Rhinocerebral Mucormycosis

Etiology

The causative agents of rhinocerebral mucormycosis are saprophytic fungi belonging to the class Phycomycetes, order Mucorales, and family Mucoraceae. Commonly implicated species include Apophysomyces elegans and members of the genera Mucor, Rhizopus, Absidia, and Cunninghamella.[5] The most prevalent route of fungal invasion is through the inhalation of spores found in soil or decaying organic matter, particularly in immunocompromised individuals.[6]

As an opportunistic infection, fungal invasion can be exacerbated by weakened host immunity and a conducive host environment, such as hyperglycemia or iron overload. This infection is particularly prolific in hot and humid climates and environments, particularly in tropical regions and during the summer months.

Epidemiology

The incidence of mucormycosis varies depending on the prevalence of various high-risk populations, making it challenging to accurately estimate and report its prevalence. In the United States, the rhinocerebral form is the most prevalent type of mucormycosis. In contrast, in India, uncontrolled diabetes mellitus is the leading risk factor for mucormycosis.[6] Among patients with hematological malignancies, the overall incidence of mucormycosis is approximately 4 cases per 100 individuals.[7][8] Acute myeloid leukemia accounts for 62% of all hematological malignancies in this population.

Pathophysiology

The fungal infection initially develops in the nasal cavity and subsequently spreads to the adjacent paranasal sinuses, where it infiltrates and proliferates. The humid environment within the nasal cavity and paranasal sinuses provides favorable conditions for the growth and invasion of fungi. The extent of mucosal and bony involvement depends on the duration of the infection, the immune response of the host, and the severity of the disease. Early fungal implantation is often observed in the maxillary sinus, characterized by a fungal mass without obvious bone erosion. The middle turbinate is the most commonly affected site in Mucor infections, followed by the middle meatus and the nasal septum. If bone infiltration is unrecognized or left untreated, the infection can spread to adjacent tissues. This progression may result in brain involvement through several routes, including the ethmoid sinuses, orbital apex, direct bone erosion, or vascular invasion.

The rapid progression of mucormycosis is a result of its characteristic pathogenesis. Fungal hyphae invade blood vessels, damaging the endothelium and causing blood clots that obstruct circulation, leading to ischemia and necrosis of surrounding tissues. This necrotic tissue serves as a nidus for fungal growth, allowing the fungus to thrive, invade adjacent tissues, and eventually enter the bloodstream. In rhinocerebral mucormycosis cases, brain invasion typically occurs through the involvement of the sphenopalatine and internal maxillary arteries. The involvement of the internal carotid artery and cavernous sinus thrombosis usually develops in advanced, long-standing cases and is uncommon in the early stages of the infection.

Patients with diabetes mellitus, particularly those with diabetic ketoacidosis, experience an increased incidence of infection. Hyperglycemia in individuals with diabetes compromises the immune system by suppressing leukocyte phagocytosis, neutrophil chemotaxis, and local inflammatory responses.

Rhizopus thrives in glucose-rich, low-oxygen environments with a ketone-reductase system—conditions commonly found in patients with diabetes. Iron is essential for the growth of both bacteria and fungi. Iron chelators such as deferoxamine increase fungal virulence by providing iron in a form suitable for growth.[9] In addition, iron chelators alter the fungistatic activity of transferrin and inhibit iron-catalyzed, peroxidase-dependent free radical production, which is crucial for fungal killing. Unsaturated serum transferrin functions typically as a fungistatic agent by inhibiting the growth of fungi. Deferoxamine also decreases the antifungal effect of amphotericin B.

Histopathology

Microscopic examination of the affected tissue reveals broad, irregularly shaped, aseptate fungal hyphae that branch at approximately 90-degree angles, often accompanied by areas of necrosis and hemorrhage.[6] In cases involving brain tissue, findings may include necrosis, infiltration by polymorphonuclear cells, multinucleated giant cells, and the presence of aseptate hyphae.[10]

History and Physical

History

Clinical signs of rhinocerebral mucormycosis are often nonspecific, making early diagnosis challenging. Initial symptoms typically include a unilateral headache localized behind the eyes, accompanied by lethargy. Additional common symptoms include nausea, fever, nasal congestion, rhinorrhea, epistaxis, nasal hypoesthesia, facial pain or numbness, black nasal discharge, and signs of sinusitis. Ocular complaints frequently involve retro-orbital or periorbital pain, amaurosis, diplopia, and blurred vision. Central nervous system (CNS) involvement may present with seizures, dizziness, altered mental status, and gait disturbances. In advanced cases, respiratory involvement may cause dyspnea, coughing, and hemoptysis, while gastrointestinal involvement can present with abdominal pain and vomiting.

Physical Examination

Typical findings in rhinocerebral mucormycosis include nasal and orbital cellulitis, along with redness and swelling of the nasal bridge and cheek. In advanced stages, these areas may darken due to tissue necrosis. A black eschar may be visible on the nasal or palatine mucosa, and severe cases may involve nasal bleeding. Intraoral examination may reveal palatal ulceration.[11]

Several studies have identified proptosis as the most prevalent orbital sign, followed by ophthalmoplegia and visual impairment.[12] Other ocular symptoms may include conjunctival chemosis, nystagmus, and a nonreactive pupil. Patients with cerebral involvement and vascular compromise may present in coma or display signs suggestive of a stroke. Neurological assessment may reveal cranial nerve palsies, particularly involving cranial nerves II through VII, which may manifest as muscle weakness of the jaw or facial sensory loss.[12]

Evaluation

Given the nonspecific nature of clinical signs, maintaining a high index of suspicion is crucial when risk factors for mucormycosis are present. If the disease is suspected, an immediate biopsy of necrotic antral tissue should be performed for histopathological confirmation. Many clinicians recommend obtaining a computed tomography (CT) scan before performing a biopsy.[13] To assess the extent of the disease, a CT scan is usually conducted immediately before receiving histopathology results, which often reveals bone erosion and sinus obliteration. Despite its higher cost, magnetic resonance imaging (MRI) is the preferred imaging modality for evaluating soft tissue involvement.[6][14]

The preferred diagnostic tool for early detection of infection is a CT scan, which can reveal double densities within the sinuses caused by mucosal thickening and hyperdense areas. During the chronic invasive sinusitis phase, the CT scan findings show sinus opacification and bone erosion. These findings help determine the appropriate technical surgical modality. However, CT scan results are not specific to mucormycosis. A false-positive result may occur in other invasive diseases, whereas false negatives, such as a seemingly normal sinus CT, can still occur despite the presence of invasive disease.

Nasal scrapings and fine-needle aspiration cytology are conducted to obtain diagnostic samples, which typically reveal the presence of fungal hyphae. Blood cultures are not a preferred diagnostic method, as they rarely yield positive results. Similarly, culture swabs taken from the sinuses often yield negative results in most cases. Cerebrospinal fluid analysis may also fail to detect fungal hyphae. In such cases, endoscopic examination of the sinuses is valuable for identifying tissue necrosis and guiding the biopsy procedure.

Treatment / Management

Medical Treatment

Rhinocerebral mucormycosis is a rapidly progressive and highly invasive infection that requires aggressive management. However, there is currently no standardized treatment protocol or sequential management plan, underscoring the need for comprehensive clinical trials to establish a clear and effective treatment strategy. Upon suspicion of a fungal infection, amphotericin B should be promptly administered to patients. A treatment course lasting 4 to 6 weeks is typically necessary to eradicate the infection.[15] Although amphotericin B remains a consistently effective antifungal agent, the ideal dosage has not been conclusively determined. A study reported good tolerance among patients receiving a daily dose of 50 milligrams. However, many studies recommend dosing at 1 mg/kg/d for patients with rhinocerebral mucormycosis. Amphotericin B can be reconstituted with distilled water to achieve a concentration of 5 mg/mL. Treatment typically begins with a daily dosage of 5 milligrams, which is then doubled daily until the target dosage of 1 milligram is reached.[16](B3)

Liposomal amphotericin B is the preferred treatment for mucormycosis due to its significantly reduced nephrotoxicity compared to conventional amphotericin B.[17] The liposomal formulation permits the administration of higher doses of amphotericin B with reduced nephrotoxicity. However, limited availability and cost constraints may restrict its use, necessitating reliance on conventional amphotericin B in some regions.[6][18] Renal function should be monitored regularly through serum electrolyte levels, creatinine, and blood urea nitrogen (BUN) levels. Warfarin may be considered for preventing thrombosis, particularly in cases involving arterial or venous thrombosis.(B3)

Surgical Treatment

Surgical removal of the fungal mass is recommended, often in conjunction with antifungal drug therapy. However, several studies advocate for immediate surgical debridement upon diagnosis, followed by gradual intravenous administration of amphotericin B.[6] Surgical intervention is an invasive procedure that involves excising the affected tissues and fungal growth, along with sinus drainage and irrigation. In some cases, surgery may impact the cosmetic appearance of a patient, especially if it requires the removal of structures such as the palate, ocular components, or the nasal cavity. Multiple surgical interventions may be necessary, with the specific procedure chosen based on the location and extent of sinus involvement. Maxillectomy or ethmoidectomy may be performed as needed, with the extent of resection determined by the degree of bone and surrounding tissue involvement.

Extensive ulceration of the palate and the formation of an oroantral fistula may necessitate a complete maxillectomy, while swelling with minimal bone erosion may require only a partial maxillectomy.[11] Effective elimination of the disease requires excision of the affected tissue with a margin of more than 1 centimeter, including some surrounding healthy tissue. Orbital exenteration is indicated in cases of severe orbital involvement; however, if the orbital contents remain unaffected, preservation of the orbital floor may be possible. In cases with intracranial involvement, craniotomy and cerebral debridement are necessary procedures.(A1)

Endoscopic sinus surgery, combined with the topical application of antifungal agents to the debrided area, has shown efficacy in the treatment of rhinocerebral mucormycosis. Technological advancements, including the development of microsurgical instruments, have facilitated the use of endoscopic sinus surgery for precise interventions within the sinuses and other targeted sites. This technique is particularly valuable for relieving obstruction of the sinus ostia and enhancing ventilation. Endoscopes provide enhanced illumination and visualization, facilitating greater precision in surgical procedures. An effective strategy for managing rhinocerebral mucormycosis involves early intervention during the initial stages of sinusitis to prevent progressive tissue invasion.

Alternative and Subsidiary Treatments

Hyperbaric oxygen therapy delivers sufficient oxygen to neutrophils, enhancing their ability to effectively combat fungal infections. Rifampicin can be used as an adjunct to systemic amphotericin B therapy. Prompt and effective management of the underlying cause of immunosuppression is crucial for a favorable clinical outcome. Treating the root causes of rhinocerebral mucormycosis requires collaboration with relevant medical specialists. For example, diabetic ketoacidosis should be managed with insulin and oral hypoglycemic agents in consultation with the appropriate physicians.

Steroids and chemotherapeutic immunosuppressants should be promptly discontinued or their doses reduced, as advised by consulting medical specialists. Immune function may be enhanced by administering granulocyte colony-stimulating factors, which stimulate the production of leukocytes.[2] Antifungal agents, such as the azoles, can occasionally serve as salvage therapy. Iron chelators may be beneficial in cases of infection associated with hemochromatosis, although their effectiveness remains uncertain.(B3)

Differential Diagnosis

Clinicians must maintain a high index of suspicion to differentiate rhinocerebral mucormycosis from other conditions with overlapping symptoms and the involvement of similar anatomical sites.

Bacterial Sinusitis and Allergic Fungal Sinusitis

In its early stages, mucormycosis may present as sinusitis and is often misdiagnosed as bacterial or allergic fungal sinusitis. Once mucormycosis is diagnosed, antibiotic therapy prescribed for presumed bacterial sinusitis should be discontinued. Allergic fungal sinusitis may present with symptoms such as proptosis and a large rhinocerebral mass. However, a diagnosis of allergic fungal sinusitis is established by a history of recurrent allergic rhinitis and sinusitis, the presence of nasal polyps, and elevated immunoglobulin E (IgE) levels. In the allergic form of sinusitis, bone erosion may occur from pressure effects, but unlike the invasive rhinocerebral form, no fungal invasion is present.

Aspergillosis

In immunocompromised individuals with fulminant fungal sinusitis, aspergillosis may present with symptoms similar to those of rhinocerebral mucormycosis, including invasion of the CNS and other tissues. Although clinical differentiation between the two infections can be challenging, histological staining helps distinguish aspergillosis from mucormycosis. Additionally, the formation of a black eschar, commonly seen in mucormycosis, is usually absent in aspergillosis. Aspergillosis is effectively treated with itraconazole, whereas amphotericin B remains the primary treatment for mucormycosis.[19]

Nasal and Paranasal Malignancies

Due to the highly invasive nature of mucormycosis, it can sometimes mimic a malignant process. The presence of a nasal mass and bleeding on gross examination may be seen in both malignancies and mucormycosis, thereby complicating the diagnosis.

Proptosis

Proptosis is a common manifestation of rhinocerebral mucormycosis. To ensure an accurate diagnosis, it is essential to rule out other causes of proptosis. Conditions such as Graves’ disease, orbital tumors, cellulitis, and subperiosteal hematoma can also cause proptosis and should be considered in the differential diagnosis.

Brain Tumor and Pseudotumor Cerebri

Pseudotumor cerebri, characterized by increased intracranial pressure, can present with symptoms similar to those of brain tumors and rhinocerebral mucormycosis, including headache, dizziness, nausea, and visual disturbances.

Cavernous Sinus Thrombosis

Mucormycosis is a recognized cause of cavernous sinus thrombosis. Other potential sources include infections originating from the nose, eyes, face, ears, or pharynx. This condition often involves both eyes and is characterized by proptosis, chemosis, and cranial nerve palsies.

Migraine Headache

Migraine is a primary headache disorder characterized by recurrent, often unilateral episodes accompanied by nausea, vomiting, and photophobia. The one-sided presentation of migraine can mimic the headache seen in rhinocerebral mucormycosis, potentially complicating the differential diagnosis.

Prognosis

Although the prognosis for this disease in most cases is poor, even with aggressive treatment, early diagnosis and prompt intervention can significantly improve outcomes. Mortality rates vary depending on the severity and extent of the disease, ranging from 30% to 70% for the rhinocerebral form and up to 90% for the disseminated form. In patients with AIDS, mortality may reach 100%. Studies show that combining surgical debridement with antifungal therapy results in a higher survival rate of 70%, compared to 57% for surgery alone and 61% for antifungal therapy alone.

Another study concluded that patients who initiate treatment within 5 days of diagnosis have a higher survival rate of 85% compared to a 49% survival rate when treatment begins after 6 days.[6] Overall mortality rates range from 80% to 145%, influenced by individual factors and the timing of diagnosis and treatment. Research also shows that patients with predisposing conditions and cerebral involvement have higher mortality rates than those without these factors.

Complications

Brain Infarction and Hematoma after Hemorrhage

Vascular invasion is a distinctive feature of rhinocerebral mucormycosis. The development of intravascular thrombi leads to ischemia and infarction of various brain regions, including the cerebrum, cerebellum, and brainstem.[10][20] Diffuse vasculitis can weaken the walls of the blood vessels, potentially leading to the formation of aneurysms. Rupture of these aneurysmal blood vessels can result in the formation of subarachnoid or subdural hematomas, as well as intracerebral hemorrhages, which can further complicate the disease.

Orbital Apex Syndrome

Ophthalmoplegia can occur due to damage to the nerves that innervate the extraocular muscles, whereas vision loss may result from involvement of the optic nerve.[21] Ptosis is caused by damage to the third cranial nerve, and decreased corneal sensation may indicate involvement of the trigeminal nerve. Proptosis can develop from venous congestion in cavernous sinus thrombosis, increased retrobulbar pressure, and loss of eyeball tone.[22][23][24] Additional ocular complications may include conjunctival hemorrhage and edema. Orbital cellulitis may arise secondary to bacterial infection or fungal invasion.

Meningitis

Meningitis is a rare manifestation of rhinocerebral mucormycosis, typically caused by either diffuse vasculitis or direct fungal infection of the meninges.[10]

Brain Abscesses

Involvement of brain tissue in rhinocerebral mucormycosis, particularly in chronic cases, can lead to the formation of brain abscesses.[25][26] Brain abscess formation may be further complicated by secondary bacterial infections, which can potentially lead to motor weakness.[27]

Garcin Syndrome

Garcin syndrome is characterized by unilateral cranial nerve palsies without the involvement of sensory and motor tracts.[28] The unilateral involvement is primarily due to mycelial growth along the cranial nerves or invasion of leptomeningeal blood vessels, rather than direct damage to brain tissue.[29]

Facial and Nasal Deformities

Permanent damage to the maxillary and nasal bones can result in noticeable changes to the facial appearance. Procedures such as orbital exenteration may cause significant disfigurement of facial structures.