Background

A 61-year-old man presents to the emergency department (ED) complaining of pain in his right eye that has persisted for 5 days, with associated redness and swelling.

Figure 1.

The patient had been examined at another ED a few days before this presentation and was diagnosed with herpes zoster, for which he was given a prescription for acyclovir and hydrocodone and discharged home.

Since he started taking acyclovir, the patient has noticed that the pain and swelling in his eye has increased. He also reports binocular diplopia and decreased visual acuity. On the day of presentation, he is nauseous and vomiting, and he cannot open the affected eye.

On physical examination, the patient has normal and stable vital signs. Visual acuity in the unaffected left eye is normal at 20/25. In the right eye, he can only perceive bright light. In addition, the affected eye demonstrates ptosis of the upper eyelid, generalized proptosis, and mild periorbital erythema with associated edema (see Figure 1). Extraocular movements of the affected eye are as shown (see video clip). The right pupil is 8 mm in diameter and nonreactive to direct and indirect light. Intraocular pressure in both eyes, as measured by a handheld tonometer (Tono-Pen), is normal at 12 mm Hg.

Discussion

Diagnosis: Cerebro-rhino-orbital phycomycosis (CROP)/mucormycosis

Figure 2.

CROP is an aggressive, invasive infection that is caused by broad, nonseptate fungi with irregularly shaped hyphae from the class Phycomycetes. The genera that typically cause infection are Rhizopus, Rhizomucor, Absidia, and Basidiobolus. The spores of these fungi are ubiquitous and gain entrance to the human body through the mouth and the nose. Individuals who are immunocompetent will phagocytize these spores; therefore, they do not develop the disease.

Infection is most common in immunosuppressed persons, specifically in patients with poorly controlled diabetes mellitus (often in the setting of metabolic acidosis), and in patients receiving the iron-chelating drug deferoxamine.^[1] Unlike immunocompetent individuals, whose bodies phagocytize the spores, immunocompromised patients have massive spore proliferation. Mucormycosis is described almost exclusively in patients with compromised immune systems or metabolic abnormalities. The spores attach to the nasal or oral mucosa, where massive germination and hyphae formation occur, allowing the fungus to directly invade the blood vessels. Areas of ischemic infarction and necrosis are seen in the infected tissue. The fungi invade the blood vessel lumina and cause thrombosis through inflammatory occlusion. Infection usually begins in the nasal cavity and the maxillary sinuses, followed by direct invasion of contiguous structures, such as the palate, the orbits, the ethmoid sinuses, and the brain. Orbital involvement occurs when the ethmoid sinuses are affected. Intracranial spread can occur through the ophthalmic artery, superior fissure, or cribriform plate.

Rhinocerebral infections are usually fulminant and have high morbidity and mortality rates, despite improved diagnostic and therapeutic interventions. Mortality rates of 30-70% are quoted in the literature, with higher mortality rates seen in older series. The mortality rate in diabetic patients appears to be lower than it is in nondiabetic patients and in patients with intracerebral involvement. Death may occur within 2 weeks if CROP is left untreated or is unsuccessfully treated. Additionally, until the 1950s, this disease was almost always fatal. Even with recovery, permanent residual effects, such as blindness and cranial nerve defects, occur in up to 70% of cases.

The clinical manifestations of CROP may include orbital and facial pain, fever, periorbital and orbital cellulitis, proptosis, purulent nasal discharge, and mucosal necrosis that appears as black eschars in the nasopharynx, the oropharynx, and the tissues surrounding the orbits and sinuses. These clinical features are not universally seen; therefore, a high index of suspicion is required. Ocular involvement leads to afferent papillary defects and loss of visual acuity. Progressive extension of necrosis into the brain can lead to cavernous sinus thrombosis and abscess formation. The patient may demonstrate an altered mental status, convulsions, aphasia, or hemiplegia.

Patients with diabetic ketoacidosis are most often affected, but opportunistic infections may also develop in association with renal deferoxamine therapy (eg, in patients with chronic renal disease) or with immunosuppression (particularly in patients with neutropenia or those receiving high-dose corticosteroid therapy).^[1,3]

The diagnostic study of choice is computed tomography (CT) scanning of the orbits and sinuses. In affected patients, CT scans demonstrate soft-tissue swelling, sinus mucosal thickening, and bone erosion. Intracranial and cavernous sinus involvement may also be present. Magnetic resonance imaging (MRI), if available, can show extension of the infection into the surrounding blood vessels, orbital fat, and intracranial areas. Urgent biopsy is usually indicated. Necrotic and edematous tissue with neutrophilic infiltrate is frequently seen with fungal elements (which are broad, nonseptate hyphae with branching at 90?).^[3,4]

The cornerstone of medical treatment for CROP is the administration of systemic amphotericin B at the highest patient-tolerable dose. Local packing of the involved mucosal membranes with an amphotericin B solution is effective for minimizing local disfigurement. When on the medication, the patient should be assessed for nephrotoxicity, as well as other systemic symptoms of toxicity, including fever, nausea and vomiting, phlebitis, anemia, and electrolyte abnormalities. Liposomal amphotericin B may be more efficacious; it is less toxic, thus allowing higher doses of the medication to be given. Additionally, local irrigation and packing of the areas to aid delivery of amphotericin to necrotic and poorly perfused tissues is recommended, because poor vascular supply may prevent systemic therapy from reaching the fungus and because local irrigation of infected tissue has been reported to be an important adjunct to treatment that may even help prevent disfiguring surgery. Treatment of the underlying disease (eg, hypoxia, acidosis, hyperglycemia, electrolyte abnormalities) and discontinuation of any immunosuppressants are also important. The physician should evaluate any steroid medication, antimetabolites, or immunosuppressants that the patient is taking, and such agents should be discontinued if appropriate. It is encouraged that the advice of an infectious disease specialist be obtained.

Aggressive, emergency surgical debridement of all necrotic tissue is necessary; sometimes, multiple procedures are needed to clear all necrotic tissue. The vaso-occlusive effect of mucormycosis leads to infrequent bleeding of the involved tissue; therefore, debridement of affected tissue until normal, well-perfused, bleeding tissue is encountered is ideal. Intraorbital irrigation of amphotericin B may be considered as an adjunct treatment. Surgery may often be disfiguring. Orbital exenteration, as well as removal of the sinuses, may be necessary. Some authors have suggested hyperbaric oxygen as an adjunctive treatment. Reconstructive surgery after complete resolution of infection should be considered.

Indeed, a multidisciplinary approach is best for the treatment of this condition. An ophthalmologist is required to evaluate for ophthalmoplegia and optic neuropathy. An oculoplastic surgeon can provide an orbital evaluation, as well as perform debridement and reconstruction. An otolaryngologist is required for biopsy or debridement of the nasal and sinus cavities. An infectious disease specialist can provide guidance for appropriate medical treatment with antifungal agents. Internal medicine specialists and endocrinologists are useful for the medical management of underlying systemic etiologies. Neurosurgery may be necessary if intracranial involvement is present. Finally, a pharmacotherapy specialist can assist with dosing of amphotericin B.

The complications of CROP include intracranial invasion, cavernous sinus thrombosis, blindness, occlusion of the central retinal artery, and airway obstruction caused by infections of the head and neck (with spread to the carotid sheath or the mediastinum through the fascial planes). The prognosis of CROP is guarded, with reported mortality rates of 30-70% (as stated earlier).^[4]

In this patient, treatment with amphotericin B was promptly initiated. CT scans of the orbits and sinuses demonstrated an air-fluid level in the right maxillary sinus, mucosal thickening of the right anterior ethmoid sinus, and preseptal cellulitis (see Figure 2A). An MRI of the head showed enhancement of the intraconal fat and rectus muscles of the right eye (see Figure 2B). The patient received emergency sinus debridement, and a biopsy was performed. Pathology demonstrated fungal angiitis and orbital inflammation that was consistent with mucormycosis. The patient underwent 3 additional operations, including exenteration of the right eye, and received hyperbaric oxygen treatments. After hospitalization for 3 weeks, he was discharged to home in good condition.

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