Background
Rhinocerebral mucormycosis is a rare opportunistic infection of the sinuses, nasal passages, oral cavity, and brain caused by saprophytic fungi. The infection can rapidly result in death. Rhinocerebral mucormycosis commonly affects individuals with diabetes and those in immunocompromised states. Rare variants of mucormycosis include lingual, pulmonary, cutaneous, gastrointestinal (GI), and disseminated forms. The image below depicts a patient with rhinocerebral mucormycosis (see the images below). (See Etiology, Treatment, and Medications.) [1, 2, 3]
Clinical view of the face of a patient with rhinocerebral mucormycosis. Notice the cutaneous hemorrhagic ulcer on the right anterior cheek resulting from perforation of the fungus through the sinus cavity.
CT scan of a patient who is suspected of having mucormycosis shows extensive involvement of the right orbit and adjacent sinuses.
Most cases of mucormycosis are acute surgical emergencies; however, several cases of a more chronic, indolent form have been reported, with signs and symptoms developing over several weeks. (See Clinical and Workup.)
Occurrence
The pathogens that cause rhinocerebral mucormycosis are prevalent in nature but may be more prone to cause infection in moist, temperate climates. The exact frequency of rhinocerebral mucormycosis in the United States is unknown.
Etiology
Saprophytic aerobic fungi of the class Phycomycetes (order Mucorales) cause rhinocerebral mucormycosis, also known as phycomycosis. The 3 genera responsible for most cases are Rhizopus, Absidia, and Mucor. Researchers have also reported cases of rhinocerebral mucormycosis caused by Rhizomucor, Saksenaea, Apophysomyces, and Cunninghamella species.
Phycomycetes are ubiquitous in nature, being commonly found in decaying vegetation, soil, and bread mold. They grow rapidly and can release large numbers of airborne spores. Thus, they are frequently found colonizing the oral mucosa, nose, paranasal sinuses, and throat. Phycomycetes do not generally cause disease in immunocompetent individuals who are able to generate phagocytic containment of the organisms. Persons at risk for infection (ie, immunocompromised individuals) typically also have decreased phagocytic activity because of an impaired glutathione pathway.
In individuals who are immunocompromised, germination and hyphae formation occur, and this allows the organism to invade the patient's blood vessels. Mucormycosis is described almost exclusively in patients with compromised immune systems or metabolic abnormalities.
Rhizopus species have an active ketone reductase system that enables them to thrive in an acidic pH and glucose-rich medium. Hyperglycemia enhances fungal growth and impairs neutrophil chemotaxis; therefore, individuals with diabetic ketoacidosis are commonly affected. Rhizopus species also favor an iron-rich environment and are frequently isolated in patients receiving deferoxamine therapy (an iron-chelating agent).
In most cases, the fungi gain entry to the body via inhalation of airborne spores through the sinuses. It has been postulated that the most common reservoir for organisms is the pterygopalatine fossa. Infection spreads along vascular and neuronal structures and infiltrates the walls of blood vessels. Infections can erode bone through walls of the sinus and can spread into the orbit and the retro-orbital area, thereby extending into the brain.
Invasion of nerves, blood vessels, cartilage, bone, and meninges, as well as perineural spread, [4, 5] are common. Direct invasion by fungal elements results in thrombosis and nerve dysfunction. Advancing infection can result in thromboses arising in the cavernous sinus, carotid arteries, and jugular vein. Carotid artery occlusion has also been reported as a complication. [6, 7, 8, 2, 3]
Risk factors
Seventy percent of mucormycosis cases occur in patients with diabetes mellitus, although this percentage is declining with the use of chemotherapy and with increasing frequency of various types of immunocompromised states. An underlying risk factor is recognized in more than 96% of mucormycosis cases. Risk factors for rhinocerebral mucormycosis include the following:
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Iron overload
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Burns
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Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS)
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Blood dyscrasias
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Transplantation
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Immunosuppression (ie, prednisone therapy)
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Chemotherapy
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Intravenous drug use - Embolic to brain
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Disease states treated with high-dose steroids
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Diabetes mellitus
This condition is a risk factor, particularly in association with poor glycemic control and acidosis, as it relates to cellular immune dysfunction. Patients with diabetes are predisposed to mucormycosis because of the decreased ability of their neutrophils to phagocytize and adhere to endothelial walls. Furthermore, the acidosis and hyperglycemia provide an excellent environment for the fungus to grow. (See the image below.)
This diabetic patient with mucormycosis presented with complete ophthalmoplegia and proptosis. Note the complete ptosis and periorbital edema on the right side.
Iron overload
Iron overload states, as observed with hemochromatosis and deferoxamine treatment in patients receiving dialysis, may be risk factors. Iron enhances fungal growth and increases susceptibility. Researchers have reported infection in patients with liver and renal failure. [9]
Burns
In individuals with burns, mucormycosis generally involves only the skin and rarely results in rhinocerebral infection. [10]
Blood dyscrasias
These include lymphoma, prolonged neutropenia, and leukemia. Researchers estimate that the incidence of mucormycosis in persons with hematologic malignancy is approximately 1%.
Transplantation
This includes solid organ (eg, liver, [11] kidney [12] ) and bone marrow transplantation. Maertens et al found that the incidence of mucormycosis in recipients of allogeneic bone marrow transplants was 1.9%. [13] However, most cases do not involve the central nervous system (CNS). Graft versus host disease (GVHD) and donor leukocyte infusions [14] are also risk factors.
Disease states treated with high-dose steroids
One case report described mucormycosis in a patient with an adrenal corticotropic hormone (ACTH)–producing pulmonary tumor associated with Cushing syndrome. [15]
Prognosis
Rhinocerebral mucormycosis carries a prognosis of high morbidity and mortality. Survival depends on the reversibility of underlying risk factors and early surgical intervention. [16, 17, 2, 3]
Complications
Rhinocerebral mucormycosis progresses rapidly and can result in carotid artery occlusion, cavernous sinus thrombosis, and CNS infarction secondary to fungal thrombosis, leading to hemiparesis, hemiplegia, coma, and death. Other complications of rhinocerebral mucormycosis include CNS hemorrhage, abscess, and cerebritis, as well as blindness and airway obstruction from head and neck infections. Permanent residual effects of the disease occur up to 70% of the time.
Neurologic function can be recovered if no irreversible damage has occurred, but morbidity is very common. Postsurgical disfigurement is likely.
Mortality
No survivors of mucormycosis were reported before 1955. (Amphotericin became available in the 1950s.) Mucormycosis has a fulminantly fatal clinical pattern. The survival rates among patients with invasive sinus disease without cerebral involvement may be as high as 50-80%. If infection spreads to the brain, the case fatality rate can exceed 80%. Death may occur within 2 weeks if mucormycosis is not treated or is unsuccessfully treated.
The prognosis of mucormycosis may improve with rapid diagnosis; early management, including combined antifungal and surgical interventions; and reversal of underlying risk factors. One case series reported a survival rate of approximately 80% when both medical and surgical interventions were administered. The cause of death in many patients is mucormycosis itself rather than the progression of the underlying disease.
The mortality rate in diabetic patients appears to be lower than in nondiabetic patients and in patients with intracerebral involvement. Patients who have been treated with amphotericin B and who have had orbital exenterations are more likely to survive. Patients with frontal sinus involvement and older patients have lower rates of survival.
A meta-analysis by Yohai et al indicated that the survival rate declines when interval from diagnosis to treatment is longer than 6 days. [18]
Epidemiology
Frequency
United States
The pathogens that cause rhinocerebral mucormycosis are prevalent in nature but may be more prone to cause infection in moist temperate climates.
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Clinical view of the face of a patient with rhinocerebral mucormycosis. Notice the cutaneous hemorrhagic ulcer on the right anterior cheek resulting from perforation of the fungus through the sinus cavity.
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A cotton blue preparation of Rhizopus species.
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A tissue hematoxylin and eosin stain of Rhizopus species.
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The appearance of a culture slant of Rhizopus species.
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Culture plates of Rhizopus species.
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Low-power photomicrograph of a Gomori methenamine silver stain of Rhizopus species.
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High-power photomicrograph of a Gomori methenamine silver stain of Rhizopus species.
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CT brain scan illustrating the appearance of cavernous sinus thrombosis.
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CT brain scan showing the appearance of a cerebral infarct.
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CT scan of a patient who is suspected of having mucormycosis shows extensive involvement of the right orbit and adjacent sinuses.
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This diabetic patient with mucormycosis presented with complete ophthalmoplegia and proptosis. Note the complete ptosis and periorbital edema on the right side.
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Characteristic appearance of mucormycosis under the microscope.
