Clomiphene Citrate Associated With Palinopsia

Aneurysmal volume expansion after endovascular treatment is caused by intra-aneurysmal thrombosis in the early postembolization period. Although postembolization mass effect on cranial nerves and other adjacent structures has been previously reported, we are unaware of reports involving the anterior visual pathway. A 66-year-old woman with a 2-week history of blurred vision without headache was found to have a large, unruptured anterior communicating artery aneurysm. One month after endovascular treatment of the aneurysm with coiling and flow diversion, the patient developed decreased vision in her right eye and a left homonymous hemianopia. Magnetic resonance imaging demonstrated compression of the right optic nerve, chiasm, and edema of the right optic tract. The patient was treated with a course of high dose corticosteroids, and over the course of several weeks, her vision improved and the optic tract edema resolved. We alert clinicians to this rare but potentially reversible visual complication of endovascular treatment of intracranial aneurysms.

Letters to the Editor The 14th Hoyt Lecture: Ischemic Optic Neuropathy: The Evolving Profile, 1966-2015: Response D r. Parsa raises important issues in his letter to the editor regarding the 14th Hoyt Lecture. He rightfully wishes to credit Hoyt for emphasizing the baseline optic disc structure in nonarteritic anterior ischemic optic neuropathy (NAION). However, he disputes the fact that Hayreh (1) documented this occurrence in his 1974 study of cupping in anterior ischemic optic neuropathy (AION) stating that the article focused on cupping after arteritic AION. He further suggests that other authors and I may have performed "only a perusal of manuscript titles and author listings, without recollection of the manuscript contents themselves. . ."when citing Hayreh's paper. However, Hayreh's publication, although focused on arteritic AION, included data on fellow eye cupping in NAION; of 12 unilateral cases of NAION, 9 fellow eye optic discs had no physiologic cup and 2 had a small cup-disc ratio of 0.2. I would refer Dr. Parsa back to Tables I and II of that article and references to that same data in subsequent reports by Beck and others (2,3). Although this in no sense diminishes Hoyt's seminal focus on the finding in 1982, the information was certainly in the literature as I stated. Knowing Dr. Hoyt and that no significant manuscript in the field escaped his gaze, I suspect that he had read it. Dr. Parsa goes on to summarize his recently proposed theory that abrupt vitreous separation from the optic disc, with direct axonal injury because of "shear and stress forces" is responsible for the syndrome of NAION, rather than ischemia, which most investigators in the field believe is the major component. This proposal, published as an editorial (4), was thought provoking but did not constitute peer-reviewed scientific evidence and, therefore, was not included in my review of the evidence-based evolution of our understanding of NAION (5). The theory does not take into account an extensive literature including fluorescein angiographic evidence of impaired optic disc perfusion in NAION (6,7) and histopathologic documentation of infarcts in NAION (8-11). Furthermore, although there is a large literature around vitreopapillary traction, studies generally describe an entirely different syndrome of disc edema and hemorrhage without the diminished optic nerve function seen in patients with NAION (12,13). That said, we clearly have much to learn about the specific Clomiphene Citrate Associated With Palinopsia W e were interested to read the article by Yun et al (1) describing palinopsia with the use of topiramate. We evaluated a patient with persistent palinopsia after the use of clomiphene citrate. 220 pathophysiology of this disorder, and it is possible that vitreopapillary mechanics may somehow be involved. I believe the neuro-ophthalmology community would welcome the evidence. Anthony C. Arnold, MD UCLA Department of Ophthalmology, Stein Eye Institute, Los Angeles, California The author reports no conflict of interest. REFERENCES 1. Hayreh SS. Pathogenesis of cupping of the optic disc. Br J Ophthalmol. 1974;58:863-876. 2. Beck RW, Savino PJ, Repka MX, Schatz NJ, Sergott RC. Optic disc structure in anterior ischemic optic neuropathy. Ophthalmology. 1984;91:1334-1337. 3. Beck RW, Servais GE, Hayreh SS. Anterior ischemic optic neuropathy. IX. Cup-to-disc ratio and its role in pathogenesis. Ophthalmology. 1987;94:1503-1508. 4. Parsa CF, Hoyt WF. Nonarteritic anterior ischemic optic neuropathy (NAION): a misnomer. Rearranging the pieces of a puzzle to reveal a nonischemic papillopathy caused by vitreous separation. Ophthalmology. 2015;122:439- 442. 5. Arnold AC. Ischemic optic neuropathy: the evolving profile, 1966-2015. The 14th Hoyt lecture. J Neuroophthalmol. 2016;36:208-215. 6. Arnold AC, Hepler RS. Fluorescein angiography in acute nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 1994;117:222-230. 7. Arnold AC, Costa RM, Dumitrascu OM. The spectrum of optic disc ischemia in patients younger than 50 years. Trans Am Ophthalmol Soc. 2013;111:93-118. 8. Quigley HA, Miller NR, Green WR. The pattern of optic nerve fiber loss in anterior ischemic optic neuropathy. Am J Ophthalmol. 1985;100:769-776. 9. Levin LA, Louhab A. Apoptosis of retinal ganglion cells in anterior ischemic optic neuropathy. Arch Ophthalmol. 1996;114:488-491. 10. Tesser RA, Niendorf ER, Levin LA. The morphology of an infarct in nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2003;110:2031-2035. 11. Knox DL, Kerrison JB, Green WR. Histopathologic studies of ischemic optic neuropathy. Trans Am Ophthalmol Soc. 2000;98:203-222. 12. Katz B, Hoyt WF. Intrapapillary and peripapillary hemorrhage in young patients with incomplete posterior vitreous detachment. Signs of vitreopapillary traction. Ophthalmology. 1995;102:349-354. 13. Wisotsky BJ, Magat-Gordon CB, Puklin JE. Vitreopapillary traction as a cause of elevated optic nerve head. Am J Ophthalmol. 1998;126:137-139. A 22-year-old man reported that whenever he saw a moving object, some blurred images trailed the real object "like shadows." He also stated that "When I watched the screen of a smart phone, I could see a dim afterimage of the screen after the phone was removed." These symptoms became more bothersome especially in darkness or in dim light. He had suffered from parotitis and orchitis four months previously, and had Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 216-221 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Letters to the Editor TABLE 1. Clinical findings of palinopsia associated with clomiphene citrate (3) Patient/Age/Sex 1/32/F 2/32/F 3/36/F Dose of Clomiphene Citrate 250 mg/mo for 10 mo 1500 mg/mo for 5 mo = total 5000 mg 250 mg/mo for 2 mo 1500 mg/mo for 1 mo 1750 mg/mo for 1 mo = total 1750 mg 250 mg/mo for 1 mo 1500 mg/mo for 9 mo = total 4750 mg Symptom Duration Fundus Examination Brain MRI Prolongation of afterimage, especially with high contrast and bright light Prolongation of afterimage, illusory movements in the peripheral field Over 2.5 yr Normal Normal Over 4 yr Normal Normal Prolongation of afterimage for moving objects Over 7 yr Normal Normal Major Symptoms mo, month; yr, year. been on clomiphene citrate 100 mg/d for preservation of sperm activity. He discontinued the clomiphene citrate after developing visual symptoms but they persisted. His medical history was unremarkable and he took no additional medication. On examination, visual acuity, color vision, pupillary reflexes, and ophthalmoscopy were normal in both eyes. No abnormalities were detected on electroencephalogram, brain MRI, and multifocal electroretinography. Tianeptine (Stablon) 12.5 mg 3 times a day for 1 month did not improve the palinopsia nor did a trial of levetiracetam 1000 mg/d. Palinopsia persisted more than 1 year after discontinuation of clomiphene citrate. Clomiphene citrate is frequently used as the first-line treatment of infertility in women, by increasing pituitary production of follicle stimulating hormone and luteinizing hormone. This, in turn, favors production and release of oocytes. This drug is also used in men with idiopathic oligospermia due to its antiestrogenic effect (2). To the best of our knowledge, there is only 1 report of palinopsia associated with clomiphene citrate (3). All the reported patients were women who had taken high-dose of clomiphene citrate on a monthly basis for the treatment of infertility (Table 1). Interestingly, palinopsia associated with clomiphene citrate may be permanent. While this may be dose dependent, the cause was yet to be elucidated (4). The mechanism by which clomiphene citrate causes palinopsia is unknown. It may be related to alterations in levels of serotonin in the brain. For example, lysergic acid diethylamide (LSD) is a serotonin (5-HT) agonist, especially for 5HT2A and 1A receptors (5) which are highly expressed in the visual cortex and have a central role in modulating the visual processing (6). It is not known how clomiphene citrate affects the 5-HT receptors in humans although this medication increases hypothalamic serotonin level in the goldfish model (7). Given this potential mechanism, we treated our patient with tianeptine, a serotonin uptake enhancer. Unfortunately, he showed no improvement on this medication nor on levetiracetam, an anticonvulsant. Letters to the Editor: J Neuro-Ophthalmol 2017; 37: 216-221 Seo-Young Choi, MD Department of Neurology, Pusan National University Hospital, Pusan National University School of Medicine and Medical Research Institute, Pusan, Korea Seong-Hae Jeong, MD Department of Neurology, Chungnam National University Hospital, Chungnam National University College of Medicine, Daejeon, Korea Ji-Soo Kim, MD, PhD Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea The authors report no conflicts of interest. REFERENCES 1. Yun SH, Lavin PJ, Schaz MP, Lesser RL. Topiramate-induced palinopsia: a case series and review of the literature. J Neuroophthalmol. 2015;35:148-151. 2. Ghanem H, Shaeer O, El-Segini A. Combination clomiphene citrate and antiocidant therapy for idiopathic male infertility: a randomized controlled trial. Fertil Steril. 2010;93:2232-2235. 3. Purvin VA. Visual disturbance secondary to clomiphrene citrate. Arch Ophthallmol. 1995;113:482-484. 4. Racette L, Casson PR, Claman P, Zackon DH, Casson EJ. An investigation of the visual disturbances experienced by patients on clomiphene citrate. Fertil Steril. 2010;93:1169-1172. 5. Gillman PK. Triptans, serotonin agonists, and serotonin syndrome (serotonin toxicity): a review. Headache. 2010;50:264-272. 6. Kometer M, Cahn BR, Andel D, Carter OL, Vollenweider FX. The 5-HT2A/1A agonist psilocybin disrupts modal object completion associated with visual hallucinations. Biol Psychiatry. 2011;69:399-406. 7. Olcese JM, Hall TR, Figueroa HR, deVlaming VL. Effects of clomiphene citrate, a nonsteroidal antiestrogen, on brain monoaminergic mechanisms in female goldfish, Carassius auratus. Comp Biochem Physiol C. 1984;77:335-337. 221 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.