Orbitomaxillary Mucormycosis (Zygomycosis) and the Surgical Approach to Treatment: Perspectives from a Maxillofacial Surgeon

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REVIEW 10.1111/j.1469-0691.2009.02989.x

Orbitomaxillary mucormycosis (zygomycosis) and the surgical approach to treatment: perspectives from a maxillofacial surgeon

A. D. Rapidis Department of Maxillofacial Surgery, Greek Anticancer Institute, St. Savvas Hospital, Athens, Greece

Abstract

Rhinocerebral or rhino-orbitocerebral (mucormycosis) zygomycosis (ROCZ) usually occurs among patients with poorly controlled diabetes mellitus (especially those with ketoacidosis), solid malignancies, iron overload or extensive burns, in patients undergoing treatment with glucocorticosteroid agents, or in patients with neutropenia related to haematologic malignancies. The disease process starts with inhalation of the fungus into the paranasal sinuses. The fungus may spread to invade the palate, sphenoid sinus, cavernous sinus, orbits or cranially to invade the brain. Pain and swelling precede oral ulceration and the resulting tissue necrosis can result in palatal perforation. Infection can sometimes extend from the sinuses into the mouth and produce painful, necrotic ulcerations of the hard palate. If untreated, infection usually spreads from the ethmoid sinus to the orbit, resulting in the loss of extraocular muscle function and proptosis. Surgical treatment includes the resection of involved tissues of the face, including skin and muscle, any skin of the nose that is involved, maxillary and ethmoid sinuses, necrotic tissue of the temporal area and infratemporal fossa, and orbital exenteration. The keys to successful therapy include suspicion of the diagnosis and early recognition of the signs and symptoms, correction of underlying medical disorders such as ketoacidosis, and aggressive medical and surgical intervention.

Keywords: Maxillectomy, mucormycosis, orbital exenteration, zygomycosis Clin Microbiol Infect 2009; 15 (Suppl. 5): 98–102

ity of cases reported have represented either isolated Corresponding author and reprint requests: A. D. Rapidis, examples or small, retrospective series. This relative scarcity Department of Maxillofacial Surgery, Greek Anticancer Institute, St. Savvas Hospital, 171 Alexandras Avenue, Athens 115 22, Greece of cases hinders the drawing of diagnostic and therapeutic E-mail: [email protected] conclusions [4]. However, with the increasing prevalence of diabetes and immunosuppressive conditions, mucormycosis has emerged as an important fungal infection. Based on clinical presentation and the involvement of a particular anatomic Introduction site, mucormycosis can be divided into at least six clinical categories: (i) rhinocerebral; (ii) pulmonary; (iii) cutaneous; Zygomycetes have a wide geographical distribution, are all (iv) gastrointestinal; (v) disseminated, and (iv) miscellaneous thermo-tolerant, and utilize a variety of nutritional sub- [5,6]. strates. In nature, they are found in the soil, animal faeces and decaying plant materials [1,2]. They spread by the pro- Risk Factors and Pathophysiology of duction of sporangiospores that are released into the envi- Rhinocerebral or Rhino-orbitocerebral ronment as airborne propagules. Humans are usually Zygomycosis resistant to the disease because Mucorales fungi are ubiqui- tous in the environment. Nosocomial infections can occur from sporangiospores released through contaminated air- Rhinocerebral or rhino-orbitocerebral zygomycosis (ROCZ) conditioning systems or contaminated wound dressings. The usually occurs among patients with poorly controlled diabe- fungus exhibits a remarkable affinity for arteries and grows tes mellitus (especially those with ketoacidosis), solid malig- along the internal elastic lamina, causing thrombosis and nancies, iron overload or extensive burns, or in patients who infarction. Infections occur equally in both sexes, irrespective take glucocorticosteroid agents or have neutropenia related of age. to haematologic malignancies. A recently identified important Mucormycosis, also known as zygomycosis and phycomy- clinical feature is the increased susceptibility to mucormyco- cosis, was first described by Paultauf in 1885 [3]. The major- sis of patients with elevated available serum iron. It has been

ª2009 The Author Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases CMI Rapidis Surgical approaches to orbitomaxillary mucormycosis 99

known for two decades that patients treated with the iron media. This direct invasion and dissection by the fungus chelator deferoxamine have a markedly increased incidence causes extensive endothelial damage, resulting in thrombus of invasive mucormycosis [7, 8]. However, it is now clear formation and ischaemia to the surrounding tissues. The that iron chelation is not the mechanism by which deferox- infarcted tissue creates an environment that promotes fungal amine enables mucormycosis infections. Although deferox- proliferation and the resultant poor vascular supply prevents amine is an iron chelator from the perspective of the human systemic medical therapy from eradicating the fungus. The host, Rhizopus spp. actually utilize deferoxamine as a sidero- nasal and sinus walls are invaded via these vessels and the phore to supply previously unavailable iron to the fungus. orbit is invaded secondarily via freely communicating fora- Patients with diabetic ketoacidosis are at high risk of devel- men and venous channels. The fungus invades the cranium oping rhinocerebral mucormycosis. Multiple lines of evidence through either the orbital apex or the cribriform plate of the support the conclusion that patients with systemic acidosis ethmoids and ultimately kills its host [14,15]. have elevated levels of available serum iron, probably as a result of the release of iron from binding proteins in the Clinical Symptoms and Signs presence of acidosis [9]. Neutropenia is another significant risk factor. The correction of neutropenia with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage The initial symptoms of ROCZ are consistent with either colony-stimulating factor (GM-CSF) is important to improve sinusitis or periorbital cellulitis and include eye or facial outcome. A breakthrough in the management of zygomycosis pain and facial numbness, followed by the onset of conjunc- in patients with neutropenia was recently achieved with tival suffusion, blurry vision and soft tissue swelling. Symp- empirical voriconazole therapy in the absence of ampho- toms that may suggest mucormycosis in susceptible tericin B (AmB) [10,11]. Initiation of early and appropriate individuals include multiple cranial nerve palsies, unilateral antifungal administration and, if required, discontinuation of periorbital facial pain, orbital inflammation, eyelid oedema, steroids or deferoxamine is advisable [12]. blepharoptosis, proptosis, acute ocular motility changes, Rhinocerebral mucormycosis continues to be the most internal or external ophthalmoplegia, headache or acute common form of the disease, accounting for between one- vision loss. Fever is variable and may be absent in up to third and one-half of all cases of mucormycosis. Approxi- half of the cases. White blood cell counts are typically ele- mately 70% of rhinocerebral cases (occasionally referred to vated, as long as the patient has functioning bone marrow as craniofacial cases) occur in diabetes patients with keto- [16,17]. acidosis. More rarely, rhinocerebral mucormycosis has also Upon visual inspection, infected tissue may appear normal occurred in patients who have received a solid organ trans- during the earliest stages of spread of the fungus. Infected plant or those with prolonged neutropenia. Recently, rhino- tissue then progresses through an erythematous phase, with cerebral disease has become an increasing problem in or without oedema, before the onset of a violaceous appear- patients undergoing haematopoietic stem cell transplantation. ance and, finally, the development of a black, necrotic eschar These cases have largely been associated with steroid use as the blood vessels become thrombosed and tissue infarc- for graft vs. host disease [13]. tion occurs. Palatal involvement is usually the result of the Infection with Zygomycetes can be acquired by inhalation, direct extension of disease from the maxillary sinus and in ingestion or the deposition of spores in wounds. The fungi the distribution of the sphenopalatine and greater palatine give rise to pathogenic lesions as a result of invasion and arteries. Pain and swelling precede oral ulceration, and the growth within the lumen and walls of major blood vessels, resulting tissue necrosis can result in palatal perforation. with ensuing thromboembolism resulting in ischaemia and tis- Infection can sometimes extend from the sinuses into the sue necrosis. Agents of zygomycosis have a predilection for mouth and produce painful, necrotic ulcerations of the hard the internal elastic lamina of the arterial blood vessels and palate. If untreated, infection usually spreads from the eth- spread by angioinvasion. The disease process in the ROCZ moid sinus to the orbit, resulting in loss of extraocular mus- form probably starts with the inhalation of the fungus into cle function and proptosis. Marked chemosis may also be the paranasal sinuses. Upon germination, the fungus may seen. The infection may rapidly extend into the neighbouring spread inferiorly to invade the palate, posteriorly to invade tissues [18]. the sphenoid sinus and beyond into the cavernous sinus, lat- Cranial nerve findings represent extensive infection and erally to involve the orbits, or cranially to invade the brain. signal a grave prognosis. Progressive vision loss, and ulti- The fungus has a propensity to grow along the elastic lamina mately blindness, may result from involvement of the optic of the blood vessels, dissecting the lamina away from the nerve, from arterial invasion resulting in infarction, or from

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cavernous sinus thrombosis. Cranial nerves V and VII may ever, the organism is rarely isolated from cultures of blood, also be affected, resulting in ipsilateral loss of facial sensation, cerebrospinal fluid, sputum, urine, faeces or swabs of ptosis and pupillary dilation. Infection can also spread post- infected areas. eriorly from either the orbit or sinuses to the central nervous system (CNS). A bloody nasal discharge may be the Surgical Treatment and Antifungal Therapy first sign that infection has invaded through the turbinates and into the brain. When there is extensive CNS involvement, the angioinvasive nature of the fungus may result in Aggressive early surgical debridement of the infected cranio- cavernous sinus thrombosis and internal carotid artery facial tissues is the cornerstone of successful treatment of encasement and thrombosis, with resulting extensive cere- ROCZ mucormycosis. This includes resection of involved tis- bral infarctions. Occasionally, cerebral vascular invasion may sues of the face, including skin and muscle, any skin of the lead to haematogenous dissemination of the infection, with nose that is involved, maxillary and ethmoid sinuses, necrotic or without development of mycotic aneurysms [19]. tissue of the temporal area and infratemporal fossa, and orbital exenteration. Orbital exenteration may be life-saving in the presence of active fungal invasion of the orbit and should Radiographic Diagnostic Methodology be considered for an actively infected orbit with a blind, immobile eye. It has been considered helpful even after intra- Preoperative contrast-enhanced computed tomography (CT) cranial spread has occurred. Whether or not to perform is useful in defining the extent of the disease. Scans show the orbital exenteration is the most difficult decision in the surgi- oedematous mucosa, fluid filling the ethmoid sinuses, and cal management of orbital mucormycosis because the proce- destruction of periorbital tissues and bony margins. Although dure may represent a life-saving measure achieved at the sinus CT is the preferred imaging modality, bony destruction cost of permanent mutilation [23]. is often seen only late in the course of the disease after soft- Surgical debridement usually proceeds quickly because of tissue necrosis has already occurred [20]. an almost bloodless field. An aggressive surgical approach Magnetic resonance imaging (MRI) is useful in identifying appears to enhance survival. The keys to successful therapy the intradural and intracranial extent of the disease, cavern- include suspicion of the diagnosis with early recognition of ous sinus thrombosis, or thrombosis of the cavernous por- the signs and symptoms, correction of underlying medical tion of the internal carotid artery. Perineural spread of the disorders such as ketoacidosis, and aggressive medical and disease can also be demonstrated with contrast-enhanced surgical intervention [24]. The use of all available therapeutic MRI scans. modalities in the treatment of this often fatal infection, Although evidence of infection of the soft tissues of the including intravenous liposomal AmB and hyperbaric oxygen orbit may sometimes be seen by CT scan, MRI is more in addition to the aggressive surgical debridement, are man- sensitive when soft tissue lesions are depicted. However, datory. Treatment with AmB at the highest tolerable dose is patients with early ROCZ may have normal MRI and CT necessary. The use of AmB is limited by frequent side-effects, scans and surgical exploration with biopsy of the areas of the most important of which is its dose-limiting nephrotoxi- suspected infection should always be performed in high-risk city. Most of the negative side-effects can be avoided by patients. Given the limitations of imaging studies, diagnosing using lipid preparations of AmB [25]. This lipid-based formu- mucormycosis almost always requires histopathological evi- lation increases circulation time and alters the biodistribution dence of fungal invasion of the tissues [21]. There are no of the associated AmB. Because drugs complexed with lipid reliable serologic, polymerase chain reaction (PCR)-based or vehicles remain longer in the vasculature, they are able to skin tests for mucormycosis. Therefore, the diagnosis should localize and reach greater concentrations in tissues with be made by biopsy of infected tissues. The biopsy should increased capillary permeability (i.e. tissues in which infection demonstrate the characteristic wide, ribbon-like, aseptate and inflammation are present) compared with regions of hyphal elements that branch at right angles. The organisms normal tissue, which are essentially impermeable to lipid- are often surrounded by extensive necrotic debris. Other complexed drugs [26]. This method of increasing the locali- fungi, including Aspergillus, Fusarium and Scedosporium spp., zation of drugs to diseased sites is referred to as ‘passive may look similar to the Mucorales on biopsy [22]. However, targeting’. It enhances delivery of the agent to the fungi, these moulds have septae, are usually thinner, and branch at infected organs and phagocytes with lower toxicity, while acute angles. The genus and species of the infecting organism maintaining antifungal efficacy by ensuring significantly higher may be determined by culture of the infected tissue. How- sustained tissue levels of the drug. Within these sites, drug

ª2009 The Author Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 15 (Suppl. 5), 98–102 CMI Rapidis Surgical approaches to orbitomaxillary mucormycosis 101

release occurs through the action of lipases from surround- can occur within several days to a few weeks, even when ing inflammatory cells. The lipid formulations may also enable appropriate treatment has been instituted. Appropriate man- better solubility into the CNS. The cerebrospinal fluid pene- agement results in a cure in only approximately half of rhino- tration of conventional AmB is known to be poor and, cerebral infections. Given the rapidly progressive nature of although the concentration of lipid-based AmB in brain tissue rhinocerebral mucormycosis and the marked increase in remains unknown, studies describe its successful use in crypto- mortality when the fungus penetrates the cranium, any diabe- coccal meningitis [27, 28]. Furthermore, the lethal dose (LD50) tes patient with a headache and visual changes is a candidate of lipid-based AmB is approximately 10–15 times higher than for prompt evaluation which should include imaging studies that of conventional AmB and has substantially reduced renal and nasal endoscopy to rule out mucormycosis. Published toxicity. Thus, the lipid formulations are ideally suited for ther- case series continue to support the need for surgical apy against infections such as ROCZ, which require large debridement to optimize outcomes [34]. For example, in a doses of drug given for long periods of time [29]. The recom- case series totalling 49 patients with rhinocerebral mucor- mended dose of liposomal AmB is 5 mg/kg/day prepared as a mycosis, the mortality rate was 70% in cases treated with 1 mg/mL infusion and delivered at a rate of 2.5 mg/kg/h. There antifungal agents alone compared with 14% in cases treated are an increasing number of reports of salvage posaconazole with antifungal agents plus surgery [35]. Similarly, in a com- therapy for refractory mucormycosis [14]. Successful out- bined series of rhinocerebral, cutaneous and pulmonary comes of posaconazole administered in conjunction with AmB mucormycosis, 11 of 17 (65%) patients treated with surgery have been seen in patients with ROCZ mucormycosis and in a plus antifungal agents survived the infection, compared with heart-kidney transplant patient who failed on amphotericin none of seven (0%) patients treated with antifungal agents therapy [30]. Currently, novel regimens for the treatment of alone [36]. The nature of the underlying disease and the mucormycosis include a combination of lipid-based amphoteri- reversibility of the immune dysfunction are also important cin plus either an echinocandin or itraconazole or both determinants of survival. One study showed that 75% of [25, 31, 32]. patients with rhinocerebral disease who had no underlying In addition, compassionate-use posaconazole is currently immune compromise survived, whereas 60% of those with available, and its potential for combination therapy with a diabetes and only 20% of patients with other immuno- polyene, caspofungin, or both, is worthy of study. Further compromised states were cured. data are needed to determine whether posaconazole, alone or in combination with AmB, may be useful for the treat- Conclusions ment of mucormycosis. Hyperbaric oxygen has been used as an adjunct to the current therapeutic approach of aggressive surgical debridement, AmB therapy and control of underlying The overall survival rate of patients with mucormycosis is predisposing conditions. Although studies have shown that approximately 50%, although survival rates of up to 85% hyperbaric oxygen exerts a fungistatic effect, its most have been reported more recently [27]. Much of the vari- important effect is to aid neovascularization with subsequent ability in outcome is due to the various forms of the disease. healing in poorly perfused acidotic and hypoxic – but viable – Rhino-orbitocerebral mucormycosis has a higher survival tissue [8]. Hyperbaric oxygen therapy for mucormycosis rate than does pulmonary or disseminated mucormycosis should consist of exposure to 100% oxygen for 90 min to because the rhinocerebral disease can frequently be diag- 2 h at pressures of 2.0–2.5 atmospheres with one or two nosed earlier and the most common underlying cause, dia- exposures daily for a total of 40 treatments. Reported toxici- betic ketoacidosis, can be treated readily. By contrast, ties of hyperbaric oxygen include teratogenicity and, rarely, pulmonary mucormycosis has a high mortality (65% at pulmonary or CNS side-effects. Although hyperbaric oxygen 1 year) because it is difficult to diagnose and it frequently is offered by only a few medical facilities, it may be war- occurs in neutropenic patients [11]. Reconstruction should ranted in patients who appear to be deteriorating despite be delayed to ensure that the patient survives, that the maximal surgical and medical therapy [23, 33]. infection is completely cleared and that the remaining tissue is healthy [37]. Subsequent Clinical Course and Prognosis Transparency Declaration

Mucormycosis is the most acutely fatal fungal infection in humans, with mortality rates of 15–34% [4, 23, 26]. Death The author declares no conﬂicts of interest.

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References 20. Franquet T, Gimenez A, Hidalgo A. Imaging of opportunistic fungal infections in immunocompromised patient. Eur J Radiol 2004; 51: 130–138. 1. Ameen M, Arenas R, Martinez-Luna E, Reyes M, Zacarias R. The 21. Mnif N, Hmaied E, Oueslati S et al. [imaging of rhinocerebral mucor- emergence of mucormycosis as an important opportunistic fungal mycosis]. J Radiol 2005; 86: 1017–1020. infection: Five cases presenting to a tertiary referral center for 22. Ghadiali MT, Deckard NA, Farooq U, Astor F, Robinson P, Casiano mycology. Int J Dermatol 2007; 46: 380–384. RR. Frozen-section biopsy analysis for acute invasive fungal rhinosinu- 2. Bhatti Z, Shaukat A, Almyroudis NG, Segal BH. Review of epidemiol- sitis. Otolaryngol Head Neck Surg 2007; 136: 714–719. ogy, diagnosis, and treatment of invasive mould infections in allo- 23. Greenberg RN, Scott LJ, Vaughn HH, Ribes JA. Zygomycosis (mucor- geneic hematopoietic stem cell transplant recipients. Mycopathologia mycosis): Emerging clinical importance and new treatments. Curr Opin 2006; 162: 1–15. Infect Dis 2004; 17: 517–525. 3. Paultauf A. Mycosis mucorina. Arch Pathol Anat 1885; 102: 543. 24. Bengel D, Susa M, Schreiber H, Ludolph AC, Tumani H. Early diagno- 4. Spellberg B, Edwards J, Jr., Ibrahim A. Novel perspectives on mucor- sis of rhinocerebral mucormycosis by cerebrospinal fluid analysis and mycosis: Pathophysiology, presentation, and management. Clin Micro- determination of 16s rrna gene sequence. Eur J Neurol 2007; 14: biol Rev 2005; 18: 556–569. 1067–1070. 5. Pagano L, Ricci P, Tonso A et al. Mucormycosis in patients with hae- 25. Spellberg B, Fu Y, Edwards JE, Jr., Ibrahim AS. Combination therapy matological malignancies: A retrospective clinical study of 37 cases. with amphotericin b lipid complex and caspofungin acetate of disse- Gimema infection program (gruppo italiano malattie ematologiche minated zygomycosis in diabetic ketoacidotic mice. Antimicrob Agents maligne dell’adulto). Br J Haematol 1997; 99: 331–336. Chemother 2005; 49: 830–832. 6. Nosari A, Oreste P, Montillo M et al. Mucormycosis in hematologic 26. Roden MM, Zaoutis TE, Buchanan WL et al. Epidemiology and out- malignancies: An emerging fungal infection. Haematologica 2000; 85: come of zygomycosis: A review of 929 reported cases. Clin Infect Dis 1068–1071. 2005; 41: 634–653. 7. Islam MN, Cohen DM, Celestina LJ, Ojha J, Claudio R, Bhattacharyya 27. Sims CR, Ostrosky-Zeichner L. Contemporary treatment and out- IB. Rhinocerebral zygomycosis: An increasingly frequent challenge: comes of zygomycosis in a non-oncologic tertiary care center. Arch Update and favorable outcomes in two cases. Oral Surg Oral Med Oral Med Res 2007; 38: 90–93. Pathol Oral Radiol Endod 2007; 104: e28–34. 28. Richardson M. Ambisome: Adds to the body of knowledge and famil- 8. Garcia-Covarrubias L, Bartlett R, Barratt DM, Wassermann RJ. iarity of use. Acta Biomed 2006; 77 (Suppl 4): 3–11. Rhino-orbitocerebral mucormycosis attributable to apophysomyces 29. Schutz P, Behbehani JH, Khan ZU et al. Fatal rhino-orbito-cerebral elegans in an immunocompetent individual: Case report and review zygomycosis caused by apophysomyces elegans in a healthy patient. of the literature. J Trauma 2001; 50: 353–357. J Oral Maxillofac Surg 2006; 64: 1795–1802. 9. Hosseini SM, Borghei P. Rhinocerebral mucormycosis: Pathways of 30. Barchiesi F, Spreghini E, Santinelli A et al. Posaconazole prophylaxis in spread. Eur Arch Otorhinolaryngol 2005; 262: 932–938. experimental systemic zygomycosis. Antimicrob Agents Chemother 10. Pongas GN, Lewis RE, Samonis G, Kontoyiannis DP Voriconazole- 2007; 51: 73–77. associated zygomycosis: A significant consequence of evolving antifun- 31. Vazquez L, Mateos JJ, Sanz-Rodriguez C, Perez E, Caballero D, San gal prophylaxis and immunosuppression practices? Clin Microbiol Infect Miguel JF. Successful treatment of rhinocerebral zygomycosis with a 2009; 15: in press. combination of caspofungin and liposomal amphotericin b. Haematolo- 11. Rutar T, Cockerham KP. Periorbital zygomycosis (mucormycosis) gica 2005; 90: ECR39. treated with posaconazole. Am J Ophthalmol 2006; 142: 187–188. 32. Nivoix Y, Zamfir A, Lutun P et al. Combination of caspofungin and an 12. Orguc S, Yuceturk AV, Demir MA, Goktan C. Rhinocerebral mucor- azole or an amphotericin b formulation in invasive fungal infections. J mycosis: Perineural spread via the trigeminal nerve. J Clin Neurosci Infect. 2006; 52: 67–74. 2005; 12: 484–486. 33. Fairley C, Sullivan TJ, Bartley P, Allworth T, Lewandowski R. Survival 13. Pagano L, Offidani M, Fianchi L et al. Mucormycosis in hematologic after rhino-orbital-cerebral mucormycosis in an immunocompetent patients. Haematologica 2004; 89: 207–214. patient. Ophthalmology 2000; 107: 555–558. 14. Petrikkos G, Skiada A, Sambatakou H et al. Mucormycosis: Ten-year 34. Tidwell J, Higuera S, Hollier LH, Jr. LH, Facial reconstruction after experience at a tertiary-care center in greece. Eur J Clin Microbiol mucormycosis in an immunocompetent host. Am J Otolaryngol 2005; Infect Dis 2003; 22: 753–756. 26: 333–336. 15. Uckay I, Chalandon Y, Sartoretti P et al. Invasive zygomycosis in 35. Talmi YP, Goldschmied-Reouven A, Bakon M et al. Rhino-orbital and transplant recipients. Clin Transplant 2007; 21: 577–582. rhino-orbito-cerebral mucormycosis. Otolaryngol Head Neck Surg 16. O’Neill BM, Alessi AS, George EB, Piro J. Disseminated rhinocerebral 2002; 127: 22–31. mucormycosis: A case report and review of the literature. J Oral 36. Pelton RW, Peterson EA, Patel BC, Davis K. Successful treatment of Maxillofac Surg 2006; 64: 326–333. rhino-orbital mucormycosis without exenteration: The use of multi- 17. Cheema SA, Amin F. Five cases of rhinocerebral mucormycosis. Br J ple treatment modalities. Ophthal Plast Reconstr Surg 2001; 17: 62–66. Oral Maxillofac Surg 2007; 45: 161–162. 37. Lari AR, Kanjoor JR, Vulvoda M, Katchy KC, Khan ZU. Orbital 18. Tugsel Z, Sezer B, Akalin T. Facial swelling and palatal ulceration in a reconstruction following sino-nasal mucormycosis. Br J Plast Surg diabetic patient. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002; 55: 72–75. 2004; 98: 630–636. 19. Liang KP, Tleyjeh IM, Wilson WR, Roberts GD, Temesgen Z. Rhino- orbitocerebral mucormycosis caused by apophysomyces elegans. J Clin Microbiol 2006; 44: 892–898.

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