Background
Rhinocerebral mucormycosis is an uncommon infection caused by the ubiquitous saprophytic fungi of the Mucorales genus. These fungi also are known as the Zygomycetes, hence the sometime name of rhinocerebral zygomycosis. Under certain conditions, the fungi can invade the sinuses, nasal passages, oral cavity, orbit, and rapidly make their way to the brain, with the result often being fatal. [1, 2, 3]
Poorly controlled diabetes is the most common underlying condition in rhinocerebral mucormycosis. Poor glucose control may lead to chronic low-grade ketoacidosis. Iron is a potent stimulator of fungal growth. In serum, with a normal pH, iron is bound and unavailable to the fungal metabolism. However, with a lower pH, iron is released from its protein carrier and becomes available to the fungi. [4]
Besides patients with poorly controlled diabetes, individuals with iron overload states, neutropenia, organ transplants, and those receiving corticosteroids are at risk. Corticosteroids hinder both glucose metabolism and neutrophil function.
Fungi of the of the Mucorales genus are angio-invasive with destruction of the endothelial cells, leading to thrombosis of blood vessels with resulting tissue necrosis. The rapidity of the fungal invasion through tissue is measured in hours and a few days.
Without rapid intervention consisting of both surgery and antifungal treatment, the prognosis is very poor.
Occurrence
The true incidence of rhinocerebral mucormycosis is unknown and varies from region to region. In the United States it is estimated to be 1.7 cases per one million population to 140 per one million in India and Pakistan. These figures may represent the state of control of underlying diabetes.
Etiology
Etiology & Pathophysiology
The saprophytic (feeding on dead and decaying organic matter) fungi of the Mucorales order are responsible for the infection. The 3 most common genera of the order are Rhizopus, Absidia, and Mucor. However, other genera also are known to cause disease. These fungal organisms are non-septate (coenocytic) with broad and bizarre shapes.
Sustained hyperglycemia impairs glutathione activity, which results in decreased phagocytic activity of neutrophils and decreased number of neutrophils. This, combined with the chronic low level ketoacidosis releasing iron, contributes to the capacity for these fungi to become pathogenic. In particular, Rhizopus species have a ketone reductase system enabling them thrive in an acidic and glucose rich environment. Rhizopus species, more than the other species, thrive in an iron rich milieu making them more common in iron overload states and in those receiving deferoxamine therapy.
Being ubiquitous in nature, and rapid growers, the fungi release airborne spores that are inhaled into the upper respiratory tract of the sinuses and oral cavity. In the correct physiologic and immune environment, these spores will germinate into the hyphal form and invade blood vessels, nerves, cartilage, bone, and meninges. Direct invasion of blood vessels leads to thrombosis with downstream tissue necrosis. The fungi also invade contiguous tissue and erode through bone, spread into the orbit and retro-orbital area, and then into the brain. [5, 6, 7]
Risk Factors
The majority (70%) of cases occur in individuals with diabetes mellitus. An underlying risk factor is recognized in nearly 96% of mucormycosis cases. Risk factors for rhinocerebral mucormycosis include the following [8, 9, 10] :
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Diabetes mellitus
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Iron overload
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Burns
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Blood dyscrasias
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Transplantation
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Immunosuppression (ie, corticosteroid 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
Especially in India, numerous cases and outbreaks of rhino-cerebral mucormycosis were noted in patients undergoing treatment for Covid. This appears to be the result of the use of high doses of corticosteroids in these patients, leading to poor glycemic control.
Iron overload
For reasons stated above, iron overload states, as seen with hemochromatosis and deferoxamine treatment in patients receiving dialysis, are risk factors.
Burns
In individuals with burns the ubiquitous spores settle onto the skin and wounds leading to localized infections. Mucormycosis generally involves only the skin and rarely results in rhinocerebral infection.
Blood dyscrasias
These are an uncommon setting for rhinocerebral mucormycosis and if seen are usually the result of prolonged neutropenia and/or treatment with high dose corticosteroids.
Transplantation
Mucormycosis has been seen in patients with solid organ or bone marrow transplantation. Most of these cases do not involve the central nervous system.
Prognosis
Rhinocerebral mucormycosis carries a prognosis of high morbidity and mortality (85%). Survival depends on the reversibility of underlying risk factors and the rapidity of early surgical intervention. [11, 12, 13]
Complications
Complications include the following:
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Rapid spread
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Carotid artery and other arterial occlusions
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Cavernous sinus thrombosis
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Neurological ramifications of the above
Patient presenting with a 10-day history of a worsening presumed bacterial sinusitis. At presentation, he was discovered to have diabetes with mild ketoacidosis.
Upon looking to the right, the patient's left eye is fixed and dilated secondary to occlusion of the ophthalmic artery.
The infection spreads rapidly and with thromboses of the various blood vessels may lead to hemiparesis, hemiplegia, coma, and death. Also seen are CNS hemorrhage, abscess formation, and cerebritis. Orbital involvement may lead to blindness and spread to the neck may lead to airway obstruction. In survivors, a permanent residual effect is present 70% of the time. Due to the extensive surgery often required, post-surgical disfigurement is common.
Mortality
Rhinocerebral mucormycosis has a fulminant fata clinical pattern. The mortality is directly dependent upon rapid diagnosis with early surgical debridement and exenteration. The survival rate also is improved if the infection has not progressed to cerebral involvement. If the infection reaches the brain the fatality rate can exceed 80%.
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. [13]
Epidemiology
The occurrence of rhinocerebral mucormycosis is dependent upon the prevalence of the different risk factors and high-risk populations. In countries and regions where there is better widespread control of diabetes, the incidence of the infection is lower. This also holds true for hematologic malignancies and organ and bone marrow transplantation.
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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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Characteristic appearance of mucormycosis under the microscope.
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Patient presenting with a 10-day history of a worsening presumed bacterial sinusitis. At presentation, he was discovered to have diabetes with mild ketoacidosis.
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Upon looking to the right, the patient's left eye is fixed and dilated secondary to occlusion of the ophthalmic artery.
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In this patient, the arrow points to necrotic debris at the opening of the left nostril. The clinician can take some of this debris and place it on a slide, add a drop of KOH and examine under the microscope.
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The KOH prep from the necrotic debris of the same patient reveals the broad, nonseptate hyphae of a Mucorales species. In this case, the organism was a Rhizopus. This made the diagnosis and was accomplished within an hour of admission.
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PAS stain of an arteriole showing hyphae thrombosing the lumen.
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GMS stain showing mucor in tissue. The arrow points to a hypha that looks like a dental root. The organism is Rhizopus.
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CT scan of the same patient showing left eye proptosis and involvement of the orbit and sinuses.
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Tissue that needed to be removed from the patient to get to fully viable tissue and beyond the progress of the fungus.
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Post-operative appearance of the same patient. The patient recovered, was fitted with a cosmetic prosthesis, and went on to resume a normal life.
