This may be due to their smaller size and consistency or the absence of cement substances.15 Ultrasonography is useful in pre-operative planning. The examination is safe, simple and can be done as an outpatient procedure.15 MRI. MRI is helpful in assessing the extent of bone destruction, periosteal reaction and soft-tissue involvement. Within the granuloma, there are many lesions measuring 2 mm to 5 mm in diameter of high signal intensity, giving a ‘dot-in-circle’ appearance. This indicates the presence of grains and is highly specific for mycetoma (Fig. 4). A new MRI grading system for the diagnosis and management of mycetoma was recently reported.16 The differential diagnosis is chronic osteomyelitis, tuberculosis, other granulomas, soft-tissue tumours and cold abscesses.17 CT. CT is useful but not specific for the early detection of bony involvement in mycetoma.

Diagnosis Histopathology. A deep surgical biopsy is always required to confirm the diagnosis and should be carried out under general or regional anaesthesia. The biopsy should be adequate, contain grains and fixed immediately in 10% formal-saline.18 Various stains can be used to identify the causative organism and host-tissue reaction, the most common being haematoxylin and eosin (H&E). Immuno-fluorescent antibody and immuno-histochemical techniques are also helpful.18-20

Fig. 4 MRI of the ankle showing the typical ‘dot-in-circle’ appearance of a mycetoma.

Three types of host tissue reaction are described; they are identical in all types of mycetoma.21 The specific type can indicate the progress of the disease and its response to treatment. Fine needle aspiration cytology. This test is simple, rapid, sensitive and well-tolerated by patients.22,23 The appearance on a cytological smear is similar to that on a histological section and allows identification of the organisms and distinction between eumycetoma and actinomycetoma. Microbiology. As many organisms can produce mycetoma, many centres consider it essential to culture the grains, which should be viable and free of contaminants.2,3,7,24,25 Deep surgical biopsy is always needed to obtain them, as those extracted through sinuses are usually contaminated and not viable. The grains should be sent for culture in normal saline. The technique is time consuming and requires experience.7 In general, eumycetoma grains may be cultured in Sabouraud dextrose agar and actinomycete grains in Lowenstein-Jensen media.8 Polymerase chain reaction (PCR). Molecular detection, identification and taxonomy of the causative organism are important to understand the aetiology and epidemiology of the disease. A specific PCR test amplifying a region of the internal transcribed spacer in the ribosomal gene complex is now available.26 Serodiagnosis. The demonstration of significant antibody titres against the causative organism may be of diagnostic value and for the follow-up of patients on medical treatment. The common sero-diagnostic techniques are counterimmuno-electrophoresis and enzyme linked immunoabsorbent assay (ELISA). These tests are tedious and need purified antigens. Cross-reactivity between the different organisms is a common problem.27,28 Differential diagnosis. In endemic areas, any swelling must be considered as mycetoma until proven otherwise.2,3,7 The THE BONE & JOINT JOURNAL

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Fig. 5a

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Fig. 5b

Clinical photographs of a patient with a massive actinomycetoma of the ankle and foot, a) before treatment (excluding the use of local native dressings), and b) after six months of treatment with amikacin sulphate and co-trimoxazole, showing an excellent response.

Orthopaedic treatment of mycetoma The treatment and outcome depend primarily on the causative organism and the site and extent of disease. Until recently, the only available treatment was amputation or repeated mutilating surgical excision. Spontaneous regression can occasionally be seen. Untreated infection will lead to massive tissue damage, deformity, disability, secondary bacterial infection and sepsis and thus can be fatal. Combined medical and surgical treatment is the gold standard. The former aims to facilitate surgery, accelerate healing and reduce the risks of recurrence.2,3,5,29

success.29-31 For eumycetoma, the most popular medical regimes are itraconazole 200 mg to 400 mg per day or voriconazole 300 mg to 400 mg per day for a mean of nine to twelve months.32,33 These drugs have many serious sideeffects, including hepatic failure, skin changes, gynaecomastia, infertility and gastric disturbance. Ketoconazole and itraconazole are not curative in most patients; they help to localise the disease by forming thickly encapsulated lesions (Fig. 2), which are more easily excised. Medical treatment for both types of mycetoma must continue until the patient is clinically, radiologically, ultrasonically and cytologically cured. Clinical cure is judged by the disappearance of the mass and healing of the sinuses.2,5,10,29 Radiological cure is judged by the re-appearance of a normal bone pattern and the disappearance of the soft-tissue mass. The absence of grains cytologically with type III tissue reaction and the disappearance of the grains and cavities ultrasonically are reliable evidence of cure.2,8,21,29

Medical treatment In general, the current treatment for mycetoma is inadequate, being neither effective nor efficient, especially for eumycetoma. The treatment is expensive, not universally available and has many side effects.29 Actinomycetoma is more amenable to treatment with antibiotics and other chemotherapeutic agents, with a success rate of about 60% to 65%29,30 (Fig. 5). Combined drug therapy is always recommended to avoid drug resistance and enhance the eradication of disease. The current most acceptable options are cycles of amikacin sulphate 15 mg/kg twice daily for three weeks and co-trimoxazole 1.5 mg/kg twice daily for five weeks. The cycle is repeated until cure is achieved. Renal failure and oto-toxicity are well recognised side effects.31 Many other drugs such as amoxicillin-clavulanic acid, rifampicin, sulphonamides, gentamicin and kanamycin have been tried as second-line treatment but without much

Surgical treatment A deep tissue biopsy is necessary for histological and immuno-histochemical studies and grains for microbiological and molecular identification. Local anaesthesia is contra-indicated as the extent of the disease along tissue planes is unpredictable. A bloodless operative field using a tourniquet is essential to identify and avoid bursting the margins of the lesions, which is an important cause of local spread and recurrence.2,3,5,8 Wide local excision is indicated for localised early lesions, resistance to medical treatment or to facilitate a better response to medical treatment in patients with massive disease. Repeated debridement and debulking is required for massive infected disease (Fig. 6). Amputation is indicated in advanced mycetoma with massive bone involvement and severe secondary infection, and can be lifesaving. The rate of amputation ranges from 10% to 25% in most series.2,3,5,8 Shaheen34 reported that in Sudan, mycetoma is the third most common cause of

differential diagnosis includes soft-tissue masses such as tuberculosis, Kaposi’s sarcoma, malignant melanoma, fibroma and foreign body granuloma. The radiological appearance of advanced mycetoma is indistinguishable from primary osteosarcoma, chronic osteomyelitis, osteoclastoma, bone cysts, tuberculous and syphilitic osteitis.2,3,7

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Fig. 6a

Fig. 6b

Photographs of extensive eumycetoma of the foot, a) pre-operatively and b) intra-operatively after excision of the mycetoma. An iodine-soaked dressing was applied to the wound and a splint. The wound was redressed daily with saline and iodine dressings and healed by secondary intention.

amputation, after diabetes and land-mine injuries. He recorded that there was significantly less phantom pain, allowing more successful prosthetic fitting, in patients with mycetoma as there was an adequate blood supply and limbs were previously pain-free.

Outcome Complete cure is difficult to achieve and recurrence after adequate treatment is common. The recurrence rate varies from 25% to 50% and can be local or distant at the regional lymph nodes. This could be due either to the biology and natural history of the disease, or to widespread disease along the fascial planes, inadequate excision due, for instance, to the use of local anaesthesia and lack of surgical experience, along with lack of compliance with medication because of financial constraints and lack of health education.2,3,15,35 The follow-up must be long enough to detect and treat recurrent disease. However, it is difficult to assess outcomes accurately because of the large number of patients lost to follow-up, many of whom may be cured, but others of whom may have recurrence of disease. In a review of 1544 patients,36 of 1242 suffering eumycetoma, 312 (25.1%) were cured, 35 (2.8%) had an amputation and 672 (54.1%) were lost to follow-up. Of the remaining 302 patients suffering with actinomycetoma, 60 (19.9%) were cured, one (0.3%) had an amputation and 169 (56.0%) were lost to follow-up. The lack of health education and financial restraints are the overwhelming causes of poor follow-up. In general, age, gender and dietary factors do not influence the outcome of treatment. Patients with early small lesions are more likely to have a good prognosis and a high rate of cure. However, some may develop recurrence, the causes of which are unclear, but may involve immunological, genetic or environmental factors that need further study. Patients with massive eumycetoma lesions and longstanding disease are more prone to recurrence after adequate treatment, most probably due to widespread

infection along the different tissue planes, poor response to antifungal drugs and secondary bacterial infection. Generally, actinomycetoma responds better to combined antibacterial agents than eumycetoma to antifungals. An association between mycetoma and HIV (and other conditions involving immunodeficiency) has not been described; thus the effect of combined pathology and treatment remains unclear. In conclusion there is a great need for major health education programmes to encourage the early reporting and treatment of patients with mycetoma to reduce the medical, social and economic burden of this disease. There is also a need for new, potent, cheap anti-fungal drugs that could be administered safely over a long period of time to patients with limited financial resources. Both these objectives are only likely to be achieved through major international aid agencies such as The World Health Organization. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. This article was primary edited by J. Scott and first proof edited by D Rowley.

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