Nonarteritic Ischemic Optic Neuropathy Associated With Clomiphene Citrate Use

We read with great interest the 14th Hoyt Lecture by Arnold (1) dealing with ischemic optic neuropathy. In particular, we were drawn to the discussion of systemic risk factors and the potential role that medications play in pathogenesis of nonarteritic ischemic optic neuropathy (NAION). We present a case of NAION related to a medication that should be included in the list of risk factors.

Letters to the Editor FIG. 2. Biopsy specimens demonstrate fungal elements with acute-angle branching septate hyphae, typical of Aspergillus. A. (hematoxylin and eosin, ·400). B. (Gomori methenamine silver, ·400). C. (immunostain for Aspergillus, ·400). characteristic of this neoplasm (3). In contrast, vascular damage and thrombosis are hallmarks of fungal infection including Aspergillus (1,4,5). Of interest, our patient had MRI characteristics suggestive of meningioma, including isointensity on noncontrasted T1-and T2-sequences with homogeneous gadolinium enhancement and vasogenic edema (6). This, in part, led to a delay in establishing the correct diagnosis. Amanda D. Henderson, MD Division of Neuro-Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida Division of Neuro-Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland Jacques J. Morcos, MD Department of Neurosurgery, Miller School of Medicine, University of Miami, Miami, Florida Oliver G. Fischer, MD, MS Division of Ocular Pathology, Bascom Palmer Eye Institute, Miami, Florida Nonarteritic Ischemic Optic Neuropathy Associated With Clomiphene Citrate Use W e read with great interest the 14th Hoyt Lecture by Arnold (1) dealing with ischemic optic neuropathy. In particular, we were drawn to the discussion of systemic 106 Department of Ophthalmology, Bassett Healthcare Network, Cooperstown, New York Byron L. Lam, MD Joshua Pasol, MD Division of Neuro-Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida The authors report no conflicts of interest. REFERENCES 1. Hersh CM, John S, Subei A, Willis MA, Kosmorsky GS, Prayson RA, Bhimraj A. Optic neuropathy and stroke secondary to invasive Aspergillus in an immunocompetent patient. J Neuroophthalmol. 2016;36:1–4. 2. Zhou Y, Morgan ML, Almarzouqi SJ, Chevez-Barrios P, Lee AG. Apical orbital aspergillosis complicating giant cell arteritis. J Neuroophthalmol. 2016;36:159–163. 3. Kotapka MJ, Kalia KK, Martinez AJ, Sekhar LN. Infiltration of the carotid artery by cavernous sinus meningioma. J Neurosurg. 1994;81:252–255. 4. Shamim MS, Siddiqui AA, Enam SA, Shah AA, Jooma R, Anwar S. Craniocerebral aspergillosis in immunocompetent hosts: surgical perspective. Neurol India. 2007;55: 274–281. 5. Nadkarni T, Goel A. Aspergilloma of the brain: an overview. J Postgrad Med. 2005;51:S37–S41. 6. Saloner D, Uzelac A, Hetts S, Martin A, Dillon W. Modern meningioma imaging techniques. J Neurooncol. 2010;99:333–340. risk factors and the potential role that medications play in pathogenesis of nonarteritic ischemic optic neuropathy (NAION). We present a case of NAION related to a medication that should be included in the list of risk factors. A 35-year-old man complained of the acute onset of an inferonasal scotoma in his left visual field. He had no significant medical history, including diabetes mellitus, Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 104-109 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor hypertension, obstructive sleep apnea, was a nonsmoker, and denied the use of phosphodiesterase inhibitors. His only medication was clomiphene citrate 25 mg daily, taken for 1 year for fertility issues. On examination, visual acuity was 20/20, right eye, and 20/25, left eye, with a left relative afferent pupillary defect (RAPD). Fundus examination revealed optic disc edema in the left eye and a normal right fundus including a cup-to-disc ratio of 0.2. Two months later, acuity was 20/20 in the left eye with a small RAPD, superior and temporal disc pallor, and an inferior altitudinal visual field defect. Patient evaluation was unremarkable and included brain and orbit MRI, carotid ultrasound, blood pressure monitoring, and hematological studies (complete blood count, basic metabolic panel, thyroid hormone levels, erythrocyte sedimentation rate, C-reactive protein, angiotensin-converting enzyme, lysozyme, Bartonella immunoglobulin M and G antibodies, antithrombin III, factor V Leiden, protein C, and protein S). The patient discontinued his clomiphene citrate and began taking aspirin 81 mg daily. Clomiphene citrate is a selective estrogen receptor modulator that competitively binds estrogen receptors at the hypothalamus and pituitary gland, resulting in increased follicular stimulating and luteinizing hormones. In men, this hormone release induces testosterone production and spermatogenesis (2). The fertility literature reports a low adverse effect rate for patients taking clomiphene citrate. Reported side effects include headache, dizziness, blurred vision, nausea, vomiting, gynecomastia, weight gain, hypertension, pancreatitis, myocardial infarction, deep vein thrombosis, pulmonary embolism, and hypertriglyceridemia (3,4). Visual symptoms occur in up to 10% of patients and include blurred vision, photophobia, diplopia, scotomata, phosphenes, and palinopsia (4,5). These symptoms are thought to be dependent on total dose and duration of exposure and resolve within days to weeks of medication cessation (4). There is a previous report of a 31-year-old woman who developed a NAION after completing a 5-day course clomiphene citrate at a dose of 50 mg per day (5). Dyschromatopsia in Multiple Sclerosis Patients: A Marker of Subclinical Involvement?: Comment W e read with interest the article by Felgueiras et al (1) regarding apparent color vision deficits detected in patients with multiple sclerosis. The authors used Hardy–Randy–Rittler (HRR) pseudoisochromatic plates to test subjects with and without known visual pathway involvement. They found that missing one or more plates was more likely with a history of optic neuritis, and they also found a correlation between HRR plate deficiencies Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 104-109 The pathophysiology of visual symptoms associated with this medication is unclear but proposed mechanisms include “vascular sludging,” an increase in thrombogenic estradiol and overproduction of vasoactive substances that leads to prothrombogenic hemoconcentration (4–6). Risk factors for NAION include several medications including phosphodiesterase inhibitors, interferon-alpha, and amiodarone (1,7). We believe that clomiphene citrate should be added to this list. Andrew F. Perin, MD Joseph G. Chacko, MD Sunali Goyal, MD Department of Ophthalmology, Harvey & Bernice Jones Eye Institute, University of Arkansas for Medical Sciences (UAMS), Little Rock, Arkansas The authors report no conflicts of interest. REFERENCES 1. Arnold AC. The 14th Hoyt Lecture: ischemic optic neuropathy: the evolving profile, 1966–2015. J Neuroophthalmol. 2016;36:208–215. 2. Kim ED, Crosnoe L, Bar-chama N, Khera M, Lipshultz LI. The treatment of hypogonadism in men of reproductive age. Fertil Steril. 2013;99:718–724. 3. Patel DP, Brant WO, Myers JB, et al. The safety and efficacy of clomiphene citrate in hypoandrogenic and subfertile men. Int J Impot Res. 2015;27:221–224. 4. Viola MI, Meyer D, Kruger T. Association between clomiphene citrate and visual disturbances with special emphasis on central retinal vein occlusion: a review. Gynecol Obstet Invest. 2011;71:73–76. 5. Lawton AW. Optic neuropathy associated with clomiphene citrate therapy. Fertil Steril. 1994;61:390–391. 6. Lee VY, Liu DT, Li CL, Hoi-Fan, Lam DS. Central retinal vein occlusion associated with clomipheneinduced ovulation. Fertil Steril. 2008;90:2011.e11–2011. e12. 7. Miller NR, Arnold AC. Current concepts in the diagnosis, pathogenesis and management of nonarteritic anterior ischaemic optic neuropathy. Eye (Lond). 2015;29:65–79. and reduced peripapillary retinal nerve fiber layer thickness and higher enhanced disability scale scores. They suggest that errors in HRR plate testing, which they categorize as dyschromatopsia, may be used as a marker for disease progression. Of note, the authors did not test contrast sensitivity, nor did they assess color vision with a hue discrimination test such as the Farnsworth D-15 or Farnsworth-Munsell 100 hue tests. We studied a population of patients with optic neuropathy (demyelinating and otherwise) and assessed correlations between HRR plate identification and contrast sensitivity as well as color discrimination on the D-15 test (2). We found that there was no correlation between errors 107 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.