Alterations in the Retinal Vascular Network and Structure in MOG Antibody-Associated Disease: An Optical Coherence Tomography Angiography Study

To determine retinal vessel density in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD)

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Alterations in the Retinal Vascular Network and Structure in MOG Antibody-Associated Disease: An Optical Coherence Tomography Angiography Study Jian Yu, PhD, Yongheng Huang, PhD, Chao Quan, PhD, Lei Zhou, PhD, Jingzi ZhangBao, PhD, Kaicheng Wu, PhD, Yuan Zong, PhD, Xujiao Zhou, PhD, Min Wang, PhD Background: To determine retinal vessel density in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Methods: Twenty-five patients with MOGAD and 20 healthy participants were enrolled. Patients with MOGAD were divided into myelin oligodendrocyte glycoprotein antibody (MOG-Ab)-positive eyes with a history of optic neuritis (ON; MOG-Ab-ON+ group) or without a history of ON (MOG-AbON2 group). Visual function, retinal vessel densities, and thickness were measured. Results: The retinal nerve fiber layer, parafoveal ganglion cell and inner plexiform layers, and vessel densities in the peripapillary and parafoveal areas were significantly Department of Ophthalmology and Vision Science (JY, YH, KW, YZ, XZ, MW), Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China; Key Laboratory of Myopia of State Health Ministry (JY, YH, KW, YZ, XZ, MW), and Key Laboratory of Visual Impairment and Restoration of Shanghai, Shanghai, China; NHC Key Laboratory of Myopia (Fudan University) (JY, YH, KW, YZ, XZ, MW), Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, China; Department of Ophthalmology (YH), Kiang Wu Hospital, Macau Special Administration Region, China; and Department of Neurology (LZ, JZB, CQ), Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China. Publication of this article was supported in part by research grants from the National Key Research & Development Plan (2017YFC0108200), the National Natural Science Foundation of China (81771296 and 81801196), the National Key Research and Development Program of China (2016YFC0901504), the Shanghai Committee of Science and Technology (19441900900), and the National Natural Science Foundation of China National Youth Project (81700862). 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). Jian Yu, Yongheng Huang (Wenghang Wong), and Chao Quan contributed equally as first authors. Address correspondence to Min Wang, PhD, Department of Ophthalmology, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai 200031, China; E-mail: [e-mail] e424 decreased in the MOG-Ab-ON+ eyes compared with healthy eyes and MOG-Ab-ON2 eyes (all P , 0.05). An increasing number of ON episodes was associated with greater decreases in these variables (all P , 0.05). Visual field mean deviation was not significantly decreased in patients with a history of 1 or 2 episodes of ON, although the relative decreases in retinal nerve fiber layer thickness, parafoveal ganglion cell and inner plexiform layer thickness, peripapillary vessel density, and parafoveal vessel density reached 33.1%, 23.2%, 17.0%, and 11.5% (all P , 0.05), respectively, in eyes with 2 episodes of ON. The mean deviation was significantly correlated with peripapillary vessel density (P , 0.05) after adjustment for other variables. Bestcorrected visual acuity was not significantly correlated with optical coherence tomography variables (all P . 0.05). Conclusions: MOG-Ab-associated ON was associated with significant decreases in retinal structure and vessel density, without significant deteriorations in visual function. The peripapillary vessel density might predict the visual outcomes in patients with MOG-Ab-associated ON. Journal of Neuro-Ophthalmology 2021;41:e424–e432 doi: 10.1097/WNO.0000000000001116 © 2021 by North American Neuro-Ophthalmology Society M yelin oligodendrocyte glycoprotein (MOG) is a membrane protein expressed on oligodendrocyte cell surfaces and the outermost surface of myelin sheaths (1). With the introduction of highly specific cell-based assays, conformationsensitive anti-MOG antibodies (MOG-Ab) have been detected in a distinct spectrum of central nervous system inflammatory demyelinating disorders, namely MOG-Ab-associated disease (MOGAD), with clinical phenotypes that partly overlap those of acute disseminated encephalomyelitis (2) or aquaporin-4 (AQP4) Ab-negative neuromyelitis optica spectrum disorders (NMOSD) (3). Results from 2 large cohorts of MOG-Abpositive adults have shown that most patients develop recurrent disease, with optic neuritis (ON) being the most frequent Yu et al: J Neuro-Ophthalmol 2021; 41: e424-e432 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution and (2) MOG-Ab-ON2 group (MOG-Ab-positive eyes with no history of ON; 14 eyes). We also divided the patients into 4 subgroups according to the number of episodes of ON (0, 1, 2, or 3+). A further 20 age- and sex-matched healthy participants (40 eyes) were included as a control group. symptom (4,5). We previously reported that, in Chinese patients with MOGAD, 78.2% (68/87) had ON (6). MOG-Ab-associated ON is often associated with severe visual impairment, prominent optic disc swelling, and extensive longitudinal optic nerve lesions with anterior enhancement and perineural soft tissue enhancement, and is generally responsive to steroids (7). Although visual acuity was preserved in most patients with MOG-Ab-associated ON, some had evidence of significant thinning of the retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC), which may indicate axonal loss and irreversible damage of the retina increased vulnerability to sustained visual impairment during relapse (8,9). Recently, Sotirchos et al (10) reported that MOG-Ab-associated ON was associated with severe reductions in the inner retinal layer thicknesses, as observed in AQP4-Ab-associated ON, but the visual outcomes differed markedly between these 2 types of ON because visual acuity was well preserved in MOG-Abassociated ON eyes. Moreover, direct pathological studies of autoantibody-mediated damage using AQP4-immunoglobulin G (IgG) and MOG-IgG indicate that the pathobiology of these disorders differ (11–13). Optical coherence tomography angiography (OCTA) is a noninvasive method of scanning retinal blood vessels at high resolution that was first reported by Jia et al. (14) Using this technique, it was reported that retinal vascular plexus density decreased in multiple sclerosis (MS)associated ON and AQP4-Ab-associated ON, and studies showed different correlations between vascular plexus density and structural and visual outcomes in these disorders (15–18). However, little is known about alterations in retinal blood vessel density in patients with MOGAD. In this study, we investigated the characteristics of the retinal vascular network and structure, and their correlations with visual outcomes in patients with MOGAD. Patient sera were tested for anti-MOG IgG at the Euroimmun Medical Diagnostic Laboratory (China) using a fixed-cell-based indirect immunofluorescence test on BIOCHIPs (EUROIMMUN AG, Lübeck, Germany). METHODS Optical Coherence Tomography Angiography Acquisition and Processing Participants Both eyes were imaged at the same visit. OCTA scans were obtained using a spectral domain system (RTVue-XR Avanti, Optovue, Fremont, CA) (14,20–22). OCTA scans of the optic disc (4.5 · 4.5 mm) and macula (6 · 6 mm) were acquired. The radial peripapillary capillary network was visualized on scans within a 0.75-mm-wide elliptical annular region extending from the optic disc boundary. The vasculature within the internal limiting membrane and the nerve fiber layer was automatically analyzed using the software. The parafoveal capillary network was visualized on scans within the annular zone (1–3 mm diameter) around the foveal center, and the superficial capillary layer from 3 mm below the internal limiting membrane to the outer boundary of the inner plexiform layer was analyzed. The software automatically calculated the thickness of the parafoveal ganglion cell and inner plexiform layer (GCIPL) across the parafoveal area to the depth of the superficial capillary layer. Vessel densities were Twenty-eight patients with MOGAD (56 eyes) were enrolled between June 2015 and June 2017 at the NMO-MS clinic at Huashan Hospital and the Eye & ENT Hospital of Fudan University, Shanghai, China. All patients received a clinical neurological examination with evaluation of the visual functional system score (VFSS) and Expanded Disability Status Scale (EDSS) (19) on the same day as the ophthalmoscopic examinations. Patients who satisfied the following criteria were eligible: no episodes of ON within 3 months before enrolment; refraction error between +1.00 and 26.00; able to cooperate with OCTA and visual field examinations; and MOG-Ab seropositive. Eyes with concomitant potentially confounding diseases (glaucoma, diabetes mellitus, retinal surgery, retinal disease, ametropia .6 diopters) were excluded. The 50 eyes were divided into 2 groups as follows: (1) MOG-Ab-ON+ group (MOG-Ab-positive eyes with a history of ON; 36 eyes); Yu et al: J Neuro-Ophthalmol 2021; 41: e424-e432 Ethics The study was performed in accordance with the Declaration of Helsinki and its amendments. Written informed consent was obtained from all participants. This study was approved by the Medical Ethics Committee of Huashan Hospital and the Eye & ENT Hospital of Fudan University. Detection of Myelin Oligodendrocyte Glycoprotein Antibody Clinical and Ophthalmologic Assessments All the patients and healthy controls underwent slit-lamp and ophthalmoscopic examinations to exclude potential eye diseases. Intraocular pressure (IOP) and axial length (AL) and best-corrected visual acuity (BCVA) were measured. The BCVA was recorded for each eye using metric notation from the Snellen chart, and then converted to the logarithm of the minimum angle of resolution (logMAR). The central visual field was assessed using a Humphrey Field Analyzer 750 with a Swedish Interactive Thresholding Algorithm standard 30–2 test program and Size III stimulus spots (Carl Zeiss Meditec, Dublin, CA), and the mean deviation (MD) was determined. The reliability criteria were false-positive and false-negative rates of ,33% and fixation losses of ,20%. e425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution calculated as the percentage area occupied by large vessels and microvessels (23), and were automatically determined using the software (V.2017.100.0.1, Optovue). The RNFL and macular thicknesses were also measured using the system. The RNFL thickness was measured within a circular region with a diameter of 3.45 mm centered on the optic disc. The quality of OCTA images was evaluated by 2 independent ophthalmologists blinded to the participants’ diagnostic category/group. Poor-quality images with a signal strength index of ,40 and images with residual motion artifacts were rejected. Six eyes of 3 patients with poor visual acuity and fixation were excluded because of severe motion artifacts. Optical coherence tomography (OCT) data acquisition and reporting aligned with the Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations (24). Statistical Analyses Statistical analyses were performed using IBM SPSS V.20.0 (SPSS, Inc, Chicago, IL). Demographic characteristics were compared between the study groups by one-way analysis of variance or the Kruskal–Wallis test. Ophthalmic and OCTA parameters were performed using generalized estimating equations (GEE) with adjustment for intrasubject intereye differences. Correlations between OCTA parameters and spectral domain OCT parameters, and between OCTA parameters and clinical parameters were determined using the GEE models. Statistical significance was set at P , 0.05. RESULTS Demographic and Clinical Characteristics of the Patients Fifty eyes of 25 patients were included in the study, and the clinical features of patients with MOGAD and healthy controls are presented in Table 1 and Supplemental Digital Content, Table E1, http://links.lww.com/WNO/A443. There were no significant differences in the age, sex, AL, mean arterial pressure (MAP), and IOP among the 3 groups (all P . 0.05; Table 2). Furthermore, BCVA was not significantly different among the 3 groups. The MD was significantly lower in the MOG-Ab-ON+ group than in the MOG-Ab-ON2 group (P , 0.05; Table 2). Overall, 17 eyes (47%) had a history of one ON episode, 11 eyes (31%) had a history of 2 episodes, and 8 eyes (22%) had a history of 3 or more episodes. Comparison of Retinal Structure and Vessel Density The RNFL, GCIPL, and vessel densities in the peripapillary and parafoveal areas were significantly decreased in the MOG-Ab-ON+ eyes compared with healthy eyes and MOG-Ab-ON2 eyes (all P , 0.05; Fig. 1), but there were no differences in these variables between the MOG-Ab-ON2 eyes and healthy eyes (all P . 0.05). The mean reduction in RNFL was 27.3 mm (25.7%) in MOG-Ab-ON+ eyes relative to that in healthy eyes. The relative decrease in RNFL (25.7%) was greater than the relative decreases in the GCIPL (19%), peripapillary vessel density (18.6%), and parafoveal vessel density (12.3%). Retinal Damage According to the Number of Optic Neuritis Episodes Among MOG-Ab-positive eyes, GEE models revealed that the mean deviation decreased with increasing number of ON episodes (b = 22.4, standard error [SE] = 1.2, P = 0.039), and with decreases in RNFL (b = 212.9, SE = 1.7, P , 0.001), GCIPL (b = 27.1, SE = 1.2, P , 0.001), parafoveal vessel density (b = 24.8, SE = 0.56; P , 0.001), and parafoveal vessel density (b = 21.8, SE = 0.35, P , 0.001). The first and second episodes of ON were associated with significant reductions in retinal thicknesses and retinal vessel densities (all P , 0.05; Fig. 2). Compared with MOGAb-ON2 eyes, the mean decreases in RNFL and GCIPL were 20.3 mm (18.3%; P , 0.001) and 15.1 mm (12.5%; P TABLE 1. Demographic and clinical characteristics of patients with MOGAD and healthy controls No. of participants No. of eyes Females, n (%) Age (years, mean ± SD) Number of affected eyes One eye, n (%) Both eyes, n (%) No history of ON episodes, n (%) Disease duration, months (median [range]) VFSS in patients with a history of ON (mean ± SD) EDSS score (median [range]) Patients with MOGAD Healthy Controls 25 50 13 (52) 39 ± 10 20 40 11 (55) 34 ± 16 10 (40) 13 (52) 2 (8) 28 (3–120) 1.32 ± 0.68 1.4 (0–7.5) — — — — — — EDSS, expanded disability status scale; MOGAD, MOG-Ab-associated disease; ON, optical neuritis; VFSS, visual functional system score; —, not applicable. e426 Yu et al: J Neuro-Ophthalmol 2021; 41: e424-e432 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Demographics and optic neuritis history characteristics Eyes enrolled Time since last ON, months (median [range]) Age (years, mean ± SD) MAP (mm Hg, mean ± SD) AL (mm, mean ± SD) IOP (mm Hg, mean ± SD) BCVA (LogMAR, mean ± SD) MD (dB, mean ± SD) PSD (dB, mean ± SD) Healthy MOG-Ab-ON2 MOG-Ab-ON+ P 40 — 39 ± 10 87 ± 8 23.54 ± 0.84 14.7 ± 2.6 0.01 ± 0.02 — — 14 — 34 ± 16 87 ± 6 23.66 ± 1.23 15.3 ± 2.6 0.01 ± 0.04 22.44 ± 1.82 2.62 ± 1.83 36 9 (3–48) 34 ± 16 85 ± 6 23.97 ± 1.01 15.6 ± 2.5 0.09 ± 0.19 27.00 ± 8.49 3.41 ± 2.54 — — 0.275 0.383 0.151 0.300 0.091 0.001* 0.296 —, not applicable; AL, axial length; BCVA, best-corrected visual acuity; IOP, intraocular pressure; MAP, mean arterial pressure; MOG-AbON2, MOG-antibody-positive eyes without a history of ON; MOG-Ab-ON+, MOG-antibody-positive eyes with a history of ON; ON, optic neuritis. *P , 0.05 was considered statistically significant. = 0.002), respectively, in eyes with one episode of ON. The corresponding values in eyes with 2 episodes of ON were 36.5 mm (33.1%; P , 0.001) and 28.0 mm (23.2%; P , 0.001). Compared with MOG-Ab-ON2 eyes, the decreases in peripapillary and parafoveal vessel densities were 5.4% (8.7%; P = 0.001) and 3.1% (6.1%; P = 0.049) in eyes with one episode of ON and were 10.5% (17.0%; P , 0.001) and 5.7% (11.5%; P , 0.001) in eyes with 2 episodes of ON, respectively. Despite these marked decreases in retinal thicknesses and vessel densities, the MD was not significantly decreased in eyes with 2 episodes of ON relative to that in MOG-Ab-ON2 eyes (P . 0.05; Fig. 2). BCVA was not significantly different among the 4 groups (all P . 0.05), which may be because patients with poor visual acuity were excluded. FIG. 1. Comparison of retinal structure and vessel density parameters of MOG-Ab-ON+ eyes, MOG-Ab-ON2 eyes, and healthy control eyes. A. Peripapillary vessel density. B. Parafoveal vessel density. C. Average RNFL thickness. D. Parafoveal GCIPL thickness. Boxes are mean ± SD, with individual values shown as symbols. GCIPL, ganglion cell and inner plexiform layer; HC, healthy control; MOG-Ab-ON2, myelin oligodendrocyte glycoprotein antibody-positive eyes with no history of optic neuritis; MOG-Ab-ON+, myelin oligodendrocyte glycoprotein antibody-positive eyes with a history of optic neuritis; RNFL, retinal nerve fiber layer. Yu et al: J Neuro-Ophthalmol 2021; 41: e424-e432 e427 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 2. Effects of number of prior ON episodes on retinal structure and vessel density parameters. A. Visual field mean deviation. B. Peripapillary vessel density. C. Parafoveal vessel density D. Average RNFL thickness. E. Parafoveal GCIPL thickness. Myelin oligodendrocyte glycoprotein antibody-positive eyes were divided into subgroups based on the number of sequential episodes of optic neuritis (none, 1, 2, or at least 3). Boxes are mean ± SD, with individual values shown as symbols. GCIPL, ganglion cell and inner plexiform layer; HC, healthy control; MOG-Ab-ON2, myelin oligodendrocyte glycoprotein antibody-positive eyes with no history of optic neuritis; MOG-Ab-ON+, myelin oligodendrocyte glycoprotein antibodypositive eyes with a history of optic neuritis; RNFL, retinal nerve fiber layer. Correlation Between Optical Coherence Tomography Angiography Parameters and Visual Function in Patients with Myelin Oligodendrocyte Glycoprotein AntibodyAssociated Optic Neuritis In MOG-Ab-positive patients, the mean deviation was significantly correlated with the average RNFL thickness (r = 0.576, P = 0.006), average GCIPL thickness (r = 0.498, P , 0.001), parafoveal vessel density (r = 0.334, P = 0.018), and peripapillary vessel density (r = 0.703, P , 0.001) (Fig. 3). We also performed multivariable analyses to adjust for the GCIPL and RNFL thicknesses and potential interactions with ON. In these adjusted GEE models, the MD was significantly correlated with peripapillary vessel density (b = 1.03, SE = 0.30, P = 0.001). BCVA was not significantly correlated with average RNFL thickness, average GCIPL thickness, parafoveal vessel density, or peripapillary vessel density (all P . 0.05). DISCUSSION In this study, we found evidence of retinal structure and vessel damage in MOG-Ab-positive patients with a history of ON, but not in MOG-Ab-positive patients without a history of ON. We also found that a greater number of ON episodes was associated with more severe visual dysfunction, as well as greater retinal structure and vessel damage. Interestingly, we found that the mean deviation was not e428 significantly decreased in patients with a history of 1 or 2 episodes of ON, although the relative decreases in RNFL thickness, GCIPL thickness, peripapillary vessel density, and parafoveal vessel density reached 33.1%, 23.2%, 17.0%, and 11.5%, respectively, in eyes with 2 episodes of ON. Although the relative reduction in RNFL thickness was greater than the change in peripapillary vessel density, the mean deviation was more strongly correlated with the peripapillary vessel density. Changes in the retinal structure in patients with MOGAb-associated ON have previously been described (9,25). The thinner RNFL and GCIPL detected in our patients are consistent with the results of prior studies showing clear structural damage in MOG-Ab-associated ON (9,16,26). However, few studies have evaluated the retinal vessels in patients with MOG-Ab-associated ON. In the current study, we detected vascular changes in eyes with MOGAb-associated ON, but we did not find any subclinical vascular damage in eyes without ON. This differs from the features reported for patients with AQP4-Ab-positive NMOSD. We previously reported that the peripapillary and parafoveal vessel densities were significantly decreased in eyes with NMOSD, including those without a history of ON. The results provided clear evidence that the retinal blood vessel density decreased in AQP4-Ab-positive NMOSD eyes before the development of ON. However, a decrease in retinal blood vessel density was not observed in the current study of eyes without ON in patients with Yu et al: J Neuro-Ophthalmol 2021; 41: e424-e432 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. Correlations between visual field mean deviation and retinal structural parameters. A. Average RNFL thickness. B. Average GCIPL thickness. C. Parafoveal vessel density. D. Peripapillary vessel density. GCIPL, ganglion cell and inner plexiform layer; RNFL, retinal nerve fiber layer. MOGAD, and in a recent study of MS (27,28). The distinct pathophysiological characteristics of MOGAD and AQP4-Ab-positive NMOSD seemed to partly explain the difference. MOGAD is likely due to an autoimmune response directed against MOG expressed on myelin sheaths. The retina is normally unmyelinated and devoid of MOG (29). The retinal damage and reduced numbers of nerve fibers and ganglion cells in the macula in MOG-Abassociated ON may be due to retrograde degenerative processes, which in turn, reduce metabolic activities. The reduced metabolic demand is expected to decrease retinal perfusion through autoregulatory mechanisms. However, AQP4-Ab-positive NMOSD is characterized by autoimmune astrocytopathy. AQP4 is highly expressed in retinal Müller cells, the cell bodies of which are located in the INL, and astrocytes, which are mainly located in the RNFL, particularly in the end-feet membranes facing blood vessels (30,31). This protein is directly targeted by AQP4-Ab as a potential cause of primary retinopathy in NMOSD. Several independent research groups have detected astrocyte- Yu et al: J Neuro-Ophthalmol 2021; 41: e424-e432 associated vascular changes and suggested that astrocytes play key roles in regulating local cerebrovascular microcirculation (32–34). Therefore, in addition to retrograde degenerative processes, the direct retinal damage caused by AQP4-Ab may be an important cause of the retinal structure and vessel damage in AQP4-Ab-positive eyes without ON. We grouped 4 eyes from patients without a history of ON with 10 eyes from patients with a history of ON in the fellow eye. Given the high incidence of bilateral ON in MOG-IgG patients, the fellow eyes may be more likely to show subclinical disease than eyes from patients with no history of ON. Thus, the inclusion of the 4 fellow eyes may skew the resulting data. However, when we compared the control eyes and 10 eyes from patients with a history of ON in the fellow eye, we obtained the same results (See Supplemental Digital Content, Figure E1, http://links.lww. com/WNO/A442). Further work is needed to confirm whether there is difference between the eyes from patients without a history of ON and the fellow eye. e429 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution BCVA was not significantly different among the 4 groups, and the mean deviation did not significantly decrease in patients with 1 or 2 episodes of ON, although the relative decreases in RNFL thickness, GCIPL thickness, peripapillary vessel density, and parafoveal vessel density reached 33.1%, 23.2%, 17.0%, and 11.5%, respectively, in patients with 2 episodes of ON. These results are similar to those reported by Sotirchos et al, (10) who found marked disagreement between the severity of inner retinal layer thinning and visual outcomes in MOG-Ab-associated ON. Although the severe reductions in the inner retinal layer thicknesses in MOG-Ab-associated ON were similar to those observed in AQP4-Ab-associated ON, the visual outcomes differed markedly, with relative preservation of visual acuity in MOG-Ab-associated ON. The reasons for these differences were unclear, and it is possible that the pathological effects of MOG, as described above, may be an important factor and the retina may not be directly damaged in these eyes. Unlike AQP4-Ab-associated ON, in which the retina may be directly affected, the retinal changes observed in MOG-Ab-associated ON are expected to be due to retrograde degenerative processes. We found that the visual function MD correlated with all the OCT parameters. However, after adjusting the correlation between the structural measures and vessel density in the multivariate model, the peripapillary vessel density was strongly correlated with MD compared with other structural markers. This result agrees with the findings of Yarmohammadi et al (35), who reported an independent relationship between visual field MD and circumpapillary vessel density in glaucoma. We propose a possible explanation for the independent association of peripapillary vessel density and visual field MD. Li and Freedman (36) found that visual stimulation can increase neural activity and cerebral blood flow under normal physiological conditions. Thus, as part of the CNS, we speculate that retinal perfusion may be sensitive to visual stimulation and retinal ganglion cell activity, although this requires further investigation. Costello et al (37) found that in MSassociated ON, when the RNFL thickness was over 75 mm, the MD was not significantly correlated with RNFL thickness, suggesting that RNFL thinning does not completely reflect the functional status of retinal ganglion cells. Therefore, the stronger correlation between vessel density and visual field damage might suggest that vessel density is a better reflection of retinal ganglion cell function than structural loss. Our study has several limitations. First, our sample size was relatively small, which is expected and unavoidable considering the rarity of MOGAD. Second, the crosssectional nature of the study limits our ability to evaluate the implications of changes in the retinal microvasculature during disease progression. Third, we included 6 eyes that underwent ophthalmic examinations within 6 months of ON and, although we did not observe obvious disc edema e430 in the eyes, we cannot exclude the possibility that subclinical disc edema may have skewed the results. Finally, although the OCTA algorithm reduces motion artifacts, poor fixation leads to severe motion artifacts, which result in inaccurate measurements. Severe damage of the ON leads to poor visual acuity and fixation, and 6 eyes of patients with poor visual acuity and fixation were excluded because of severe motion artifacts. A lack of cases with severe damage could bias our results. In conclusion, our study provides compelling evidence that MOG-Ab-associated ON is associated with severe RNFL, GCIPL, peripapillary vessel, and parafoveal vessel damage after ON, but visual function was relatively good. The peripapillary vessel density might predict visual outcomes in patients with MOG-Ab-associated ON. Further studies are necessary to confirm and expand on our findings, and potentially identify new therapeutic targets for ON. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. Yu, Y. Huang, C. Quan, and M. Wang; b. Acquisition of data: J. Yu, Y. Huang (Wenghang Wong), L. Zhou, J. ZhangBao, K. Wu, Y. Zong, X. Zhou, C. Quan, and M. Wang; c. Analysis and interpretation of data: J. Yu, Y. Huang (Wenghang Wong), L. Zhou, J. ZhangBao, K. Wu, Y. Zong, X. Zhou, C. Quan, and M. Wang. Category 2: a. Drafting the manuscript: J. Yu, Y. Huang (Wenghang Wong), L. Zhou, J. ZhangBao, K. Wu, Y. Zong, X. Zhou, C. Quan, and M. Wang; b. Revising it for intellectual content: J. Yu, Y. Huang (Wenghang Wong), C. Quan, and M. Wang. Category 3: a. Final approval of the completed manuscript: J. Yu, Y. Huang (Wenghang Wong), C. Quan, and M. Wang. REFERENCES 1. Schluesener HJ, Sobel RA, Linington C, Weiner HL. A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J Immunol. 1987;139:4016–4021. 2. Baumann M, Sahin K, Lechner C, Hennes EM, Schanda K, Mader S, Karenfort M, Selch C, Hausler M, Eisenkolbl A, Salandin M, Gruber-Sedlmayr U, Blaschek A, Kraus V, Leiz S, Finsterwalder J, Gotwald T, Kuchukhidze G, Berger T, Reindl M, Rostasy K. Clinical and neuroradiological differences of paediatric acute disseminating encephalomyelitis with and without antibodies to the myelin oligodendrocyte glycoprotein. J Neurol Neurosurg Psychiatry. 2015;86:265–272. 3. Kitley J, Waters P, Woodhall M, Leite MI, Murchison A, George J, Küker W, Chandratre S, Vincent A, Palace J. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelinoligodendrocyte glycoprotein antibodies. JAMA Neurol. 2014;71:276. 4. Sepulveda M, Armangue T, Martinez-Hernandez E, Arrambide G, Sola-Valls N, Sabater L, Tellez N, Midaglia L, Arino H, Peschl P, Reindl M, Rovira A, Montalban X, Blanco Y, Dalmau J, Graus F, Saiz A. Clinical spectrum associated with MOG autoimmunity in adults: significance of sharing rodent MOG epitopes. J Neurol. 2016;263:1349–1360. 5. Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K, Pache F, Stich O, Beume L, Hümmert MW, Ringelstein M, Trebst C, Winkelmann A, Schwarz A, Buttmann M, Zimmermann H, Kuchling J, Franciotta D, Capobianco M, Siebert E, Lukas C, Korporal-Kuhnke M, Haas J, Fechner K, Brandt AU, Schanda K, Yu et al: J Neuro-Ophthalmol 2021; 41: e424-e432 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. Aktas O, Paul F, Reindl M, Wildemann B. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflamm. 2016;13:280. Wang L, ZhangBao J, Zhou L, Zhang Y, Li H, Li Y, Huang Y, Wang M, Lu C, Lu J, Zhao C, Quan C. Encephalitis is an important clinical component of myelin oligodendrocyte glycoprotein antibody associated demyelination: a single‐ center cohort study in Shanghai, China. Eur J Neurol. 2018;26:168–174. Zhou L, Huang Y, Li H, Fan J, Zhangbao J, Yu H, Li Y, Lu J, Zhao C, Lu C, Wang M, Quan C. MOG-antibody associated demyelinating disease of the CNS: a clinical and pathological study in Chinese Han patients. J Neuroimmunol. 2017;305:19–28. Ramanathan S, Reddel SW, Henderson A, Parratt JDE, Barnett M, Gatt PN, Merheb V, Kumaran RA, Pathmanandavel K, Sinmaz N, Ghadiri M, Yiannikas C, Vucic S, Stewart G, Bleasel AF, Booth D, Fung VSC, Dale RC, Brilot F. Antibodies to myelin oligodendrocyte glycoprotein in bilateral and recurrent optic neuritis. Neurol Neuroimmunol Neuroinflamm. 2014;1:e40. Pache F, Zimmermann H, Mikolajczak J, Schumacher S, Lacheta A, Oertel FC, Bellmann-Strobl J, Jarius S, Wildemann B, Reindl M, Waldman A, Soelberg K, Asgari N, Ringelstein M, Aktas O, Gross N, Buttmann M, Ach T, Ruprecht K, Paul F, Brandt AU. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 4: afferent visual system damage after optic neuritis in MOG-IgG-seropositive versus AQP4-IgG-seropositive patients. J Neuroinflamm. 2016;13:282. Sotirchos ES, Filippatou A, Fitzgerald KC, Salama S, Pardo S, Wang J, Ogbuokiri E, Cowley NJ, Pellegrini N, Murphy OC, Mealy MA, Prince JL, Levy M, Calabresi PA, Saidha S. Aquaporin-4 IgG seropositivity is associated with worse visual outcomes after optic neuritis than MOG-IgG seropositivity and multiple sclerosis, independent of macular ganglion cell layer thinning. Mult Scler J. 2019:1626802748. Epub ahead of print. Bennett JL, Lam C, Kalluri SR, Saikali P, Bautista K, Dupree C, Glogowska M, Case D, Antel JP, Owens GP, Gilden D, Nessler S, Stadelmann C, Hemmer B. Intrathecal pathogenic antiaquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol. 2009;66:617–629. Saadoun S, Waters P, Owens GP, Bennett JL, Vincent A, Papadopoulos MC. Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain. Acta Neuropathol Commun. 2014;2:35. Spadaro M, Winklmeier S, Beltran E, Macrini C, Hoftberger R, Schuh E, Thaler FS, Gerdes LA, Laurent S, Gerhards R, Brandle S, Dornmair K, Breithaupt C, Krumbholz M, Moser M, Krishnamoorthy G, Kamp F, Jenne D, Hohlfeld R, Kumpfel T, Lassmann H, Kawakami N, Meinl E. Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein. Ann Neurol. 2018;84:315–328. Jia Y, Tan O, Tokayer J, Potsaid B, Wang Y, Liu JJ, Kraus MF, Subhash H, Fujimoto JG, Hornegger J, Huang D. Split-spectrum amplitude-decorrelation angiography with optical coherence tomography. Opt Express. 2012;20:4710–4725. Kwapong WR, Peng C, He Z, Zhuang X, Shen M, Lu F. Altered macular microvasculature in neuromyelitis optica spectrum disorders. Am J Ophthalmol. 2018;192:47–55. Huang Y, Zhou L, ZhangBao J, Cai T, Wang B, Li X, Wang L, Lu C, Zhao C, Lu J, Quan C, Wang M. Peripapillary and parafoveal vascular network assessment by optical coherence tomography angiography in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders. Br J. Ophthalmol. 2019;103:789–796. Murphy OC, Kwakyi O, Iftikhar M, Zafar S, Lambe J, Pellegrini N, Sotirchos ES, Gonzalez-Caldito N, Ogbuokiri E, Filippatou A, Yu et al: J Neuro-Ophthalmol 2021; 41: e424-e432 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. Risher H, Cowley N, Feldman S, Fioravante N, Frohman EM, Frohman TC, Balcer LJ, Prince JL, Channa R, Calabresi PA, Saidha S. Alterations in the retinal vasculature occur in multiple sclerosis and exhibit novel correlations with disability and visual function measures. Mult Scler. 2019:911861508. Lanzillo R, Cennamo G, Moccia M, Criscuolo C, Carotenuto A, Frattaruolo N, Sparnelli F, Melenzane A, Lamberti A, Servillo G, Tranfa F, De Crecchio G, Brescia MV. Retinal vascular density in multiple sclerosis: a 1-year follow-up. Eur J Neurol. 2019;26:198–201. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33:1444–1452. Yu J, Gu R, Zong Y, Xu H, Wang X, Sun X, Jiang C, Xie B, Jia Y, Huang D. Relationship between retinal perfusion and retinal thickness in healthy subjects: an optical coherence tomography angiography study. Invest Ophthalmol Vis Sci. 2016;57:T204–T210. Yu J, Xiao K, Huang J, Sun X, Jiang C. Reduced retinal vessel density in obstructive sleep apnea syndrome patients: an optical coherence tomography angiography study. Invest Ophth Vis Sci. 2017;58:3506. Yu J, Jiang C, Wang X, Zhu L, Gu R, Xu H, Jia Y, Huang D, Sun X. Macular perfusion in healthy Chinese: an optical coherence tomography angiogram study. Invest Ophthalmol Vis Sci. 2015;56:3212–3217. Jia Y, Morrison JC, Tokayer J, Tan O, Lombardi L, Baumann B, Lu CD, Choi W, Fujimoto JG, Huang D. Quantitative OCT angiography of optic nerve head blood flow. Biomed Opt Express. 2012;3:3127–3137. Cruz-Herranz A, Balk LJ, Oberwahrenbrock T, Saidha S, Martinez-Lapiscina EH, Lagreze WA, Schuman JS, Villoslada P, Calabresi P, Balcer L, Petzold A, Green AJ, Paul F, Brandt AU, Albrecht P. The APOSTEL recommendations for reporting quantitative optical coherence tomography studies. Neurology. 2016;86:2303–2309. Zhao G, Chen Q, Huang Y, Li Z, Sun X, Lu P, Yan S, Wang M, Tian G. Clinical characteristics of myelin oligodendrocyte glycoprotein seropositive optic neuritis: a cohort study in Shanghai, China. J Neurol. 2018;265:33–40. Oertel FC, Outteryck O, Knier B, Zimmermann H, Borisow N, Bellmann-Strobl J, Blaschek A, Jarius S, Reindl M, Ruprecht K, Meinl E, Hohlfeld R, Paul F, Brandt AU, Kümpfel T, Havla J. Optical coherence tomography in myelin-oligodendrocyteglycoprotein antibody-seropositive patients: a longitudinal study. J Neuroinflamm. 2019;16. Feucht N, Maier M, Lepennetier G, Pettenkofer M, Wetzlmair C, Daltrozzo T, Scherm P, Zimmer C, Hoshi M, Hemmer B, Korn T, Knier B. Optical coherence tomography angiography indicates associations of the retinal vascular network and disease activity in multiple sclerosis. Mult Scler J. 2019;25:224–234. Wang X, Jia Y, Spain R, Potsaid B, Liu JJ, Baumann B, Hornegger J, Fujimoto JG, Wu Q, Huang D. Optical coherence tomography angiography of optic nerve head and parafovea in multiple sclerosis. Br J Ophthalmol. 2014;98:1368–1373. FitzGibbon T, Nestorovski Z. Morphological consequences of myelination in the human retina. Exp Eye Res. 1997;65:809– 819. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I, Weinshenker BG. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364:2106–2112. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005;202:473–477. Takano T, Tian G, Peng W, Lou N, Libionka W, Han X, Nedergaard M. Astrocyte-mediated control of cerebral blood flow. Nat Neurosci. 2006;9:260–267. e431 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution 33. Anderson CM, Nedergaard M. Astrocyte-mediated control of cerebral microcirculation. Trends Neurosci. 2003;26:340– 344. 34. Straub SV, Nelson MT. Astrocytic calcium signaling: the information currency coupling neuronal activity to the cerebral microcirculation. Trends Cardiovas Med. 2007;17:183–190. 35. Yarmohammadi A, Zangwill LM, Diniz-Filho A, Suh MH, Yousefi S, Saunders LJ, Belghith A, Manalastas PI, Medeiros FA, Weinreb RN. Relationship between optical coherence e432 tomography angiography vessel density and severity of visual field loss in glaucoma. Ophthalmology. 2016;123:2498–2508. 36. Li B, Freeman RD. Neurometabolic coupling between neural activity, glucose, and lactate in activated visual cortex. J Neurochem. 2015;135:742–754. 37. Costello F, Coupland S, Hodge W, Lorello GR, Koroluk J, Pan YI, Freedman MS, Zackon DH, Kardon RH. Quantifying axonal loss after optic neuritis with optical coherence tomography. Am J Ophthalmol. 2006;142:715. Yu et al: J Neuro-Ophthalmol 2021; 41: e424-e432 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.