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Ischemic Index and Distribution of Retinal Capillary Non-perfusion in Neovascular Glaucoma: a Retrospective Study

Purpose: To evaluate the pattern of retinal ischemia in newly diagnosed neovascular glaucoma (NVG). Methods: This is a retrospective single-center cross-sectional study of patients seen at LAC+USC Medical Center from January 2015 to April 2020. Patients with newly diagnosed NVG and ultra-wideeld uorescein angiography (UWFA) without prior panretinal photocoagulation were included. A total of 11 eyes from 10 patients met inclusion criteria. Three zones centered on the fovea were dened: posterior pole (within 2 disc-fovea lengths), mid periphery (between 2 and 3 disc-fovea lengths), and far periphery (>3 disc-fovea lengths). Ischemic index was calculated in these zones using ImageJ software. Results: The etiology of NVG was from proliferative diabetic retinopathy (n=9) and central retinal vein occlusion (n=2). Patients were aged between 48-74 years old. Ischemic index was found to be 91% in the far periphery, 77% in the mid periphery, and 42% at the posterior pole. The total average ischemic index was 76%. There was a statistically signicant difference between the far periphery and posterior pole and mid periphery and posterior pole. Conclusions: High levels of retinal ischemia were found with newly diagnosed NVG. The pattern of ischemia was more pronounced in the far periphery than posterior pole.

edema [21]. However, there is no prior study using UWFA to characterize newly diagnosed NVG. It is important to understand the pattern and level of ischemia in newly diagnosed NVG, especially in the far periphery. The purpose of this study was to address these issues by using UWFA on a series of newly diagnosed NVG patients.

Methods:
This is a retrospective study, conducted at Los Angeles County + University of Southern California (LAC + USC) Medical center from January 2015 to April 2020 under Institutional Review Board (IRB) approval and in accordance with the ethical standards of the Declaration of Helsinki. UWFA records were reviewed for patients with a diagnosis of NVG during this period of time. Meticulous chart review was conducted to ensure these patients had a chart recorded diagnosis of NVG with angle neovascularization and an IOP over 21 mmHg. Patients with UWFA after 2 weeks of diagnosis were excluded. Those with PRP prior to the UWFA were excluded from the study because it would make it di cult to properly assess the laser treated areas for non-perfusion and could alter the dynamics of NVG formation. Poor quality images such as images with media opacities were excluded. From a total of 77 NVG patients with UWFA, 11 eyes from 10 patients met inclusion and exclusion criteria.
In the study center, UWFA is performed using Optos 200 Tx after intravenous injection of 5ml sodium uorescein 10%. The best image in terms of quality and eld of view was chosen for analysis. Images were processed using ImageJ software (National Institutes of Health, Bethesda, MD). First, three perfusion zones were identi ed on the uorescein angiogram. The distance from the optic nerve to the fovea was measured. Zone 1 was de ned as the posterior pole, within 2 disc-fovea lengths from the foveal center. The mid periphery, Zone 2, consisted of an annulus between 2 and 3 disc-fovea lengths from the fovea. Zone 3, de ned as the far periphery, was > 3 disc-fovea lengths from the fovea. The area of capillary perfusion was outlined on the image. Ischemic index (ISI) was calculated as a proportion of non-perfusion to total area. Portions of the image that were obscured were not included in analysis. Figure 1 shows an example of UWFA after obscured peripheral areas were cropped.
Statistical Analysis: The ISI in Zones 1, 2, and 3 were calculated along with 95% con dence intervals and compared using a one-way ANOVA with Bonferroni post-test, using a signi cance value of p < 0.05 with Microsoft Excel.

Results:
Patient demographics are shown in Table 1. Patient age ranged from 48 to 74 years old with a mean age of 58 years old. 6 patients were male. 8 of 10 patients had a history of hypertension. Etiology of NVG was PDR in 9 of 11 eyes and CRVO in 2 eyes. 3 eyes had anti-VEGF treatment prior to UWFA, one on the same day as UWFA, and 2 one day prior to UWFA. 4 of 11 eyes had NVE, and 10 of 11 eyes had NVD.
For eyes with NVG due to PDR, average ISI was 72% (CI 60.1% − 84.7%) for the entire measured retina, 32% (CI 15.3% − 49.2%) in the posterior pole, 72% (CI 55.7% − 89.3%) in the mid-periphery, and 92% (CI 85.2% − 98.0%) in the far periphery. There was statistical signi cance between Zone 1 and Zone 2 as well as Zone 1 and Zone 3 (p = 0.004 and p < 0.0001 respectively). However, Zone 2 and Zone 3 did not meet criteria for statistical signi cance (p = 0.053). with a range of 0-63.9%. They used a cutoff ISI of 35% to differentiate ischemic versus non-ischemic CRVO [9]. For patients with CRVO and macular edema, Aghdam et. al found that non-perfusion in the farperiphery of greater than 5 disc diameters was related to an increased number of ranibizumab injections for macular edema, compared with less than 4 disc diameters of non-perfusion [24]. Singer et. al calculated ISI for RVO patients with refractory macular edema during treatment and found an average ISI for CRVO patients of 22.5% with macular edema and 16.1% once macular edema had resolved [10].
The ndings in this study of overall ISI in NVG are comparable with the literature for patients with anterior segment neovascularization due to CRVO. Tsui et al evaluated the ISI in CRVO in a retrospective study using UWFA and found an average ISI of 78% for the 10 eyes with anterior segment neovascularization without glaucoma [7]. We comparably found an average ISI of 76% in our cohort of patients. However, unlike in Tsui's study, our patients had NVG, and in 9 out of 11 eyes, the etiology of NVG was PDR and only two eyes had CRVO.
Strengths of this study include the ability to nd patients with newly diagnosed NVG with UWFA imaging prior to panretinal photocoagulation. In addition, no patient had anti-VEGF longer than 1 day prior to UWFA, allowing us to evaluate the UWFA for neovascularization of the retina and disc as well. Numbers of patients were limited, given meticulous screening of patients and logistical challenges obtaining UWFA in the acute setting of NVG, especially given corneal edema and media opacities.
We de ned the mid-peripheral and peripheral retina using the disc to fovea distance. We chose this method because it allowed us to compare different sized eyes on a proportional scale.
Limitations to the study include the small sample size (n = 11 eyes) and retrospective nature of the study.
We removed obscured areas of the UWFA, and the superior and inferior areas were more frequently obscured compared to nasal and temporal areas due to the patients' eyelashes and eyelids. If the nonperfusion was signi cantly different in these areas, this could skew the data.
Finally, there is an image warp in UWFA emanating from projection of a three-dimensional image on a two dimensional computer screen; this distortion is more pronounced in the far periphery. This could potentially affect studies measuring surface area. To overcome this, some authors have used stereographically projected images. However, prior work has shown that ISI calculated in the manner of our study correlates with stereographically projected images [12]. Even if there is any error from using ISI, it is less likely to skew our data for zone comparisons because both perfused and non-perfused areas would be affected.

Conclusions:
In conclusion, this is the rst study in our knowledge to use UWFA in patients with newly diagnosed NVG.
The data here demonstrates high levels of peripheral ISI in newly diagnosed NVG. Future directions and implications of this data may include directing panretinal photocoagulation to the far periphery to treat the areas of retina with the highest levels of ischemia for patients with NVG or concern for development of NVG. Further studies are needed to determine how UWFA ndings and retinal ischemia may predict patients who are at high risk for developing NVG, not only in the setting of CRVO, but also in the setting of PDR.

Declarations:
Funding: Unrestricted Grant to the Department of Ophthalmology from Research to Prevent Blindness, New York, NY Con ict of Interest: The authors declare that they have no con ict of interest. Example UWFA after cropping obscured areas. Posterior pole, mid periphery and far periphery are labeled.
In addition, areas of capillary perfusion are demarcated Figure 2 ISI versus location, error bars represent standard error of the mean. In the periphery, there is a higher ISI than the posterior pole. Posterior pole was statistically signi cant when compared with mid periphery and with far periphery (indicated with *). Mid periphery and far periphery were not statistically signi cant