J Oral Maxillofac Surg 60:328-330, 2002

Rhinocerebral Mucormycosis in a Patient With Latent Diabetes Mellitus: A Case Report

Stavros Tryfon, MD,* Ioannis Stanopoulos, MD, Elias Kakavelas, MD, Anastasia Nikolaidou, MD, and Ioannis Kioumis, MD
Rhinocerebral mucormycosis is a rare opportunistic fungal infection that attacks mainly immunocompromised or diabetic patients. Three genera are described as human pathogens: Rhizopus, Absibia, and Mucor. These members of the family Mucorales belong to the class Phycomycetes. They are typically saprophytic in the human upper respiratory and digestive tracts. The incidence of mucormycosis is very low.1 Entry of the fungus into the central nervous system (rhinocerebral mucormycosis) most often follows extension from its initial site of invasion in the nose or paranasal sinuses and through the adjacent bones into the brain.2 Latent diabetes mellitus may lead to ketoacidosis in the case of stress, systemic infections, or use of corticosteroids. There has been only 1 report of mucormycosis in a diabetic patient who was receiving corticosteroids.3 We present the case of a latent diabetic in whom ketoacidosis and rhinocerebral mucormycosis developed after a tooth extraction.
local anesthesia without complications, but 2 days later, she was admitted to the hospital because of fever and inammation in the extraction region. On evaluation, the patients temperature was 37.1C, blood pressure was 120/80 mm Hg, and pulse rate was 95 beats/min. A soft, painless, uctuant region was palpated in the left upper gingiva. In addition, induration, tenderness, and erythema were noticed in the contiguous region. The abscess was drained, and empiric oral therapy with metronidazole (500 mg/3 times daily) and amoxicillin/clavulanic acid (625 mg/3 times daily), was started. Initial laboratory data were hematocrit of 37.4%; hemoglobin, 12.9 g/dL; white blood cells, 9,250/ L (75/15/6/ 2.2); platelets, 332,000/ L, sedimentation rate, 45 mm/hr, glucose, 108 mg/dL; blood urea nitrogen, 33 mg/dL; creatine, 1 mg/dL; potassium, 3.9 mEq/L; sodium, 140 mEq/L; calcium, 9 mg/dL; serum glutamate pyruvate transaminase, 11 IU/L; serum glutamate-pyruvate transaminase, 15 IU/L; alkaline phosphatase, 85 IU/L; lactate dehydrogenase, 147 IU/L; creatinine phosphokinase, 53 IU/L; and bilirubin, 0.4 mg/dL. The next day, the patient was still febrile and tachypnic and looked severely ill. The laboratory data indicated the presence of leukocytosis (white blood cells, 20,900/ L [89% polymorphonuclear, 5% lymphocytes, 5% mononuclear]) and diabetic ketoacidosis (glucose, 381 mg/dL; pH 7.11; PO2, 80 mm Hg; PCO2, 17 mm Hg; bicarbonate, 11 mmol/L). The antibiotic therapy was changed to ceftriaxone (1 g twice daily), vancomycin (1 g twice daily), and metronidazole (500 mg 3 times daily) intravenously. On routine clinical examination, a black necrotic lesion was observed that extended from the mucosa of the extraction area to the soft palate. A tissue specimen was obtained surgically from the soft palate for culture and microscopic examination. Eight hours later, evidence of rhinofacial and orbital cellulitis, marked swelling of the conjunctiva, and loss of vision in the left eye were observed. The patient was gradually becoming lethargic and was eventually intubated. Because of the rapid expansion of the facial cellulitis, amphotericin-B (0.25 mg/kg daily) was added to the antibiotic therapy, in consideration that mucormycosis might be the infection. Despite the antibiotic therapy and control of the ketoacidosis with an intravenous insulin infusion, the black necrotic lesions gradually increased during the next 2 days to involve the nasal mucosa, the hard palate, all of the left cheek, and the left orbit (Fig 1). The biopsy specimen was positive for mucormycosis (Fig 2). Ten days after admission, the patient died.

Report of a Case
A 57-year-old woman presented to the Oral and Maxillofacial Surgery Clinic of Hospital G. Papanikolaou, Thessaloniki, Greece, with symptoms of periodontitis. She had a negative medical history and did not use alcohol or drugs. The upper left second premolar tooth was extracted under

Received from Hospital G. Papanikolaou, Thessaloniki, Greece. *Chest Physician, Respiratory Failure Unit. Chest Physician, Internist, Respiratory Failure Unit. Assistant Professor, Chief of ICU, Respiratory Failure Unit. Pathologist, Pathology Department. Chest Physician, Internist, Respiratory Failure Unit. Address correspondense and reprint requests to Dr Tryfon: Nik.Pyrza 3, Panorama 55236, Thessaloniki, Greece; e-mail: strifon@med.auth.gr
2002 American Association of Oral and Maxillofacial Surgeons

0278-2391/02/6003-0019$35.00/0 doi:10.1053/joms.2002.30600

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Discussion
Mucormycosis has been associated with numerous predisposing clinical factors, including diabetes, diabetic ketoacidosis, leukemia, lymphoma, and immunosuppressive therapy.1,4 Hyperglycemia or acidosis per se is not sufcient to induce fungal replication within the macrophage.5 Normal human serum can inhibit the growth of Rhizopus.6 In contrast, serum obtained from patients with diabetic ketoacidosis is not inhibitory and may actually enhance fungal growth.7 Early evidence of the presence of the disease can be found on radiographs of the sinuses.8 The most frequently involved sinuses are the ethmoid sinuses and the maxillary sinus.3 Once the fungus begins to grow, its hyphae, with an afnity for blood vessels, invade the tissues. Direct penetration and growth through the blood vessel wall account for the propensity for thrombosis and tissue necrosis, as occured in this patient. Central nervous system mucormycosis occurs as an extension of the fungus from its initial site of invasion in the nose or paranasal sinuses through adjacent bones into the brain.2,9 This complication was recognizable in our patient on the basis of the decreasing consciousness and the development of multiple focal neurologic ndings in the cranial nerves (especially nerves V and VII). Destruction of bone in this region is often revealed on repeated computed tomography scanning, which was not possible to have done in this patient because of her hemodynamic instability. The laboratory studies are nonspecic. Denite diagnosis requires histologic examination of involved tissue and visualization of broad, nonseptate hyphae with right-

FIGURE 2. Photomicrograph showing the branching nonseptate hyphae of mucormycosis in the biopsy sample from the soft palate (hematoxylin-eosin stain, original magnication 250).

angle branching. In this case, a tissue specimen was obtained surgically from the soft palate. The standard therapy for invasive mucormycosis is amphotericin-B.10 Because the fungus is relatively refractory to medical treatment, higher-than-usual dosages of amphotericin-B have been recommended, typically 1.0 to 1.5 mg/kg/d.11 The antifungal efcacy of amphotericin-B in mucormycosis is complicated by variability in sensitivity among isolates and among spores and hyphal forms, by unknown penetration of infected tissue, and by poor immunocompetence.4 Despite the high dose of amphotericin-B, this patient did not respond well. Recent reports emphasize the importance of aggressive surgical treatment (orbital exenteration, maxillectomy, antrectomy, partial rhinectomy, or a combination).12,13 It is apparent that 2 factors determine the outcome in patients: early diagnosis and resolution of predisposing problems. There is a positive correlation between survival and the time between diagnosis and initiation of treatment. This interval has been reported to range from 2 to 72 hours;3 there is only 1 report of spontaneously resolving mucormycosis.14 Overall, the mortality rate has been about 50%,1 although more recent studies have claimed that up to 85% of patients can be successfully treated.10,11 In this patient, by the time the disease was suspected, extensive tissue destruction had occurred; in addition, the pace of the disease was very rapid, and the patients general condition was so poor that medical therapy failed and surgical options were not possible.

References
1. Lehrer RI, Howard DH, Sypherd PS, et al: Mucormycosis. Ann Intern Med 93:93, 1980 2. Berthier M, Palmieri O, Lylyk P, et al: Rhino-orbital phycomycosis complicated by cerebral abscess. Neuroradiology 22:221, 1982

FIGURE 1. Black necrotic lesions involving the nose, hard palate, left cheek, and left orbit.

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3. Shpitzer T, Stern Y, Anavi Y, et al: Mucormycosis: Experience with 10 patients. Clin Otolaryngol 20:374, 1995 4. Meyer RD, Rosen P, Armstrong D: Phycomycosis complicating leukemia and lymphoma. Ann Intern Med 77:871, 1972 5. Waldorf AR: Host-parasite relationship in opportunistic mycoses. CRC Crit Rev Microbiol 13:133, 1985 6. Chinn RYW, Diamond RD: Generation of chemotactic factors by Rhizopus oryzae in the presence and absence of serum: Relationship to hyphal damage mediated by human neutrophils and effects of hyperglycemia and ketoacidosis. Infect Immunol 38:1123, 1982 7. Gale GR, Welch A: Studies of opportunistic fungi, I: Inhibition of R. oryzae by human sera. Am J Med Sci 45:604, 1961 8. Lazo A, Wilner HI, Metes JJ: Craniofacial mucormycosis: Computed tomographic and angiographic ndings in two cases. Radiology 139:623, 1981 9. Gregory JE, Golden A, Haymaker W: Mucormycosis of the central nervous system: A report of three cases. Bull Johns Hopkins Hosp 73:405, 1943 10. Fisher EW, Toma A, Fisher PH, et al: Rhinocerebral mucormycosis: Use of liposomal amphotericin B. J Laryngol Otol 105: 575, 1991 11. Ericsson M, Anniko M, Gustafsson H, et al: A case of chronic progressive rhinocerebral mucormycosis treated with liposomal amphotericin B and surgery. Clin Infect Dis 16:585, 1993 12. Meyer RD, Armstrong D: Mucormycosis: Changing status. CRC Crit Rev Clin Lab Sci 4:421, 1973 13. Pillsbury HC, Fischer ND: Rhinocerebral mucormycosis. Arch Otolaryngol 103:600, 1977 14. Mendoza-Ayala R, Tapia R, Salathe M: Spontaneously resolving pulmonary mucormycosis. Clin Infect Dis 29:1335, 1999