Comparison of Peripapillary Vessel Density of Acute Nonarteritic Anterior Ischemic Optic Neuropathy and Other Optic Neuropathies With Disc Swelling Using Optical Coherence Tomography Angiography: A Pilot Study

The purpose of this study is to quantitatively compare the peripapillary vessel density (PPVD), measured with optical coherence tomography angiography (OCT-A), between acute nonarteritic anterior ischemic optic neurop- athy (NAION) and other causes of disc swelling ("others").

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Comparison of Peripapillary Vessel Density of Acute Nonarteritic Anterior Ischemic Optic Neuropathy and Other Optic Neuropathies With Disc Swelling Using Optical Coherence Tomography Angiography: A Pilot Study Jasmine C. Chuang, MB, BS, Noel C. Y. Chan, FRCSEd(Ophth), Carol Y. Cheung, PhD, Jerry K. H. Lok, FCOphth(HK), Carmen K. M. Chan, MRCP, FRCSEd(Ophth) Background: The purpose of this study is to quantitatively compare the peripapillary vessel density (PPVD), measured with optical coherence tomography angiography (OCT-A), between acute nonarteritic anterior ischemic optic neuropathy (NAION) and other causes of disc swelling (“others”). Methods: In this prospective comparative case series, patients with unilateral disc swelling due to acute NAION (n = 7) and “others” (n = 7) underwent OCT-A scanning of the optic nerve head with a swept-source OCT (Triton DRIOCT), in addition to functional assessment. OCT-A images were analyzed using an automated customized MATLAB program. Comparison was made between total and 6 sectoral PPVD (radial peripapillary capillary [RPC] and choroid layers) of affected and fellow eyes; and between the 2 groups’ affected eyes. Five NAION patients had repeated assessments at 1, 3, and 6 months. Results: Acute NAION eyes had a significantly lower total and superonasal PPVD (both layers) compared to fellow eyes. No such difference was observed in “others” group for the RPC layer. NAION eyes also had significantly lower total RPC PPVD than affected eyes in the “others” group. Over 6 months, NAION eyes had persistently lower RPC PPVD compared to fellow eyes but the reduced choroidal PPVD resolved by 1 month. Hong Kong Eye Hospital (JCC, JKHL, CKMC), Hong Kong, China; Department of Ophthalmology and Visual Sciences (JCC, NCYC, CYC, JKHL, CKMC), the Chinese University of Hong Kong, Hong Kong, China; and Department of Ophthalmology and Visual Sciences (NCYC), the Prince of Wales Hospital and Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China. Support from the Kowloon Central Cluster research grant. Presented in part as an Oral Presentation at the Hong Kong Ophthalmological Symposium, December 15, 2018, Hong Kong, China. The authors report no conflicts of interest. Address correspondence to Carmen K. M. Chan, MRCP, FRCSEd(Ophth), Hong Kong Eye Hospital, 147K, Argyle Street, Hong Kong, China; E-mail: [e-mail] e470 Conclusion: The study demonstrated reduced superonasal and total RPC PPVD in acute NAION, which persisted over 6 months. Because there is currently no single diagnostic test for NAION, use of OCT-A images to analyze RPC PPVD may potentially help distinguish acute NAION from other causes of disc swelling by quantitatively demonstrating capillary dropout in the RPC layer. Journal of Neuro-Ophthalmology 2021;41:e470–e482 doi: 10.1097/WNO.0000000000001106 © 2020 by North American Neuro-Ophthalmology Society O ptical coherence tomography angiography (OCT-A) is a noninvasive imaging system that can provide visualization of the retinal and choroidal microvasculature. It has been shown to be useful in viewing retinal capillary dropout (e.g., reduction in vessel density and foveal avascular zone enlargement) in diabetic retinopathy as well as glaucomatous optic neuropathy (e.g., with reduction in peripapillary vessel density [PPVD]) (1–5). In general, optic atrophy of any cause can lead to corresponding decrease in peripapillary retinal flow (6–8). In particular, microvascular defects and dropouts, pattern alterations of peripapillary capillary vessels, and decrease in PPVD have been found in several studies examining the use of OCT-A in patients with ischemic optic neuropathies (9–12). However, there is currently no standardized method to quantify optic nerve head (ONH) OCT-A findings, and the majority of published studies were retrospective or simply focused on nonarteritic anterior ischemic optic neuropathy (NAION) alone. In this prospective study, we aimed to use a swept-source OCT to differentiate disc swelling caused by NAION from other neuropathies with disc swelling, by quantifying PPVD using a customized analysis software program. We hypothChuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution esized that OCT-A could detect a reduction of PPVD in acute NAION patients when compared to patients with other causes of optic disc swelling. We also followed up the NAION patients for 6 months to document the changes in peripapillary vasculature longitudinally. METHODS Subjects This was a prospective comparative case series with patients recruited from Hong Kong Eye Hospital between June 2016 and July 2018. The study was approved by Kowloon East/Kowloon Central research ethics committee. Written informed consent was obtained from each recruited patient. Patients with unilateral optic disc swelling were recruited. For the NAION group, only patients with visual loss of #2 weeks were included. The diagnosis of NAION was based on history of acute painless unilateral visual loss, accompanied by disc swelling and objective optic nerve dysfunction (e.g., decrease in visual acuity [VA], relative afferent pupillary defect, and visual field abnormalities). Other conditions, including arteritic AION were excluded clinically and on further investigations (including blood tests) if indicated. The diagnosis of other optic neuropathies was based on clinical history, objective optic nerve dysfunction, and positive neuroimaging studies. Patients with one or more coexisting ocular conditions that may alter the imaging quality or interfere with optic nerve microvasculature were excluded. These conditions include VA of ,20/200, significant cataract and/or media opacity, glaucoma, retinal diseases including retinitis pigmentosa, diabetic retinopathy, previous vascular occlusions, previous laser treatment to the retina excluding barrier laser to the peripheral retina only, previous intraocular surgery except uncomplicated cataract extraction and intraocular lens implantation, severe myopia (spherical equivalent of 26.00 D or worse or fundal features of severe myopia), and tilted discs. Patients with unknown clinical diagnosis and pseudodisc swelling were also excluded. All recruited subjects underwent VA assessment by Snellen chart, automated visual field assessment by Humphrey Visual Field Analyzer (30-2 SITA), color vision assessment by Ishihara pseudoisochromatic plates, OCT, and OCT-A of the ONH. Subjects were assessed at presentation (#2 weeks onset), 1, 3, and 6 months. Snellen VAs were converted into logarithm of the minimum angle of resolution units for statistical analysis. Optical Coherence Tomography, Optical Coherence Tomography Angiography, and Image Processing OCT-A was performed with the Triton swept-source OCT (DRI-OCT; Topcon, Inc, Tokyo, Japan) using a tunable laser and photodetectors with a wavelength of 1050 nm. Three diopters wide and 3.0 · 3.0 mm (320 · 320) OCTangiography scan protocol was used for retinal imaging. En Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 face images through the retina, internal limiting membrane (ILM), retinal pigment epithelium, and choroid were extracted. The OCT-A software segmented the retina and choroid into different layers and generated images for (1) “nerve head” (total retinal thickness); (2) “vitreous”; (3) radial peripapillary capillary (“RPC”); and (4) “choroid.” The RPC layer, which corresponds best to the retinal nerve fiber layer (RNFL), and the choroid layer were used for analysis. The RPC segmentation was delineated with an inner border at the level of the ILM and an outer border at the posterior boundary of the RNFL. The choroid layer was defined as a segment with an inner border at the Bruch membrane (BM) and an outer border 390.0 mm below the BM. Images were analyzed by a single investigator. Images of poor quality with low signal strength ,50 and/or with motion artifacts were excluded. The built-in software did not provide quantitative analysis of the OCT-A images. En face images were exported in grayscale and imported into an automated customized MATLAB program for analysis. A nonlocal means denoising filter was applied to reduce background noise, sharpen blood vessels, and improve signal-to-noise ratio. The denoised image was then binarized using Phansalkar adaptive local thresholding method with white pixels representing blood vessels and black pixels representing background or nonperfused regions. Vessel density was calculated as the percentage of area not defined as nonperfused regions over total area of interest (Fig. 1). The measured area for PPVD was defined as a 3-mm diameter circle extending from optic disc boundary and was divided into 6 sectors: superonasal (NS), superotemporal (TS), temporal (T), nasal (N), inferonasal (NI), and inferotemporal (TI) (Fig. 2). Each patient also underwent OCT of the ONH using Cirrus HD-OCT (Carl Zeiss Meditec). The total peripapillary RNFL (pRNFL) thickness was used for calculation of ratio of total PPVD over total pRNFL thickness. Statistical Analysis Data analysis was performed using paired t test with GraphPad Prism 7.04. Age- and sex-adjusted data analysis was performed using multivariable linear regression analysis with R-program Version 3.5.1. P , 0.05 was statistically significant. RESULTS Twenty-three patients with unilateral disc swelling were recruited during the study period. Eight patients with unknown clinical diagnosis, concurrent disc pathologies, or pseudodisc swelling and 1 patient with poor OCT-A image quality were excluded. A total of 7 patients with acute unilateral NAION and 7 patients with other unilateral optic neuropathies (“others” group) including 3 optic nerve sheath meningioma, 2 optic neuritis, and 2 papillitis patients were included. e471 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Sectoral divisions of the optic disc: superonasal (NS), superotemporal (TS), temporal (T), inferotemporal (TI), inferonasal (NI), and nasal (N). FIG. 1. Quantification of capillary network from optical coherence tomography angiography using our custom MATLAB program delineating the difference between affected and unaffected eyes of the same patient. NAION, nonarteritic anterior ischemic optic neuropathy. Mean age of the NAION group and “others” group were 58.4 ± 4.2 and 46.4 ± 5.6 years, respectively. The NAION group was male predominant and the “others” group was female predominant with male-to-female ratio of 6:1 and 1:6, respectively. Age- and sex-adjusted data analysis was performed in view of this difference in age and sex. Significant differences between the VA and the visual field mean deviation were not noted between the 2 groups (Table 1). PPVD was assessed using the MATLAB program (Fig. 3). We compared the RPC and choroid PPVD between affected and unaffected eyes for total peripapillary area and for the 6 different sectors using paired t test. For NAION group, we found significantly lower RPC PPVD in the superonasal sector (46.2 ± 5.3%, 57.2 ± 2.1%, P = 0.03) and in the total RPC peripapillary area e472 (54.6 ± 1.8%, 58.6 ± 1.3%, P = 0.01). Similarly, we found significantly lower choroid PPVD in the superonasal (57.2 ± 21.3%, 85.9 ± 6.3%, P = 0.02) and superotemporal sectors (55.8 ± 11.9%, 85.2 ± 8.1%, P = 0.004) and in total choroid peripapillary area (66.9 ± 11.7%, 85.2 ± 8.0%, P = 0.02). On the contrary, there were no significant differences found in RPC PPVD between affected and unaffected eyes in the “others” group for total and sectoral peripapillary area (P . 0.05). We were, however, able to find significantly lower choroid PPVD in most sectors and in total choroid peripapillary area in the “others” group (P . 0.05) (Table 2). There was no significant difference between pRNFL when comparing affected eyes of the NAION group with those of the “others” group, but we found a significantly lower total RPC PPVD (54.6 ± 1.8%, 57.7 ± 2.1%, TABLE 1. Patient demographics Demographics Subjects (n) Affected Unaffected Age Gender† Male Female Visual acuity (Snellen) Visual field mean deviation, dB NAION Others* 7 patients 7 eyes 7 eyes 58.4 ± 4.2 7 patients 7 eyes 7 eyes 46.4 ± 5.7 6 1 20/30 11.4 ± 2.4 1 6 20/40 13.5 ± 5.2 *Others include 3 optic nerve sheath meningioma, 2 optic neuritis, and 2 papillitis. † Significant difference between gender of the 2 groups. NAION, nonarteritic anterior ischemic optic neuropathy. Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 RPC Layer PPVD (%) NS NAION (n = 7) Affected Unaffected P Other optic neuropathies (n = 7) Affected Unaffected P TS NI TI Choroid Layer PPVD (%) N T Total NS TS NI TI N T Total 46.2 ± 5.3 56.5 ± 3.2 48.3 ± 3.9 62.3 ± 1.8 52.8 ± 3.3 61.5 ± 3.3 54.6 ± 1.8 57.2 ± 21.3 55.8 ± 11.9 62.1 ± 12.8 77.6 ± 8.6 73.3 ± 18.2 75.2 ± 16.0 66.9 ± 11.7 57.2 ± 2.1 61.2 ± 1.5 55.9 ± 3.2 62.6 ± 2.3 54.3 ± 2.6 60.2 ± 1.0 58.6 ± 1.3 85.9 ± 6.3 85.2 ± 8.1 77.9 ± 15.9 83.2 ± 9.7 90.4 ± 6.4 88.9 ± 10.1 85.2 ± 8.0 0.03 0.23 0.12 0.91 0.47 0.70 0.01 0.02 0.004 0.08 0.28 0.07 0.11 0.02 56.3 ± 1.6 61.1 ± 2.6 54.7 ± 4.8 62.4 ± 5.4 49.9 ± 3.1 61.4 ± 5.2 57.7 ± 2.1 73.8 ± 11.4 73.9 ± 11.8 72.2 ± 13.1 77.9 ± 11.5 80.9 ± 10.7 80.0 ± 12.4 76.4 ± 9.8 61.7 ± 2.7 62.6 ± 1.4 56.6 ± 2.1 61.9 ± 1.6 59.5 ± 2.3 61.4 ± 3.1 60.6 ± 1.7 87.2 ± 6.0 87.2 ± 4.7 86.6 ± 5.1 87.4 ± 2.7 92.8 ± 4.2 86.6 ± 6.7 88.0 ± 2.8 0.14 0.39 0.68 0.92 0.096 0.99 0.07 0.05 0.04 0.02 0.07 0.02 0.22 0.03 Bold indicates statistically significant difference. N, nasal; NAION, nonarteritic anterior ischemic optic neuropathy; NI, inferonasal; NS, superonasal; PPVD, peripapillary vessel density; RPC, radial peripapillary capillary; T, temporal; TI, inferotemporal; TS, superotemporal. Original Contribution e473 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 2. Comparison of RPC and choroid PPVD (%) between affected and fellow (unaffected) eyes of NAION patients and of other optic neuropathy patients Original Contribution FIG. 3. Color fundus photograph (A) and peripapillary vessel density in MATLAB rendered image (blue = nonperfused area and red = perfused area) (B) of a normal eye (a), an eye with nonarteritic anterior ischemic optic neuropathy (b), and an optic neuritis eye (c). P = 0.030) in the NAION group. In an attempt to correlate the level of ischemia with the amount of disc swelling, we calculated the ratio of total PPVD over total pRNFL thickness, which was also lower in the NAION group (0.23 ±0.02%/micron, 0.31 ± 0.05%/micron, P = 0.016). However, when comparing the total choroid PPVD (66.9 ± 9.5%, 76.4 ± 9.8%) and ratio of total PPVD over total pRNFL thickness (0.28 ± 0.07%/micron, 0.28 ± 0.07%/ micron) between NAION and “others” group, no difference was found, although PPVD was lower in NAION eyes (P . 0.05) (Table 3). For longitudinal analysis, we planned to follow both groups of patients for 6 months. Unfortunately, in the “others” group, too few patients returned for follow-up for meaningful analysis. For NAION, 5 patients were included in the longitudinal analysis (2 lost to follow-up). We TABLE 3. Comparison of RPC and choroid PPVD between NAION patients and other optic neuropathy patients Group NAION (n = 7) Other optic neuropathies (n = 7) P pRNFL (Microns) Total RPC PPVD (%) Total RPC PPVD (%)/pRNFL (Microns) Total Choroid PPVD (%) Total Choroid PPVD (%)/pRNFL (Microns) 250.0 ± 25.5 212.3 ± 28.7 0.17 54.6 ± 1.8 57.7 ± 2.1 0.03 0.23 ± 0.02 0.31 ± 0.05 0.02 66.9 ± 9.5 76.4 ± 9.8 0.20 0.28 ± 0.07 0.41 ± 0.17 0.51 Data are adjusted for age and sex. Total PPVD/pRNFL is the ratio between total PPVD over average pRNFL. Bold indicates statistically significant difference. NAION, nonarteritic anterior ischemic optic neuropathy; PPVD, peripapillary vessel density; pRNFL, peripapillary retinal nerve fiber layer; RPC, radial peripapillary capillary. e474 Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 RPC Layer PPVD (%) NS TS NI TI Choroid Layer PPVD (%) N T Total NS TS NI TI N T Total Acute (baseline) NAION 45.8 ± 4.5 59.0 ± 7.3 49.6 ± 8.6 61.9 ± 5.1 54.4 ± 6.8 61.0 ± 6.9 55.3 ± 2.7 50.4 ± 20.4 52.3 ± 10.1 57.6 ± 12.4 78.0 ± 10.4 70.0 ± 20.9 75.8 ± 18.8 64.0 ± 12.4 1 month NAION 48.6 ± 8.7 58.5 ± 7.0 48.2 ± 9.9 60.6 ± 4.6 53.9 ± 7.6 58.8 ± 7.0 54.2 ± 3.8 82.5 ± 15.3 84.2 ± 6.2 72.7 ± 23.5 77.6 ± 20.8 89.8 ± 5.3 88.2 ± 7.3 82.5 ± 12.1 Unaffected 57.4 ± 3.9 59.3 ± 0.8 52.3 ± 7.2 59.9 ± 4.8 56.9 ± 5.8 59.3 ± 1.9 57.5 ± 3.1 86.7 ± 3.8 89.6 ± 1.0 84.4 ± 4.9 86.3 ± 7.3 91.7 ± 3.5 92.5 ± 2.7 88.6 ± 3.1 P* 0.003‡ 0.79 0.35 0.84 0.19 0.50 0.003‡ 0.52 0.13 0.24 0.33 0.50 0.22 0.26 P† 0.85 0.92 0.54 0.71 0.64 0.70 0.54 0.002‡ 0.004‡ 0.14 0.95 0.06 0.18 0.01‡ 3 months NAION 51.0 ± 7.2 52.3 ± 7.4 58.1 ± 8.0 63.9 ± 10.3 51.3 ± 6.8 52.4 ± 8.3 54.9 ± 3.8 91.5 ± 6.6 88.3 ± 4.4 85.7 ± 9.5 90.6 ± 5.2 92.3 ± 3.3 91.5 ± 6.6 89.3 ± 4.4 Unaffected 67.0 ± 8.2 67.2 ± 9.9 57.4 ± 6.0 61.2 ± 5.9 64.3 ± 6.7 64.9 ± 6.7 63.7 ± 6.1 93.7 ± 1.7 91.9 ± 2.4 86.1 ± 4.2 87.7 ± 4.0 93.2 ± 4.0 93.7 ± 1.7 90.3 ± 2.2 P* 0.02‡ 0.07 0.87 0.60 0.02‡ 0.03‡ 0.02‡ 0.33 0.26 0.94 0.11 0.75 0.51 0.65 P† 0.20 0.04‡ 0.14 0.77 0.44 0.25 0.81 0.01‡ 0.003‡ 0.003‡ 0.06 0.06 0.20 0.01‡ 6 months NAION 53.4 ± 8.1 54.8 ± 8.9 57.2 ± 4.0 61.8 ± 4.9 49.1 ± 7.1 58.0 ± 4.7 55.7 ± 4.4 88.8 ± 3.3 89.1 ± 3.4 86.3 ± 8.0 89.7 ± 4.3 90.1 ± 3.4 89.0 ± 7.9 88.8 ± 3.5 Unaffected 60.4 ± 6.0 61.0 ± 3.4 57.6 ± 11.3 63.4 ± 8.0 62.1 ± 7.9 63.7 ± 5.7 61.4 ± 6.2 86.2 ± 12.5 87.7 ± 11.0 88.4 ± 4.8 89.7 ± 6.7 92.0 ± 5.9 93.7 ± 2.8 90.0 ± 5.2 P* 0.008‡ 0.21 0.94 0.38 0.05‡ 0.07 0.008‡ 0.72 0.83 0.54 0.99 0.65 0.34 0.85 P† 0.05 0.40 0.07 0.99 0.19 0.55 0.78 0.01‡ 0.002‡ 0.006‡ 0.11 0.10 0.26 0.01‡ Original Contribution *P-value for comparison of PPVD of NAION eyes with fellow unaffected eyes. † P-value for comparison of PPVD of chronic phase NAION eyes (1, 3 or 6 months) with acute phase (baseline) NAION eyes of the same patients. N, nasal; NAION, nonarteritic anterior ischemic optic neuropathy; NI, inferonasal; NS, superonasal; PPVD, peripapillary vessel density; RPC, radial peripapillary capillary; T, temporal; TI, inferotemporal; TS, superotemporal. e475 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 4. Comparison of RPC and choroid PPVD (%) between affected and fellow, unaffected eyes of NAION patients (n = 5) at 1, 3, and 6 months Original Contribution FIG. 4. Analysis of a patient with left eye nonarteritic anterior ischemic optic neuropathy. Top left: color fundus photograph; top right: corresponding inferior visual field defect; bottom left: optical coherence tomography optic nerve head and retinal nerve fiber analysis; bottom right: MATLAB rendered image showing decreased peripapillary vessel density in the superior sectors. compared the affected eyes of the NAION group with fellow unaffected eyes at 1, 3, and 6 months. We found persistent significantly lower RPC PPVD in the superonasal sector and in total peripapillary area at 1, 3, and 6 months (Table 4). There was no significant difference between the RPC PPVD of NAION eyes compared to that at presentation (P . 0.05). However, there was no significant difference between choroid PPVD at 1, 3, and 6 months when comparing affected eyes with unaffected eyes (P . 0.05) (Table 4). DISCUSSION Our study demonstrated that using our automated, customized MATLAB program, OCT-A could detect a statistically significant lower RPC and choroid PPVD in acute NAION eyes when compared to fellow unaffected eye, and to eyes with disc swelling of other causes. The significantly lower RPC and choroid PPVD in the superonasal sector is consistent with predominantly inferior visual field loss for NAION (Fig. 4). This is also consistent with the presumed pathophysiology of NAION, which is hypothesized to be ischemic in nature (13). The loss of PPVD is likely multifactorial, which may, in part, be due to a vicious cycle involving impaired perfusion in the short posterior ciliary arteries and infarct in the retrolaminar portion of the ONH. This leads to swelling of ischemic axons, e476 which then compresses on the superficial capillary layer, leading to further tissue ischemia (14). Our findings are mostly in line with published OCT-A studies. Dropout of peripapillary microvasculature has been demonstrated in studies using OCT-A for acute NAION (6,9,11,15–18). Various other studies have also compared NAION with other optic neuropathies using OCT-A and found reduced vasculature in NAION (10,12,19–21). Our study differs from them by being prospective in nature, had a comparison group with disc swelling, used quantitative analysis, and included longitudinal data for the NAION group. A summary of published studies using OCT-A for NAION can be found in Table 5 for comparison. Similar to our study, Fard et al’s quantitative crosssectional study (10) used a custom MATLAB program for quantification and found reduced PPVD in NAION compared to papilledema and control and reduced VD in NAION compared to optic neuritis. Their study differed from ours in that they used Optovue OCT (AngioVue; Optovue, Inc, Fremont, CA) and chose to use a 3.45-mm diameter peripapillary area. They did not have longitudinal data. To the best of our knowledge, no other study used the Topcon Triton SS-OCT to quantify ONH vasculature in NAION. In our study, we also noted reduced choroid PPVD in the superior sectors and in total peripapillary area for NAION eyes as compared to fellow unaffected eyes. Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 Study Sample Size Studies with only NAION patients Wright Mayes 10 NAION eyes et al (16) Gaier et al (25)25 NAION eyes (7 acute and 18 nonacute) Study Design OCT-A Instrument Retrospective, crosssectional AngioVue (Optovue, Inc) Retrospective comparative case series AngioVue (Optovue, Inc) Qualitative or Disease Quantitative Onset Time Layer Analyzed (VD) Findings Flow impairment seen in the RPC corresponding to structural OCT RNFL and GCC and to automated visual field deficits in 80%, 100%, and 90% of eyes, respectively. Flow impairment seen in the PCC corresponding to structural deficits of RNFL and GCC and to visual field defects in 70%, 80%, and 60%–80% of eyes, respectively. Statistically significant reduction in Quantitative Not specified Superficial macrovasculature (major angiographic signal was found in (acute acutely affected eyes compared to retinal vessels), defined as unaffected eyes in papillary and presence of superficial peripapillary regions. microvasculature optic disc No difference was found in (capillaries), edema) choriocapillaris angiographic signal choriocapillaris and in major VD between nonacute NAION eyes and unaffected eyes. Nonacute NAION eyes showed a significant reduction in peripapillary patent capillary density compared to unaffected and acutely affected eyes. Qualitative 1 wk–10 yrs RPC and PCC (average 23 mo) Quantitative At least 3 mosPeripapillary and macular whole en face image, with RPC, cpVD, macular complete SCP, macular DCP, and resolution CC of papilledema NAION eyes were found to have a significant reduction of VD in RPC, cpVD, SCP, and DCP. No significant difference was found between the VD of CC in NAION vs control eyes. Original Contribution Studies comparing anterior ischemic neuropathy eyes with normal eyes 26 NAION eyes and Retrospective AngioVue (Optovue, Augstburger 24 control eyes observational Inc) et al (17) e477 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. TABLE 5. Summary of published studies using OCT-A for NAION eyes Study Sample Size Study Design OCT-A Instrument Qualitative or Disease Quantitative Onset Time Layer Analyzed (VD) Findings Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 NAION group demonstrated Rebolleda et al6 NAION eyes and Prospective AngioPlex Cirrus HD- Quantitative Acute stage: VD (total length of (11) 10 control eyes case-control OCT (Carl Zeiss within 1 wk; perfused vasculature per statistically significant decrease unit area), PD (total area in PCD, VD, and PD compared with Meditec, Inc) atrophic stage: at 3 of perfused vasculature fellow unaffected and control per unit area), superficial group at acute and atrophic stage. mos Atrophic NAION eyes have PCD significantly decreased peripapillary vessels compared with the acute stage in the temporal sector, possibly due to damage at the watershed zone. NAION eyes had statistically Song et al (18)41 NAION eyes (14 Retrospective AngioVue (Optovue, Quantitative Acute: within ONH and RPC significant lower vessel densities Inc) 21 d; acute and 27 in both RPC and ONH compared to chronic: chronic) and 30 control eyes and fellow unaffected over 21 d control eyes eyes. without papilledema Within 2 wks Whole ONH and RPC Microvascular dropout was seen in Retrospective AngioVue (Optovue, Qualitative Balducci et al 4 NAION eyes, 1 NAION and AAION eyes. and (9) AAION eye, and 8 observational Inc) OCT-A could identify the boundary of quantitative case–control control eyes ischemia and sectoral peripapillary capillary network reduction at the ONH, which was comparable to the optic disc filling defects detected by FA. Statistically significant ONH and RPC VD reductions were detected in NAION eyes compared to controls. Vessel densities of peripapillary Optovue (unspecified) Quantitative Acute, timing Whole ONH and RPC Hata et al (6) 15 NAION eyes and Prospective retina and inside the optic disc not 19 control eyes observational specified case series were significantly reduced in NAION compared to normal. Peripapillary VD showed reduction predominantly in the superior sectors corresponding to the visual field defect. Original Contribution e478 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 Study Sample Size Study Design OCT-A Instrument Qualitative or Disease Quantitative Onset Time Layer Analyzed (VD) Findings RTVue (Optovue, Inc) Quantitative Within 1 wk Peripapillary Retina layer, Global reduction of mean peripapillary choroid peripapillary flow density in NAION and after layer eyes compared to normal control resolution eyes. of disc Reduced total and sectorial edema choroidal peripapillary vascular flow density with spontaneous improvement upon resolution of optic disc edema. Spontaneous improvement of average total peripapillary flow density with resolution of optic disc edema (N = 3). Studies comparing NAION eyes with other neuropathies Prospective AngioVue (Optovue, Quantitative Within 2 wks Macular and parafoveal There is a statistically significant Fard et al (19) 20 NAION eyes, comparative Inc) superficial and deep reduction in whole superficial and 39 papilledema vasculature deep macula vasculature in eyes, and 22 NAION eyes compared to normal eyes papilledema eyes and control eyes. PPVD was significantly lower in Fard et al (10) 29 NAION eyes, 44 Cross-sectional AngioVue (Optovue, Quantitative Within 2 wks RPC and whole ONH Inc) thickness NAION eyes, followed by papilledema eyes, papilledema eyes and control 8 optic neuritis eyes. eyes, and 48 VD is significantly lower in wholenormal eyes image ONH and in the inferonasal sector in NAION compared to optic neuritis. Fard et al (21) 31 chronic NAION Cross-sectional AngioVue (Optovue, Quantitative More than 6 Whole image (ONH) and POAG and NAION eyes were found to Inc) mo whole-annulus PCD have significantly lower PCD eyes, 42 compared to control eyes and moderate and fellow unaffected eyes. severe POAG Inferior sector PCD was significantly eyes, and 77 lower in NAION eyes compared to control eyes POAG eyes. Sharma et al 6 NAION eyes and Prospective (15) 19 control eyes Original Contribution e479 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Study Gandhi et al (20) Sample Size Study Design OCT-A Instrument Qualitative or Disease Quantitative Onset Time Qualitative 21 NAION eyes and Retrospective Topcon DRI OCT observational Triton plus (Topcon 18 papilledema Corporation) eyes Retrospective Rougier et al Qualitative (8 (12) NAION, 12 papillitis, and 25 papilledema); quantitative (4 NAION and 6 papillitis) Layer Analyzed (VD) Not specified Peripapillary choroidal layer (mean duration: 15.4 ± 11.7 d) Within 10 d AngioPlex Cirrus HD- Qualitative and OCT (Carl Zeiss quantitative Meditec, Inc) and Plex Elite 9000 device (Carl Zeiss Meditec, Inc) Radial RPC Findings NAION eyes were noted to have diffuse loss of microvasculature cuff and vascular network around the optic disc with or without an additional area of sectoral loss of vasculature extending from the disc. Papilledema eyes only showed loss of microvasculature cuff. Disappearance or moderate pattern alteration of peripapillary capillary vessels were noted in NAION and papillitis compared to papilledema. No differences for vessel perfusion density and capillary flux index were found compared to unaffected contralateral eyes. Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 Similarities between the study design of the published studies and this study in bold. CC, choriocapillaris; cpVD, circumpapillary RPC; DCP, deep capillary plexus; FA, fluorescein angiography; GCC, ganglion cell complex; NAION, nonarteritic anterior ischemic optic neuropathy; OCT-A, optical coherence tomography angiography; PCC, peripapillary choriocapillaris; PD, perfusion density; POAG, primary open angle glaucoma; ONH, optic nerve head; RNFL, retinal nerve fiber layer; RPC, radial peripapillary capillary; SCP, superficial capillary plexus; VD, vessel density. Original Contribution e480 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. (Continued ) Original Contribution However, the “others” group also had significantly reduced choroid PPVD in most sectors and in total peripapillary area. Although NAION eyes had lower choroid PPVD as compared to the “others” group, this was not statistically significant. With resolution of disc swelling, the reduced choroid PPVD in NAION eyes spontaneously recovered. Several studies have confirmed with fluorescein angiography that choroidal circulation should not be affected in NAION (22–24). This reduction of choroidal PPVD may be due to compression by the disc edema (mainly sectoral in NAION and diffuse in “others” group) rather than ischemia leading to transient choroid hypoperfusion. This was also proposed by Sharma et al who similarly found reduced choroidal peripapillary vascular flow density with spontaneous improvement on resolution of optic disc edema (15). However, we cannot rule out the reduction of measured choroidal PPVD was an artifact due to signal reduction from disc edema. In terms of evolution of RPC PPVD with time, we observed that the RPC PPVD of NAION eyes remained significantly reduced in the superonasal sector and in total peripapillary area compared to fellow eyes at 1, 3, and 6 months. This demonstrates persistent sectoral microvascular changes over time, which is in line with the findings by Augstburger et al (17). We observed no significant difference or even mild improvement when comparing sectoral and total PPVD at follow-up with baseline PPVD. By contrast, Gaier et al found increased superficial patent capillary density among acute eyes and attenuation of superficial patent capillary density in nonacute eyes (25). They defined “acute” as any cases with disc swelling and hence, may be studying a different phase of the disease. Nonetheless, we recognize that the results of our study may be convoluted by signal obscuration from peripapillary edema. We, however, believe that this may account for some but not all the reduced PPVD observed, especially because sectoral reduction in RPC PPVD remained consistent even at 6 months when the disc edema had subsided. Nevertheless, longitudinal studies with larger sample size are needed to fully examine the temporal relationship between vascular changes in NAION eyes, and additional studies are needed to evaluate the impact of edema on PPVD measured by the Topcon Triton SS-OCT. The limitations of our study include its small sample size and it was conducted only at a single center. Our sample size was limited by this study’s prospective nature and we excluded all patients presenting at .2 weeks of symptom onset and those with poor quality scans. Comparison was performed between NAION eyes and a heterogenous others group. The automated, customized MATLAB program was also originally designed to study glaucomatous optic neuropathy and not neuro-ophthalmologic conditions; hence, segmentation of the ONH does not have the horizontal cut further segmenting the nasal and the temporal regions into superior and inferior halves. In our study, we used OCT Chuang et al: J Neuro-Ophthalmol 2021; 41: e470-e482 pRNFL as an indicator of optic disc edema. We understand that peripapillary retinal thickness or tissue volume would be a more accurate representation, especially because OCT pRNFL segmentation algorithms may fail in cases of severe optic disc edema (26–28). However, as we were unable to extract data on tissue volume using the data we acquired, we used pRNFL as an alternative after verifying the segmentation on individual scan images. Despite these limitations, this was a pilot study comparing NAION with other optic neuropathies showing on OCT-A a significantly reduced total and sectoral RPC PPVD in acute NAION eyes, which was persistent at 6 months. We intend to extend this study to describe the microvascular changes in NAION and in the other optic neuropathies longitudinally demonstrating evolution. CONCLUSION This study demonstrated that OCT-A can potentially offer additional diagnostic information by showing quantitatively lower PPVD in ischemic sectors in NAION eyes, which corresponded to the presumed pathophysiology of NAION and area of visual field loss. Because there is no single diagnostic test for NAION currently, the use of OCT-A images to analyze PPVD, especially of the RPC layer, may potentially help distinguish acute NAION from other causes of disc swelling, by demonstrating sectoral capillary dropout. Nonetheless, further studies with larger sample size and longitudinal data are needed. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: N. C. Y. Chan, C. Y. Cheung, J. K. H. Lok, and C. K. M. Chan; b. Acquisition of data: N. C. Y. Chan, J. K. H. Lok, and C. K. M. Chan; c. Analysis and interpretation of data: J. C. Chuang, N. C. Y. Chan, C. Y. Cheung, and C. K. M. Chan. Category 2: a. Drafting the manuscript: J. C. Chuang, N. C. Y. Chan, C. Y. Cheung, and C. K. M. Chan; b. Revising it for intellectual content: J. C. Chuang, N. C. Y. Chan, C. Y. Cheung, J. K. H. Lok, and C. K. M. Chan. Category 3: a. Final approval of the completed manuscript: J. C. Chuang, N. C. Y. Chan, C. Y. Cheung, J. K. H. Lok, and C. K. M. Chan. REFERENCES 1. Dingerkus VL, Munk MR, Brinkmann MP, Freiberg FJ, Heussen FMA, Kinzl S, Lortz S, Orgül S, Becker M. Optical coherence tomography angiography (OCTA) as a new diagnostic tool in uveitis. J Ophthalmic Inflamm Infect. 2019;9:10. 2. Schneider EW, Fowler SC. 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