Risk Factors for Fellow Eye Involvement in Nonarteritic Anterior Ischemic Optic Neuropathy

Background: Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in individuals older than 50 years. Demographic, ocular, and systemic risk factors for NAION have been identified, and we sought to determine which, if any, of these factors also increase risk of NAION in the fellow eye. Methods: We performed a retrospective chart review of patients with 'ischemic optic neuropathy' (based on International Classification of Disease [ICD] codes) seen at a single eye center between 2007 and 2017. Patients who met diagnostic criteria for unilateral NAION without fellow eye optic neuropathy at diagnosis were included. Demographic information, ocular comorbidities, and systemic diagnoses were recorded, in addition to whether the fellow eye developed NAION during the follow-up period. Univariate and multivariate Cox proportional hazard regression were used to calculate hazard ratios (HRs) for fellow eye involvement. Results: Three hundred eighteen patients were identified by ICD codes, and 119 were included in the study. Twenty-nine (24%) patients developed NAION in the fellow eye over the mean follow-up period of 3.6 years (range: 1 month-11 years). Significant risk factors for fellow eye NAION included the presence of bilateral optic disc drusen (ODD, HR 2.78, 95% confidence interval [CI] 1.12-6.90, P = 0.02) and noncompliance with continuous positive airway pressure (CPAP) in patients with moderate-to-severe obstructive sleep apnea (HR 4.50, 95% CI 1.79-11.3, P = 0.0015). Conclusions: Bilateral ODD and noncompliance with CPAP when indicated are associated with increased risk of NAION in the fellow eye. Patients with these risk factors should be counseled on the potentially devastating visual consequences of bilateral NAION, and compliance with CPAP should be stressed when appropriate.

Clinical Research: Epidemiology Meets Neuro-Ophthalmology Section Editors: Heather E. Moss, MD, PhD Stacy L. Pineles, MD, MS Risk Factors for Fellow Eye Involvement in Nonarteritic Anterior Ischemic Optic Neuropathy Melinda Y. Chang, MD, John L. Keltner, MD Background: Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in individuals older than 50 years. Demographic, ocular, and systemic risk factors for NAION have been identified, and we sought to determine which, if any, of these factors also increase risk of NAION in the fellow eye. Methods: We performed a retrospective chart review of patients with "ischemic optic neuropathy" (based on International Classification of Disease [ICD] codes) seen at a single eye center between 2007 and 2017. Patients who met diagnostic criteria for unilateral NAION without fellow eye optic neuropathy at diagnosis were included. Demographic information, ocular comorbidities, and systemic diagnoses were recorded, in addition to whether the fellow eye developed NAION during the follow-up period. Univariate and multivariate Cox proportional hazard regression were used to calculate hazard ratios (HRs) for fellow eye involvement. Results: Three hundred eighteen patients were identified by ICD codes, and 119 were included in the study. Twenty-nine (24%) patients developed NAION in the fellow eye over the mean follow-up period of 3.6 years (range: 1 month-11 years). Significant risk factors for fellow eye NAION included the presence of bilateral optic disc drusen (ODD, HR 2.78, 95% confidence interval [CI] 1.12-6.90, P = 0.02) and noncompliance with continuous positive airway pressure (CPAP) in patients with moderate-to-severe obstructive sleep apnea (HR 4.50, 95% CI 1.79-11.3, P = 0.0015). Conclusions: Bilateral ODD and noncompliance with CPAP when indicated are associated with increased risk of NAION in the fellow eye. Patients with these risk factors should be counseled on the potentially devastating visual consequen- Department of Ophthalmology and Vision Science, University of California, Davis, Sacramento, California The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Melinda Y. Chang, MD, Department of Ophthalmology and Vision Science, University of California, Davis, 4860 Y Street, Suite 2400, Sacramento, CA 95817; E-mail: [e-mail] Chang and Keltner: J Neuro-Ophthalmol 2019; 39: 147-152 ces of bilateral NAION, and compliance with CPAP should be stressed when appropriate. Journal of Neuro-Ophthalmology 2019;39:147-152 doi: 10.1097/WNO.0000000000000715 © 2018 by North American Neuro-Ophthalmology Society W hile nonarteritic anterior ischemic optic neuropathy (NAION) is a common cause of acute optic neuropathy (1,2), its pathophysiology is not fully understood, although vascular insufficiency is believed to contribute (3-5). Supporting the vascular hypothesis is the reported association between NAION and systemic vascular risk factors, including diabetes mellitus (6,7), hypertension (6,8,9), hyperlipidemia (9-11), ischemic heart disease (7-10), and cerebrovascular disease (6,7). Many other systemic comorbidities have been proposed as risk factors for NAION, including hypercoagulability (8,9), arrhythmia (12), anemia (13), nocturnal hypotension (14-16), and smoking (17). Ocular disorders reported in association with NAION include optic disc drusen (ODD) (18-20), retinal vein occlusion (RVO) (8), and macular degeneration (8). Demographic factors associated with higher risk of NAION include increased age (8) and male sex (8,21). The Ischemic Optic Neuropathy Decompression Trial (IONDT) reported that the incidence of fellow eye NAION was 15% at 5 years after the first eye was affected (22). It is unclear whether the risk factors for NAION in the first eye also predispose to NAION in the fellow eye. For example, increased age is associated with increased risk of NAION (8); however, in patients with unilateral NAION, younger age reportedly increases risk of second eye involvement (23,24). The IONDT found that diabetes mellitus and poor visual acuity in the first affected eye were associated with developing NAION in the fellow eye (22). Because the IONDT report on fellow eye involvement was published in 2002, new risk factors for NAION, such as obstructive sleep apnea (OSA) have been identified (25-27). Some risk factors are more common in younger (less than 50 147 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology years) patients with NAION (23). For the most part, it is unknown whether more recently identified risk factors for NAION contribute to risk of fellow eye involvement. The purpose of our study was to identify demographic, ocular, and systemic factors that are associated with fellow eye NAION. METHODS This study was approved by the University of California, Davis Institutional Review Board and adhered to the tenets of the Declaration of Helsinki and Health Insurance Portability and Accountability Act. We performed a retrospective chart review of all patients seen at our eye center between 2007 and 2017 with a diagnosis of "ischemic optic neuropathy" based on International Classification of Diseases (ICD) codes (ICD-9 code 377.41 and ICD-10 code H47.01). The earliest date for chart review was chosen due to adoption of the electronic medical record at our institution in 2007. Patients were included if they met clinical criteria for unilateral NAION, including acute vision loss with an afferent pupillary defect (APD), optic disc edema progressing to atrophy, and a visual field defect consistent with an optic neuropathy. Some patients presented months after vision loss, and acute optic disc edema was not observed. In such cases, patients were required to have normal neuroimaging and laboratory workup (at minimum erythrocyte sedimentation rate [ESR], C-reactive protein [CRP], anti-nuclear antibody [ANA], and rapid plasma reagin [RPR]) in addition to acute vision loss with an APD and at least one of the following: an altitudinal visual field defect, sectorial optic nerve head pallor, or a crowded optic disc in the fellow eye ("disc at risk") (28). Exclusion criteria for all patients were giant cell arteritis or any alternative cause of optic neuropathy. We also excluded patients who had optic atrophy of the fellow eye or bilateral optic disc edema at presentation. We collected the following data from patients' charts: age; sex; presence of systemic comorbidities including diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease; cerebrovascular disease (history of cerebrovascular accident or transient ischemic attack), arrhythmia, anemia, hypercoagulability, chronic renal failure, migraine, and moderate-to-severe OSA; and presence of ophthalmic comorbidities including ODD, age-related macular degeneration, RVO, and glaucoma. Among patients with moderate-tosevere OSA, we also recorded whether patients were compliant with continuous positive airway pressure (CPAP) treatment, which was defined as patient self-reported CPAP use most (4 or more) nights per week. Systemic comorbidities were recorded at the time of diagnosis of NAION in the first eye. Patients who had NAION were recommended to undergo systemic workup by their primary care physicians, and the results of this workup were used in this study. CPAP compliance was also assessed at the time of fellow eye involve148 ment, and the later assessment was used in this study. Ocular comorbidities were assessed at the time of initial NAION and all subsequent follow-up visits. No new ocular comorbidities occurred during the follow-up period; therefore, the assessment at the time of first eye NAION was used in this study. Data were collected using FileMaker Pro (Apple Inc, Cupertino, CA) and Microsoft Excel (Redmond, WA), and statistical analyses were performed using GraphPad Prism (La Jolla, CA) and Medcalc (Ostend, Belgium). Kaplan-Meier survival analysis was used to estimate the 5-year probability of NAION in the fellow eye. Patients were censored at the last date of follow-up, or at the time the fellow eye developed NAION. Cox proportional hazard regression was used to calculate the hazard ratio (HR) for potential risk factors for fellow eye NAION. Factors that were significant at P , 0.2 on univariate analysis, in addition to age and sex, were entered into a multivariate model. Risk factors also were analyzed separately in young (less than or equal to 50 years) and older (greater than 50 years) patients. In addition, analyses were repeated with the exclusion of patients who did not present acutely with optic disc edema. Kaplan-Meier curves were used to demonstrate differences in survival without fellow eye NAION based on presence of significant risk factors. Log-rank test was used to calculate differences between survival curves. P-values less than 0.05 were considered significant. RESULTS ICD-9 and ICD-10 codes identified 318 patients with a diagnosis of "ischemic optic neuropathy" evaluated between 2007 and 2017. Of these, 138 met criteria for diagnosis of NAION. Nineteen patients with NAION had fellow eye optic neuropathy (edema or atrophy) at diagnosis; so, a total of 119 patients met inclusion criteria. The mean follow-up time was 3.6 years (range: 1 month-11 years). Figure 1 shows the reasons for exclusion of the remaining patients. The majority of patients were excluded because they had optic neuropathy that did not meet the criteria for NAION due to absence of acute vision loss or disc edema, or absence of workup (especially neuroimaging) in cases of optic atrophy from suspected previous NAION. Overall, 29 (24%) patients developed NAION in the fellow eye over the follow-up period. The median time to development of NAION in the fellow eye was 10 months. The estimated 5-year probability of NAION in the fellow eye was 27% (95% confidence interval [CI] 19%-38%) (See Supplemental Digital Content, Figure E1, http:// links.lww.com/WNO/A351). Table 1 shows the HRs by univariate Cox proportional hazard regression for development of NAION in the fellow eye for the demographic, systemic, and ocular factors included in this study. There was no increased risk of fellow eye NAION by age or sex. Two factors were found to significantly increase risk of NAION in the fellow eye on univariate analysis. The first Chang and Keltner: J Neuro-Ophthalmol 2019; 39: 147-152 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology (HR 6.22, 95% CI 2.43-15.9, P = 0.0001). In the multivariate Cox regression model, CPAP noncompliance remained a significant risk factor (HR 7.53, 95% CI 2.76- 20.5, P = 0.0001). There was a trend toward increased risk in patients with bilateral ODD (HR 2.37, 95% CI 0.84- 6.7, multivariate model), but this did not reach statistical significance (P = 0.10). Table 2 shows the risk factors analyzed separately by age. In young patients (less than or equal to 50 years), bilateral ODD were a significant risk factor for fellow eye NAION (HR 8.31, 95% CI 1.52-45.3, P = 0.01), whereas CPAP noncompliance could not be assessed because all patients in this age group were compliant. In older patients, CPAP noncompliance was a significant risk factor for NAION in the fellow eye (HR 4.16, 95% CI 1.55-11.1, P = 0.0048), whereas bilateral ODD were not (P = 0.61). DISCUSSION FIG. 1. Flowchart demonstrating categorization of 318 patient charts identified by searching the electronic medical record for patients with an International Classification of Disease (ICD) diagnosis code for "ischemic optic neuropathy." Reasons for exclusion are shown on the right. Based on chart review, 138 patients met criteria for the diagnosis of nonarteritic anterior ischemic optic neuropathy (NAION), and 19 of these had optic disc edema or atrophy in the fellow eye at diagnosis; so, a total of 119 patients were included in this study. was the presence of bilateral ODD (HR 2.78, 95% CI 1.12-6.90, P = 0.02) (See Supplemental Digital Content, Figure E2, http://links.lww.com/WNO/A352). The second was noncompliance with CPAP in patients with moderateto-severe OSA (HR 4.50, 95% CI 1.79-11.3, P = 0.0015) (See Supplemental Digital Content, Figure E3, http:// links.lww.com/WNO/A353). When considering only patients with moderate-to-severe OSA, the HR for fellow eye NAION in CPAP noncompliant vs compliant patients was 25.1 (95% CI 3.0-209, P = 0.0031). This is further illustrated in Supplemental Digital Content (see Figure E4, http://links.lww. com/WNO/A354). Multivariate Cox regression modeling found that both risk factors remained significantly associated with fellow eye NAION (bilateral ODD HR 3.33, 95% CI 1.27-8.75, P = 0.009; CPAP noncompliance HR 5.59, 95% CI 2.07- 15.1, P = 0.0005). The HRs were calculated for fellow eye NAION for the factors included in this study, with exclusion of 25 patients who did not present with acute optic disc edema (See Supplemental Digital Content, Table E1, http://links.lww. com/WNO/A355). On univariate analysis, CPAP noncompliance was a significant risk factor for fellow eye NAION Chang and Keltner: J Neuro-Ophthalmol 2019; 39: 147-152 In a retrospective review of patients with unilateral NAION seen over a 10-year period, we found 2 significant risk factors for fellow eye involvement: bilateral ODD and CPAP noncompliance in patients with moderate-to-severe OSA. We found that bilateral ODD significantly increased the risk of fellow eye NAION in young patients, whereas CPAP noncompliance was a significant risk factor in older patients. Noncompliance with CPAP was the strongest risk factor for fellow eye NAION in this study (HR 4.50, P = 0.0015). Compliance is an important issue in patients with OSA; one study reported 5-year rate of compliance of only 54% (29). CPAP was recommended in our patients with moderate-tosevere OSA, which included 29% of our cohort. Previous studies have reported differing rates of OSA in patients with NAION, ranging from 30% to 89% (26,27,30-33). The disparity is likely due to differences in criteria for diagnosis of OSA. Some authors diagnosed OSA based on symptomatology (32), whereas others used overnight polysomnography (PSG), with varying definitions of OSA based on respiratory disturbance index or apnea-hypopnea index (AHI) (26,27,30,31,33). In our study, most patients underwent PSG at a university sleep center where the cutoff for diagnosis of moderate-to-severe OSA in which CPAP was recommended was AHI greater than 15. Although several previous studies have identified OSA as a risk factor for NAION, only one previous report examined the effect of noncompliance with CPAP as a risk factor for NAION in the fellow eye. Aptel et al (26) examined 89 patients with NAION, all of whom underwent nocturnal PSG. Diagnosis of OSA was made when AHI was greater than 15, and severe OSA was diagnosed when AHI exceeded 30. Noncompliance with CPAP in patients with severe OSA was found to significantly increase risk of fellow eye NAION when entered in a multivariate model (HR 5.54, P = 0.04). Our study differs in that 149 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 1. Hazard ratios and P values for risk factors for fellow eye nonarteritic anterior ischemic optic neuropathy (NAION) in patients with unilateral NAION, by univariate Cox proportional hazard regression Risk Factor # Fellow Eye NAION/Total # With Risk Factor Hazard Ratio (95% Confidence Interval) P 29/Not applicable 6/33 7/29 18/74 16/67 7/35 0.98 (0.95-1.02) 0.68 (0.27-1.67) 1.034 (0.47-2.60) 0.71 (0.33-1.55) 1.05 (0.50-2.22) 0.80 (0.34-1.89) 0.41 0.40 0.82 0.40 0.90 0.61 3/15 2/10 0/0 2/11 1/7 4/13 0/8 1/6 1/6 0/0 6/11 6/10 6/10 0.74 (0.23-2.46) 1.20 (0.28-5.05) N/A 0.41 (0.10-1.74) 0.50 (0.07-3.69) 1.74 (0.60-5.08) N/A 0.65 (0.09-4.77) 0.76 (0.10-5.54) N/A 2.78 (1.12-6.90) 4.50 (1.79-11.3) 25.1 (3.01-209) 0.62 0.81 N/A 0.23 0.50 0.34 N/A 0.65 0.79 N/A 0.02* 0.0015* 0.0031* Age Sex (female) Diabetes Hypertension Hyperlipidemia Obstructive sleep apnea (moderate to severe) Arrhythmia Anemia Hypercoagulability Migraine Chronic renal failure Coronary artery disease Cerebrovascular disease Age-related macular degeneration Glaucoma Retinal vascular occlusion Bilateral ODD CPAP noncompliance vs all others CPAP noncompliance vs CPAP compliance *P , 0.05. CPAP, continuous positive airway pressure; N/A, not applicable; ODD, optic disc drusen. TABLE 2. Hazard ratios and P values for risk factors for fellow eye nonarteritic anterior ischemic optic neuropathy (NAION) in patients with unilateral NAION, by univariate Cox proportional hazard regression, in young (less than or equal to 50 years) and older (greater than 50 years) patients Hazard Ratios (95% Confidence Interval) Sex (female) Diabetes Hypertension Hyperlipidemia Obstructive sleep apnea (moderate to severe) Arrhythmia Anemia Hypercoagulability Migraine Chronic renal failure Coronary artery disease Cerebrovascular disease Age-related macular degeneration Glaucoma Retinal vascular occlusion Bilateral ODD CPAP noncompliance vs all others CPAP noncompliance vs CPAP compliance Young (#50 Years) Older (.50 Years) 0.64 (0.08-5.34), P = 0.67 3.23 (0.70-14.89), P = 0.15 1.40 (0.31-6.28), P = 0.66 0.47 (0.09-2.54), P = 0.37 N/A* N/A* N/A* N/A* 0.37 (0.05-3.1), P = 0.31 N/A* N/A* N/A* N/A* N/A* N/A* 8.31 (1.52-45.3), P = 0.01† N/A* N/A* (0.25-1.89), P = 0.46 (0.26-2.29), P = 0.63 (0.28-1.86), P = 0.50 (0.57-3.29), P = 0.48 (0.45-2.79), P = 0.80 (0.19-2.26), P = 0.49 (0.37-6.84), P = 0.57 N/A* 0.40 (0.05-3.18), P = 0.33 0.48 (0.07-3.60), P = 0.43 1.74 (0.58-5.21), P = 0.35 N/A* 1.27 (0.17-9.46), P = 0.82 0.75 (0.10-5.59), P = 0.77 N/A* 1.50 (0.35-6.47), P = 0.61 4.16 (1.55-11.1), P = 0.0048† 17.5 (2.08-147), P = 0.0088† 0.69 0.77 0.72 1.37 1.12 0.66 1.58 *Unable to calculate due to insufficient number of patients with this risk factor in this age group. † P , 0.05. CPAP, continuous positive airway pressure; N/A, not applicable; ODD, optic disc drusen. 150 Chang and Keltner: J Neuro-Ophthalmol 2019; 39: 147-152 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology noncompliant patients with both moderate and severe OSA demonstrated increased risk of fellow eye NAION. The pathophysiology of NAION in untreated OSA is unknown, but may relate to vascular compromise of the optic nerve through mechanisms such as endothelial dysfunction and vasoconstriction due to reduced nitric oxide (34,35). OSA also is associated with reduced flow-mediated vasodilation, increased arterial stiffness, and systemic inflammation (36). All these factors may potentially contribute to abnormalities of autoregulation of blood flow at the optic nerve head (37). The second risk factor for fellow eye NAION identified in this study was the presence of bilateral ODD, especially in young patients. Purvin et al (18) published the largest study to date of NAION in eyes with ODD, which included 20 patients with NAION and ODD. Sixteen patients had bilateral ODD, and 4 (25%) had documented bilateral sequential NAION. An additional 2 patients had optic atrophy in the fellow eye at diagnosis; so, a total of 6 (38%) patients with bilateral ODD had presumed bilateral NAION. In our study, 6 of 11 (55%) patients with bilateral ODD had bilateral sequential NAION. The pathophysiology of NAION in eyes with ODD may involve crowding of axons in the optic nerve by space-occupying drusen, compromise of vasculature in the optic nerve head by physical compression or ocular duction-induced repetitive shear forces (18,20,38). The overall 5-year probability of fellow eye involvement in NAION was 27% (95% CI 19%-38%) in this study, which is higher than that reported by the IONDT (15%) (22). The reason for this discrepancy is likely incomplete follow-up in our cohort because we suspect patients who developed NAION in the fellow eye were more likely to follow-up. In the Kaplan-Meier analysis, patients were censored at their last follow-up visit, and the mean followup time in this study was 3.6 years. Several factors, such as diabetes mellitus and young age of onset, were previously reported to increase the risk of NAION in the fellow eye but not found to be significantly associated in this study (22,23). Cestari et al (8) reported, in a retrospective review of over a million patients in a managed care network, that diabetes alone was not a risk factor for NAION; however, diabetes with end-organ involvement did increase the risk. It is possible that many of our diabetic patients in this study did not have end-organ damage; however, we did not collect this data. It is also unclear why young patients in our study did not have increased risk of fellow eye NAION. We assessed 318 patients diagnosed with "ischemic optic neuropathy" by ICD coding, but only 138 (43%) met criteria for NAION. Of the remaining patients, 25 (8%) had other causes of ischemic optic neuropathy (giant cell arteritis or posterior ischemic optic neuropathy). Thus, 155 (49%) patients were either mistakenly identified by ICD codes, or did not have sufficient evidence in the electronic medical record to support the diagnosis of NAION. This Chang and Keltner: J Neuro-Ophthalmol 2019; 39: 147-152 has important implications for future large-scale epidemiologic studies using ICD codes to identify patients with ischemic optic neuropathy. One potential limitation of our study is that 25 (21%) patients were not seen acutely with optic disc edema, which is considered a criterion for diagnosis of NAION (39). These patients all had workup to exclude other causes of optic neuropathy and clinical evidence supporting the diagnosis of NAION. Nonetheless, we cannot exclude the possibility that some of them were misdiagnosed. Therefore, we repeated all statistical analyses without these 25 patients, and found the same trend of risk factors associated with fellow eye NAION: CPAP noncompliance and bilateral ODD. Other limitations of our study include its retrospective nature, relatively small numbers of patients with some risk factors, and inconsistent follow-up. In addition, we did not collect data on smoking status or 24-hour blood pressure monitoring for nocturnal hypotension, both of which have been identified as risk factors for NAION (14,17). We also could not assess the effect of phosphodiesterase-5 inhibitors on fellow eye NAION. Only 4 patients included in this study reported taking phosphodiesterase-5 inhibitors at the time of diagnosis of NAION in the first eye; however, we did not have data on whether the patients continued to use them after NAION diagnosis. Furthermore, we assessed systemic comorbidities at the time of first eye NAION, and cannot determine whether later development of comorbidities may have contributed to fellow eye NAION in some patients. Finally, we did not perform sleep study and B-scan ultrasonography in all patients; therefore, we may have missed some patients with OSA and ODD. In conclusion, we assessed demographic, ocular, and systemic factors believed to increase risk of NAION incidence, and evaluated whether they increased risk of fellow eye NAION. We found that fellow eye involvement was significantly more likely in patients with moderate-to-severe OSA who were noncompliant with CPAP, and also in patients with bilateral ODD. Such patients should be counseled on the potentially devastating visual consequences of bilateral NAION, and compliance with CPAP should be stressed. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M.Y. Chang; b. Acquisition of data: M.Y. Chang and J.L. Keltner; c. Analysis and interpretation of data: M.Y. Chang and J.L. Keltner. Category 2: a. Drafting the manuscript: M.Y. Chang and J.L. Keltner; b. Revising it for intellectual content: M.Y. Chang and J.L. Keltner. Category 3: a. Final approval of the completed manuscript: M.Y. Chang and J.L. Keltner. REFERENCES 1. Johnson LN, Arnold AC. Incidence of nonarteritic and arteritic anterior ischemic optic neuropathy. Population-based study in 151 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. the state of Missouri and Los Angeles County, California. J Neuroophthalmol. 1994;14:38-44. Hattenhauer MG, Leavitt JA, Hodge DO, Grill R, Gray DT. Incidence of nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 1997;123:103-107. Knox DL, Kerrison JB, Green WR. Histopathologic studies of ischemic optic neuropathy. Trans Am Ophthalmol Soc. 2000;98:203-220; discussion 221-202. Arnold AC. Pathogenesis of nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol. 2003;23:157-163. Arnold AC, Hepler RS. Fluorescein angiography in acute nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 1994;117:222-230. Hayreh SS, Joos KM, Podhajsky PA, Long CR. Systemic diseases associated with nonarteritic anterior ischemic optic neuropathy. Am J Ophthalmol. 1994;118:766-780. Guyer DR, Miller NR, Auer CL, Fine SL. The risk of cerebrovascular and cardiovascular disease in patients with anterior ischemic optic neuropathy. Arch Ophthalmol. 1985;103:1136-1142. Cestari DM, Gaier ED, Bouzika P, Blachley TS, De Lott LB, Rizzo JF, Wiggs JL, Kang JH, Pasquale LR, Stein JD. Demographic, systemic, and ocular factors associated with nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 2016;123:2446-2455. Giambene B, Sodi A, Sofi F, Marcucci R, Fedi S, Abbate R, Prisco D, Menchini U. Evaluation of traditional and emerging cardiovascular risk factors in patients with non-arteritic anterior ischemic optic neuropathy: a case-control study. Graefes Arch Clin Exp Ophthalmol. 2009;247:693-697. Salomon O, Huna-Baron R, Kurtz S, Steinberg DM, Moisseiev J, Rosenberg N, Yassur I, Vidne O, Zivelin A, Gitel S, Davidson J, Ravid B, Seligsohn U. Analysis of prothrombotic and vascular risk factors in patients with nonarteritic anterior ischemic optic neuropathy. Ophthalmology. 1999;106:739-742. Deramo VA, Sergott RC, Augsburger JJ, Foroozan R, Savino PJ, Leone A. Ischemic optic neuropathy as the first manifestation of elevated cholesterol levels in young patients. Ophthalmology. 2003;110:1041-1046; discussion 1046. Callizo J, Feltgen N, Ammermann A, Ganser J, Bemme S, Bertelmann T, Pfeiffer S, Duvinage A, Groschel K, Hoerauf H, Wachter R. Atrial fibrillation in retinal vascular occlusion disease and non-arteritic anterior ischemic optic neuropathy. PLoS One. 2017;12:e0181766. Brouzas D, Charakidas A, Ladas I, Apostolopoulos M. Nonarteritic anterior ischemic optic neuropathy associated with chronic anemia: a case series of myelodysplastic syndrome patients. Clin Ophthalmol. 2009;3:133-137. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol. 1994;117:603-624. Hayreh SS, Podhajsky P, Zimmerman MB. Role of nocturnal arterial hypotension in optic nerve head ischemic disorders. Ophthalmologica. 1999;213:76-96. Hayreh SS, Podhajsky PA, Zimmerman B. Nonarteritic anterior ischemic optic neuropathy: time of onset of visual loss. Am J Ophthalmol. 1997;124:641-647. Chung SM, Gay CA, McCrary JA III. Nonarteritic ischemic optic neuropathy. The impact of tobacco use. Ophthalmology. 1994;101:779-782. Purvin V, King R, Kawasaki A, Yee R. Anterior ischemic optic neuropathy in eyes with optic disc drusen. Arch Ophthalmol. 2004;122:48-53. Newman WD, Dorrell ED. Anterior ischemic optic neuropathy associated with disc drusen. J Neuroophthalmol. 1996;16:7-8. Gittinger JW Jr, Lessell S, Bondar RL. Ischemic optic neuropathy associated with optic disc drusen. J Clin Neuroophthalmol. 1984;4:79-84. 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. 152 22. 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. 23. Arnold AC, Costa RM, Dumitrascu OM. The spectrum of optic disc ischemia in patients younger than 50 years (an Amercian Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2013;111:93-118. 24. Preechawat P, Bruce BB, Newman NJ, Biousse V. Anterior ischemic optic neuropathy in patients younger than 50 years. Am J Ophthalmol. 2007;144:953-960. 25. Wu Y, Zhou LM, Lou H, Cheng JW, Wei RL. The association between obstructive sleep apnea and nonarteritic anterior ischemic optic neuropathy: a systematic review and metaanalysis. Curr Eye Res. 2016;41:987-992. 26. Aptel F, Khayi H, Pepin JL, Tamisier R, Levy P, Romanet JP, Chiquet C. Association of nonarteritic ischemic optic neuropathy with obstructive sleep apnea syndrome: consequences for obstructive sleep apnea screening and treatment. JAMA Ophthalmol. 2015;133:797-804. 27. Bilgin G, Koban Y, Arnold AC. Nonarteritic anterior ischemic optic neuropathy and obstructive sleep apnea. J Neuroophthalmol. 2013;33:232-234. 28. Feit RH, Tomsak RL, Ellenberger C Jr. Structural factors in the pathogenesis of ischemic optic neuropathy. Am J Ophthalmol. 1984;98:105-108. 29. Wolkove N, Baltzan M, Kamel H, Dabrusin R, Palayew M. Longterm compliance with continuous positive airway pressure in patients with obstructive sleep apnea. Can Respir J. 2008;15:365-369. 30. Palombi K, Renard E, Levy P, Chiquet C, Deschaux C, Romanet JP, Pepin JL. Non-arteritic anterior ischaemic optic neuropathy is nearly systematically associated with obstructive sleep apnoea. Br J Ophthalmol. 2006;90:879-882. 31. Mojon DS, Hedges TR III, Ehrenberg B, Karam EZ, Goldblum D, Abou-Chebl A, Gugger M, Mathis J. Association between sleep apnea syndrome and nonarteritic anterior ischemic optic neuropathy. Arch Ophthalmol. 2002;120:601-605. 32. Li J, McGwin G Jr, Vaphiades MS, Owsley C. Non-arteritic anterior ischaemic optic neuropathy and presumed sleep apnoea syndrome screened by the Sleep Apnea scale of the Sleep Disorders Questionnaire (SA-SDQ). Br J Ophthalmol. 2007;91:1524-1527. 33. Arda H, Birer S, Aksu M, Ismailogullari S, Karakucuk S, Mirza E, Gumus K, Oner A. Obstructive sleep apnoea prevalence in non-arteritic anterior ischaemic optic neuropathy. Br J Ophthalmol. 2013;97:206-209. 34. Jelic S, Padeletti M, Kawut SM, Higgins C, Canfield SM, Onat D, Colombo PC, Basner RC, Factor P, LeJemtel TH. Inflammation, oxidative stress, and repair capacity of the vascular endothelium in obstructive sleep apnea. Circulation. 2008;117:2270-2278. 35. Ip MS, Lam B, Chan LY, Zheng L, Tsang KW, Fung PC, Lam WK. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med. 2000;162:2166-2171. 36. Wang J, Yu W, Gao M, Zhang F, Gu C, Yu Y, Wei Y. Impact of obstructive sleep apnea syndrome on endothelial function, arterial stiffening, and serum inflammatory markers: an updated meta-analysis and metaregression of 18 studies. J Am Heart Assoc. 2015;4:pii: e002454. 37. Prada D, Harris A, Guidoboni G, Siesky B, Huang AM, Arciero J. Autoregulation and neurovascular coupling in the optic nerve head. Surv Ophthalmol. 2016;61:164-186. 38. Sibony PA, Wei J, Sigal IA. Gaze-evoked deformations in optic nerve head drusen: repetitive shearing as a potential factor in the visual and vascular complications. Ophthalmology. 2018;125:929-937. 39. Miller NR, Arnold AC. Current concepts in the diagnosis, pathogenesis and management of nonarteritic anterior ischaemic optic neuropathy. Eye (Lond). 2015;29:65-79. 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