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]
View Image | Clinical view of the face of a patient with rhinocerebral mucormycosis. Notice the cutaneous hemorrhagic ulcer on the right anterior cheek resulting f.... |
View Image | 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.)
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.
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:
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.)
View Image | This diabetic patient with mucormycosis presented with complete ophthalmoplegia and proptosis. Note the complete ptosis and periorbital edema on the r.... |
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]
In individuals with burns, mucormycosis generally involves only the skin and rarely results in rhinocerebral infection.[10]
These include lymphoma, prolonged neutropenia, and leukemia. Researchers estimate that the incidence of mucormycosis in persons with hematologic malignancy is approximately 1%.
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.
One case report described mucormycosis in a patient with an adrenal corticotropic hormone (ACTH)–producing pulmonary tumor associated with Cushing syndrome.[15]
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]
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.
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]
United States
The pathogens that cause rhinocerebral mucormycosis are prevalent in nature but may be more prone to cause infection in moist temperate climates.
Symptoms of rhinocerebral mucormycosis are often nonspecific, complicating early diagnosis. The most common presentation includes facial pain, headache, lethargy, visual loss, proptosis, and/or palatal ulcer. Perinasal cellulitis and paresthesia are also common early clinical signs of rhinocerebral mucormycosis. The incubation period is measured in days. The clinical course can progress from normal to symptomatic in a week and from sinus opacification to uncal herniation and death in just a few days.[19, 20, 21, 22]
General symptoms of rhinocerebral mucormycosis include the following:
Facial symptoms of the disease include the following:
Nasal symptoms of rhinocerebral mucormycosis include:
Ocular symptoms include the following:
CNS symptoms include the following:
Many individuals with rhinocerebral mucormycosis have underlying diabetes mellitus, usually with acidosis and poor glycemic control. Patients with diabetic ketoacidosis accompanied by mental status changes should improve within 24-48 hours of treatment; if they do not, consider CNS pathology.
Nasal and palatal findings of rhinocerebral mucormycosis include the following:
Ocular findings include the following:
Neurologic findings include the following:
Immediately evaluate patients at risk if any signs or symptoms develop. Early detection and treatment are essential. Laboratory study results are generally nonspecific for rhinocerebral mucormycosis but may show metabolic acidosis and hyperglycemia. Blood culture findings are commonly negative. Polymerase chain reaction (PCR) assay 16s ribosomal ribonucleic acid (rRNA) gene sequence analysis may be helpful.[24]
Cerebrospinal fluid (CSF) may show an increased opening pressure, modest neutrophilic pleocytosis, normal or slightly elevated protein levels, or low glucose levels. In most cases, however, CSF study findings are normal.[24]
Imaging studies help to support the diagnosis of rhinocerebral mucormycosis and to precisely determine the extent of disease.
Fine-needle aspiration can yield a diagnosis, but definitive therapy should not be withheld pending results.[25, 26]
Perform urgent exploration and biopsy if mucormycosis is suspected. Send frozen and permanent sections and fresh tissue. If clinical suspicion is high, but the initial specimens are negative, take additional specimens to include the arteries.
Computed tomography (CT) scanning demonstrates soft tissue extent, mucosal thickening, opacification of sinuses, and bony destruction of the sinuses and orbit. (In general, bone erosion is a late finding.) A CT scan may also demonstrate cavernous sinus thrombosis, enhancement of vessels, and CNS lesions (eg, cerebritis, cerebral edema). (See the images below.)
View Image | CT brain scan illustrating the appearance of cavernous sinus thrombosis. |
View Image | CT brain scan showing the appearance of a cerebral infarct. |
View Image | CT scan of a patient who is suspected of having mucormycosis shows extensive involvement of the right orbit and adjacent sinuses. |
Contrast-enhanced magnetic resonance imaging (MRI) shows findings similar to those on a CT scan. MRI also helps to define early vascular intracranial invasion and infection along peripheral nerves before clinical signs develop.
Sinus radiography reveals mucosal thickening with or without air-fluid levels. Sinus opacification, especially ethmoid or sphenoid, may be observed.
Direct microscopic examination can be performed to identify the hyphae of infectious agents. The following tissue preparations can be used (see the images below):
View Image | A tissue hematoxylin and eosin stain of Rhizopus species. |
View Image | A cotton blue preparation of Rhizopus species. |
View Image | The appearance of a culture slant of Rhizopus species. |
View Image | Culture plates of Rhizopus species. |
View Image | Low-power photomicrograph of a Gomori methenamine silver stain of Rhizopus species. |
View Image | High-power photomicrograph of a Gomori methenamine silver stain of Rhizopus species. |
Frozen-tissue biopsy at the time of surgery should demonstrate tissue invasion by nonseptate hyphae with right- or obtuse-angle branching. In contrast, Aspergillus hyphae are thinner and less septated and can cause granulomas. The tissue culture result is positive for the fungus. Histology demonstrates invasion along the elastic lamina of blood vessels with subsequent thrombosis and tissue necrosis.
View Image | Characteristic appearance of mucormycosis under the microscope. |
Treatment of rhinocerebral mucormycosis includes the following:
No studies address the appropriate dose or formulation of antifungal therapy; therefore, a wide range of doses and formulations are used until the underlying cause of the immune suppression is under control. Antifungal therapy alone and surgical therapy by itself are ineffective.
Correcting hypoxia, acidosis, hyperglycemia, and electrolyte abnormalities is critical to the successful management of this condition. Discontinuation or maximally reducing chemotherapy and immunosuppressive therapy is desirable if clinically possible. Any steroid medication, antimetabolites, or immunosuppressants that the patient is on should also be addressed and discontinued if appropriate.[3]
Granulocyte colony-stimulating factor (GCSF) can be administered to reconstitute host defenses and to enhance leukocytosis.[27] Dexamethasone has been used to treat brain edema.
Hyperbaric oxygen (HBO) therapy has been used in an attempt to control the infection. Experts suggest that HBO may exercise fungistatic activity by reducing tissue hypoxia and acidosis. However, no studies have addressed its efficacy.
If the disease is limited to the sinus and orbit (ie, sino-orbital), débridement and systemic antifungals, combined with local amphotericin irrigation, may control the process.[28, 29]
Promptly initiate antifungal therapy. Amphotericin B is the only reliable systemic antifungal agent approved for the treatment of mucormycosis, and the highest possible tissue levels should be achieved. Remember to assess for nephrotoxicity. Other systemic toxicities include fever, nausea and vomiting, phlebitis, anemia, and electrolyte abnormalities. Liposomal amphotericin B may be more efficacious; it is less toxic, allowing higher doses of the medication to be given.[30, 31]
Consider local irrigation and packing of the areas to aid delivery of amphotericin to necrotic and poorly perfused tissues. Because poor vascular supply may prevent systemic therapy from reaching the fungus, local irrigation of infected tissue has been reported as an important adjunct to treatment and may even prevent disfiguring surgery.[30, 28, 29]
Garner and Machin investigated the use of prophylactic posaconazole (a second-generation azole antifungal) during an outbreak of mucormycosis, reporting that none of 15 children considered to be at high risk who received the drug developed mucormycosis.[32] Several studies have reported salvage therapy with posaconazole in patients with zygomycosis refractory or intolerant to other treatments. Whether posaconazole is superior to amphotericin B is still being studied.[33, 34]
Isavuconazole (Cresemba), another azole antifungal, has also been reported to be efficacious in the treatment of rhinocerebral mucormycosis that is refractory to amphotericin B and posaconazole.[35] In March 2015, it was approved by the FDA for invasive mucormycosis infections caused by Mucorales fungi (eg, Rhizopus oryzae, Mucormycetes species).[45]
Although specifically approved for the treatment of aspergillosis and candidiasis, some studies have reported the efficacy of caspofungin, an echinocandin antifungal, in combination with amphotericin B.[31, 36]
The mainstay of therapy is extensive débridement of all infected and necrotic tissue, with drainage of all sinus and abscess fluid collections. Immediately obtain consultation with a surgeon. Conservative attempts to spare tissue may result in retention of the organism and subsequent treatment failure. A delay in surgery may decrease the likelihood of survival in all forms of invasive mucormycosis.
Multiple débridements are sometimes required. Because of the vasoocclusive effect of mucormycosis, the involved tissue rarely bleeds, so débridement until normal, well-perfused, bleeding tissue is encountered is ideal. Intraorbital irrigation of amphotericin B may be considered as an adjunct treatment.
Orbital exenteration, along with removal of the sinuses, may be necessary. No standard exists to guide physicians on the best timing of exenteration.[37, 38, 39]
Intraoperative frozen sections help to determine involved tissues and margins. Wide excision should ideally occur before CNS invasion. The role of endoscopic sinus surgery is unclear, although it may provide an initial diagnostic role.[40]
Surgery often is disfiguring. Consider reconstructive surgery only after complete resolution of infection.[41]
In their discussion on mucormycosis treatment, Bullock and Warwar aptly stated that patients, family members, and all involved health care personnel must understand that the physical and psychological morbidity of wide, disfiguring surgical débridement must be weighed against the life-threatening nature of the mucormycosis.[42]
Among patients who survive the initial presentation of rhinocerebral mucormycosis, the extent of the disease dictates additional inpatient care. Further surgical débridement, surgical repair, and wound care may be required. Continued medical therapy with close monitoring for drug toxicity or recurrence of disease is recommended. If eye enucleation is necessary to surgically clear the infection, postoperative reconstruction of the orbit and fitting of an eye prosthesis can be highly valuable in restoring the patient's psychosocial health.[43]
Serial imaging and evaluation is performed as needed to assess the extent of the disease and to decide if reoperation is necessary. After amphotericin B is discontinued, close assessment for recurrence needs to be performed. Treatment often is long term and disfiguring.
Once the patient is stable, continue amphotericin therapy in the outpatient setting, administered either as a home infusion or in an ambulatory infusion center. At this point, the frequency of amphotericin infusion is often reduced to every other day or more, depending on renal function.
Follow-up MRI or CT scanning at the end of therapy should demonstrate significant improvement and lack of inflammation.
Treatment may require 7 months of therapy or more. Moreover, chronic presentations and late sequelae after successful therapy have been observed; therefore, patients require long-term monitoring to detect recurrence or signs of indolent residual infection.
A multidisciplinary approach is the best. Specialties to consider include the following:
Although aggressive surgical intervention for rhinocerebral mucormycosis is required, patients also should receive adjuvant antifungal therapy. While the currently approved azoles are active against the phaeohyphomycoses that cause fungal sinusitis, they have no activity against Mucor molds. Amphotericin B is fungistatic for Mucor molds but is the only reliable systemic antifungal agent. Amphotericin is a highly toxic agent that is administered intravenously in its conventional form or in 1 of 3 lipid-complex formulations.
Amphotericin has also been administered via intracavitary (ie, via catheter into the space), interstitial, and intrathecal routes.[44] Reports document the use of nebulized amphotericin B for sinonasal disease. Large doses of amphotericin are required for cure of rhinocerebral mucormycosis; use the drug at the maximum dose tolerated for this life-threatening infection.
Only conventional amphotericin B is approved by the US Food and Drug Administration (FDA) as initial therapy for rhinocerebral mucormycosis (RCM); thus, it is considered the standard therapy for invasive mucormycosis. Lipid formulations are approved if the creatinine level rises to greater than 2.5 mg/dL, if adverse events are severe and persistent, or if the disease progresses despite a total dose greater than 500 mg. Experience with the lipid formulations is growing, but no head-to-head studies have been performed.
Many experts initiate therapy with a lipid-complex formulation in patients with preexisting renal impairment. Some experts argue that lipid-formulation amphotericin offers better penetration across the blood-brain barrier and into the sinus.
Isavuconazole (Cresemba) is a triazole antifungal agent. Isavuconazole is the active moiety of the prodrug isavuconazonium sulfate. It is indicated for invasive mucormycosis infection caused by Mucorales fungi (eg, R oryzae, Mucormycetes species).
Isavuconazole’s approval in March 2015 was based on an open-label noncomparative study in adult patients with invasive aspergillosis and renal impairment or in patients with invasive fungal disease caused by other rare fungi. A subpopulation of 37 patients with invasive mucormycosis treated with isavuconazole showed all-cause mortality was 38%. The efficacy of isavuconazole in the treatment of invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.[45]
Experimental antifungal agents have demonstrated in vitro activity against the Mucor molds and may offer additional treatment options in the future. The evidence for iron chelators (ie, deferoxamine) as a potential therapeutic intervention has been increasing in animal studies. While deferoxamine is an iron chelator from the perspective of the human host, it actually serves as a siderophore, delivering free iron to Mucor. Animal studies have shown that administration of iron chelators to mice with Rhizopus infection markedly improved survival and may be just as effective as liposomal amphotericin B.
Clinical Context: Liposomal amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus and can be fungistatic or fungicidal. This agent binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Clinical Context: This agent is amphotericin B in phospholipid complexed form; it is a polyene antibiotic with poor oral availability. Amphotericin B is produced by a strain of Streptomyces nodosus; it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Clinical Context: This is a lipid preparation consisting of amphotericin B within unilamellar liposomes. It delivers higher concentrations of the drug, with a theoretical increase in therapeutic potential and decreased nephrotoxicity.
Amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus, and it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Clinical Context: Amphotericin B colloidal dispersion is a lipid preparation consisting of amphotericin B attached to lipid discoid structures. Amphotericin B is a polyene antibiotic with poor oral availability. It is produced by a strain of Streptomyces nodosus, and it can be fungistatic or fungicidal. The drug binds to sterols (eg, ergosterol) in the fungal cell membrane, causing leakage of intracellular components and fungal cell death. Toxicity to human cells may occur via this same mechanism.
Clinical Context: Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.
Clinical Context: Triazole antifungal agent. Isavuconazole is the active moiety of the prodrug isavuconazonium sulfate. It is indicated for invasive mucormycosis infection caused by Mucorales fungi (eg, R oryzae, Mucormycetes species).
Clinical Context: Shown to be effective in the treatment of rhinocerebral mucormycosis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.
The mechanism of action for these agents may involve the inhibition of fungal cell membrane formation and the impairment of the integrity of fungal cell membrane. The antifungals may give rise to an alteration of RNA and deoxyribonucleic acid (DNA) metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.