SURVEY OF OPHTHALMOLOGY

VOLUME 56  NUMBER 4  JULYAUGUST 2011

CLINICAL CHALLENGES
PETER SAVINO AND HELEN DANESH-MEYER, EDITORS

Unilateral Proptosis in a 60-year-old Man

Carole G. Cherfan, MD,1 Ahmad M. Mansour, MD,1 Muhammad H. Younis, MD,1 and Bobby S. Korn, MD, PhD, FACS2
1

Department of Ophthalmology, American University of Beirut-Medical Center, Beirut, Lebanon; and 2Shiley Eye Center, Department of Ophthalmology, University of California San Diego, La Jolla, CA, USA

(In keeping with the format of a clinical pathologic conference, the abstract and key words appear at the end of the article.)

Case Report
A 60-year-old man presented with dizziness and dyspnea upon exertion and was diagnosed with a myelodysplastic disorder. One and a half years later, during a course of chemotherapy, he experienced painless, erythematous periorbital swelling of the right eye associated with excess tearing and fever. Three days later the swelling worsened, and proptosis became evident (Fig. 1). Visual acuity was 20/20 bilaterally with normal pupils, ocular motility, and fundus examination. The patient was on liposomal amphotericin B, tazocin, vancomycin, and acyclovir for persistent high grade fever. Review of systems was unremarkable except for his acute leukemia. Two weeks prior to the onset of proptosis, computed tomography (CT) revealed acute sinusitis, and he underwent nasal endoscopy with surgical debridement of the sinus cavities (Fig. 2). Paranasal sinus biopsy was taken for pathology and culture. What is the differential diagnosis? What is the most appropriate next step in the evaluation of this patient?
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2011 by Elsevier Inc. All rights reserved.

Comments
COMMENTS BY BOBBY S. KORN, MD

The differential diagnosis of unilateral proptosis in an immunocompromised patient should focus on infectious etiologies. Non-infectious causes such as thyroid-related orbitopathy and primary and secondary orbital tumors are lower in this differential. A thorough history should be obtained, including prior malignancies, sinus disease, orbital trauma, prior placement of orbital implants, and other orbital surgery. The differential includes the following.

MUCORMYCOSIS

Mucormycosis is at the top of the differential in this immunocompromised patient with proptosis. Mucormycosis is caused by ubiquitous fungi in the order mucorales.15 Mucormycosis is angioinvasive, causing vascular thrombosis, tissue necrosis, and fungal dissemination. The mortality rate is as high as 90% in some series.2,3 Risk factors for mucormycosis include diabetes mellitus (especially with ketoacidosis), renal

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Aspergillosis may present in two ways. The rst is a disseminated form, often in immunocompromised patient, that causes a widespread necrotizing angiitis in small vessels. The second form is the inltrating mass that usually originates from the adjacent sinus, causing globe displacement. Allergic fungal sinusitis may present with orbital symptoms, but is not invasive.20
INFECTIOUS CELLULITIS Fig. 1. Erythematous periorbital swelling of the right eye with proptosis.

disease, deferoxamine therapy, and immunocompromised states. Inasmuch as polymorphonuclear leukocytes are essential in the clearance of hyphae, mucormycosis occurs most commonly in those with acute leukemia who developed neutropenia secondary to chemotherapy.16,23 Rhino-cerebral, maxillo-facial, and pulmonary mucormycosis are the most frequent clinical forms, but neutropenic patients are at risk for disseminated infection occurring in up to 40% of patients with hematologic malignancies.15 Prompt diagnosis and treatment are essential. Yohai et al reviewed rhino-orbital-cerebral mucormycosis.23 The most frequent ophthalmic ndings were external ophthlamoplegia with decreased vision, proptosis, and periorbital edema. The lowest survival rates were associated with periorbital necrosis and cavernous sinus thrombosis. Sinsusitis was present in 79% of patients.

Bacterial cellulitis is another consideration. The process usually begins in the sinuses and leads to continuous pyemic destruction of tissue planes with subperiosteal, orbital, and intracranial abscess formation. Vision loss can occur from increased intraorbital tension, direct optic neuritis, or vasculitis.8
TUBERCULOSIS AND SYPHILIS

ASPERGILLUS

Infection by the saprophyte Aspergillus may also cause proptosis in an immunocompromised patient.

Fig. 2. CT of the orbits and sinuses show acute right ethmoid sinusitis.

Tuberculosis infection is still a problem worldwide, especially in immunosuppressed patients. Orbital involvement can occur from hematogenous spread or direct extension from adjacent sinuses. Involvement of the orbit with syphilis is rare, but can present as periostitis of the orbital bones. Fistulization, bone resorption, and secondary orbital spread may result.20 With the history of ethmoid sinus disease and the recent onset of proptosis and periorbital swelling, orbital cellulitis from extension of adjacent sinus disease is an important consideration in this patient.1 Prompt reimaging of the orbit and sinuses is the next step in his evaluation. As he had previously underwent CT scan of the orbit (Figure 2), a repeat CT scan of the orbit, sinus, and cavernous sinus is indicated. CT is a reasonable modality to evaluate the orbit and sinuses and allows comparison with the previous exam, although MRI with contrast may be superior in the evaluation of the cavernous sinus. Subperiosteal abscess (SPA) formation must be considered in any patient who is not improving on systemic antimicrobial therapy. Mixed microbial infections allow for synergy as aerobic organisms deplete oxygen that is toxic to most anaerobes, whereas anaerobes produe beta-lactamase, inactivating antibiotics.9 In such cases, emergent drainage of the SPA is indicated in the setting of optic nerve or retinal vascular compromise.7 Review of the initial CT scan shows complete opacication of the right ethmoid sinus with partial opacication of the left anterior ethmoidal air cells (Fig. 2). As the patient previously underwent endoscopic sinus surgery, the etiology of the sinusitis should be evident upon examination of the culture and pathology of the debrided tissues. The culture results must be interpreted cautiously

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given the patients prior treatment with broad spectrum antimicrobial and antifungal therapy. While keeping in mind zygomycotic infections, the pathologic specimens should be carefully evaluated for evidence of fungal angioinvasion, tissue destruction, thrombosis, and infarction.5 The nasal mucosa and hard palate should be evaluated for the classic black eschar of necrotic skin seen in mucormycosis, although this was seen in only 19% in one series.23

Case Report (Continued)

A repeat CT showed persistent pansinusitis with involvement of the right preseptal area with enhancement of the right medial rectus (Fig. 3). The sinus pathology revealed non-septate hyphae with branching at 90 degrees consistent with Mucor species, as well as severe chronic inammation with focal necrosis and numerous fungal organisms consistent with mucormycosis (Fig. 4). Cultures grew a heavy growth of coagulase negative Staphylococcus and Rhizopus, as well as moderate growth of Aspergillus and Enterococcus. What should be done at this point? What are the indications for orbital exenteration?
Fig. 4. The sinus pathology revealed non-septate hyphae with branching at 90 degrees consistent with Mucor species amid chronic inammatory reaction.

Comments (Continued)
COMMENTS BY DR. KORN

With the conrmation of mucormycosis in pathologic sections, prompt treatment is required. Infectious disease consultation should be sought. A complete blood panel, including work-up for

Fig. 3. Repeat (12 days later) CT of orbits and sinuses showed bilateral pansinusitis with involvement of the right preseptal area.

diabetes and ketoacidosis, should be performed. Any acidosis must be promptly treated to reduce unbound iron that is critical for the proliferation of mucormycosis.23 Surgical debridement is the mainstay of treatment. Fig. 3 shows the updated CT scan that demonstrates bilateral ethmoid sinus involvement and right medial orbital involvement. Widespread debridement of the diseased orbital tissue, along with sinus surgery, should be promptly performed. Infected tissue bleeds little due to the vaso-occlusion that occurs with mucormycosis. Tissue is removed until normal bleeding is encountered and can be guided by intraoperative frozen tissue controls of margins. Adjunctive measures include delivery of local amphotericin B with indwelling catheters, particularly when conservative debridement and extenterationsparing efforts are done.21 The use of hyperbaric oxygen has been suggested to synergize with systemic amphotericin treatement by increasing the efciency of leukocyte-mediated oxidative killing.23 The addition of newer anti-fungal agents such as posaconazole, which have been used successfully as salvage therapy, should be considered.4,17 Finally, correction of the neutropenia in this patient by granulocyte transfusions or use of granulocyte colony-stimulating factor may boost host immunity.12 Owing to the high mortality rate of rhino-orbital mucormycosis, orbital exenteration must be considered in all cases. In a survey of the preceptors of the American Society of Ophthalmic Plastic and Reconstructive Surgery, no standard of care could be established to guide physicians on when exenteration may benet a mucormycosis patient.6 Certainly, in a non-seeing eye with disseminated orbital disease, orbital exenteration would be a reasonable

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consideration. However, in a seeing eye with local disease, the decision to perform exenteration is difcult.

Case Report (Concluded)

The patient underwent generous surgical debridement of the infected sinuses and received intravenous liposomal amphotericin B and posaconazole. Exenteration was strongly advised by both the otolaryngologist and the orbital surgeon, but the patient refused. The proptosis and periorbital swelling subsided gradually, with complete resolution after 10 days. Ocular motility remained intact with visual acuity of 20/20 bilaterally. He was discharged on liposomal amphotericin B and posaconazole (Fig. 5). Ten days later, he presented to the emergency room in a blastic crisis with secondary severe hyperkalemia. Work-up failed to reveal any sign of mucormycosis. Subsequently, he sustained respiratory and cardiac arrests and expired. No autopsy was performed.

Discussion
Rhino-orbital fungal infections can cause devastating complications in diabetics and immunocompromised hosts.21 These infections need to be recognized as both life- and sight-threatening.22 Initial presentation may be subtle, only to progress precipitously.13 Computed tomography and magnetic resonance imaging are helpful in determining the extent of tissue involvement and the efcacy of treatment, but its diagnostic role remains limited.13 Successful management of rhino-orbital mucormycosis relies on early diagnosis and aggressive medical and surgical interventions.18 Delays in diagnosis are associated with higher mortality rates.13 Underlying metabolic derangements or predisposing conditions must be addressed (e.g., hyperglycemia and acidosis in diabetic subjects).13

The treatment of mucormycosis comprises a combination of systemic antifungal agents and aggressive surgical debridement of involved tissues.10,21 Amphotericin B remains the antibiotic of choice.22 As a result of its systemic toxicity, an alternative form of the drug, intravenous liposomal encapsulated amphotericin B, is preferred in many instances,14,18,22 and this may be combined with posaconazole, a new extendedspectrum triazole.11,14,18,19 This combination requires further clinical evaluation as evidence of their in vivo agonist effects are still lacking.19 Other investigational modalities include the administration of amphotericin B into the orbital space and the use of hyperbaric oxygen. Extensive surgical debridement of all infected and necrotic tissue is considered mandatory.10,13,14,23 Frozen section guided surgical debridement has been described as part of the management of mucormycosis.18 In this technique, surgical resection can be monitored with the use of frozen sections, dictating the need for further serial debridement.18 Together, medical therapy and surgical debridement increase the survival rate (78%) compared to medical management alone (57.5%).13 The most difcult and crucial decision to be made in the management of orbital mucormycosis is whether to perform orbital exenteration. Exenteration can be lifesaving, but is a mutilating procedure.6 No evidence-based clinical guidelines currently exist concerning the indications for orbital exenteration in orbital mucormycosis.6 In rapidly progressive disease involving the orbit, exenteration may be essential for survival.13 The clinician must balance the morbidity associated with exenteration against the risk to the patients life. Localized infection should be aggressively excised, whereas extensive disease necessitates exenteration.22 As no clear guidelines are available, the decision to exenterate at present relies on the clinical judgment of the treating physician and the wishes of the patient.6

Disclosure
The authors reported no propriety or commercial interest in any products mentioned or concepts discussed in this article.

References
1. Chandler JR, Langenbrunner DJ, Stevens ER. The pathogenesis of orbital complications in acute sinusitis. Laryngoscope. 1970;80:1414--28 2. Eucker J, Sezer O, Graf B, et al: Mucormycoses. Mycoses. 2001;44:253--60 3. Ferry AP, Abedi S. Cerebral mucormycosis (phycomycosis): ocular ndings and review of the literature. Surv Ophthalmol. 1961;6:1--24

Fig. 5. Resolution of the periorbital swelling and proptosis (12 days after Fig. 1).

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15. Pagano L, Ofdani M, Fianchi L, et al. Mucormycosis in hematologic patients. Haematologica. 2004;89:207--14 16. Pagano L, Ricci P, Tonso A, et al. Mucormycosis in patients with haematological malignancies: a retrospective clinical study of 37 cases. Br J Haematol. 1997;99:331--6 17. Page Rl, Schwiescow J, Hilts A. Posaconazole as salvage therapy in a patient with disseminated zygomycosis: case report and review of the literature. Pharmacotherapy. 2007; 27:290--8 18. Pelton RW, Peterson EA, Patel BCK, et al. Successful treatment of rhino-orbital mucormycosis without exenteration. Ophthalmic Plast Reconstr Surg. 2001;17:62--6 19. Rickets V, Atta J, Herrmann S, et al. Successful treatment of disseminated mucormycosis with a combination of liposomal amphotericin B and posaconazole in a patient with acute myeloid leukaemia. Mycoses. 2006;49:27--30 20. Rootman JR. Specic Inammations of the Orbit, in Rootman JR (ed). Diseases of the Orbit: A Multidisciplinary Approach. Philadelphia, Lippincott Williams and Wilkins, 2002, pp 467--78 21. Seiff SR, Choo PH, Carter SR. Role of local amphotericin B therapy for sino-orbital fungal infections. Ophthalmic Plast Reconstr Surg. 1999;15:28--31 22. Warwar RE, Bullock JD. Rhino-orbital-cerebral mucormycosis: a review. Orbit. 1998;17:237--45 23. Yohai RA, Bullock JD, Aziz AA, et al. Survival factors in rhinoorbital-cerebral mucormycosis. Surv Ophthalmol. 1994;39: 3--22 Reprint address: Ahmad M. Mansour, MD, OphthalmologyAUB, POB 113-6044, Beirut, Lebanon. e-mail: ammansourmd@ gmail.com.

4. Gelston CD, Durairaj VD, Simoes EA. Rhino-orbital mucormycosis causing cavernous sinus and internal carotid thrombosis treated with posaconazole. Arch Ophthalmol. 2007;125:848--9 5. Greenberg RN, Scott LJ, Vaughn HH, et al. Zygomycosis (mucormycosis): emerging clinical importance and new treatments. Curr Opin Infect Dis. 2004;17:517--25 6. Hargrove RN, Wesley RE, Klippenstein KA, et al. Indications for orbital exenteration in mucormycosis. Ophthalmic Plast Reconstr Surg. 2006;22:286--91 7. Harris GJ. Age as a factor in the bacteriology and response to treatment of subperiosteal abscess of the orbit. Trans Am Ophthalmol Soc. 1993;91:441--516 8. Harris GJ. Subperiosteal abscess of the orbit: age as a factor in the bacteriology and response to treatment. Ophthalmology. 1994;101:585--95 9. Harris GJ. Subperiosteal abscess of the orbit: older children and adults require aggressive treatment. Ophthal Plast Recon Surg. 2001;17:395--7 10. Kohn R, Hepler R. Management of limited rhino-orbital mucormycosis without exenteration. Ophthalmology. 1985; 92:1440--4 11. Kok J, Gilroy N, Halliday C, et al. Early use of posaconazole in the successful treatment of rhino-orbital mucormycosis caused by Rhizopus oryzae. J Infect. 2007;55:e33--6 12. Liles WC, Huang JE, VanBurik JH, et al. Granulocyte colony--stimulating factor administered in vivo augments neutrophil-mediated activity against opportunistic fungal pathogens. J Infect Dis. 1997;175:1012--5 13. Munir N, Jones NS. Rhinocerbral mucormycosis with orbital and intracranial extension: a case report and review of optimum management. J Laryngol Otol. 2007;121:192--5 14. ONeil BM, Alessi AS, George EB, et al. Disseminated rhinocerebral mucormycosis: a case report and review of the literature. J Oral Maxillofac Surg. 2006;64:326--33

Abstract. A 60-year-old immunocompromised patient developed rapidly progressive proptosis that was secondary to mucormycosis. This life-threatening fungal infection usually is associated with chemosis, proptosis, ophthalmoplegia, and visual loss. The fungus may invade ocular structures, sinuses, and extend into the brain. The standard of care includes correction of the underlying condition, administration of liposomal amphotericin B with posaconazole, and surgical debridement of infected and necrotic tissue. We present a case of unilateral proptosis due to mucormycosis in an immunocompromised patient. The patient was successfully managed medically without exenteration. The indications for exenteration are currently unclear, and no clinical guidelines exist. (Surv Ophthalmol 56:374--378, 2011. 2011 Elsevier Inc. All rights reserved.) Key words. amphotericin B proptosis


exenteration

lymphoproliferative disorder

mucormycosis