A rapidly fatal palatal ulcer: Rhinocerebral mucormycosis

rapidly fatal palatal ulcer: Rhinocerebral mucormycosis .

A. J. Van der Westhuijzen, BChD, F. W. Grotepass, BChD, MChD, G. Wyma, BChD, and A. Padayachee, BDS, MChD, Tygerberg, Republic of South Africa DEPARTMENTS STELLENBOSCH

OF ORAL

SURGERY

AND

ORAL

PATHOLOGY,

FACULTY

OF DENTISTRY,

UNIVERSITY

OF

A case of a patient with a palatal ulcer who was in a diabetic ketoacidotic coma is described. This ulcer proved to be the presenting sign of rhinocerebral mucormycosis. The patient had hemifacial swelling, ocular signs, and gross tissue destruction and died less than 4 weeks after she was first seen. (ORAL SURC ORAL MED ORAL PATHOL 1989;68:32-6)

P

alatal ulceration is not an uncommon clinical finding and may develop as the result of local or systemic influences. Wood and Goaz’ separated oral ulcers into two categories: short-term ulcers (i.e., those that persist no longer than 3 weeks and regress spontaneously) and chronic ulcers (those that remain for weeks or months). Necrotic oral ulcers that may occur in debilitating systemic diseasesuch as uncontrolled diabetes mellitus, uremia, and blood dyscrasias are usually of the short-term variety but may persist if the predisposing condition is not controlled. Since the host resistance is diminished, any small break in the oral mucosa may result in a necrotic ulcer if it becomes superficially infected by the oral flora. Such a nonspecific ulcer of the palate could well be the initial sign of mucormycosis before the ulcer assumes the characteristic features of a black necrotic eschar. A complete medical history is therefore essential in attempting a differential diagnosis of palatal ulceration. Mucormycosis, caused by saprophytic fungi of the family Mucoraceae, is a uniformly fatal disease unless diagnosed early to allow prompt, aggressive therapy. The purpose of this article is to report an unrecognized case of mucormycosis that proved fatal in an elderly woman with diabetes. A review of the literature pertaining to mucormycosis of the maxillofacial region is also performed. CASEREPORT

A 79-year-old woman was admitted to Tygerberg Hospital on January 6, 1986, in a ketoacidotic coma. She was 32

grossly obese, dehydrated, and unresponsive to verbal commands. The patient had insulin-dependent diabetes and a strong family history of diabetes mellitus; she had had three previous episodesof diabetic coma. She was also taking a hydrochlorothiazide compound for mild hypertension. Before the present episode she had been feeling unwell for approximately 1 week and had suffered anorexia, epigastric pain, diarrhea, and drowsiness. Hematologic and biochemical evaluation revealed grossly abnormal blood electrolyte levels, metabolic acidosis, and renal abnormalities. Both red blood cells and pus were evident in her urine. Chest radiographs were interpreted as normal, as were all other investigations: The patient was admitted and rehydrated; insulin administration was titrated to blood glucose concentrations. In addition, drug therapy consisting of ampicillin and furosemide was instituted to control a urinary tract infection. On the second day after admission the patient was responsiveand able to communicate, although she still complained of fatigue. Seven days after admission palsy of the left facial nerve was noted, and the patient was then referred to the Department of Ophthalmology with suspected raised intraocular pressure and decreased vision of the left eye. Examination revealed no orbital mass, but proptosis of the left eye due to periorbital cellulitis was detected. Visual acuity could not be assessedbecauseof poor cooperation by the patient. The fundi and intraocular pressure of the left eye were similar to those of the normal right eye. No other ophthalmologic abnormalities were noted. When a palatal ulcer was detected 2 weeks after the patient was first examined, she was referred to the Department of Maxillofacial Surgery for further examination. A large ulcer was visible in the region of the left palate, and there was edema over the left malar prominence (Fig. 1). Palpation of the left maxillary and periorbital regions revealed tenderness.Proptosis and pain of the left eye were

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Fig. 2. Photograph shows black necrotic ulcer partially covering the left palate and alveolar ridge.

Fig. 1. Photograph taken 2 weeksafter admission shows proptosis with surrounding periorbital swelling of the left eye and dark, blood-stained discharge from the left nostril.

present, and ocular movement was restricted. There was no evidence of cervical lymphadenopathy. The ulcer measured 2.0 X 3.0 cm and exhibited a stringy, dark-brown baseand undermined edges.The ulcer partially covered the left hard and soft palates and extended onto the left alveolar ridge (Fig. 2). Results of serologic tests for syphilis were negative. A fungal infection was suspected,and ketoconazole therapy was instituted. Metronidazole was added to the drug regimen to cover anaerobic and protozoa1 infections. A cytologic smear was inconclusive, and a biopsy was performed. Facial radiographs revealed opacification of the left nasal passageand left ethmoid sinuses, but unfortunately the views were of suboptimal quality because of poor patient cooperation (Fig. 3). The histopathology report on the palatal biopsy specimens showed superficial ulceration of the oral mucosawith prominent underlying necrosis and a dense underlying chronic inflammatory cell infiltrates. Also present were large nonseptate hyphae (branching at obtuse angles) and rounded sporangia occurring in groups. These histologic features were consistent with mucormycosis (Fig. 4). In view of the patient’s severe physical debilitation, it

Fig. 3. Occipitomental radiograph of patient taken 2 weeks after admission shows opacification of left nasal passageand ethmoid sinuses.

was decided to defer surgery initially but to commence intravenous antifungal chemotherapy consisting of 50 mg amphotericin B daily. The dosage was incrementally increased to 40 mg administered twice a day. Despite antimycotic therapy the patient’s condition continued to deteriorate, and she died 2 weeks later. The cause of death was rhinocerebral mucormycosis with diabetes mellitus as a contributory cause.

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ORAL SURG ORAL MED

ORAL PATHOL July 1989

Fig. 4. Section stained with hematoxylin and eosin (original magnification X250) shows chronic inflammatory infiltrate and nonseptatehyphaecharacteristicof mucormycosis.

I. Summary of clinical features associatedwith rhinocerebral mucormycosis

Table

Dark, blood-tinged nasal discharge Facial pain and anesthesia of the affected side Periorbital or perinasal swelling and edema Ptosis of the eyelid Fixed, dilated pupil Loss of extraocular movements Progressive lethargy Black necrotic palate, alveolar ridge or turbinates (which may be mistaken for dried blood) Decreased visual acuity progressing to blindness and loss of cornea1reflex

DISCUSSION Factors predisposing

to mucormycosis

Mucormycosis is a relatively uncommon opportunistic fungal infection that rarely arises in healthy persons.‘*3 An underlying disease, especially leukemia, lymphoma,4-6or diabetes mellitus4s6*’ (frequently with ketoacidosis, as in this case), is almost always associated with this condition. Less common predisposing conditions include cancer chemotherapy and immunosuppressant therapy, among others.5~6’8-10 Although rhinocerebral and pulmonary mucormycosis are the most common forms of this disease, other types include cutaneous,9gastrointestinal, and disseminated mucormycosis.” Ketoacidotic diabetes appears to be the most common predisposing factor in rhinocerebral mucormycosis.12

Pathology

and diagnosis

The etiologic organism is a saprophytic, true fungus of the family Mucoraceae.9*‘I These fungi are abundant in nature and may be found in soil, manure, fruit, bread,13and decaying organic matter.14 Diagnosis requires histologic demonstration of tissue invasion by fungi with characteristic broad (5 to 50 pm), nonseptate hyphae with right-angle branching.“, I4These characteristics are demonstrated best with methanamine silver staining.5 Histopathologically mucormycosis is characterized by invasion of blood vessel walls that dissects the internal elastic lamina from the tunica media vasorum.‘* Subsequent thrombosis causes ischemia and necrosis of the affected parts and leaves masses of black, infarcted tissue containing rapidly multiplying fungi.15 Clinical

features

Rhinocerebral mucormycosis is the most distinctive form of mucormycosis.6*I69” A black eschar on the palatal or nasal mucosa and drainage of black necrotic pus from the eye are diagnostic clues.9The initial symptoms may often be nonspecific (e.g., headache, malaise,18and lethargy).lg However, the characteristic clinical features of rhinocerebral mucormycosis are summarized in Table I.12 McDonogh and coworkerP suggested that all diabetic patients in a ketoacidotic state with symptoms or signs of rhinosinusitis should be suspectedof

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having mucormycosis until proved otherwise, as this is usually a rapidly fatal infection. The infection usually begins in the nasal sinus9,” or palate9 and extends to the paranasal sinuses; it spreads via the angular, lacrimal, and ethmoid vessels as well as by direct extension from the sinuses into the retroorbital region.12As orbital involvement progresses, loss of function of the second, third, fourth, and sixth cranial nerves may occur, with resultant proptosis, ptosis, pupillary dilatation, and visual loss as well as periorbital cellulitis. The trigeminal and facial nerves may become involved later.9 Ocular symptoms can be differentiated from those associated with pyogenic cavernous sinus thrombosis by early rather than late visual loss and by evidence of retinal artery occlusion.9 Intracranial involvement follows penetration of the ophthalmic vesselsor cribriform plate.‘* Even in the presenceof brain involvement, results of cerebrospinal fluid studies are usually nonspecific.9 Other conditions that should be considered in a differential diagnosis include malignancy, syphilis, tuberculosis, lethal midline granuloma, aspergillosis, and candidiasis.‘* Radiology

Distinctive radiographic features include nodular thickening of the sinus mucosa, cloudy sinusitis without fluid levels, and spotty destruction of the bony walls of the paranasal sinuses. Generally the frontal sinusesare not involved. Radiographic manifestations may resemble those of epidermoid carcinoma.9 Treatment

and prognosis

Successful treatment depends on early diagnosis, control of the underlying disease,aggressivesurgical debridement, and systemic antifungal therapy.9pI’, I3 The decision to delay surgery in view of the patient’s severephysical debilitation proved to be unfortunate in this case. Control of the patient’s underlying disease is often the most difficult aspect of treatment. The pathogenetic relationship between mucormycosis and diabetes mellitus remains unclear, although ketoacidosis resulting from uncontrolled diabetes mellitus is known to impair immunity by causing abnormal polymorphonuclear chemotaxis,20 decreased polymorphonuclear phagocytic activity,*’ and reduced myeloperoxidase activity.** Laboratory investigations suggest that abnormal macrophage activity associatedwith diabetic keto acidosis may be more important than hyperglycemia per se.23,24

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35

An effort should be made to remove as much devitalized and necrotic tissue as possible; this effort should include drainage of sinuses.” Amphotericin B is the most reliable single therapeutic agent in treating mucormycosis.9~L3If no anaphylaxis is noted after a test dose, subsequent dosesare incrementally increased until a daily dose of 0.7 to 1.0 mg/kg/day is reached.9x’3The optimal duration and total amount of amphotericin B necessary in the treatment of mucormycosis are unknown. However, most studies suggest a total dose of 2.0 to 4.0 gm.9 In the past mucormycosis was almost uniformly fatal62I6 and was usually recognized only at the time of autopsy.” A report by Parfrey” showed a dramatic improvement in prognosis over the last 15 years and a concomitant shift from postmortem to antemortem diagnosis that allows aggressive therapy. SUMMARY

A nonspecific palatal ulcer could well be the presenting sign of mucormycosis. It is therefore essential that dental practitioners be alert to the early signs and symptoms of this disease, especially when evaluating patients in high-risk categories (i.e., those suffering from diabetes mellitus, hematologic malignancies, and immunosuppression). Mucormycosis must be diagnosed early, as a successfulconclusion is critically dependent on the early institution of aggressive therapy. I thank Dr. R. E. Wood for his time, patience, and invaluable assistance, without which preparation of this man&script would have been impossible. REFERENCES 1.

2.

Wood NK, Goaz PW. Oral ulcers and fissures.In: Wood NK, Goaz PW, eds. Differential diagnosis of oral lesions. St Louis: CV Mosby, 1980;98-120. Baum JL. Rhino-orbital mucormycosis occurring in an otherwise apparently healthy individual. Am J Ophthalmol 1967; 63:335-9.

3.

4.

5. 6.

I.

Blodi FC, Hannah FT, Wadsworth JAC. Lethal orbitocerebral phycomycosis in otherwise healthy children. Am J Ophthalmol 1969;67:698-705. Marchevsky AM, Boltone EJ, Gelber SA, Giger DK. The changing spectrum of disease, etiology and diagnosis of mucormycosis. Hum Path01 1980,11:457-64. Meyer RD, Armstrong D. Mucormycosis-changing status. Crit Rev Chn Lab Sci 1973:4:421-51. Straatsma BR, Zimmerman LE, Gass JDM. Phymycosis, a clinicopathologic study of fifty-one cases. Lab Invest 1962; 11:963-85. Baker RD. Diabetes and mucormycosis. Diabetes 1960;9: 143-5.

8.

Haim S, Better OS, Lichtig C, Erlik D, Barzilai A. Rhinocerebral mucormycosis following kidney transplantation. Isr J Med Sci 1919;6:646-9.

36 Van der Westhuijzen et al. 9. Lehrer RI, Howard DH, Sypherd PS, Edwards JE, Segal GP, Winston DJ. Mucormycosis. Ann Intern Med 1980;93:93-6. 10. Espinoza CG, Halkias DG. Pulmonary mucormycosis as a complication of chronic salicylate poisoning. Am J Clin Path01 1983;80:508-11. 11. Parfrey NA. Improved diagnosis and prognosis of mucormycosis: a clinicopathologic study of 33 cases. Medicine 1986; 65:113-6. 12. Webb DJ, Colman MF, Thompson K, Wescott WE. Acute, liferthreatening disease first appearing as odontogenic pain. J Am Dent Assoc 1984;109:936-8. 13. Anaissie EJ, Shikhani AH. Rhinocerebral mucormycosis with internal carotid occlusion: report of two cases and review of the literature. Laryngoscope 1985;95:1107-13. 14. Bigby TD, Serota ML, Tiernay LM Jr, Matthay MA. Clinical spectrum of pulmonary mucormycosis. Chest 1986; 89~435-9. 15. McDonogh M, Human P, Odendaal W. Mucormycosis in diabetes. S Afr Med J 1985;67:78. 16. Baker RD. Mucormycosis (opportunistic phycomycosis). In: Lubarsch 0, Henke F, eds,.Handbuch der speziellen pathologischen Anatomie und Histologie. Berlin: Springer-Verlag, 1971:832-918. 17. McNulty JS. Rhinocerebral mucormycosis, predisposing factors. Laryngoscope 1982;92:1140-3. 18. Carnone KM, Pennington LR, Gimenez LF, Burrow CR, Watson AJ. Mucormycosis in renal transplant patients-a report of two cases and review of the literature. Q J Med 1985;224:825-31. 19. Pillsbury HC, Fischer ND. Rhinocerebral mucormycosis. Arch Otolaryngol 1977;103:600-4.

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20. Mowat AG, Baum J. Chemotaxis of PMN leukocytes from patients with diabetes mellitus. N Engl J Med 1971;284: 621-7. 21. Bybee JA, Rodger DE. The phagocyte activity of PMN leukocytes obtained from patients with diabetes mellitus. J Lab Clin Med 1964;64:1-13. 22. Cech P, Stalder H, Widmann J, Rohner A, Miescher RA. Leukocyte myeloperoxidase deficiency and diabetes mellitus associated with Con&da olbicans liver abscess. Am J Med 1979;66:149-53. 23. Waldorf AR, Ruderman N, Diamond RC. Specific susceptibility to mucormycosis in murine diabetes and bronchoalveolar macrophage defence against Rhizopus. J Clin Invest 1984;74:150-60. 24. Sheldon WH, Bauer H. The development of the acute inflammatory responseto experimental cutaneous mucormycosis in normal and diabetic rabbits. J Exp Med 1959: 110:845-52. Reprint requests to:

Dr. A. Van der Westhuijzen Department of Oral Surgery Faculty of Dentistry University of Stellenbosch Private Bag X1 Tygerberg 7505, Republic of South Africa