Dyschromatopsia in Multiple Sclerosis Patients: A Marker of Subclinical Involvement?: Comment

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. Letters to the Editor on HRR plate testing and D-15 scores but detected a moderate correlation between reduced HRR score and lower contrast sensitivity. We believe in that lower HRR scores are more likely to indicate reduced contrast sensitivity rather than a reduction in color identification or discrimination. The report by Felgueiras et al (1) corroborate the findings of several groups in which reduced contrast sensitivity has been found to be present in a majority of patients with multiple sclerosis, even when there is no visual dysfunction on high-contrast visual acuity testing or a history of optic neuritis (3). We believe that the data presented by Felgueiras et al supports the use of HRR plates as a quick means of assessing contrast sensitivity in a busy clinical setting and in identifying patients who might benefit from treatments to compensate for their contrast sensitivity deficits. Prem S. Subramanian, MD, PhD Department of Ophthalmology, University of Colorado School of Medicine, Aurora, Colorado Jiawei Zhao, MD Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland Dyschromatopsia in Multiple Sclerosis Patients: A Marker of Subclinical Involvement?: Response W e thank Dr. Subramanian and colleagues for their critical appraisal and interest in our article (1). They suggested that Hardy–Rand–Rittler (HRR) pseudoisochromatic plates are not a sensitive indicator of acquired color vision deficits in patients with optic neuropathies. While we agree that a hue discrimination test such as the FarnsworthMunsell (FM) 100 hue test is more sensitive than HRR plate testing, we chose the latter given the fact that it is widely available and easy to perform (2). Moreover, several studies have shown that HRR plates are an effective test of color vision as long as visual acuity is better than 20/50 (3). Use of HRR plates, when compared with the FM 100 hue test, is easier and quicker to perform, and almost all normal subjects would likely make no errors, while in the FM 100 hue test normal subjects would make a few mistakes (2). Zhao et al (4) also bring up an interesting hypothesis that HRR plate testing may be used to screen patients with multiple sclerosis for deficits in contrast sensitivity. One limitation of our study is that contrast sensitivity was not assessed. We look forward to future studies to further address this issue. 108 Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, Maryland Sarita B. Davé, MD New York Eye and Ear Infirmary, New York, New York Jiangxia Wang, MS Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, Maryland The authors report no conflicts of interest. REFERENCES 1. Felgueiras H, Parra J, Cruz S, Pereira P, Santos AF, Rua A, Meira D, Fonseca P, Pedrosa C, Cardoso JN, Almeida C, Araújo M, Santos E. Dyschromatopsia in multiple sclerosis patients: a marker of subclinical involvement? J Neuroophthalmol. 2016;36:275–279. 2. Zhao J, Davé SB, Wang J, Subramanian PS. Clinical color vision testing and correlation with visual function. Am J Ophthalmol. 2015;160:547–552.e1. 3. Balcer LJ, Frohman EM. Evaluating loss of visual function in multiple sclerosis as measured by low-contrast letter acuity. Neurology. 2010;74:S16–S23. Helena Felgueiras, MD Neurology Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal Joana Parra, MD Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal Simão Cruz, MD Neurology Department, Hospital Fernando Fonseca, Lisboa, Portugal Pedro Pereira, MD Neurology Department, Hospital Garcia de Orta, Almada, Portugal Ana F. Santos, MD Neurology Department, Hospital de Braga, Braga, Portugal Adriana Rua, MD Neurology Department, Centro Hospitalar do Porto, Porto, Portugal Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 104-109 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.