Rhinocerebral Mucormycosis

Abstract

Case ReportRhinocerebral Mucormycosis Zuhair Moustafa Abunijem, MBChB, DTM&H, DTCD Saad Al-Shohaib, and FRCP(C) Lewis B. MorrowFACP Zuhair Moustafa Abunijem Search for more papers by this author , Saad Al-Shohaib Search for more papers by this author , and Lewis B. Morrow Search for more papers by this author Published Online:1 Sep 1995https://doi.org/10.5144/0256-4947.1995.496SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutIntroductionRhinocerebral mucormycosis is a potentially lethal disease resulting from infection with fungi of class Phycomycetes, order mucorales. The disease is characterized by rapid progression and high mortality. Mucormycosis is an opportunistic infection and its pathogenic nature becomes evident when the patient’s general resistance has been altered by metabolic disorders or chemotherapeutic agents.1 The organism is an aerobic saprophytic fungus. It is normally seen as bread mold and is a common inhabitant of soil and decaying vegetation. It can also be cultured from the human nose, throat, oral cavity and stool on a routine basis. The infection is most often associated with patients whose overall health is significantly compromised, especially in those who have uncontrolled diabetes mellitus,2–4 corticosteroid treatment, uremia,5–7 liver cirrhosis, malnutrition, hematologic malignancies,8 burns and organ transplantation.9–12 Mucormycosis is reported rarely in an apparently normal host,13,14 complicating septic abortion15 and intravenous drug abuse.16 Here we describe three cases of invasive mucormycosis seen in our hospital over the last four years.Case ReportsCase 1A 50-year-old Saudi female with diabetes mellitus for over 30 years had been maintained on insulin for the past five years. She also had hypertension, ischemic heart disease and renal impairment. On 19 January 1993, her diabetes became unstable and she developed repeated vomiting. She was seen in another hospital where investigations revealed significant leukocytosis and elevated urea (113 mmol/L) and creatinine (769 μmol/L). Her symptoms were attributed to uremia but she refused hemodialysis and was discharged against medical advice. She was admitted to our hospital on 10 February 1993 with a five-day history of drowsiness and swelling of the left eye.On physical examination she was acutely ill with tachypnea and she had a uremic odor to her breath. The conjunctiva of the left eye was grossly injected. The palpebral fissure was completely closed by orbital edema. She was drowsy but arousable and she had nuchal rigidity. The left pupil was dilated at 6 mm, the right was 3 mm and the light reflex was sluggish bilaterally. The rest of the neurological examination was normal except for depression of the tendon reflexes. The plantar responses were equivocal. The initial diagnosis was orbital cellulitis with possible meningitis associated with diabetic ketoacidosis.Investigations revealed Na 130 mmol/L, K 7.3 mmol/L, bicarbonate 3.0 mmol/L, serum urea 60.4 mmol/L, serum creatinine 785 μmol, blood pH 7.14, WB 54,000/mL with 97% neutrophils. Urine dipstick revealed protein ++, glucose +++ and ketones +. Blood glucose was 49.2 mmol/L. On lumbar puncture, the CSF protein was 779 mg/L, the glucose 30 mmol/L and the white cell count 12. The CSF culture was sterile. A CT scan of the brain showed changes of pansinusitis affecting all the paranasal sinuses with nasal cavity mucosal thickening (Figure 1). The rest of the scan showed a mild degree of proptosis of the left eye with no intracranial lesion.FIGURE 1 CT scan of brain shows evidence of pansinusitis with nasal cavity mucosal thickening.Download FigureThe patient required mechanical ventilation and was placed on continuous arteriovenous hemofiltration (CAVH) with insulin supplements. She was started empirically on ceftazidime, clindamycin and amphotericin B 20 mg per day. ENT and ophthalmic examination showed that the left nasal wall and turbinates were completely necrotic, black and emanated a foul smell. The left cheek was debrided and biopsy specimens were taken of the turbinate which confirmed the presence of mucormycosis. Amphotericin B was continued at a dose of 20 mg/day but in spite of intensive treatment she became more toxic and died on 15 February 1993. The final diagnosis was extensive rhinocerebral mucormycosis with uncontrolled diabetes mellitus and renal failure.Case 2A 64-year-old Yemeni male with diabetes mellitus, on insulin since 1990, was admitted to this hospital on 16 March 1993 with a six-day history of headache with pain in the right temporal area, fever and proptosis of the right eye. Physical examination revealed marked swelling of the right cheek. The right eye had marked proptosis with injection of the conjunctiva, paralysis of the extraocular muscles and diminution of corneal sensation. There was a purulent discharge from the right nostril. Blood glucose was 21.9 mmol/L and the white cell count 13.7 × 109. He had strongly positive tests for urinary glucose and ketones. X-rays revealed necrosis of the right inferior turbinate. MRI of the head showed evidence of pansinusitis which predominantly affected the right-sided sinuses. The left sphenoid sinus was spared (Figure 2). The rest of the study showed evidence of inflammatory process involving the right cheek, soft tissue of the right orbit and retro-orbital fat and the cavernous sinus; nevertheless, no evidence of cavernous sinus thrombosis was noted. The patient also had cortical atrophy with low-density abnormalities at the occipital poles and dilatation of the ventricles, presumably due to old infarctions. The diagnosis of mucormycosis with uncontrolled diabetes was made and the biopsy specimen taken from the nasal turbinates confirmed the presence of mucormycosis. He was started on ceftazidime, amphotericin B, fluconazole and clindamycin. Over the next few days, increased fluid developed in the right nasal antrum. In spite of these medications and intensive care, the patient expired on 22 March 1993.FIGURE 2 MRI of head shows evidence of pansinusitis.Download FigureCase 3A 38-year-old diabetic Saudi male had the lower left third molar extracted in October 1989. He was seen elsewhere the following day with complications of a residual remnant of the tooth. Antibiotic therapy was started. Two days after the extraction, his face became swollen with edema extending to the left eye and was soon followed by loss of vision in the left eye. Left facial paralysis occurred subsequently and he was admitted to another hospital for two months where he was treated symptomatically and subsequently transferred to our hospital. He was a known diabetic, well controlled on oral hypoglycemic agents for the past two years. On physical examination he was toxic, pale, confused and disoriented. The left half of the face was grossly edematous and there was mild neck stiffness. He had proptosis of the left eye with marked conjunctival injection and the upper and lower eyelids were markedly edematous. The cornea in the left eye was opaque and the pupil was dilated and irregular. The left fundus could not be seen. Extraocular movements were restricted. The right eye had minimal proptosis, a moderate degree of congestion and irregular scarring of the cornea. The right fundus was normal and the movement of the extraocular muscles of the right eye was partially limited. The rest of the cranial nerves and the sensory and motor systems were normal. An initial diagnosis of cavernous sinus thrombosis was made. He had significant leukocytosis with a markedly raised ESR at 147 mm. Blood glucose was normal. Blood cultures were negative. On lumbar puncture the CSF pressure was elevated. CSF protein was 110 mg/L and the glucose 3.8 mmol/L There were 15 white cells and 150 red cells with negative culture. CT examination showed extensive involvement of the frontal, ethmoidal, sphenoidal and maxillary sinuses on the left side with changes extending into the left nasal cavity and retropharynx. The left orbit showed a soft tissue swelling due to the edema and proptosis. The intracranial structures in the brain were found to be normal. There was sloughing of the palate with perforation into the left antrum. Biopsies of this area were positive for mucormycosis. He was started on amphotericin B and systemic antibiotics. However, the patient's condition did not improve. The patient had a radical resection of the left half of the face including removal of the eye owing to panophthalmitis. Part of the hard palate and the alveolar process of the left maxilla were also removed. Before surgery he had carotid angiography which showed arteritis involving the left anterior and middle cerebral arteries and total thrombosis of the left internal carotid artery from the point of bifurcation of the common carotid artery. The patient was intensively treated with amphotericin B for about four months and eventually recovered. On recent follow-up, he has no evidence of recurrence of the mucormycosis infection after four years of observation.DiscussionRhinocerebral mucormycosis is a potentially devastating disease process of the nose and the paranasal sinuses occurring in immunocompromised patients or patients with extensive metabolic acidosis. Gregory et al. in 1943 first described three fatal cases of cerebral mucormycosis.17 The disease rapidly spreads to the orbit18 and brain19,20 and is eventually fatal unless clinical recognition is early and specific treatment is instituted rapidly. In our series, the diagnosis was delayed and contributed to the poor prognosis.The lesions in rhinocerebral mucormycosis are usually necrotic or hemorrhagic with mucosal ulceration. The fungus has a great affinity for arteries. It penetrates their muscular walls, grows within the lumina and causes acute arteritis and thrombosis. Later it invades veins and lymphatics, resulting in the characteristic lesions of combined infarction and inflammation. Isaacson and Stern have suggested that local tissue acidosis contributes to proliferation of mucormycosis.21 Systemic or local acidosis may interfere with phagocyte mobilization and function. In all three cases, there was evidence of invasion and they all had metabolic acidosis. Mucormycosis creates a vicious circle because it obstructs blood vessels, causing a decrease in tissue oxygenation, which leads to more acidosis. The acidosis allows the fungus to proliferate and damage more vessels.Rhinocerebral mucormycosis spreads by local extension and intravascular propagation through the cribriform plate and sinuses into the meninges and brain. All three cases had evidence of meningeal and brain involvement.Although rhinocerebral mucormycosis is the most common form of this disease, other types include pulmonary, cutaneous, gastrointestinal, localized and disseminated mucormycosis. Ketoacidotic diabetes appears to be the most common predisposing factor in rhinocerebral mucormycosis. All three patients had diabetic ketoacidosis.Clinically, rhinocerebral mucormycosis has three stages: 1) Local mucosal and sinus infection. Pain occurs in the face and sinuses and is associated with stuffiness, nasal discharge and headache. The classic "black" turbinate and palatal ulcer22 due to infarction of tissue is seen. 2) Advanced orbital involvement, "orbital apex syndrome" involvement of cranial nerves III, IV, V and VI, muscles and orbital vessels manifested as corneal anesthesia, conjunctival hemorrhage, exophthalmos, complete ophthalmoplegia, fixed dilated pupils and blindness. 3) Brain involvement with spread of the infection through the superior orbital fissure or the cribriform plate causing a cavernous sinus thrombosis23 or internal carotid artery thrombosis24,25 and a picture of cerebral infarction with other cranial nerve involvement. Our patients presented in Stage 3.Diagnosis requires vigilance when "sinusitis" is seen in a diabetic patient. Culture of swabs or pus are rarely of help. Biopsy of involved tissues is essential and reveals necrosis, perivascular polymorph infiltration and the characteristic nonseptate fungal hyphae (Figure 3). Plain sinus radiographs usually show mucosal thickening rather than a fluid level. The recommended imaging techniques are computed tomography (CT)26,27 or magnetic resonance (MR).28 MR has the advantage of detecting early vascular and intracranial invasion.29,30FIGURE 3 Hyphae of mucormycosis from nasal lesion. Biopsy showing nonseptate hyphae with right angle branching.Download FigureIn our series, the diagnosis was made on tissue histology alone. No tissue samples were sent to outline the organism.Management has three aspects: first, control of underlying disease; second, systemic antifungal therapy (amphotericin B); third, the surgical debridement of dead tissue31 with orbital exenteration if ophthalmoplegia and loss of vision have occurred. This last aspect is important since the orbit is the portal of entry of infection to the central nervous system. Hyperbaric oxygen therapy32 has been advocated as an adjunct to the above. The exact mechanism of hyperbaric oxygen is unclear but may be multifactorial. It increases the oxygenation in infected tissue.The increased oxygen tension improves killing by the polymorphonuclear leukocytes and possibly the macrophages. In addition, increased oxygen tension allows the fibroblast to lay down new collagen, which provides the framework for new vessel formation, leading to wound healing. Hyperbaric oxygen improves the oxygen tension in the ischemic tissue, which may alleviate the acidosis in infected tissue. Hyperbaric oxygen has also been shown to augment the action of amphotericin B. In addition, hyperoxemia inhibits fungal growth.33Amphotericin B is fungistatic and needs to be given for at least two months, usually at doses of around 0.5 to 1.0 mg/kg on alternate days. Renal failure is the major toxic effect. Other toxic effects include hypokalemia, hypomagnesemia, liver impairment, fever and chills. The development of liposomal amphotericin B34 has enabled amphotericin to be more effective and less toxic, with a consequent enhancement of the therapeutic index to over 20-fold. The mechanism of action of the drug complex is considered to be an enhancement of intracellular delivery of the drug to phagocytes, although several other mechanisms may be simultaneously activeThe prognosis of mucormycosis has improved markedly. Most diagnoses before 1970 were made postmortem but now survival of up to 89% has been reported in diabetics treated with surgery and amphotericin B.35 Liposomal drug delivery may help to improve this figure still further despite its current high cost.In our series, the prognosis was very poor because these cases were referred late and the diagnosis was made at an advanced stage. We would like to alert physicians to the existence of this disease in Saudi Arabia and the importance of early diagnosis. 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Krishna, Consultant Physician and Neurologist, for providing the material for Case 3 and to Ms Jane Dunster for her excellent secretarial assistance in preparing the manuscript.InformationCopyright © 1995, Annals of Saudi MedicineThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.PDF download