Curbside Consultation

How Do I Manage an Orbital Apex Syndrome?

Roger E. Turbin, MD, FACS

A 35-year-old diabetic woman with a history of diabetic ketoacidosis (DKA) presents with new onset painful ophthalmoplegia and loss of vision in her right eye. There might be a bit of proptosis as well. What should I be worried about and how soon does she need to be seen?

The development of ophthalmoplegia and visual loss in a diabetic patient with ketoacidosis (DKA) is a neuro-ophthalmic emergency. It should be assumed to be due to a life-threatening invasive fungal infection until proven otherwise. Although such a patient may “walk into my office,” I more frequently encounter this scenario in patients already hospitalized with DKA or suffering other immunosuppressive comorbid conditions, including cancer, chemotherapeutic treatment, long-term corticosteroid and broad-spectrum antibiotic therapy, chronic renal dialysis, and solid organ or bone marrow transplantation.

Accurate diagnosis begins with clinical localization, although the disease process may have already extended beyond ophthalmic and orbital structures to involve the cavernous sinus, paranasal sinuses, or cerebrovascular structures. Orbital apex syndrome (OAS) denotes involvement of the optic nerve in addition to some or all of the cranial nerves within the cavernous sinus/superior orbital fissure (III, IV, V, VI). Indeed, there is a lengthy differential diagnosis (Table 49-1) that will require confirmatory neuroimaging, laboratory support, and often histopathologic documentation. My urgent ophthalmic examination includes an assessment of pupillary function (a surrogate for visual acuity or visual field if the patient is obtunded), assessment ofproptosis and orbital congestion, motility analysis (III, IV, VI palsy versus motility disturbance due to congestion of the extraocular muscles), funduscopic examination (optic nerve and retinal perfusion, choroidal folds, cherry red macular spot), and other neurologic symptoms (including sympathetic dysfunction). I always assess trigeminal nerve function (corneal anesthesia, facial numbness) as areas of numbness (V1) signify extension to the cavernous sinus or beyond (V2, V3), as well as facial nerve and lower cranial nerve function. In addition, a direct visual inspection of the nasal and oropharyngeal mucosa, including soft and hard palate, is performed immediately to detect areas of necrosis. An emergent ear, nose, and throat (ENT) consultation must be obtained for endoscopic examination of the paranasal sinuses (Figure 49-1). Facial and endoscopic abnormalities are documented photographically for serial examination during follow-up.

Endoscopic photograph of necrotic middle turbinate and ethmoid mucosa in a patient with biopsyproven Rhizopus (Mucor). Initial intraoperative tissue analysis was suggestive of Aspergillus nigrans

Figure 49-1. Endoscopic photograph of necrotic middle turbinate and ethmoid mucosa in a patient with biopsyproven Rhizopus (Mucor). Initial intraoperative tissue analysis was suggestive of Aspergillus nigrans.

I hospitalize or utilize the emergency room to coordinate ENT, neurosurgical, neurologic, medical, and infectious disease service consultations as well as emergent neuroimaging to include contrast-enhanced studies of the head and orbit. Both magnetic resonance imaging (MRI) and computed tomography (CT) are useful and provide adjunctive information for surgical planning, with MRI providing more soft tissue detail and CT providing detail of bone anatomy. Frequently we obtain both studies, and may supplement with vascular imaging (computed tomography angiography [CTA], magnetic resonance angiography [MRA], magnetic resonance venography [MRV], or cerebral angiography) as necessary. I pay special attention to the location of concurrent paranasal disease as most fungal infection spreads from the paranasal sinuses. I have found the destruction of the fat plane posterior to the maxillary sinus to be an indicator of invasive fungal disease and a sign that opacification of sinuses represents more than just incidental sinusitis (Figure 49-2). This radiographic sign may be missed or neglected unless specifically sought. Increased signal and enhancement in the orbital apex, extraocular muscles, and orbital tissues adjacent to sinus disease does not require bone destruction as spread may occur through intact bone via nutrient vascular foramina. In addition, unusual hypointense “black” signal on T2-weighted MRI images may serve as a hint that fungus is present due to signal change (paramagnetic susceptibility artifact) from the manganese in some species of fungal colonies (Figures 49-3 and 49-4).

Contrast-enhanced axial CT scan shows loss of the normal fat plane behind the left maxillary sinus in the region of the pterygopalatine fossa (arrows) despite apparently intact bone in a patient with biopsy-proven Rhizopus. Compare this area to the normal black signal of the intact fat plane on the left of the figure (squares). There is also abnormal thickening and enhancement in the soft tissue of the face anterior to the maxillary sinus, as well as the left turbinate, maxillary sinus, and ethmoids (not shown)

Figure 49-2. Contrast-enhanced axial CT scan shows loss of the normal fat plane behind the left maxillary sinus in the region of the pterygopalatine fossa (arrows) despite apparently intact bone in a patient with biopsy-proven Rhizopus. Compare this area to the normal black signal of the intact fat plane on the left of the figure (squares). There is also abnormal thickening and enhancement in the soft tissue of the face anterior to the maxillary sinus, as well as the left turbinate, maxillary sinus, and ethmoids (not shown).

Contrast-enhanced coronal T1 fat-suppressed MRI of a patient with invasive Aspergillus shows diffuse areas of abnormal signal within all sinuses, turbinates, and right orbital apex (asterisk). Abnormal signal has extended beyond the plane of the skull base to involve the subfrontal extradural area (arrow) and both frontal lobes (squares)

Figure 49-3. Contrast-enhanced coronal T1 fat-suppressed MRI of a patient with invasive Aspergillus shows diffuse areas of abnormal signal within all sinuses, turbinates, and right orbital apex (asterisk). Abnormal signal has extended beyond the plane of the skull base to involve the subfrontal extradural area (arrow) and both frontal lobes (squares).

(A) Coronal T2-weighted image of a patient with chronic allergic fungal sinusitis from Aspergillus fumigatus. Paramagnetic susceptibility artifact in Aspergillus species can produce black signal (arrow) on T2 images simulating air. (B) T1 image of the same patient demonstrates that the area of Aspergillus infection is no longer black (arrow), and this discordance suggests fungal infection

Figure 49-4. (A) Coronal T2-weighted image of a patient with chronic allergic fungal sinusitis from Aspergillus fumigatus. Paramagnetic susceptibility artifact in Aspergillus species can produce black signal (arrow) on T2 images simulating air. (B) T1 image of the same patient demonstrates that the area of Aspergillus infection is no longer black (arrow), and this discordance suggests fungal infection.

Some clarification concerning taxonomy of invasive fungal infection is relevant. The term mucormycosis describes any fungal infection of the order Mucorales, which belongs to the class Zygomycetes and may be termed zygomycosis. The terms Rhizopus, Rhizomucor, Mucor, and Absidia refer to the genus. Rhizopus oryzae is the predominant pathogenic species and accounts for 60% of all forms of mucormycosis and 90% of rhinocerebral forms. Aspergillosis refers to infection by Deuteromycetes, or imperfect fungi in which no sexual reproductive phase has been discovered. The 3 main pathogenic species are fumigatus, flavus, and niger. The early differentiation between the 2 most frequent invasive fungal pathogens, Aspergillus and Zygomycetes, has become increasingly important given the trend toward first line use of non-amphotericin B therapies with disparate fungal sensitivities (Table 49-2). In additional, a noninvasive allergic form of chronic fungal sinusitis in atopic individuals exists (predominantly Aspergillus species) that responds to debridement and corticosteroid therapy (see Figure 49-4). This distinction is critical since corticosteroids are contraindicated in invasive fungal disease.

Historically, patients developing invasive fungal infection at the orbital apex suffer severe morbidity and frequent mortality. Survival requires early diagnosis and immediate treatment. Experienced authors have discussed treating infected tissues as a “malignancy” with extirpation of all involved tissues. This results in exenteration or even more extensive deforming craniofacial resection in patients with other comorbid conditions. I have moved away from this paradigm, utilizing surgery as an early diagnostic modality with a more limited resection of tissue that is ischemic or necrotic. In addition to broad spectrum or species-directed systemic angifungal therapy (see Table 49-2), it is my standard to use adjuvant direct antifungal application which I will discuss below. It has been my experience that despite standard textbook discussions citing that pathogens are easily differentiated based on microscopic morphology, the thinner, septate, acute branching angled Aspergillus hyphae will swell with frozen preparation and frequently be misinterpreted as Mucor or vice-versa (see Figure 49-1). This distinction is critical in order to begin appropriate therapy.

I consider surgical and systemic antifungal treatment supportive therapy until the primary immunosuppressive state can be reversed. Of note, the topical local application of amphotericin B discussed next may not represent Food and Drug Administration “approved” uses. If the underlying immunosuppressive state is not reversed with
aggressive therapy (eg, treatment of DKA), it is very difficult to halt disease progression. In addition, the pathologic local environment at the site of infection may preclude adequate local antibiotic delivery to necrotic tissue through affected blood vessels. In addition, in Mucor infections, local changes produce acidotic conditions that promote fungal proliferation even after systemic DKA is corrected.

I always irrigate the affected soft tissues and sinuses intraoperatively with a liter of 0.25 to 0.50 mg/cc amphotericin B prepared by the pharmacy for surgical irrigation. I also typically perform postoperative retrobulbar or peribulbar injection of 2 to 6 cc of amphotericin B at 2 mg/cc prepared for injection in a sterile hood. I have injected this preparation as frequently as daily or in alternate day regimen up to 6 to 8 applications without significant adverse affect. I will direct the retrobulbar needle into the affected areas, administer a test dose with blood pressure monitoring present, and consider a peribulbar lidocaine injection if trigeminal sensation remains intact. Some authors have advocated an indwelling orbital catheter for irrigation, but I have found the retrobulbar or peribulbar injection adequate. Theoretically, a catheter might decrease the chance of an intradural injection through the nerve sheath or an ocular perforation, but it adds the added risk of an indwelling orbital foreign body. I do leave a postoperative catheter in place to irrigate the sinuses, which may require preirrigation application of topical anesthetic spray.

Summary

                * An orbital apex syndrome  in a diabetic or immunocompromised patient may represent a life-threatening fungal infection, and remains the primary diagnosis of exclusion.

                * High clinical suspicion and early diagnosis of fungal infection is required to prevent significant morbidity or mortality.

                * Diagnosis and treatment requires coordination of a multi-specialty approach.

                * Advances in systemic antifungal therapy provide new potential alternatives to nephrotoxic monotherapy with amphotericin B.

                * In fungal rhino-sino-orbital infection, biopsy,  limited debridement, and systemic antifungal administration coupled with adjuvant local antifungal therapy may provide an alternative to mutilating extirpative surgical procedures.

Bibliography

Treatment Guidelines from the Medical Letter. Antifungal Drugs. 2008;6(issue 65):1-8.

Turbin RE, Khoobiar SA, Langer P, et al. Adjuvant therapy for invasive sino-orbital fungal infection. J Neuroophthalmol. 2002;22:178-179.

Yeh S, Foroozan R. Orbital apex syndrome. Curr Opin Ophthalmol. 2004;15:490-498.

Supported in part by Research to Prevent Blindness, Inc, New York, NY; Fund for the New Jersey Blind, Newark, NJ; Lions Eye Research Foundation of New Jersey, Newark, NJ; The Eye Institute of New Jersey, Newark, NJ; and the Gene C. Coppa Memorial Fund, Newark, NJ.