Rhino-Orbital-Cerebral Mucormycosis

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Article initiated by:

Arjun V Jogimahanti, Ashwini Kini, MD

All contributors:

Andrew Go Lee, MD, Bayan Al Othman, MD, Claudia Prospero Ponce, MD, Ashwini Kini, MD, Kelvin Chong, MB ChB FHKAM(Ophth), Michael T Yen, MD, Seong Lee, MD, Jake Uy Sebastian, MD (DPBO)

Assigned editor:

Claudia Prospero Ponce, MD, Kelvin Chong, MB ChB FHKAM(Ophth)

Review:

Assigned status Up to Date

 by Kelvin Chong, MB ChB FHKAM(Ophth) on October 13, 2024.

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Disease Entity

Disease

Rhino-orbital-cerebral-mucormycosis (ROCM), previously referred to as orbital zygomycosis, refers to the presentation of pathologic symptoms in the orbit as a result of fungal infections caused by fungi in the order Mucorales, most commonly by the species Rhizopus oryzae. ROCM usually occurs in an immunocompromised host and presents with initial symptoms such as vision loss, ptosis, diplopia, and external ophthalmoplegia. Left untreated, ROCM can progress to acute vision loss, metastasis (brain, sinuses) and death.

Etiology

The primary species responsible for the development of ROCM is the fungus Rhizopus oryzae. This fungus is a fast growing, aseptate filamentous fungus that is responsible for nearly 90% of all rhinocerebral cases and has an overall mortality rate of over 50%. Rhizopus oryzae is commonly found in tropical and subtropical regions, such as Australia, India, and the coastal parts of Texas. Like most diseases of fungal origin, mucormycosis is usually introduced to the body through inhalation of spores. The two characteristics most often responsible for the proliferation and development include its propensity for induction of angiogenesis and rapid growth rate.

Risk Factors

Risk Factors:

• Diabetes Mellitus II, particularly with diabetic ketoacidosis
• History of Kidney Transplant
• Immunosuppressant therapy
• Intravenous Drug Users
• Human immunodeficiency virus (HIV) infection
• Neutropenia
• Hemochromatosis
• Deferoxamine therapy

Pathophysiology

Ketoacidosis is a very common predisposing factor for invasion and spread by mucor. Under acidotic conditions, iron fails to bind to its sequestering proteins like transferrin and becomes available to invading pathogens like mucor, which depend on iron for survival. This makes ketoacidosis a very susceptible predisposing condition for development of ROCM. This is also the mechanism for iron overload conditions to cause ROCM (e.g., hemochromatosis, multiple blood transfusions, desferroxamine). Mucormycosis commonly begins after the paranasal inhalation of spores and the formation of coenocytic hyphae that can spread. Once inhaled, they initially proliferate in the sinuses and can find their way to the orbit either through direct invasion or via the nasolacrimal duct. It can gain access to the brain either via spread from the orbital apex, cavernous sinus, through the cribriform plate, or through the blood vessels.

The primary mechanism of spread is through angioinvasion of blood vessels: vasotropic. It causes causes thrombosis, ischemia and disseminates necrosis with poor bleeding. Therefore, frequently in orbital invasion the eye lacks of the typical “hyperemia” (redness) of infection. The angioinvasion also gives the fungus access to additional heme as a source of iron.

FIGURE 1: Histology slide showing orbital tissue with vascular thrombosis and necrosis. Periodic Acid Schiff (PAS) stain highlights(fuchsia) the vascular walls and (asterix line) and the branching fungus invading(arrow heads) the vascular lumen(L). Diffuse necrosis and poor inflammatory reaction in the background with destruction of normal anatomy. Courtesy of Claudia M Prospero Ponce MD. Uploaded Aug 15, 2022.

One critical step that allows for angioinvasion to occur is the penetration of and damage to the endothelial cells and extracellular matrix proteins lining the blood vessels. One receptor that is known to be involved in the penetration process is a protein known as glucose-regulated protein (GRP78).

Once spread to the orbit, the disease is classified as ROCM. Initial ophthalmic problems presenting in ROCM are due to the tissue inflammation resulting from necrosis of the adjacent tissue to the orbit and reduced blood flow. Potentially serious ophthalmic problems associated with ROCM include occlusion of the central artery of the retina and infraction of the orbit including the optic nerve and can ultimately cause complete vision loss. From the orbit, ROCM can spread to the brain through the cribriform plate and orbital apex, causing potential complications such as internal carotid artery occlusion, cranial nerve palsy, chiasmal infarction, intracranial aneurysm, fungal meningitis, and even death.

Primary prevention

A chronic immunocompromised state is the most common predisposing condition for ROCM (e.g. HIV, diabetes mellitus II, organ transplant recipients taking immunosuppressants, deferoxamine treatment).

Diagnosis

Signs & Symptoms

The early clinical signs of Mucormycosis include sinusitis, nasal discharge, and epistaxis. The hallmark of spread beyond the sinuses involve a characteristic black eschar over the skin over the orbit, palate, and nasal mucosa. The eschar may propagate to the surrounding skin.

FIGURE 2: Mucormycosis with characteristic black eschar in patient with uncontrolled diabetes. Available at AAO Website, last accessed Aug 15, 2022.

The maxillary and ethmoid sinuses are more frequently involved as evidenced on CT/MRI studies . Initial external ophthalmic signs of ROCM may include the following with ophthalmoplegia and proptosis being the most common eye signs reported .

• Periorbital Edema
• Cellulitis
• External Ophthalmoplegia
• Proptosis
• Ptosis
• Orbital apex syndrome
• Eyelid gangrene
• Cavernous sinus thrombosis
• Nasal and oral mucosa gangrene are seen as a black eschar, therefore it is important to also assess the oral and nasal mucosa of patients

FIGURE 3: Patient with rhinocerebral mucormycosis with A. Mucormycosis eroding the hard palate and a confirmatory B, Biopsy specimen demonstrated typical nonseptated hyphae (with silver stain). Courtesy of Lanning B. Kline, MD, Available at AAO Website, last accessed Aug 15, 2022.

Systemic

• Malaise
• Fever

There can be occlusion of the central artery of the retina, or the branch retinal arteries which on funduscopic exam typically reveals opacification of the superficial retinal layers and the characteristic cherry-red spot on the macula. Rarely, vision loss can also occur from infarction or direct fungal invasion of the optic nerve or chiasm.

Another manifestation of mucormycosis in the nasal-orbit area is a black eschar that may present in the nose mucosa or upper palate. Therefore, careful examination of these areas are advised when ROCM is suspected.

Diagnostic procedures

It is important to notice that because the fungus stays predominately intravascular, a CT scan without contrast may not reveal any lesion if no mass is formed, but may however show bone erosion if profound.

Imaging studies may include CT/MRI of orbit, brain, and sinuses demonstrate involvement of maxillary and ethmoid sinus, orbit, cavernous sinus, and less frequently involve the frontal and sphenoid sinus. In order to obtain a true diagnosis of mucormycosis, a fine needle aspiration biopsy of infected tissues must be obtained for histopathology and culture. Characteristic of this disease is aseptate hyphal elements that branch at right angles.

The most common areas to be involved are nasal cavity, maxillary sinus, ethmoid sinus, and orbit.

On MRI, it is common to see isointense lesions (when compared to brain) in T1-weighted images. Most of the patients show hypointense T2-weighted images. When the cavernous sinus is involved, MRI will show “lack of enhancement”.

The case below is an example where mucormycosis extended into the orbit, optic nerve, and intracranially near the chiasm which was partially seen on CT and well-highlighted by orbital and brain MRI. The surgical approach was planned based on the images:

FIGURE 4: Right-sided sino-orbital zygomycosis in a patient with diabetic ketoacidosis. A, In this photograph, complete right upper eyelid ptosis and ophthalmoplegia are present in the patient. B, Wide surgical debridement consisting of orbital exenteration and sinus surgery was life-saving. CT (C) and MRI (D) axial scans show orbital and sinus involvement as well as cavernous sinus thrombosis (arrow). Courtesy of Bobby S. Korn, MD, PhD, Available at AAO Website, last accessed Aug 15, 2022.

Some of the signs noted on a study of 43 patients with mucormycosis in the midface and skull base included:

• No sinus wall destruction
• Inflammatory changes
• Cavernous sinus and the carotid artery involvement
• Isolated hard palate only (one patient)

Finally, the gold standard diagnostic procedure is biopsy and culture. Histopathological confirmation included H+E (hematoxylin-eosin), PAS (periodic acid-Schiff) and GMS (Grocott-Gomori's methenamine silver stain), among others.

FIGURE 5: Histology slide showing orbital tissue of orbital mucormycosis patient. Periodic Acid Shiff (PAS) stain, high magnification, Showing in fuchsia the branching fungus causing acute inflammatory reaction and necrosis of surrounding tissue, mostly fat and few remaining muscle fibers. Courtesy of Claudia M Prospero Ponce MD. Uploaded Aug 15, 2022.

Differential diagnosis

Main differential is Aspergillus.

Ruling out Aspergillus and other fungi, is essential for diagnosis of ROCM. Circulating antigen detection test and 1,3 beta-D-glucan detection test cannot confirm the distinction between the Aspergillus and Rhizopus Oryzae. In conditions when tissue biopsy cannot be obtained due to the patient's condition, samples such as sputum or even bronchoalveolar lavage may allow for delineation between the two. Biopsy of Aspergillus will demonstrate a 45-degree branching dichotomous (two, symmetric, almost-equal branches) septate fungus.

Management

General treatment

The standard treatment for the early stages of ROCM is antifungal therapy and debridement (e.g., liposomal amphotericin B), and if localized, may be done endoscopically. Combination therapy of amphotericin with capsofungin has shown to be associated with better outcomes and can be considered.

As a general rule, the goal of surgery is the removal of all visible necrotic tissues. Since necrotic tissue does not usually bleed, the surgical endpoint is to debride until normal or profuse bleeding is obtained. In the event of spread to the craniofacial tissues and the orbit, surgical treatment becomes essential. Because mucormycosis spreads through blood vessels and tissues, surgical debridement of infected sites is considered to avoid further complications.

The surgical approach may vary. The presence of extensive orbital involvement may require orbital exenteration with bone removal. The extent of extra-orbital excision may be guided by imaging (i.e. MRI). Once the infection evolves into ROCM and the patient demonstrates symptoms consistent with deep orbital involvement, orbital exenteration may be considered to avoid the more lethal sequelae of ROCM when intracranial vessels, such as the Circle of Willis is affected. Liposomal amphotericin B infusion can be continued throughout the course of surgical treatment.

Prognosis

The long-term outlook for patients with ROCM depends on the severity of disease dissemination and the sites involved. Medical and surgical treatment of the ROCM, as well as the underlying immunosuppressive conditions are associated with better survival rates. In conducted studies in recent years, overall survival is 59.5% with treatment and only 21% without. Factors associated with poor prognosis include:

• Delay in diagnosis and initiation of treatment
• Treatment with amphotericin B alone
• Eyelid/facial gangrene
• Intracranial/intracranial invasion
• Hemiplegia