Structure-Function Analysis of Nonarteritic Anterior Ischemic Optic Neuropathy and Age-Related Differences in Outcome

The optic nerve head is vulnerable to ischemia leading to anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in those older than 50 years of age. We performed a cross-sectional study of 55 nonarteritic anterior ischemic optic neuropathy (NAION) eyes in 34 patients to assess clinical outcome and perform structure-function correlations. The peak age of NAION onset was between 50 and 55 years. Sixty-seven percent of patients presented with their first event between the ages of 40 and 60 years, and 32% presented at ≤50 years. Those with NAION onset at age ≤50 years did not have significantly better visual outcome per logMAR visual acuity, automated perimetric mean deviation (PMD) or optical coherence tomography (OCT) measurements. Kaplan-Meier survival curve and multivariate Cox proportional regression analysis showed that age >50 years at NAION onset was associated with greater risk of second eye involvement, with hazard ratio of 20. Older age at onset was significantly correlated with greater thinning of the ganglion cell complex (GCC) (P = 0.022) but not with logMAR visual acuity, PMD, or thinning of retinal nerve fiber layer (RNFL). Using area under receiver operating characteristic curve analyses, we found that thinning of RNFL and GCC was best able to predict visual outcome, and that mean RNFL thickness >65 μm or macular GCC thickness >55 μm significantly correlated with good visual field outcome. We showed that NAION onset at age >50 years had a greater risk of second eye involvement. Patients with OCT mean RNFL thickness >65 μm and mean macular ganglion cell complex thickness >55 μm had better visual outcomes.

Original Contribution Structure-Function Analysis of Nonarteritic Anterior Ischemic Optic Neuropathy and Age-Related Differences in Outcome Ming-Hui Sun, MD, PhD, Yaping Joyce Liao, MD, PhD Background: The optic nerve head is vulnerable to ischemia leading to anterior ischemic optic neuropathy (AION), the most common acute optic neuropathy in those older than 50 years of age. Methods: We performed a cross-sectional study of 55 nonarteritic anterior ischemic optic neuropathy (NAION) eyes in 34 patients to assess clinical outcome and perform structure-function correlations. Results: The peak age of NAION onset was between 50 and 55 years. Sixty-seven percent of patients presented with their first event between the ages of 40 and 60 years, and 32% presented at #50 years. Those with NAION onset at age #50 years did not have significantly better visual outcome per logMAR visual acuity, automated perimetric mean deviation (PMD) or optical coherence tomography (OCT) measurements. Kaplan-Meier survival curve and multivariate Cox proportional regression analysis showed that age .50 years at NAION onset was associated with greater risk of second eye involvement, with hazard ratio of 20. Older age at onset was significantly correlated with greater thinning of the ganglion cell complex (GCC) (P = 0.022) but not with logMAR visual acuity, PMD, or thinning of retinal nerve fiber layer (RNFL). Using area under receiver operating characteristic curve analyses, we found that thinning of RNFL and GCC was best able to predict visual outcome, and that mean RNFL thickness .65 mm or macular GCC thick- Department of Ophthalmology (MHS, YJL), Stanford University School of Medicine, Stanford, California; and Department of Ophthalmology (MHS), Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan. Y. J. Liao was supported by the NANOS Pilot Grant and Weston Havens Foundation. M.-H. Sun was supported by a grant from Chang Gung Memorial Hospital and Ministry of Science and Technology of Taiwan (104-2918-I-182A-001). 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 full text and PDF versions of this article on the journal's Web site (www. jneuro-ophthalmology.com). Address correspondence to Yaping Joyce Liao, MD, PhD, Department of Ophthalmology, Byers Eye Institute, Stanford University School of Medicine, 2452 Watson Court, Palo Alto, CA 94303-5353; E-mail: [e-mail] 258 ness .55 mm significantly correlated with good visual field outcome. Conclusions: We showed that NAION onset at age .50 years had a greater risk of second eye involvement. Patients with OCT mean RNFL thickness .65 mm and mean macular ganglion cell complex thickness .55 mm had better visual outcomes. Journal of Neuro-Ophthalmology 2017;37:258-264 doi: 10.1097/WNO.0000000000000521 © 2017 by North American Neuro-Ophthalmology Society A ge is an important risk factor for diseases affecting the optic nerve, including ischemic optic neuropathy and glaucoma (1,2). Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in those older than 50 years of age, with an annual incidence estimated at 2.3-10.2 cases per 100,000 persons .50 years of age (3-5). Many studies have examined known risk factors for NAION in different age groups in order to better understand which factors are particularly important in both onset and prognosis (5). Known optic disc and systemic risk factors for NAION include older age, disc-at-risk, vascular risk factors, anemia, and obstructive sleep apnea (5-13). Precipitating factors include nocturnal arterial hypotension, prolonged surgical procedures, blood loss, use of various medications, and ocular surgery (8,14). Historically, age older than 50 years has been used as a cut-off for NAION clinical trials, although onset in individuals less than 50 years of age is not rare. Studies have shown that younger onset, defined as onset at age ,45 or ,50 years, is found in 12.7%-23% of patients with NAION and may be associated with better visual outcome (15-18). Structure-function studies using visual field and optical coherence tomography (OCT) measurements have been done in NAION patients, and there is some evidence that older age at onset may correlate with worse outcome (19-22). In this study, we looked at the age of onset in Sun and Liao: J Neuro-Ophthalmol 2017; 37: 258-264 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution NAION patients and examined the visual and structural outcomes as related to age. We also analyzed various OCT measurements to help determine which ones may correlate with better visual outcome. METHODS This is a retrospective cross-sectional study of 55 NAION eyes in 34 patients who were evaluated at Byers Eye Institute at Stanford University Medical Center between April 2009 and June 2015. The study adhered to the tenets of the Declaration of Helsinki and was approved by the Stanford Institutional Review Board. Patient data was deidentified before analysis. Patients with NAION were diagnosed per history and examination (3-5). We excluded individuals with giant cell arteritis, optic neuritis, and other neurologic or ophthalmic disorders (e.g., glaucoma, diabetic retinopathy, macular degeneration, multiple sclerosis), which may affect optic nerve or vision measurements. We also excluded patients with optic disc drusen and peri- or postoperative AION patients (23-25). All patients underwent detailed history, examination, and clinical testing to document demographic data, ocular characteristics, systemic and ocular risk factors, second eye involvement, recurrence in the same eye, and visual outcome. All patients were followed for . 12 months, except for one patient who was last seen 7 months after onset of NAION, which is sufficient to measure changes in clinical outcome and OCT (18,26). Visual Function We measured final visual acuity following resolution of NAION ($6 months from onset of vision loss) using the Snellen chart to calculate the logMAR visual acuity (the logarithm of reciprocal decimal visual acuity). We performed automated perimetry using Humphrey Automated Field Analyzer Swedish interactive threshold algorithm 24-2 or 30-2 programs (Carl Zeiss Meditech, Inc, Dublin, CA). The perimetric mean deviation (PMD) was calculated by averaging the mean deviation for each eye for all patients. The superior (13 points) and inferior (10 points) arcuate visual fields for RNFL structure-function comparison, and the superior and inferior hemifields (6 points) for macular GCC structure-function analysis were calculated according to a previously published method (19). Optical Coherence Tomography We performed spectral-domain OCT analysis (Cirrus HDOCT, Model 5000; Carl Zeiss, Jena, Germany) to quantify structural changes using automated segmentations: cup-todisc ratio; optic disc (27,28); rim area; thickness of peripapillary retinal nerve fiber layer (RNFL); and thickness of the ganglion cell complex (GCC), which consisted of the ganglion cell layer, and inner plexiform layers. Studies were included if there was good signal strength and autoSun and Liao: J Neuro-Ophthalmol 2017; 37: 258-264 segmentation per visual inspection. Based on the methods described in a previous report (19), we calculated the average thickness of RNFL and GCC for the affected and unaffected eyes. We also calculated sectoral RNFL and GCC thickness and correlated these measurements with corresponding visual field regions (13 points superior and 10 points inferior arcuate visual fields for RNFL and 6 points superior or inferior hemifields for GCC) (19,29). Statistical Analyses Statistical analyses were calculated using SPSS 15.0 (SPSS, Inc, Chicago, IL). All tests were two-tailed, and significance was set at 0.05. We used the Mann-Whitney U test for non-normal continuous variable comparisons. Kaplan- Meier survival analyses and multivariate Cox proportional regression model were used to calculate the hazard risk of the fellow eye involvement. We employed the receiver operating characteristic (ROC) curves to estimate the threshold, in order to generate the optimal sensitivity and specificity using the Youden index (30-32). Youden index equals true positive fraction (sensitivity) 2 false positive fraction (1-specificity), which maximizes sensitivity and specificity across multiple cut-off points so that the area under the curve from this analysis is not affected by decision criterion (30-32). Area under receiver operating characteristic (AUROC) curves were used to determine the optimum cut-off value for the threshold of OCT parameters in predicting outcome per visual field (good outcome: PMD better than 25 dB) and visual acuity (good outcome: visual acuity better than or equal to 20/40) criteria. To account for pseudo-replication when both eyes from one subject are treated as independent data points, we used the generalized estimating equation (GEE), which provides correct 95% confidence intervals for regression coefficients of interest and increases precision (33), accounting for intereye correlation within subjects (34). We used GEE to analyze the difference in the final visual acuity (logMAR), PMD in visual field testing, GCC and RNFL thickness on OCT measurement between all eyes with onset at age #50 years and all eyes with onset age .50 years considering the potential correlation of the right eye and left eye from the same person (34-37). Similarly, we used this method to analyze the correlation of onset age of all eyes with final logMAR VA, PMD, GCC, and RNFL thickness on OCT measurements. RESULTS Age of Onset, Second Eye Involvement, Ocular and Systemic Risk Factors Peak age of NAION onset was between 50 and 55 years (See Supplemental Digital Content, Figure E1A, http:// links.lww.com/WNO/A228), and the age of onset for first eye was 56.6 ± 2.0 years (median: 54 years, range: 36-80 years). Sixty-seven percent (21/31) of patients presented 259 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution with their first event between age 40 and 60 years, and 32.3% (10/31) presented at age #50 years. The average age of second eye involvement was 55.9 ± 1.9 years (median: 54.5 years, range: 45-74 years), and 3 patients (16%) had second eye involvement at age #50 years. Using Kaplan-Meier survival curve (See Supplemental Digital Content, Figure E1B, http://links.lww.com/ WNO/A228), we calculated that the mean time to second eye involvement was 68.3 months in those with onset at #50 years (mean 68.3 ± 37.1 months, 25% quartile range: 144.0 ± 117.2 months, 75% quartile range: 11.0 ± 4.4 months), and 40.2 months in those with onset at .50 years (mean 40.2 ± 9.9 months, 25% quartile range: 84.0 ± 37.0 months, 75% quartile range: 5.0 ± 2.1 months). Using multivariate Cox proportional regression analysis after adjusting for different known AION risk factors (diabetes mellitus, hypertension, hyperlipidemia, obstructive sleep apnea, disc-at-risk), we found that NAION patients with first eye involvement at age .50 years had greater risk of second eye involvement compared with those with onset at age #50 years with a hazard ratio of 20.3 (95% CI, 0.32- 1290.34, P = 0.155). We were unable to identify any ocular or systemic factors that differed between patients #50 years vs .50 years, in developing NAION (Table 1). Younger Onset Was Not Significantly Associated With Better Visual Outcome In our modest-sized study, visual outcome was not significantly better in those with NAION onset at age #50 years compared with those with onset at .50 years. In NAION eyes with onset at #50 years, 70% had final visual acuity better or equal to 20/40, compared with 48% in eyes with onset at .50 years (GEE: P = 0.248). In those with onset at #50 years, 10% had visual acuity worse than 20/ 200, compared with 29% of those .50 years. LogMAR visual acuity at $6 months after AION also was not significantly different between those with onset at #50 years compared with onset at .50 years (#50: 0.42 ± 0.19, n = 12 eyes; .50: 0.75 ± 0.14, n = 37 eyes; GEE: P = 0.176). Visual field measurement at $6 months after NAION was also not significantly different between those with onset at #50 years compared with those with onset at .50 years (#50: 213.1 ± 3.0 dB, .50: 215.9 ± 1.8 dB, GEE: P = 0.460). Structural changes on OCT revealed there was no difference in mean thickness of RNFL and GCC in resolved NAION patients with onset at #50 years compared with those with onset at .50 years (RNFL #50: 58.9 ± 3.0 mm, .50: 58.8 ± 1.6 mm; GCC #50: 60.4 ± 2.0 mm, .50: 56.7 ± 1.4 mm) (Table 2). In those .50, there was a significantly smaller rim area, which is another way to measure axonal loss in resolved NAION eyes (#50: 1.35 ± 0.05 mm2; .50: 1.15 ± 0.05 mm2, GEE: P = 0.003) (Table 2). There was an excellent linear correlation between RNFL and GCC thickness (r = 0.862, GEE: P , 0.001), so greater thinning on GCC was significantly associated with greater RNFL thinning (See Supplemental Digital Content, Figure E2A, http://links.lww.com/WNO/A229). Smaller optic disc rim area was significantly correlated with RNFL measurement (r = 0.258, GEE: P = 0.048) and GCC (r = 0.551, GEE: P = 0.001) (See Supplemental Digital TABLE 1. Comparison of risk factors for NAION between onset age #50 and .50 years Onset Age of First Eye Ocular Risk Factors Crowded disc (%) Average cup/disc ratio Vertical cup/disc ratio Mean disc area (range), mm2 Vascular Risk Factors (%) Hyperlipidemia Hypertension Diabetes mellitus Cerebrovascular diseases OSA (%) AHI score ODI Oxygen saturation PLM index #50 yr (n = 10)* .50 yr (n = 21)* P value 5 (83.3)† 0.1 ± 0.02 0.1 ± 0.03 1.71 ± 0.11 (1.32-2.30) 5 (41.7)‡ 0.28 ± 0.05 0.26 ± 0.05 1.62 ± 0.06 (1.16-2.17) 0.120 0.038 0.029 0.540 4 (40) 3 (30) 1 (10) 2 (20) 9 (100)§ 32.5 ± 9.9 15.5 ± 10.3 86.8 ± 0.8 2.1 ± 2.1 12 (57.1) 10 (47.6) 8 (38.1) 0 (0) 17 (81.0) 30.4 ± 6.8 16.2 ± 7.3 84.0 ± 2.0 19.9 ± 9.5 0.306 0.297 0.116 0.097 0.218 0.708 1.000 0.721 0.167 *One patient with unknown age of onset (total n = 31). † Calculated in unaffected contralateral eyes in 6 patients. ‡ Calculated in unaffected contralateral eyes in 12 patients. § One patient had unknown history of sleep apnea, n = 9. AHI, apnea/hypopnea index (represents the number of abnormal respiratory events per hour sleep, normal is ,5 in an adult); NAION, nonarteritic anterior ischemic optic neuropathy; ODI, oxygen desaturation index (represents the number of times oxygen saturation drops by 3% or more from baseline per hour of sleep; OSA, obstructive sleep apnea diagnosed with overnight polysomnography; PLM index, periodic limb movement index. 260 Sun and Liao: J Neuro-Ophthalmol 2017; 37: 258-264 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Comparison of final visual outcome and OCT measurements in patients experiencing NAION with onset at age #50 and .50 years Final logMAR visual acuity Visual field, mean deviation, dB* Superior average† Superonasal Superotemporal Inferior average Inferonasal Inferotemporal OCT, average RNFL thickness, mm Superior Nasal Inferior Temporal OCT, average GCC thickness, mm Superior Superonasal Superotemporal Inferior Inferonasal Inferotemporal Rim Area, mm2 Onset #50 yr (n = 12 Eyes) Onset .50 yr (n = 37 Eyes) P (General Estimation Equation) 0.42 ± 0.19 213.1 ± 3.0 25.8 ± 2.3 29.2 ± 3.4 25.2 ± 2.6 29.5 ± 2.2 214.2 ± 3.5 27.7 ± 2.0 58.9 ± 3.0 59.5 ± 2.6 55.5 ± 2.6 68.8 ± 7.9 52.1 ± 2.3 60.4 ± 2.0 58.1 ± 2.2 61.2 ± 3.1 54.5 ± 2.7 64.1 ± 3.3 62.8 ± 2.9 62.0 ± 3.3 1.35 ± 0.05 0.75 ± 0.14 215.9 ± 1.8 28.7 ± 1.6 211.7 ± 2.2 27.6 ± 1.5 213.9 ± 1.9 217.6 ± 2.1 213.0 ± 2.0 58.8 ± 1.6 59.9 ± 1.7 55.5 ± 1.5 68.3 ± 3.9 50.5 ± 1.5 56.7 ± 1.4 56.6 ± 1.1 57.2 ± 1.6 53.1 ± 1.3 58.3 ± 1.7 56.7 ± 1.9 57.8 ± 2.1 1.15 ± 0.05 0.176 0.460 0.304 0.502 0.427 0.144 0.448 0.065 0.979 0.874 0.992 0.955 0.573 0.154 0.535 0.310 0.611 0.132 0.081 0.345 0.003 *Total mean deviation in total deviation plot. † Values (dB) in total deviation plot were converted to a linear scale (e.g., 0 dB becomes 1.0, 220 dB becomes 0.01) followed by averaging these values in separate 4 quadrants (superonasal, superotemporal, inferonasal, inferotemporal), superior 2 quadrants (superonasal + superotemporal), and inferior 2 quadrants (inferonasal + interotemporal), then were converted back to a log and decibel scale. GCC, ganglion cell complex (GCL + IPL); NAION, nonarteritic anterior ishemic optic neuropathy; OCT, optical coherence tomography; RNFL, retinal nerve fiber layer. Content, Figure E2B-C, http://links.lww.com/WNO/ A229). Regression analyses looking at all eyes with resolved NAION and visual acuity better than counting fingers revealed that there was no linear correlation of increasing age with worse visual outcome as measured by logMAR visual acuity (r = 0.211, GEE: P = 0.267), PMD (r = 20.228, GEE: P = 0.160), or RNFL thickness (r = 20.078, P = 0.571), but there was significant correlation of increasing age with greater thinning of GCC (r = 20.369, GEE: P = 0.022) (See Supplemental Digital Content, Figure E3, http://links.lww.com/WNO/A230). Structure-Function Analysis Using PMD and OCT Measurements We performed structure-function analyses using for structure: mean RNFL, mean GCC, partial RNFL, and partial GCC measurements; and for function: PMD for the eye or recalculated superior and inferior visual field mean deviations (11,27). We showed that there was a linear relationship between PMD and OCT measurements, which was plotted on semilog scales that best displayed such data by accounting for the residual thickness due to nonneuronal elements (See Supplemental Digital Content, Figure E4, http://links.lww.com/WNO/A231). Superior and inferior Sun and Liao: J Neuro-Ophthalmol 2017; 37: 258-264 RNFL and GCC measurements had better fit with recalculated visual field mean deviations than that for the whole eyes. The best fit for the inferior arcuate visual field and corresponding superior RNFL was 60.2 · 10 (0.1 · dB) + 56.5 mm, and for superior arcuate visual field and inferior RNFL, 62.8 · 10 (0.1 · dB) + 56.5 mm. The best fit for inferior hemifield and corresponding superior GCC was 28.6 · 10 (0.1 · dB) + 53.3 mm, and for superior hemifield and inferior GCC, 27.2 · 10 (0.1 · dB) + 53.3 mm. ROC Curve Analyses We performed ROC curve analysis to identify which OCT measurements best correlated with good visual outcome in resolved NAION. For visual acuity better than or equal to 20/40, the AUROC curves were, in decreasing order: GCC (0.78, 95% CI, 0.616-0.944, P = 0.009), RNFL (0.78, 95% CI, 0.613-0.947, P = 0.009), and optic disc rim area (0.65, 95% CI, 0.446-0.853, P = 0.161) (See Supplemental Digital Content, Figure E5, http://links.lww.com/WNO/A232). Based on these ROC curves, the optimal cut-off values for poor visual outcome included: GCC thinner than 52.5 mm (sensitivity 0.833, specificity 0.692), RNFL thinner than 61.5 mm (sensitivity 0.556, specificity 1.000), or rim area smaller than 1.24 mm2 (sensitivity 0.667, specificity 0.692). We also 261 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution looked at sectoral calculations for AUROC for both RNFL and GCC and found that they were not superior to the mean thickness of RNFL and GCC, with best AUROC for predicting better visual acuity (data not shown). For PMD better than 25 dB, the AUROC curves were, in decreasing order: RNFL (0.852, 95% CI, 0.000-1.000, P = 0.025), GCC (0.713, 95% CI, 0.437-0.989, P = 0.175), and rim area (0.704, 95% CI, 0.416-0.991, P = 0.147) (See Supplemental Digital Content, Figure E5B, http://links.lww.com/WNO/A232). Based on these ROC curves, the optimal cut-off values for poor visual outcome were RNFL thinner than 65.5 mm (sensitivity 0.833, specificity 0.889), GCC thinner than 54 mm (sensitivity 0.833, specificity 0.667), and rim area smaller than 1.13 mm2 (sensitivity 0.833, specificity 0.778). Using good visual outcome with visual acuity better than or equal to 20/40, AUROC for PMD was 0.800 (95% CI, 0.659-0.941, P = 0.001), with optimal cut-off mean deviation value of 211.86 dB (sensitivity 0.667, specificity 0.857). This meant that central visual acuity can be relatively preserved in resolved NAION, despite significant visual field loss. The AUROC curve analyses also supported our structure-function analyses, and indicated that there could be good visual outcome as measured by visual acuity or visual field criteria despite significant retinal thinning as measured by OCT. DISCUSSION Previous population studies have documented that NAION is the most common, acute optic neuropathy in those older than 50 years of age (9,12,15-17). It typically presents in those between 55 and 70 years of age (9,12,15,17,18,38), and 12.7%-23% presents in younger than age 45 or 50 years (15-18). Approximately 30% of our patients with idiopathic NAION had onset at age #50 years. In our study, two-thirds of patients presented between 40 and 60 years of age, providing support that age below 40 years, not 50, may be more appropriately considered "young" for the onset of this optic neuropathy. Patients with onset age younger than 40 years are more likely to have associated triggers such as optic disc drusen, perioperative insult, and other factors (3-5,16-18). For this reason, we excluded such NAION patients from our study. A previous report of younger onset NAION (18), the IONDT trial (39,40), and another study that examined visual outcome and age in optic neuropathies (41) showed that NAION patients with younger age of onset had better visual outcome. Contralateral involvement occurred earlier in the older group (41, current study). OCT showed that those with older onset have thinner RNFL measurements (19). In our report, NAION patients with onset at age #50 years did not have significantly better visual prognosis or 262 RNFL and GCC measurements compared with those with onset at .50 years. Older age at NAION onset was significantly correlated with greater thinning of GCC (P = 0.022) but not with logMAR visual acuity, visual field, or RNFL. Measurements of NAION eyes using OCT (20,42-46) and structure-function analyses have helped to better understand changes following NAION and the differences between NAION and other optic neuropathies (19- 22,47,48). We looked at several OCT measurements in resolved NAION eyes and found that both RNFL and macular GCC measurements were better in predicting visual outcome than rim area, cup-to-disc ratio, and optic disc area. Our report confirms previous publications (19,48) that structure-function relationship between RNFL thickness and PMD is linearly correlated and best fitted as an exponential curve when plotted on a semilog scale, with residual thickness that is attributable to other retinal structures (glia, blood vessels). In addition to measurement of RNFL, we demonstrated that macular GCC also correlated well with visual function in NAION patients. Our results showed that visual acuity can remain better or equal to 20/40 despite significant structural thinning. Similarly, visual field can remain excellent (PMD less than 25 dB) despite significant structural thinning, and there is a critical threshold for retinal thinning below which there is more severe loss of visual function. Using correlation analysis between the superior and inferior visual field and corresponding OCT measurements (19,48), we found that the critical threshold for worse than 25 dB visual field loss is RNFL less than 76 mm superiorly or inferiorly (see equations in Results). This is similar to what has been shown in different optic neuropathies where the critical threshold for superior RNFL is 70 mm, and inferior RNFL is 80 mm for NAION, approximately 70 mm for glaucoma, and 75 mm for optic neuritis (19,48,49). Our study also examined structurefunction analysis in resolved NAION using semilog plot equation (See Supplemental Digital Content, Figure E4B, http://links.lww.com/WNO/A231) and found that the critical threshold for worse visual outcome (PMD greater than or equal to 25 dB) was superior or inferior to GCC less than 62 mm. Using AUROC curves analysis with data from the entire eye (not separated into superior or inferior fields), we found that the optimal threshold for mean thickness of RNFL and macular GCC was 66 mm and 54 mm, respectively, which correlated with PMD of greater than or equal to 25 dB, with high sensitivities and specificities, with RNFL slightly better than GCC. Limitations of our study include the retrospective design and modest number of patients. Another limitation is the arbitrary nature of choosing age .50 years as the cut-off value for data analysis. Previous studies have used age cutoff values of 45, 50, and 65 years. In our study, we used a cut-off value of 50 years because it is by far the most commonly used value (15,17,18). Age .50 years has also been used as the cut-off for enrollment into NAION Sun and Liao: J Neuro-Ophthalmol 2017; 37: 258-264 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution clinical trials, including the IONDT trial (39) and the phase 2/3 QRK 207 NAION clinical trial (50). STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: M.-H. Sun and Y. J. Liao; b. Acquisition of data: M.-H. Sun and Y. J. Liao; c. Analysis and interpretation of data: M.-H. Sun and Y. J. Liao. Category 2: a. Drafting the manuscript: M.-H. Sun and Y. J. Liao; b. Revising it for intellectual content: M.-H. Sun and Y. J. Liao. Category 3: a. Final approval of the completed manuscript: M.-H. Sun and Y. J. Liao. ACKNOWLEDGMENTS The authors thank M.A. Shariati and R.W. Nelson for their kind help in data collection. They would also like to thank Hsiao-Jung Tseng in Biostatistical Center for Clinical Research in Chang Gung Memorial Hospital Linkou Medical Center (CLRPG3D0042) and Professor KuangHung Hsu in the Department of Health Care Management in Chang Gung University for their help in statistical analysis. REFERENCES 1. 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