January 2007 Vol 7 correct A.indd Mucormycosis of the Jaw after Dental Extractions: Two Case Reports *Abdulaziz A Bakathir MUCORMYCOSIS (PHYCOMYCOSIS, ZYGO-mycosis) is a rare invasive opportunistic infection caused by fungi of the order mu- corales. The incidence of mucormycosis is very low.1-3 Mucormycosis mainly attacks immunocompromised patients with a rapid fulminant course.1 The most com- monly reported form of the disease is rhinocerebral mucormycosis, which is characterised by progressive fungal invasion of the hard palate, paranasal sinuses, orbit, and brain.2-4 Successful management of this ful- minant infection requires early recognition of the dis- ease, aggressive medical and surgical interventions to prevent the high morbidity and mortality associated with the disease process.5,6 This paper presents two cases of mucormycosis diagnosed after dental extractions in a compromised host, which after comprehensive surgical and medical management led to favourable outcomes. C A S E R E P O R T 1 A 14 year old male patient with a two months diagno- sis of acute myeloid leukaemia was referred to the Oral Health clinic, Sultan Qaboos University Hospital, with a chief complaint of severe toothache in the upper right premolar region, which was not controlled by simple analgesics. The patient was under chemotherapy, anti- viral, antifungal and anti-biotic agents. His blood inves- tigations clearly demonstrated pancytopenia with low Oral Health Department, Sultan Qaboos University Hospital, Sultan Qaboos University, P.O Box 35, Al-Khod-123, Muscat, Sultanate of Oman. *Email: abakathir@squ.edu.om Abstract. Mucormycosis is a rare opportunistic fungal infection, which is mainly reported to occur in patients with immunocom- promised conditions such as uncontrolled diabetes mellitus and leukaemias. In this paper, two cases of mucormycosis are reported after dental extractions. The first case of mucormycosis occurred in the maxilla and mandible of a 4 year old male patient undergoing chemotherapy for acute myeloid leukaemia. The second case occurred in the mandible of a 49 year old male patient with a recently diagnosed type-2 diabetes mellitus, presenting with ketoacidosis and underlying undiagnosed acute lymphoblastic leukaemia. The outcome of these reported cases of mucormycosis was favourable after comprehensive surgical and medical management. Keywords: Mucormycosis, rhinocerebral mucormycosis, complication of dental extraction, case report, Oman C A S E S T U D Y خلع بعد الفكني عظم في ااطيه الفطرية داء - حالتني عن تقرير االسنان مثل املناعة جهاز في املرضى املصابني عادة بها يصاب والتي ، ــدوث احل نادرة االنتهازية الفطرية االلتهابات من ااطية الفطرية ــر داء ــص: يعتب امللخ بعد الفكني في عظم تشخيصها ااطية مت الفطرية داء من حالتني نناقش هذا التقرير في وسرطان الدم. عليه املسيطر السكري غير داء مرضى عمره رجل فهو الثانية احلالة أما . الكيمياوي بالعالج وعولج النقياني احلاد الدم ــرطان بس مصاب 14 سنة عمره ــاب لش احلالة االولى . ــنان االس خلع بسرطان الدم ايضا مصاب أنه وتبني ، الكيتونِيّ احلُماضٌ عالمات عليه ظهرت أن بعد ، الثاني) (النوع السكر مصاب بداء انه اكتشف حديثا ، 49 سنة الشامل. والدوائي اجلراحي العالج اجراء بعد احلالتني كال في جيدة النتيجة كانت . احلاد فاوِيّ اللِمْ يَّ األَرومِ . عمان ، حالة تقرير ، االسنان خلع اختالطات ، الدماغية االنفية ااطية الفطريات ، ااطية املفردات املفتاحية: الفطريات SULTAN QABOOS UNIVERSITY MEDICAL JOURNAL DECEMBER 2006 VOL 6, NO. 2 SULTAN QABOOS UNIVERSITY© A B D U L A Z I Z A B A K AT H I R 78 platelets (38x109). Dental examination showed multi- ple carious teeth with a very tender and badly broken down upper right second premolar. After appropriate platelets transfusion, the upper right premolar was removed atraumatically under local anaesthesia by an Oral & Maxillofacial Surgeon. Two weeks post den- tal extractions, he developed a temperature of 38.1°C and complained of severe pain from the site of extrac- tion with partial blockage of his right nostril. Clinical examination showed a febrile, fully conscious patient with Glasgow Coma scale of 15, mild right infra-or- bital swelling and paraesthesia of the right infra-or- bital nerve. No abnormality was observed over the right eye and nasal examination showed blockage of the right nostril with no evidence of any necrosis or nasal discharge. Intraoral examination demonstrated a tender swelling of the upper right buccal mucosa with black necrotic gingival tissue and area of necrotic bone extending from the extraction site to the adjacent teeth. In addition, the gingival necrosis had started to involve the palatal mucosal near the extraction site. Gingival and bone biopsies were taken for histopatho- logical diagnosis. A computed tomography (CT) scan was requested and this showed a soft tissue swelling of the right infra-orbital region and marked soft tis- sue obliteration of the right maxillary sinus, which had started to extend medially causing obstruction of the right medial conchae and invasion of the ethmoi- dal air cells [Figures 1&2]. Over the next few days, the patient’s condition remained much the same and the area of intraoral necrosis showed a marked increase in size. The histopathology diagnosis was positive for mucormycosis. Upon confirmation of the diagnosis of mucormycosis, the patient was started on intravenous liposomal amphotericin-B (AmBisome), after consul- tation with the infectious diseases team. He consented to surgical debridement under general anaesthesia and the haematology team prepared the patient for this procedure. The surgical debridement involved removal of the upper right canine, first premolar and molar, curettage of all necrotic tissues and partial maxillectomy. Ear Nose and Throat colleagues joined us to assist with the debridement using Functional Endoscopic Sinus Surgery. The area was then packed with antiseptic Bismuth Iodine Paraffin Pack (BIPP). Over the course of the next few days, the patient con- dition was stabilised and the sinus was continuously irrigated with 0.2% Chlorhexidine antiseptic mouth wash, 3% hydrogen peroxide solutions and the pack was regularly changed every ten days over a period of 8 weeks. The right infraorbital nerve paraesthesia had recovered well some 6 weeks post-surgical deb- ridement. Eight weeks post-surgical curettage, the CT scan was repeated and this showed an improve- ment in the appearance of the right paranasal sinuses. The residual small oro-antral fistula was temporarily sealed by an obturator and its surgical repair was de- ferred until the patient came off chemotherapy, when all the required dental treatment was to be carried out. Unfortunately, the patient’s leukaemia relapsed and more aggressive chemotherapy was planned. Dur- ing the chemotherapy course, the patient complained of pain and swelling related to the carious lower right first molar and this was subsequently removed under local anaesthesia. Over the next few days the swelling and pain subsided. Ten days post extraction, a small area of necrosis started to develop buccal to the site of extraction, which continued to enlarge over the next few days with evidence of necrotic bone. Biopsy of the necrotic area was carried out and was again positive for mucormycosis. The patient was re-started on Am- Bisome and as the patient leukaemic status showed improvement the plan was for debridement of the site of fungal infection, followed by multiple extractions and fillings under general anaesthesia. The mucormy- cosis site was widely debrided, the second premolar and molar were extracted and the area was packed with BIPP. His post-operative period was uneventful, with the pack being replaced every ten days until the Figure 1: Axial CT of case 1 showing obliteration of the right maxillary sinus (black arrowhead) and soft tissue swelling over the right infra- orbital region (white arrowhead) M U C O R M Y C O S I S O F T H E J AW A F T E R D E N TA L E X T R A C T I O N S : TW O C A S E R E P O R T S 79 area had completely healed with healthy tissue, seven weeks post-surgical curettage. The patient’s condition continued to improve and he underwent a successful bone marrow transplant eight months following the initial diagnosis of leukaemia. C A S E R E P O R T 2 A 49-year old male patient was seen in the out-patient maxillofacial clinic at the oral health department, fol- lowing referral from a family medicine clinic. His chief complaint was pain at the site of a recent extraction socket and paraesthesia of the right lower lip. The patient gave a history of extraction of the lower right second molar two weeks previously at a local private clinic. His medical history revealed a recent diagnosis of type-2 diabetes mellitus (DM) and the patient was taking metformin and glipizide tablets. Clinical exam- ination showed an afebrile, weak and pale patient with a sclera icterus. Intraoral examination demonstrated an area of soft tissue necrosis posterior to the mo- bile lower right first molar. A panoramic radiograph showed a non-healing socket of the lower right second molar with evidence of a small area of bone destruction and generalised horizontal bone loss indicating adult periodontitis. The patient was admitted with a provi- sional diagnosis of mandibular osteomyelitis and was started on intravenous augmentin and metronidazole. On admission, his complete blood count showed low haemoglobin (Hb 2.54 g/dl), marked neutropenia and pancytopenia (white cell count 1.52 x109/l, platelets 44.2 x109). His biochemical tests showed raised blood glucose (21 mmol/l), and his glycated haemoglobin was 19%. On the basis of these findings he was referred for an urgent opinion from the endocrine and the hae- matology teams. He was seen by an endocrinologist and the diagnosis of diabetic ketoacidosis was con- firmed. The patient was started on insulin to control his diabetes. The haematology team collected a bone marrow sample, which later confirmed the diagnosis of acute lymphoblastic leukaemia and the patient was then planned for chemotherapy. The area of necrosis was debrided under local anaesthesia with appropriate platelet cover to raise the platelet count to > 50 x109. At the time of debridement, an area of black patches was seen over the bone in the right retro-molar region and a biopsy was accordingly taken for histopathology diagnosis. This was later to confirm the diagnosis of mucormycosis [Figure 3]. Following confirmation of mucormycosis, the patient was started empirically on amphotericin B (AmBisome) and further debridement of the site was planned with removal of the mobile lower right first molar and packing the area with BIPP. The debrided site was regularly packed and irrigated with antiseptic solutions (0.2% Chlorhexidine and 3% Hydrogen peroxide) every 10 days for a period of 9 weeks, until the wound healed with the formation of healthy granulation tissue. D I S C U S S I O N Mucormycosis is an acute, opportunistic infection caused by a saprophytic fungus. In human beings there are three genera which are described as pathogens: Rhizopus, Absibia, and Mucor. These are members of the family mucorales of the class phycomycetes.2 Rhiz- opus is the predominant micro-organism, accounting for 90% of the cases of rhinocerebral mucormycosis.4,7 This pathogen can be found in fruits, soil, dust, and manure. In addition, it can be cultured from the oral cavity, nasal passages, throat and stools of healthy pa- tients without a sign of disease.8 The infectious proc- ess usually results from inhalation of spores through the nose or mouth, or sometimes through a skin laceration.9 Despite the fact that mucormycosis is ubiquitous and grows rapidly, it seldom causes infection in healthy patients. Therefore, if an infection with mucormycosis does occur, it usually indicates a serious underlying medical condition as reported in our two cases. Mu- cormycosis has been described in debilitated patients Figure 2: Coronal CT of case 1 showing oblitera- tion of the right sinus causing blockage of the medial conchae and extension to the right eth- moid sinus (arrowhead) A B D U L A Z I Z A B A K AT H I R 80 with medical conditions such as diabetes, leukaemia, lymphoma, renal failure, immunosuppressive therapy, malnutrition and severe burns.3,8-10 Up to 40 – 50% of patients who present with mucormycosis have DM.1,8 Studies have shown that DM alters the immunologi- cal capability to resist mucormycosis through a re- duction of the phagocytic ability of granulocytes in the presence of acidosis and there is an inability of diabetic serum to inhibit Rhizopus in vitro.11,12 In ad- dition, Rhizopus species thrive best in an acidic and glucose-rich environment. During the state of diabetic ketoacidosis (DKA), the acidic environment and the increase in the levels of free iron ions favour fungal growth.13 Neutrophils are also known to play an im- portant role in the host protective response against fungal colonisation. As a result of this, patients with leukaemia have an increased susceptibility to develop fungal infections, such as mucormycosis, because of the dysfunctional neutrophils and myelosuppression resulting from chemotherapy which in turn causes a profound neutropenia.1,13 There are at least six clinical forms of mucormy- cosis: rhinocerebral, pulmonary, gastrointestinal, cu- taneous, central nervous system, disseminated and miscellaneous, occurring at specific organ sites e.g. kidney and liver.1,2,8 The term rhinocerebral mucormy- cosis (RM) should be used when the paranasal sinuses, orbit and brain are involved.2-4 Amongst the paranasal sinuses, the most frequently involved are the maxillary and ethmoid sinuses.1 RM is the most common form in patients with DKA , accounting for 70% of reported cases.9 Patients with rhinocerebral mucormycosis usually present with malaise, headache, facial pain, swelling and low grade fever.8 The disease usually begins in the nasal mucosa or palate and extends to the paranasal sinuses spreading through the surrounding vessels. In addition, mucormycosis can involve the retro-orbital region by direct extension.9,14 With orbital involve- ment cranial nerves III, IV and VI functions may be impaired or lost resulting in proptosis, ptosis, pupillary dilatation, orbital cellulitis and loss of vision.8 As mu- cormycosis develops, the fungal hyphae start to invade local tissue. Direct penetration and growth through the wall of blood vessels account for the propensity for thrombosis and tissue necrosis as occurred in our two cases [Figure 3]. Haematogenous spread to the cavernous sinus and fatal cavernous sinus thrombosis has been widely reported.4,8-9 Beside haematogenous spread, RM can also spread by perineural invasion.15 An area of ulceration or an extraction socket in the mouth can be a port of entry for mucormycosis into the maxillofacial region, particularly when the patient is immunocompromised.16 Kim et al. (2001) reported 4 cases of RM over a period of ten years, which were diagnosed post-dental extractions. In all these 4 cas- es, the patients had an uncontrolled DM with two of them in a DKA state at the time of presentation. Even though mucormycosis of the head and neck common- ly occurs in the maxillofacial region, there are only few reported cases of RM in the mandible. 17-18 In our re- ported cases both patients developed mucormycosis in the mandible. Radiographically, maxillary mucormycosis typical- ly shows opacification of the paranasal sinuses without fluid level, thickening of the sinus mucosa and bone distraction of the sinus walls [Figures 1 & 2]. As some of these radiographic features may resemble sinusitis, McDonogh et al. warned that any diabetic patient in a ketoacidotic state presenting with clinical and radio- graphic features of rhinosinusitis should be suspected as having mucormycosis until proven otherwise.19 Definitive diagnosis of RM is usually obtained by a tissue biopsy which identifies the characteristic hyphae.7 Histologically, mucormycosis is character- ised by extensive tissue necrosis and the presence of numerous, large (5-30 µm), thinned-wall fungal hy- phae, which are non-septate, branched at right angles and have a ribbon-like appearance [Figure 4]. Figure 3: Photomicrograph from retro-molar area showing area of bone necrosis with infesta- tion of fungal hyphae (Haematoxylin and eosin stain, original magnification _400) M U C O R M Y C O S I S O F T H E J AW A F T E R D E N TA L E X T R A C T I O N S : TW O C A S E R E P O R T S 81 Successful management of rhinocerebral mucormy- cosis includes both medical and surgical modalities. The initial medical approach to mucormycosis con- sists of aggressive treatment of the underlying predis- posing medical condition and the use of systemic an- tifungal agents. The use of amphotericin B in patients with mucormycosis has been widely published and accepted as the best form of treatment with an overall survival rate of up to 72%.7-9 Based on recent published data, Spellberg et al. highlighted the recommended use of liposomal amphotericin B such as AmBisome in the management of mucormycosis.20 Surgical man- agement is crucially important and should involve early debridement of all infected and necrotic tissues. This may have to be repeated based on progression of the disease. In some cases, radical resection may be required, which can include partial or total maxillec- tomy, mandibulectomy and orbital exenteration.3, 21 In our reported cases, the management was started early in the course of disease and involved aggressive local debridement with repeated antiseptic packing un- til the wound healed with healthy granulation tissue. In addition, the correction of the underlying medical condition, along with the use of liposomal amphoter- icin B therapy, resulted in good control of the disease with a favourable outcome. C O N C L U S I O N Early recognition of mucormycosis is necessary to limit the spread of infection, which can lead to high morbidity and mortality. Therefore, dental surgeons and medical practitioners should be familiar with signs and symptoms of the disease and should main- tain a high index of suspicion in patients with DM, as it is estimated that 10% of the Omani population have diabetes. Finally, a multi-disciplinary team approach along with early diagnosis, reversal of the underlying medical condition accompanied by aggressive surgical intervention and the use of amphotericin B are the key to improving the outcome of patients with mucormy- cosis. A C K N OW L E D GE M E N T S The author would like to thank Prof. K.F. 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