Are Erectile Dysfunction Medications Causally Related to Nonarteritic Anterior Ischemic Optic Neuropathy?

To delineate the factors contributing to overdiagnosis of idiopathic intracranial hypertension (IIH) among patients seen in a neuro-ophthalmology service at a tertiary center.; ; We retrospectively reviewed new patients referred with a working diagnosis of IIH over 8 months. The Diagnosis Error Evaluation and Research taxonomy tool was applied to cases referred with a diagnosis of IIH and a discrepant final diagnosis.; ; Of 1,249 patients, 165 (13.2%) were referred either with a preexisting diagnosis of IIH or to rule out IIH. Of the 86 out of 165 patients (52.1%) with a preexisting diagnosis of IIH, 34 (39.5%) did not have IIH. The most common diagnostic error was inaccurate ophthalmoscopic examination in headache patients. Of 34 patients misdiagnosed as having IIH, 27 (27/34 [79.4%]; 27/86 [31.4%]) had at least 1 lumbar puncture, 29 (29/34 [85.3%]; 29/86 [33.7%]) had a brain magnetic resonance imaging, and 8 (8/34 [23.5%]; 8/86 [9.3%]) had a magnetic resonance/computed tomography venogram. Twenty-six had received medical treatment, 1 had lumbar drain, and 4 were referred for surgery. In 8 patients (8/34 [23.5%]; 8/86 [9.3%]), an alternative diagnosis requiring further evaluation was identified.; ; Diagnostic errors resulted in overdiagnosis of IIH in 39.5% of patients referred for presumed IIH, and prompted unnecessary tests, invasive procedures, and missed diagnoses. The most common errors were inaccurate ophthalmoscopic examination in headache patients and thinking biases, reinforcing the need for rapid access to specialists with experience in diagnosing optic nerve disorders. Indeed, the high prevalence of primary benign headaches and obesity in young women often leads to costly and invasive evaluations for presumed IIH.

Point Counter-Point Section Editors: Andrew G. Lee, MD Gregory Van Stavern, MD Are Erectile Dysfunction Medications Causally Related to Nonarteritic Anterior Ischemic Optic Neuropathy? Michael S. Lee, MD, Michael Vaphiades, DO A possible association between erectile dysfunction (ED) medications and the development of nonarteritic anterior ischemic optic neuropathy (NAION) has been recognized since the first reports in the early 2000s. There is still debate about whether there is a true, causal relationship between the two, or whether the relationship is coincidental. Because erectile dysfunction medications are some of the most widely prescribed medications in the United States and worldwide, this has important public health implications and also influences how we advise patients at risk for nonarteritic anterior ischemic optic neuropathy. Two experts debate this topic. Pro: ED Medications Are Causally Related To NAION: Michael S. Lee, MD The United States (U.S.) Food and Drug Administration (FDA) has approved 3 medications for the treatment of male erectile dysfunction (ED): sildenafil citrate (Viagra; Pfizer, New York, NY), tadalafil (Cialis; Eli Lilly, Indianapolis, IN), and vardenafil hydrochloride (Levitra; Bayer Healthcare Pharmaceuticals, Wayne, NJ). These phosphodiesterase type 5 inhibitors (PDE5i) relax vascular smooth muscle leading to dilation of the corpus cavernosum and penile erection. Common adverse events include headache, flushing, nasal congestion, myalgias and distortion of colors, which reflect the presumed vasodilatory effects. Profound systemic hypotension can occur in cases of concomitant nitrate or alpha-blocker use. Nonarteritic anterior ischemic optic neuropathy (NAION) occurs in approximately 2.3-10 out of 100,000 individuals annually (1,2). Although the exact pathophysiology remains elusive, most would agree that a structural predisposition of a small cup-to-disc ratio and diminished blood flow to the optic nerve head likely play a major role, with the latter likely involving impaired autoregulation from a combination of aging, various microvascular risk factors, and intraocular pressure (3). Rare postmarketing reports of NAION following PDE5i use have led to many debates about whether they are causally related to NAION or not (3-5). Many argue that systemic diseases such as diabetes, hypertension, hyperlipidemia, and cardiovascular disease commonly occur among individuals with NAION using ED agents, suggesting that the occurDepartments of Ophthalmology and Visual Neurosciences, Neurology, and Neurosurgery (MSL), University of Minnesota, Minneapolis, Minnesota; and Department of Ophthalmology (MV), University of Alabama at Birmingham, Birmingham, Alabama. Supported in part by an unrestricted grant from the Research to Prevent Blindness, Inc., New York, NY. The authors report no conflict of interest. Address correspondence to Michael S. Lee, MD, 420 Delaware Street SE, MMC 493, Minneapolis, MN 55455; E-mail: [e-mail] 202 rence of NAION with PDE5i use is coincidental (5). Others have also noted that the paucity of reported cases despite the millions, if not billions, of PDE5i doses consumed argues against an association (4). However, reports of a close temporal relationship to PDE5i ingestion and symptom onset (6,7), bilateral and simultaneous NAION (8,9), and rechallenge data (10,11) support that a relationship exists. The National Registry of Drug-Induced Ocular Side Effects utilizes the criteria in Table 1 to attribute an ophthalmic adverse effect to a drug, and I will address each as it relates to PDE5i use and NAION. Dose-response relationship Unfortunately, these data do not exist systematically for PDE5i and NAION. Anecdotally, Bollinger and Lee (10) reported a patient with transient visual field loss following tadalafil ingestion every several days. When the patient failed to achieve an erection, he took the tadalafil again after only 3 days and developed NAION. This is weak evidence supporting a dose-response effect and most papers do not even describe this level of dose detail. I do not believe a dose- response relationship can be determined or ruled out. Temporal association Several reports describe the onset of symptoms within a short amount of time after drug administration (7-11). In many cases, patients will use PDE5i shortly before falling asleep and do not recognize visual loss from NAION on awakening the following morning. A strong, close temporal association likely exists for some cases but many other purported cases do not have such a close temporal onset to ED use. Plausible mechanism of action Gerometta et al (13) gave 9 healthy, masked volunteers oral sildenafil of 100 mg or placebo on separate days and Lee and Vaphiades: J Neuro-Ophthalmol 2016; 36: 202-207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point TABLE 1. National Registry of Drug-Induced Ocular Side Effects criteria to attribute adverse effect to a drug 1. There is a dose-response relationship-the frequency or intensity of the unwanted effect is correlated with increasing drug dose 2. There is a temporal association-the side effect occurs within a reasonable amount of time after drug administration 3. There is a plausible mechanism of action to explain the adverse effect 4. There is no alternative explanation for the adverse effect 5. There is a positive dechallenge effect 6. There is a positive rechallenge effect 7. Similar unwanted effects occur from other drugs in the same class Adapted from (12). measured the intraocular pressure (IOP) and blood pressure (BP). Neither the IOP nor BP changed in the placebo group. In the sildenafil group, IOP increased 26% (P , 0.005) at 1-hour postingestion and returned to normal at 2 hours. The systolic and diastolic BP declined by 15% and 13% respectively at 90 minutes postingestion. In another study, Phillips et al (14) gave 14 normal volunteers 100 mg of sildenafil or placebo on separate study days. They showed that sildenafil could cause a 31% elevation of plasma norepinephrine levels and that sympathetic activity was significantly heightened at rest and during physical, mental, and metabolic stress (attempting to simulate stressors seen in sexual activity). None of these healthy volunteers suffered vision loss from NAION. However, the elderly vasculopathic patient with a disc at risk, sclerotic optic disc vasculature, and poor baseline autoregulation, I believe, could plausibly develop NAION from the use of PDE5i affecting blood flow and autoregulation (3). No alternative explanation The main argument for an alternative explanation is that NAION often occurs spontaneously in this particular patient population and may be unrelated to PDE5i use (4). Bilateral, simultaneous, spontaneously occurring NAION is rare. Su et al (8) reported a 76-year-old patient with vasculopathic risk factors who lost vision in both eyes secondary to posterior ischemic optic neuropathy within 36 hours of consuming sildenafil. Negative workup included neuroimaging, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and Leber hereditary optic neuropathy (LHON) testing. Tarantini et al (9) described a 60year-old man with diabetes who took sildenafil of 50 mg on 3 consecutive days. Sixteen hours following his final dose, he noted sudden decline in vision OU and received a diagnosis of bilateral NAION and serous retinal detachment in the right eye. These events are unlikely to have occurred spontaneously and appear related to the PDE5i ingestion. Recently, a large, prospective observational study sponsored by Pfizer Inc. studied individuals with recent (,3 weeks) NAION (6). Each patient served as his own control. If the patient consumed a PDE5i within 1 day of NAION onset, then that qualified as a "case." If the patient consumed PDE5i between 2 and 30 days before symptom onset, then Lee and Vaphiades: J Neuro-Ophthalmol 2016; 36: 202-207 that served as a "control." Of 673 patients with NAION, 76 took a PDE5i within 2 months of NAION and 64 received a definite or possible diagnosis of NAION. Approximately 1/3 (34.4%) took PDE5i within 1 day of NAION vs 1/5 (20.2%) who took it 2-30 days before NAION. The odds ratio (OR) was 2.36 (1.33, 4.19, P = 0.003). Since each patient served as his own control, the argument that confounding microvascular risk factors caused NAION is negated and, therefore, the PDE5i use was the main difference. This well-designed study argues strongly that PDE5i use doubles the risk of NAION and is causally related. Dechallenge effect No data exist regarding this, and this is not something that we may ever know. Most patients do not take PDE5i daily and therefore do not get a chance to "dechallenge." The visual symptoms do not typically resolve completely because retinal ganglion cell death occurs. A dechallenge effect cannot be assessed. Rechallenge effect Most reports do not describe a rechallenge with PDE5i after an episode of NAION. Bollinger and Lee (10) reported recurrent visual field defects in a man who consumed tadalafil 4 times (10). Pepin and Pitha-Rowe (11) described a 63-yearold hypertensive man who used sildenafil 100 mg. The following day, he developed NAION. He consumed sildenafil on 2 other occasions and experienced significant, sudden worsening of his visual field within 24 hours of each dose. Similar effects from same class drugs Given the findings of close temporal relationship, plausible mechanism, no alternative mechanism in the only prospective case-controlled study, positive rechallenge effect, and NAION following consumption of all 3 PDE5i (class effect), I believe that there is a strong case that PDE5i have a causal relationship in the development of NAION. The lack of dose response and a dechallenge effect do not dissuade me because they cannot be easily measured and have not really been reported. Lack of data in these instances does not equate to lack of relationship. On July 8, 2005, the FDA issued the following statement: "The Food and Drug Administration today approved 203 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point updated labeling for Cialis, Levitra, and Viagra to reflect a small number of postmarketing reports of sudden vision loss, attributed to NAION (nonarteritic ischemic optic neuropathy), a condition where blood flow is blocked to the optic nerve. FDA advises patients to stop taking these medicines and call a doctor or healthcare provider right away if they experience sudden or decreased vision loss in one or both eyes. Further, patients taking or considering taking these products should inform their healthcare professionals if they have ever had severe loss of vision, which might reflect a prior episode of NAION. Such patients are at an increased risk of developing NAION again" (15). In March 2015, the FDA issued another warning/precaution: "An observational study evaluated whether recent use of PDE5i as a class was associated with acute onset of NAION. The results suggest an approximate 2-fold increase in the risk of NAION within 5 half-lives of PDE5i use" (16). The European equivalent of the FDA, The European Medicines Agency has issued the following statement regarding sildenafil use: "It must also not be taken by patients who have ever had loss of vision because of a problem with blood flow to the nerve in the eye." (NAION) (17). These statements by regulatory authorities in the Western world indicate a clear concern for a causal relationship between PDE5i use and NAION. Why, then, are there so few cases reported? I believe that very few practitioners actually report this event. I know that I have seen several cases where PDE5i were taken in close temporal proximity to symptom onset, but I have not reported all of these in the literature. I would imagine that the overwhelming majority of providers do the same. Additionally, I agree with Hayreh (3) that this is more apt to be the "straw that breaks the camel's back." There is likely a confluence of structural, hemodynamic, and autoregulatory disturbances that come together at a singular moment and lead to visual loss, which explains why patients do not lose vision despite using PDE5i on many previous occasions. In my own practice, I advise individuals who have experienced NAION in one eye to avoid the PDE5i to theoretically reduce the risk of NAION in the fellow eye. Con: ED Medications Are Not Causally Related To NAION: Michael Vaphiades, DO The relationship between NAION and PDE5i remains controversial. In 2000, Drs. Egan and Pomeranz (18) reported the first case of NAION associated with sildenafil use. Since then, there have been numerous publications including a recent review of the subject matter, presented at this past North American Neuro-ophthalmology Society (NANOS) meeting in 2015 in San Diego by Dr. Pomeranz. Much of the reasoning for the presumed temporal relationship between NAION and PDE5i stems from the belief that nocturnal hypotension predisposes to NAION and PDE5i taken the previous night produces hypotension (3,19). A small number of cases of what appears to be NAION are temporally associated with PDE5i use (20). However, this relationship between NAION and PDE5i is weak for some of these cases, and those with an association with NAION may well have been related to nocturnal hypotension. This possibility arises from the results of a 24-h ambulatory blood pressure monitoring study conducted by Hayreh (21) although other studies failed to support this (22). In addition, most reported cases of NAION unassociated with PDE5i use occur on waking in the morning presumably from nocturnal hypotension. Hayreh also indicated that most individuals who use PDE5i are middleaged and elderly men with systemic cardiovascular risk factors, which may independently predispose to the development of NAION (3). Thus, with the lack of specificity of effect, one may conclude that the association between PDE5i and NAION may be one of chance alone. In addition, the proposed cases of PDE5i-induced NAION are not all coherent with the pharmacokinetics of the drug's half-life and there is a lack of a dose-response gradient. 204 There have been "rechallenge" cases of PDE5i and NAION reported but no "dechallenge" cases I am aware of. One such "rechallenge" case involved a 67-year-old man with known NAION risk factors including elevated lipids and a "disc at risk" in the fellow eye. He developed transient inferior visual field loss in the right eye within 2 hours of taking the first 4 doses of tadalafil. After the fifth dose, he developed NAION in the right eye with persistent inferior visual field loss (10). The authors concluded that given the large number of prescriptions dispensed for PDE5i and the small number of NAION-PDE5i-associated cases reported, "a definite causal link has not been proved." The other "rechallenge" case was a 63-year-old Caucasian man with ED who had used 25 mg sildenafil episodically for 5 years without incident (11). On restarting the drug, he developed NAION. The authors concede however that "As with patients in other reports, our patient did have risk factors for spontaneous NAION (hyperopia and a small cup-to-disc ratio)" and "had used sildenafil for years without developing NAION." Dr. Lee references the Su et al (8) case of a 76-year-old man with a significant vascular risk who developed sequential visual loss from posterior ischemic optic neuropathy (PION). Both optic discs initially appeared pink (optic nerve edema never observed). This is not a case of NAION and thus is not as pertinent to this discussion. The question is, what is the nature of the association between PDE5i and NAION and how strong an association is it? Can PDE5i cause NAION in healthy individuals in isolation from vasculopathic or anatomic optic nerve risk factors? In 2010, Giuliano et al (23) reported on 67 Lee and Vaphiades: J Neuro-Ophthalmol 2016; 36: 202-207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point double-blind placebo-controlled trials (.14,000 men) conducted by the manufacturer and from the manufacturer's postmarketing safety database, which identified 39,277 sildenafil patients with adverse events. Several safety topics of special interest were selected for more detailed analysis, including NAION development as an adverse event. Analyses of the databases did not reveal any causal link between sildenafil and NAION. A paper published in 2015 in the Journal of Sexual Medicine, sponsored by Pfizer, and for which I was a study investigator, showed a 2-fold increased risk of acute NAION within 5 half-lives of PDE5i use compared with use in a more prior time period and an estimation that weekly use of PDE5i adds 3 NAION cases per 100,000 men 50 years and older annually (6). In 2015, in this journal, Nathoo et al (24) published a pharmacoepidemiological nested case-control study used to examine the association in a health claim database of physician diagnoses and prescription medication dispensing of PDE-5i and NAION in 1109 cases of NAION matched to 1,237,290 controls identified within the database. They found that patients were more likely to have hyperlipidemia, diabetes, hypertension, myocardial infarction, and cerebrovascular accident in the year preceding their NAION, but their data did not suggest any association between having a prescription filled for PDE5i medication and receiving a diagnosis code for NAION. In fact, tadalafil showed a trend toward being protective of NAION. So we are back to the question, what is the relationship between NAION and PDE5i? There appears to be an association between the 2; however, it may not be as strong as some would surmise. After all, of the 39 cases of NAION associated with ED drug use reported in peer-reviewed journals, most had vasculopathic risk factors, but some did not. Yet, why would an individual require the use of a PDE5i drug for ED if their vascular system was normal? Hence, these individuals likely had some vascular disease. This is further supported by the research performed on 15 healthy volunteers investigating the possible effects of sildenafil on the arterial blood supply to the eye by Grunwald et al (25,26). In a masked, randomized crossover trial, 15 young, healthy male volunteers (mean age, 39 years) underwent ocular blood flow measurements after oral ingestion of sildenafil citrate at a 100 mg dose. None developed permanent or transient vision loss. They concluded that 100 mg sildenafil causes no significant effect on ocular circulation. These data will likely not be reproduced because recruiting healthy volunteers to take a PDE5i looking for the development of NAION, in light of the current knowledge on the topic, will never gain institutional review board (IRB) approval. Probably the most compelling argument in this exercise is that the pathophysiology of NAION is still unknown. In a 2015 review of NAION, Miller and Arnold (10) stated: "The mechanisms involved in the development of optic disc ischemia in NAION are unclear. Whether ischemia results from local arteriosclerosis with or without thrombosis, embolization from a remote source, generalized hypoperfusion, vasospasm, failure of autoregulation, or some combination of these processes is not known." In regard to NAION and PDE5i use, they indicate that "In all reported cases (of NAION and PDE5i use), the optic discs have had the typical "crowded" configuration commonly seen in NAION. The postulated mechanism in these cases is systemic hypotension in patients with structurally predisposed optic discs, possibly complicated by an exaggerated nocturnal dip in blood pressure. Thus, the number of reported cases of NAION associated with the use of an ED drug is extremely small." Dr. Lee asks "Why, then, are there so few cases reported?" Perhaps because PDE5i use may only predispose individuals to NAION if they are already at risk for NAION. Yet, PDE5i is likely not as great a risk, or may not be a risk at all, for the development of NAION for healthy individuals without vascular risk factors. Rebuttal: Dr. Lee Dr. Vaphiades refers to the laser Doppler flowmetry studies by Grunwald et al (25,26) to support his arguments. These investigators found no difference in optic nerve head (ONH) blood flow in normal volunteers who took sildenafil or placebo. Elegant studies in rhesus monkeys however have shown that laser Doppler flowmetry does not accurately measure circulation in the deeper layers of the ONH (27). The authors found reduced ONH blood flow after experimental occlusion of the central retinal artery (CRA) and combined occlusion of the CRA and posterior ciliary arteries (PCA). However, occlusion of the PCA alone did not significantly affect ONH blood flow. Because NAION presumably results Lee and Vaphiades: J Neuro-Ophthalmol 2016; 36: 202-207 from PCA dysfunction, laser Doppler flowmetry cannot be used as evidence for or against an ischemic effect of sildenafil on the relevant blood flow for NAION. Finally, Dr. Vaphiades cites the study by Nathoo et al (24), but these data are limited by methodological flaws and several confounding variables. Specifically, cases of NAION diagnosis were not matched to the controls with regard to vasculopathic risk factors (NAION cases were significantly more likely to have 5 ischemic risk factors over controls). Although tadalafil was described as trending toward protective for NAION diagnosis, this was not clinically significant. Finally, it is important to note that this study was based on insurance claims and not clinically defined and verified cases of NAION. 205 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point In conclusion, there has been only one prospective, multicentered study determining the effect of PDE5i on NAION (6). It was rigorously performed and showed an increased risk of NAION with PDE5i use. Cases served as their own controls and this study provides strong evidence that a causal relationship exists between PDE5i use and NAION. Rebuttal: Dr. Vaphiades As usual, being the very thoughtful physician he is, Dr. Lee raises many excellent points and mounts a very compelling argument. He points out deficiencies in the various quoted studies presented and recognizes that "there has been only one prospective, multicentered study determining the effect of PDE5i on NAION." This study was published in 2015 in the Journal of Sexual Medicine6 and I am flattered that Dr. Lee chose a study where I served as an investigator; however, in reality, few if any studies are perfect but they are published and worthy of mention. I also agree with Dr. Lee's recognition of Dr. Hayreh's expertise on the topic on NAION. This point-counterpoint has been beneficial for me in that it has allowed me to review the many papers on NAION, many if not most were written by Dr. Hayreh. Dr. Hayreh divides the likelihood for the development of NAION into categories; predisposing risks and precipitants. For example, a small cup-to-disk ratio (disc at risk), angle closure glaucoma (28,29) optic disc drusen, arterial (30) hypertension, diabetes mellitus, ischemic heart disease, hyperlipidemia, or atherosclerosis would represent predisposing risks (31). Once you have a risk, then the NAION precipitants come into play which may be the "last straw" as Dr. Hayreh indicates. Nocturnal hypotension and PDE5i are in the precipitant category but not in the predisposing risk category. The main point of our discussion is to answer the question "how should we, as neuro-ophthalmologists, advise patients who take PDE5i?" In a patient who has had a prior episode of NAION with a small cup-to-disc ratio in the fellow eye, I always discuss PDE5i as a potential precipitating factor for an event in the fellow eye (14.7%) (30) or even rarely the same eye (6.4%) (31) because prior NAION and small optic cups both represent a predisposing risk for NAION. Therefore, taking a PDE5i in this patient population may serve as an NAION precipitant. Even patients with no history of NAION but vascular risk factors and small optic cups, I discuss PDE5i use and nocturnal hypotension as potential precipitants in the development of NAION because these are easily modifiable by altering a medication. However, in a patient without any predisposing risks, like a healthy 20-year-old with congenitally large optic disc cups, the risk of NAION is virtually nonexistent, so PDE5i use would not be a precipitant as demonstrated in the Grunwald studies. In conclusion, my answer to the question of "Are erectile dysfunction (ED) medications causally related to NAION?" is "It depends on the patient." Conclusion (Andrew G. Lee, MD and Greg Van Stavern, MD) Although it is likely that there is a causal relationship between ED medications and NAION on a population basis, the true risk in any one individual patient is dependent on age, vascular risk factors, structural crowding of the optic disc, and other predisposing factors which may or may not have been identified. It is reasonable to recommend avoiding ED medications in patients with REFERENCES 1. Lee MS, Grossman D, Arnold AC, Sloan FA. Incidence of nonarteritic anterior ischemic optic neuropathy: increased risk among diabetic patients. Ophthalmology. 2011;118:959-963. 2. Johnson LN, Arnold AC. Incidence of nonarteritic and arteritic anterior ischemic optic neuropathy. Population-based study in the state of Missouri and Los Angeles County, California. J Neuroophthalmol. 1994;14:38-44. 3. Hayreh SS. Erectile dysfunction drugs and non-arteritic anterior ischemic optic neuropathy: is there a cause and effect relationship? J Neuroophthalmol. 2005;25:295-298. 206 NAION in one eye, particularly if they report prior use of a PDE5i. Individual patients, however, should make an individualized risk-benefit decision and a quality-of-life decision on PDE5i use. There is probably not enough evidence yet to give specific, quantitative individual risk advice to patients about the use of PDE5i and no history of NAION. 4. Lee AG, Newman NJ. Erectile dysfunction drugs and nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 2005;140:707-708. 5. Danesh-Meyer HV, Levin LA. Erectile dysfunction drugs and risk of anterior ischaemic optic neuropathy: casual or causal association? Br J Ophthalmol. 2007;91:1551-1555. 6. Campbell UB, Walker AM, Gaffney M, Petronis KR, Creanga D, Quinn S, Klein BE, Laties AM, Lewis M, Sharlip ID, Kolitsopoulos F, Klee BJ, Mo J, Reynolds RF. Acute nonarteritic anterior ischemic optic neuropathy and exposure to phosphodiesterase type 5 inhibitors. J Sex Med. 2015;12:139-151. Lee and Vaphiades: J Neuro-Ophthalmol 2016; 36: 202-207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Point Counter-Point 7. Pomeranz HD, Bhavsar AR. Nonarteritic ischemic optic neuropathy developing soon after use of sildenafil (Viagra): a report of seven new cases. J Neuroophthalmol. 2005;25:9-13. 8. Su DHW, Ang PS, Tow SLC. Bilateral posterior ischemic optic neuropathy associated with use of sildenafil. J Neuroophthalmol. 2008;28:75. 9. Tarantini A, Faraoni A, Menchini F, Lanzetta P. Bilateral simultaneous nonarteritic anterior ischemic optic neuropathy after ingestion of sildenafil for erectile dysfunction. Case Rep Med. 2012;2012:747658. 10. Bollinger K, Lee MS. Recurrent visual field defect and ischemic optic neuropathy associated with tadalafil rechallenge. Arch Ophthalmol. 2005;123:400-401. 11. Pepin S, Pitha-Rowe I. Stepwise decline in visual field after serial sildenafil use. J Neuroophthalmol. 2008;28:76-77. 12. Fraunfelder FW, Shults T. Non-arteritic anterior ischemic optic neuropathy, erectile dysfunction drugs, and amiodarone: is there a relationship? J Neuroophthalmol. 2006;26:1-3. 13. Gerometta R, Alvarez LJ, Candia OA. Effect of sildenafil citrate on intraocular pressure and blood pressure in human volunteers. Exp Eye Res. 2011;93:103-107. 14. Phillips BG, Kato M, Pesek CA, Winnicki M, Narkiewicz K, Davison D, Somers VK. Sympathetic activation by sildenafil. Circulation. 2000;102:3068-3073. 15. Available at: http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/2005/ucm108458.htm. Accessed August 10, 2015. 16. Available at: http://www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Summary_for_the_public/human/ 000202/WC500049824.pdf. Accessed August 10, 2015. 17. Available at: http://www.fda.gov/Safety/MedWatch/ SafetyInformation/ucm200593.htm. Accessed August 14, 2015. 18. Egan R, Pomeranz H. Sildenafil (Viagra) associated with anterior ischemic optic neuropathy. Arch Ophthalmol. 2000;118:291-292. 19. Miller NR, Arnold AC. Current concepts in the diagnosis, pathogenesis and management of nonarteritic anterior ischaemic optic neuropathy. Eye (Lond). 2015;29:65. Lee and Vaphiades: J Neuro-Ophthalmol 2016; 36: 202-207 20. Pomeranz HD, Smith KH, Hart WM Jr, Egan RA. Sildenafilassociated nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2002;109:584-587. 21. Hayreh SS, Podhajsky P, Zimmerman MB. Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica. 1999;213:76-96. 22. Landau K, Winterkorn JMS, Mailloux LU, Vetter W, Napolitano B. 24-Hour blood pressure monitoring in patients with anterior ischemic optic neuropathy. Arch Ophthalmol. 1996;114:570-575. 23. Giuliano F, Jackson G, Montorsi F, Martin-Morales A, Raillard P. Safety of sildenafil citrate: review of 67 double-blind placebocontrolled trials and the postmarketing safety database. Int J Clin Pract. 2010;64:240-255. 24. Nathoo NA, Etminan M, Mikelberg FS. Association between phosphodiesterase-5 inhibitors and nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2015;35:12-15. 25. Grunwald JE, Siu KK, Jacob SS, Dupont J. Effect of sildenafil citrate (Viagra) on the ocular circulation. Am J Ophthalmol. 2001;31:51-55. 26. Grunwald JE, Metelitsina T, Grunwald L. Effect of sildenafil citrate (Viagra) on retinal blood vessel diameter. Am J Ophthalmol. 2002;133:809-812. 27. Petrig BL, Riva CE, Hayreh SS. Laser Doppler flowmetry and optic nerve head blood flow. Am J Ophthalmol. 1999;127:413-425. 28. Slavin ML, Margulis M. Anterior ischemic optic neuropathy following acute angle-closure glaucoma. Arch Ophthalmol. 2001;119:1215. 29. Kim R, Van Stavern G, Juzych M. Nonarteritic anterior ischemic optic neuropathy associated with acute glaucoma secondary to Posner-Schlossman syndrome. Arch Ophthalmol. 2003;121:127-128. 30. Newman NJ, Scherer R, Langenberg P, Kelman S, Feldon S, Kaufman D, Dickersin K; Ischemic Optic Neuropathy Decompression Trial Research Group. The fellow eye in NAION: report from the ischemic optic neuropathy decompression trial follow-up study. Am J Ophthalmol. 2002;134:317-328. 31. Hayreh SS, Podhajsky PA, Zimmerman B. Ipsilateral recurrence of nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 2001;132:734-742. 207 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.