T. Creo Martínez¹, C. Salazar Fernández², R. del Rosario Regalado¹, A. Rollón Mayordomo², Y. Marín Lapeira³

Recibido: 29.08.05

Aceptado: 15.11.05

1 Médico Residente Servicio Cirugía Oral y Maxilofacial.
2 Médico Adjunto Servicio Cirugía Oral y Maxilofacial.
3 Médico Residente Servicio Radiodiagnóstico. Hospital Universitario Virgen Macarena, Sevilla, España.

Correspondencia:
Teresa Creo Martínez
C/ Doctor Fedriani 19, 2º 2ª
41009 Sevilla, España.

Introduction

Diffuse sclerosing osteomyelitis (DSO) is a disease of unknown etiology that is difficult to diagnose and treat as the literature available on the matter is confused, and there is a considerable lack of knowledge with regard to its cause and its natural evolution.¹ For most authors there are two theories for explaining its origin.^2-6

The clinical and radiological findings suggest and infectious origin,² which is difficult to confirm by means of bacteriological data, as not in all cases has isolating a causative microorganism been possible. And in those cases where this has not been possible there are authors² who believe that the sample has possibly been contaminated when taken. Those defending this support the low level of virulence theory that starts off an autoimmunological process leading to the characteristic lesions and clinical symptoms. This is supported by the improvement shown by patients under corticoid treatment. As a result of this, the disease is related in some cases with the SAPHO syndrome (synovitis, acne, palmoplantar pustulosis, hyperostosis, osteitis) and because of this there is a response (although on many occasions just a temporary response) to antibiotic treatment.^3-5 It has been postulated that osseous hyperplasia attributed to chronic tendoperiostitis^6,7 is behind those cases in which the causative agent is not isolated, as there is no response to bacterial therapy. This would have been caused by muscular dysfunction and parafunctional habits, and while there is an improvement with occlusal therapy and muscle relaxants, the detractors of this theory postulate that there is more intramedullarly sclerosis than periosteal, and that neither is occlusal treatment definitive as most patients eventually suffer more crises.

The disease is characterized by recurrent pain and hemimandibular tumefaction (although it can present in other locations) and it is accompanied usually by trismus, pressure, paresthesia and regional nodal swelling.⁸ The clinical course is episodic with intervals of varied duration during which improvement is seen, and intervals when there is exacerbation. It tends to have a protracted course and there have even been descriptions of cases of spontaneous regression. Clinically it is characterized by an absence of pus, the formation of fistulae or bone sequestra¹ (which is fundamental when diagnosing this disease) with these being significant for the differential diagnosis of secondary osteomyelitis. Radiologically nothing that is characteristic is observed, except that osteosclerotic lesions appear (these are associated with healing), with osteolytic «moth-eaten» areas (that increase during periods of exacerbation of the disease and that decrease on improvement), and periosteal reaction.

Histologically chronic infection is described, together with bone marrow fibrosis and heterotopic bone formation, bone turn-over and an increase in bone resorption, pagetoide bone formation, and even the formation of microabscesses as described by Eyrich et al.,^3-5 which never manifests clinically as pus.⁹

The purpose of this study is to show the benefits of longterm roxithromycin treatment for this complex disease, as a result of a clinical case.

Clinical case

White female, 30 years old, attended our Out Patient department in February 2002 as a result of recurrent mandibular suppurative inflammation after removal of tooth 36, resistant to conventional antibiotic treatment (clavulanic amoxi). The panorex carried out was compatible with osteitis of the left side (Fig. 1). Treatment was commenced with Dalacin 300 mg/8 h and corticoid treatment for three months. As by June 2002 there was no improvement, a biopsy was carried out together with curettage of the area. The anatomopathologic result was of giant cell granuloma tissue, as a result of which the treatment mentioned previously was continued for another six months. Given that the patient was experiencing relapse crises with intense pain and inflammation in the ascending ramus of the left mandible with no pus or fistula formation, in December 2002 a new control CAT scan was carried out. The result indicated an osteolytic lesion in the external cortex of the left mandibular ramus (Fig. 2) with soft tissue infiltration and nodal swelling in the neck of 1 cm. A decision was taken to carry out a biopsy of the lesion under general anesthesia and samples were taken for different microbiological studies. The result of the biopsy was of tissue with giant cells and the microbiological studies were negative (ZN and PAS staining, anaerobic, aerobic, microbacterial and fungal studies). The patient was diagnosed with chronic osteomyelitis and she underwent decortication of the left mandibular ramus followed by the administration of penicillin G 3 million units/4 h IV for a week followed by cloxacillin 1 gram/4 h/IV for 72 hours followed by penicillin V 500mg/4h taken orally, orbenin 250 mg/4 h for another 4 months. The anatomopathologic result of the lesion was of epithelioid nonnecrotizing chronic granulomatous inflammation and interstitial fibrosis. The patient evolved favorably from a clinical perspective but she developed mild trismus and an occlusal split was prescribed. In September 2003 she was suffering from intense pain and inflammation of the right mandibular ramus. The CAT scan revealed chronic osteomyelitis that was affecting both rami of the mandible, together with sclerotic reaction in the left half of the mandible and osteolytic reaction in the right ramus. In November 2003 she was prescribed roxithromycin 150 mg/12 h with amenen 30 mg/12 h. After a month of treatment the patient reported considerable improvement in the symptoms, the control analysis showed a high C-reactive protein, normal calcium metabolism, with LDH and phosphorus increases, and normal monthly hepatic control. The control MRI scan (Fig. 3) showed sclerotic changes in the left ramus and condyle with destruction of the medial and external cortical areas, compatible with the surgical treatment, and sclerotic reaction in the right ramus by the mandibular angle with irregularities in the external cortex and inflammation of the masseter muscle and bilateral lymph node swelling. The bone scan with gamma camera (Fig. 4) showed a slight increase in the vascular phase by the right upper, external area of the orbit, left malar and right mandibular ramus. In the bone phase these was an increase in the left and right malar, and an increased uptake in the left condyle and right femur, which did not show any clinical symptoms following treatment with roxithromycin.

The patient was seen periodically. The symptoms improved considerably together with the pain in the mandible, and there was only frontal pain. In may 2004 monitoring with SPET was carried out and increased uptake was detected in the left frontal bone phase and to a lesser degree the right malar and right mandibular angle. There was an improvement in the left mandible and malar area. To date (March 2005) the patient is free of facial pain and is continuing her treatment with roxithromycin. Radiologically there are sclerotic lesions in the bone foci previously mentioned, but there are no new osteolytic foci. After March the patient decided to suspend the treatment as she wanted to conceive and she is to date (May 2005) asymptomatic.

Discussion

VSO treatment is complex, as many therapies have been tried without any satisfactory results in the long term. In the short term there are therapies that can eliminate the symptoms temporarily, but in many cases the symptoms of the disease return, either in the same place or, as occurs in many occasions, in a contralateral manner.⁸

Up until now different treatments such as NSAIDs, corticoid treatment, prolonged treatment with antimicrobic therapy, hyperbaric oxygen and occlusal splints have been used. What appears be most effective is surgical treatment to eliminate the presumed focus of infection by means of the decortication of the affected area,⁹ but even in these cases a homolateral relapse has been reported in 50-75% of cases.¹⁰

In view of the evolution of the disease, its relationship with SAPO³ according to recent studies, and its behavior regarding the different treatments, it appears to be a pathology with autoimmune characteristics, that starts as an infection with a low pathogen level setting off a immunological reaction. This would explain the findings, and that the cultures taken were frequently sterile, or that germs with low infectious levels were isolated.¹¹ In view of this and following the theory of T. Yoshii et al.,¹⁰ it would seem that DSO behaves as a biofilm disease, a process whereby bacteria grow in an appropriate medium (biofilm) in which the antimicrobial agents are not very effective. Slow bacterial growth is allowed despite the adverse conditions, enabling resistance to antibiotics. This slow growth allows chronic bacterial infection to be established such as osteomyelitis, or in other cases diffuse bronchiolitis for which treatment with Roxithromycin and other macrolides has proved effective, not for their antimicrobial effect but rather for the anti-inflammatory effect they have. Roxithromycin appears to destroy biofilm; it inhibits the production of various cytokines such as interleukin 1-B, TNF and interleukin-6,^12,13 that all play a very important role in bone resorption, inhibiting lymphocytic activation, chemotaxis of neutrophils, stimulating macrophages to produce other beneficial cytokines. This effect became obvious during the follow-up of our patient, as the radiologic study showed how the osteolytic lesions had disappeared at the same time as the symptoms. However, the osteosclerotic lesions remained or new ones had appeared, which does not contradict our theory as, according to the latest studies,¹⁴ these lesions are now being considered as a type of bone healing.

The problem for us and for other authors that have described long-term antibiotic treatment as a therapy for DSO, is knowing how long antibiotic treatment should be maintained for these patients, so that relapses are avoided. Yoshii et al¹⁰ presented a study with 11 patients that were treated with roxithromycin for 10-12 months and all patients showed a reduction in the symptoms, and in 7 they disappeared completely. Our patient was treated favorably with roxithromycin for 18 months.

When treatment with roxithromycin is given, it should be kept in mind that collateral problems should be avoided such as hepatic conditions, or intolerance of another sort. In view of this, we conducted a monthly follow-up to repeat tests, keeping in mind the evolution of the disease and the previous treatment the patient had been given. We followed the recommendations of T. Yoshii et al.,¹⁰ and roxithromycin treatment was maintained for 18 months. The patient’s symptoms improved completely, there was no relapse at the initial sites, although sclerotic foci did appeared in other areas such as the malar and frontal bones, without there being any clinical symptoms, or just slight symptoms, and her tests have been normal with the exception of slightly raised LDH.

Other authors such as Montonen⁹ favor decortication and hyperbaric oxygen as treatment, in conjunction with antibiotics, not just antibiotics on their own. Other authors such as Montes et al⁷ consider that the use of antibiotics is not necessary as they feel that it is not a disease with an infectious origin.

In view of the results obtained and the evolution of the patient, we recommend considering decortication with roxithromycin in the long term as a line of treatment for VSO, given the efficacy demonstrated and the tolerable secondary effects. Every case should, however, be reviewed individually given the complexity of the disease while taking into consideration this therapeutic option as a first choice.

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