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Show Journal of Nciim- Ophthalmology 17( 3): 178- 182, 1997. © 1997 Lippincotl- Raven Publishers, Philadelphia Painless Orbital Apex Syndrome From Mucormycosis Kyle Balch, M. D., Paul H. Phillips, M. D., and Nancy J. Newman, M. D. A 66- year- old woman with a history of non- insulin-dependent diabetes mellitus, hypertension, and hypothyroidism presented with a painless orbital apex syndrome without any sign of orbital cellulitis or acute systemic disease. Her blood glucose was mildly elevated, but there was no diabetic ketoacidosis. Neuroimaging revealed only mild sinus disease. Transnasal sphenoidal mucosal biopsy showed an inflammatory mass with cellular atypia on frozen sections, suggesting squamous cell carcinoma. However, review of the permanent sections showed broad, nonsep-tate hyphae consistent with mucormycosis. The patient was treated with a 3- month course of intravenous amphotericin B and no further surgery. Examination 3 months after presentation revealed complete resolution of her ocular motility deficits and partial resolution of her optic neuropathy. Mucormycosis should be suspected in any case of orbital apex syndrome, especially in the diabetic patient. Key Words: Mucormycosis- Orbital apex syndrome- Cranial neuropathy- Optic neuropathy- Diabetes mellitus. Manuscript received October 14, 1996; accepted November 8, 1996. From the Departments of Ophthalmology ( K. B., P. H. P., N. J. N.), Neurology ( N. J. N.), and Neurosurgery ( N. J. N.), Emory University School of Medicine, Atlanta, Georgia, U. S. A. Address correspondence and reprint requests to Dr. Nancy J. Newman, Neuro- Ophthalmology Unit, Emory Eye Center, 1365- B Clifton Rd. NE, Atlanta, GA 30322, U. S. A. Rhinoorbitocerebral mucormycosis is an often fatal infection of acute onset caused by one of the saprophytic fungi of the Mucorales order, most commonly Rhizopus, Mucor, and Absidia ( 1,2). Although these fungi are ubiquitous, they are typically only pathogenic in immunocompromised individuals. Presenting signs and symptoms include fever, headache, facial pain, periorbital and facial swelling, nasal mucosal ulceration/ necrosis, ophthalmoplegia, and diminished visual acuity. We report a patient with an isolated orbital apex syndrome in whom frozen section pathology suggested a carcinoma, but final pathology revealed mucormycosis. CASE REPORT A 66- year- old woman was referred for evaluation of a right orbital apex syndrome. Past medical history was remarkable for non- insulin- dependent diabetes mellitus, hypertension, and hypothyroidism. She had no history of diabetic ketoacidosis and never required insulin treatment. Current medications were Gly-nase, Procardia, Tenoretic, Trental, and Synthroid. She was in her usual state of good health until 9 days prior to referral, when she had " sinus pressure" and a scant yellow nasal discharge. She consulted her family physician, who diagnosed sinusitis and treated her with a cephalosporin antibiotic and Vancanase nasal spray. Three days later ( 6 days prior to referral), she consulted her ophthalmologist for new- onset horizontal, binocular diplopia. Her examination was normal except for decreased abduction of the right eye. CT revealed mild right sphenoid, ethmoid, and left maxillary sinusitis ( Fig. 1) but no lesions in the brain or orbits. She was diagnosed with a diabetic microvascular sixth cranial nerve palsy, and the plan was to observe. Four days prior to referral, she went to the local emergency room complaining of " drooping" of the right upper lid. She had no ocular or facial pain, and her " sinus pressure sensation" had resolved. Examination revealed normal vision in both eyes, complete right upper lid ptosis, and reduced ductions of the right eye in all fields of gaze. The pupils were equal 775 MUCORMYCOSIS 179 FIG. 1. CT, without contrast. Left: Axial view with mucosal thickening of the right ethmoid sinus ( arrow) and an opacity of the right sphenoid sinus ( arrowhead). Right: Coronal view with an opacity of the right sphenoid ( arrow) and left maxillary ( arrowhead) sinuses. and reactive, with no relative afferent pupillary defect. She was afebrile, her serum glucose was 250 mg/ dl, and she did not have a leukocytosis. She was discharged from the emergency room with the new diagnosis of a microvascular sixth and a microvascular pupil- sparing third cranial nerve palsy. On the day of referral, she complained of decreased vision in the right eye. She had no headaches, ocular pain, or fever. Neuro- ophthalmologic examination revealed a visual acuity of count fingers at 1 ft in the right eye and 20/ 40 in the left eye. Pupils were equal and reactive, with a right relative afferent pupillary defect. There was 2 mm of proptosis of the right eye, with nontender soft retropulsion and complete right upper lid ptosis. She had no conjunctival injection, chemosis, or uveitis. The right eye had reduced ductions that were 10% of normal in all fields of gaze ( Fig. 2). There was right eye intorsion on attempted depression. Ductions of the left eye were full. Corneal sensation was decreased in the right eye. She had mild nuclear sclerotic cataracts in both eyes. Dilated fundus exam was normal, with pink flat nerves in both eyes. She was afebrile, and the remainder of her neurologic and general physical exam was unremarkable, with no ulcerated lesions of the oral or nasal mucosa. Her serum glucose was 240 mg/ dl, but there was no evidence of ketoacidosis, and her white blood count was 8,800 cells/ mm3. MRI showed mild patchy opacification of the right sphenoid and left maxillary sinuses. There were no intracranial or orbital lesions. However, because the right shenoid sinusitis was in close maximity to the right orbital apex, a transnasal sphenoidal mucosal biopsy was performed the following day. Intraopera-tively, an erosion on the sphenoid sinus wall was covered with grayish tan tissue, which was submitted for biopsy. Frozen section biopsy revealed an inflammatory mass with cellular atypia, suggestive of squamous cell carcinoma ( Fig. 3). However, the permanent sections showed broad, nonseptate hyphac consistent with mucormycosis ( Fig. 3). The patient was treated with a 3- month course of i. v. amphotericin B. She had slow improvement of her neurologic deficits, and repeat neuroimaging revealed gradual resolution of her sinus disease. Surgical debridement was not pursued. After 3 months of treatment, her visual acuity improved to 20/ 100 in the right eye. She had only 2 mm of ptosis of the right upper lid and full ductions of both eyes ( Fig. 4). There was mild right optic nerve pallor. DISCUSSION Mucormycosis is an acute mycotic infection that typically affects immunocompromised individuals ( 1,2). The most common predisposing conditions are diabetes mellitus, hematologic malignancies, and treatment with immunosuppressive drugs. Risk factors for infection in diabetics include poor glucose control and diabetic ketoacidosis. Rarely, mucormycosis occurs in otherwise healthy individuals ( 1,3- 5). The pathogenetic organisms are saprophytic fungi within the order Mucorales, which includes the three genera most commonly responsible for mucormycosis: Rhizopus, Mucor, and Absidia. There is no clinical distinction among the diseases caused by the different genera. Mucormycosis occurs in several clinical forms, including rhinoorbitalcerebral, pulmonary, dissemin- J Neum- Oplulmlmol, Vol. 17, No. 3. 1997 180 K. BALCH ET AL. .-'. J FIG. 2. Patient on day of referral. She has limited ductions of the right eye in all fields of gaze. There is no periorbital edema, conjunctival injection, or chemosis. ated, cutaneous, and gastrointestinal ( 1,2). Ocular disease most commonly occurs in rhinoorbitalcere-bral mucormycosis. In rhinoorbitalcerebral mucormycosis, fungal spores are inhaled into the nasal mucosa. Immunocompetent hosts typically generate a phagocytic response, which kills the spores. In immunocompromised hosts, the spores may germinate into hyphae within the nasal mucosa. The hyphae may then invade the surrounding sinuses, the orbits, and the brain by direct extension or via blood vessels and nerves. These fungi have a propensity to invade blood vessels, causing thrombosis, ischemia, and hemorrhage. In the extensive review of rhinoorbitalcerebral mucormycosis by Yohai et al. ( 1), the most common ocular signs and symptoms were ophthalmoplegia, decreased vision, proptosis, periorbital edema, conjunctival chemosis, orbital cellulitis, periorbital/ or-bital pain, eye pain, and trigeminal anesthesia. Common systemic signs and symptoms were nasal or oral mucosal necrosis, sinusitis, fever, mental status changes, facial swelling and pain, leukocytosis, facial nerve paresis, stroke, and headache. Our case presented atypically, with a painless orbital apex syndrome without any signs of orbital cellulitis. Bodenstein et al. ( 6) described seven patients with mucormycosis who presented with an orbital apex syndrome and minimal signs of orbital congestion. However, most of their patients had some periorbital edema, conjunctival injection, chemosis, or proptosis suggestive of orbital cellulitis. Downie et al. ( 7) reported a patient with rhinoorbitalcerebral mucormycosis who had an orbital apex syndrome and no proptosis or conjunctival chemosis. In the review by Yohai et al. ( 1), patients frequently had facial pain ( 23%), headache ( 17%), periorbital/ orbital pain ( 11%), or eye pain ( 8%). As this was a retrospective review of the literature, the frequency of pain may have been underestimated. Our patient had a pupil- sparing oculomotor nerve palsy simulating a diabetic microvascular neuropathy. Johnston et al. ( 8) described a 74- year- old woman with mucormycosis who presented initially with a painful abducens nerve palsy followed by a pupil- sparing oculomotor nerve palsy. This occurrence is not suprising considering the propensity of this fungus to invade blood vessels and cause thrombosis and ischemia. The oculomotor nerve damage in these cases is probably secondary to ischemia, as opposed to due to direct fungal invasion of the nerve. Other atypical features of our patient's presentation include the absence of fever, leucocytosis, and her relatively good health. Although she is a diabetic, her serum glucose was only mildly elevated and she had no ketoacidosis. Neuroimaging of patients with rhinoorbitalcerebral mucormycosis may reveal sinus disease with nonspecific mucosal thickening or an orbital infiltrate ( 9- 11). Frequently, as in our case, neurologic deficits are often out of proportion to radiographic findings. Although neuroimaging in our patient showed sinus disease, CT and MRI failed to demonstrate her orbital apex lesion. However, neuroimaging was helpful in determining a biopsy site. J Neuro- Ophthalmol, Vol. 17, No. 3, 1997 MUCORMYCOSIS 181 I * FIG. 3. Top: Frozen section biopsy of right sphenoid sinus tissue. There is an inflammatory mass with cellular atypia suggestive of carcinoma. Bottom: Parmanent section biopsy of right sphenoid sinus tissue ( H& E) with large nonseptate hyphae ( arrow) and surrounding chronic inflammation. Biopsy of nasal, oral, or sinus lesions showing tissue invasion by fungus is necessary for diagnosis of rhi-noorbitalcerebral mucormycosis ( 1). Histopathology typically shows large, sparsely septate hyphae with right angle branching. Occasionally, as in this case, there may be a reactive chronic inflammatory infiltrate, with cellular atypia, suggestive of carcinoma on frozen sections. Potassium hydroxide preparations of fresh tissue may facilitate the diagnosis by demonstrating the hyphae intraoperatively. The hyphae are well demonstrated on permanent sections with hema-toxylin- eosin, Gomori methenamine silver, and periodic acid- Schiff preparations. Cultures are unreliable for diagnosis as these fungi are frequent contaminants. Standard treatment includes reversal of the underlying condition, antifungal therapy with intravenous Amphotericin B, and wide local excision of necrotic tissue ( 1). The amount of excision required for cure is a matter of considerable debate, with some authors recommending aggressive debridement, frequently including exenteration of the affected orbit ( 12). However, Kohn and Hepler ( 13) reported a series of eight cases successfully treated with aggressive surgery, but without exenteration. Rarely, patients have been successfully treated without any surgical debridement ( 1,3,5). As our patient was healthy and her diabetes was easily controlled, we elected to defer surgery and monitor her clinical course. Her neurologic deficits and her sinusitis improved with Amphotericin B, and surgical debridement was unnecessary. Unfortunately, there are no established criteria to determine which patients need extensive surgery. Our case demonstrates that mucormycosis can present as a painless orbital apex syndrome without any signs of orbital cellulitis or systemic disease in a patient with well- controlled diabetes and that the prognosis is not universally poor. Early diagnosis is essential for successful treatment and has been associated with a better prognosis. Acknowledgment: This work was supported in part by a departmental grant ( Ophthalmology) from Research to Prevent Blindness, Inc., New York, New York. J Neuro- Ophlhalmol, Vol. 17, No. 3, 1997 182 K. BALCH ET AL. J FIG. 4. Patient after 3 months of i. v. amphotericin treatment. She now has full ductions of both eyes. REFERENCES 1. Yohai RA, Bullock JD, Aziz AA, Markert RJ. Survival factors in rhino- orbital- ccrebral mucormycosis. Surv Ophthalmol 1994; 39: 3- 22. 2. Sugar AM. Mucormycosis. Clin Infect Dis 1992; 14: S126- 9. 3. Zak SM, Katz B. Successfully treated spheno- orbital mucormycosis in an otherwise healthy adult. Ann Ophthalmol 1985; 17: 344- 8. 4. Quattrocolo G, Pignatta P, Dimanico U, Tarenzi L, Baggiorc P. Rhinocerebral mucormycosis and internal carotid artery thrombosis in a previously healthy patient. Acta Neurol Belg 1990; 90: 20- 6. 5. Baum JL. Rhino- orbital mucormycosis, occurring in an otherwise apparently healthy individual. Am J Ophthalmol 1967; 63: 335- 9. 6. 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