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Show Early Diagnosis of Subclinical Interferon Alpha-Associated Optic Neuropathy Using Fluorescein Angiography Dean M. Cestari, MD, Simmons Lessell, MD, Dimosthenis Mantopoulos, MD Abstract: We report a case of a 57-year-old man who presented with decreased visual acuity in the left eye secondary to nonarteritic anterior ischemic optic neuropathy (NAION) while on therapy with interferon-a for hepatitis C. Fundus fluorescein angiography revealed late leakage of both optic discs, consistent with bilateral disease. One week later, the patient developed clinical signs and symp-toms consistent with NAION in the fellow eye. Fluorescein angiography may play an important role in identifying sub-clinical NAION in patients taking interferon-a. Journal of Neuro-Ophthalmology 2015;35:280-283 doi: 10.1097/WNO.0000000000000238 © 2015 by North American Neuro-Ophthalmology Society Interferon alpha (IFN-a) is a mainstay of treatment for hepatitis C and, given its antiproliferative and immuno-modulating properties, it has found wide applications in the treatment of other neoplastic and autoimmune diseases. Since the first description of IFN-a associated retinopathy in 1990 (1), there have been reports of other possible ocular side effects including retinal artery and vein occlusion (2,3), macular edema (4), Vogt-Koyanagi-Harada syndrome (5), myasthenia gravis (6), corneal toxicity (7) and nonarteritic anterior ischemic optic neuropathy (NAION) (8). We describe a case of presumed IFN-a-associated NAION in a patient who initially presented clinically with unilateral signs and symptoms. However, fundus fluorescein angiography (FA) performed at the time of presentation demonstrated dye leakage of the optic disc of the symptom-atic right eye and leakage of the left optic disc of the asymp-tomatic left eye. One week later, the patient experienced vision loss in the left eye. CASE REPORT A 57-year-old man complained of vision loss in the inferior visual field of his left eye. His medical history was significant for hepatitis C complicated by cirrhosis, and his treatment included INF-a (180 mg subcutaneously every week), Ta-crolimus, filgrastim, and ribavirin for 24 weeks. Review of systems was negative for headaches, jaw claudication, scalp tenderness, arthralgias, weight loss, or fatigue. Visual acuity was 20/20, right eye and 20/200, left eye. Color vision was intact in the right eye and reduced in the left eye, but there was no relative afferent pupillary defect. Automated visual field testing showed inferior field loss, much more marked in the left eye (Fig. 1A). Ophthalmos-copy revealed a normal appearing right optic disc with a cup to disc ratio of approximately 0.3, while the left disc was swollen (Fig. 2A). Because IFN-a is known to cause a reti-nopathy in a high percentage of patients, a fluorescein angiogram was obtained. To our surprise, it showed late bilateral optic disc leakage (Fig. 2B). Patient testing included erythrocyte sedimentation rate, C-reactive protein, viscosity level, cryoglobulins, and hep-atitis C viral load. All studies were within normal limits. Brain and orbit magnetic resonance imaging with and without contrast were unremarkable. Given the suspicion of IFN-a-associated NAION, IFN-a was discontinued. One week later, the patient returned complaining of decreased vision in the right eye. Visual acuity was 20/80, right eye and 20/200, left eye. There was bilateral dyschromatopsia, and visual fields showed progression of bilateral inferior field defects (Fig. 1B). Both optic discs were now swollen (Fig. 2C). The patient received a ten-day Neuro-Ophthalmology Service (DMC, SL, DM), Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; and the Department of Ophthalmology and Visual Science (DM), Havener Eye Institute, The Ohio State University, Wexner Medical Center, Columbus, Ohio. The authors report no conflicts of interest. Address correspondence to Dimosthenis Mantopoulos, MD, The Ohio State University, Wexner Medical Center, Havener Eye Institute, Department of Ophthalmology and Visual Science, 915 Olentangy River Road, Columbus, OH 43212; E-mail: dimosthenis. mantopoulos@osumc.edu 280 Cestari et al: J Neuro-Ophthalmol 2015; 35: 280-283 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. course of oral prednisone. Five months later, visual acuity and color vision were unchanged although visual fields had worsened (Fig. 1C), and there was bilateral optic disc pallor (Fig. 2D). DISCUSSION The interferons are a group of glycoproteins with complex antiviral, antitumor, and antiangiogenic properties. In 1995, Purvin (9) reported the development of acute bilateral sequential vision loss, likely from NAION, in two patients receiving IFN-a for malignant neoplasm. Since then, approx-imately 42 unilateral or bilateral cases of IFN-a-associated optic neuropathy have been published (8,10-14). According to the World Health Organization criteria, this association is considered "possible." Although the pathophysiology of IFN-a- associated ocular toxicity is unknown, a number of mech-anisms have been proposed including vasoocclusive (15), hypotensive (10,16), and immunologic (8). NAION is characterized by decreased visual acuity, dyschromatopsia, a relative afferent pupillary defect and a swollen optic disc. Visual fields classically show an inferior altitudinal defect. Although the pathomechanism of NAION is unknown, it is presumed to result from circulatory insufficiency or infarct within the retrolaminar portion of the optic nerve head that is supplied by the short posterior ciliary arteries (SPCA). Fluorescein angiography in NAION typically shows delayed and incomplete disc filling, late leakage of the optic disc, and no delay in choroidal filling. The normal choroidal filling time is suggestive of a relative vascular insufficiency distal to the split-off of the paraoptic branches from the SPCA (17-19). Initially, our patient had no symptoms or definite clinical signs of bilateral NAION. Although the absence of an RAPD is consistent with bilateral involvement, there was no dyschromatopsia or optic disc edema in the asymptomatic fellow eye. However, FA demonstrated late leakage of both optic discs consistent with bilateral optic neuropathies and explains the absence of an RAPD. Given the usefulness of FA in this case to diagnose bilateral involvement, we suggest that patients with unilateral NAION presumed secondary to IFN-a should also have an FA looking for evidence of subclinical involvement of the fellow eye. This is because bilateral simultaneous NAION, whether clinical or subclinical, is much more likely to be secondary to drug toxicity from IFN-a rather than idiopathic. In cases with unilateral NAION, the clini-cian often struggles to decide whether NAION is idiopathic or possibly secondary to IFN-a making the decision to recommend discontinuing this medication more difficult. However, bilateral simultaneous involvement is suggestive of a toxic effect of IFN-a and should prompt the treating physician to discontinue treatment to try to salvage vision. Although guidelines for routine ophthalmologic screen-ing have been established for other medications with known FIG. 1. Automated (Humphrey 24-2) visual fields. A. At pre-sentation, there is evidence of inferior field loss bilaterally, more prominent in the left eye. B. One week later, there is worsening of inferior field loss bilaterally. C. Five months later, visual fields show central and inferior defects in each eye. Cestari et al: J Neuro-Ophthalmol 2015; 35: 280-283 281 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. ocular toxicity, there is no similar consensus for screening patients who are taking IFN-a for hepatitis C. Cases of clinically unilateral NAION and asymptomatic optic disc edema in the fellow eye have been reported in patients not receiving treatment with interferon-a (20). However, our case demonstrates that a patient taking IFN-a also can have asymptomatic disc edema and FA might be an important tool for the early diagnosis of impending IFN-a-associated NAION. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: D. M. Cestari, S. Lessell, D. Mantopoulos; b. Acquisition of data: D. M. Cestari. c. Analysis and interpretation of data: D. M. Cestari, S. Lessell, D. Mantopoulos. FIG. 2. Funduscopy and fluorescein angiography. A. At presentation, there is mild elevation of the right optic disc superiorly while the left disc is swollen with peripapillary hemorrhages. B. In the late phase of the fluorescein angiogram, there is dye leakage of both optic discs. C. One week later, there is bilateral optic disc edema. D. Five months after presentation, both discs are mildly pale. 282 Cestari et al: J Neuro-Ophthalmol 2015; 35: 280-283 Clinical Observation Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Category 2: a. Drafting the manuscript: D. M. Cestari, S. Lessell, D. Mantopoulos; b. Revising it for intellectual content: D. M. Cestari, S. Lessell, D. Mantopoulos. Category 3: a. Final approval of the completed manuscript: D. M. Cestari, S. Lessell, D. 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