Long-Term Visual Prognosis in Patients With Aquaporin-4-Immunoglobulin G-Positive Neuromyelitis Optica Spectrum Disorder

Background: To identify the factors associated with visual prognosis for functional and structural outcomes of optic neuritis (ON) in patients with aquaporin-4-immunoglobulin (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD). Methods: We included the eyes that experienced at least 1 episode of ON and were followed for at least 2 years after the first attack of ON in patients with AQP4-IgG-positive NMOSD. We performed a retrospective review of clinical data, including ophthalmological examination and orbital MRI, of 34 eyes of 22 patients. Functional outcomes were measured as final visual acuity, visual field index, and mean deviation and structural outcomes as final retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness. Results: The mean age at onset of the first ON was 42.7 ± 13.7, and all patients were female. The poor visual acuity was significantly associated with the worse final visual acuity and thinner RNFL and GCIPL. Older age also showed a negative correlation with RNFL thickness. The number of attacks was not statistically significant for functional and structural outcomes. The lesion involving the intracanalicular optic nerve to the chiasm on orbital MRI showed worse visual acuity and a thinner GCIPL. Rapid high-dose intravenous methylprednisolone pulse therapy within 3 days was statistically significant, with better visual acuity and more preserved GCIPL thickness. Conclusions: Our results indicate that the severity of ON rather than the number of recurrences might be critical for the visual prognosis of patients with AQP4-IgG-positive NMOSD. Rapid treatment within 3 days may improve visual outcomes, and a younger age at onset may have better visual outcomes.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Long-Term Visual Prognosis in Patients With Aquaporin-4Immunoglobulin G–Positive Neuromyelitis Optica Spectrum Disorder Yeji Moon, MD, PhD, Yeonji Jang, MD, Haeng-Jin Lee, MD, PhD, Sung-Min Kim, MD, PhD, Seong-Joon Kim, MD, PhD, Jae Ho Jung, MD, PhD Background: To identify the factors associated with visual prognosis for functional and structural outcomes of optic neuritis (ON) in patients with aquaporin-4-immunoglobulin (AQP4-IgG)–positive neuromyelitis optica spectrum disorder (NMOSD). Methods: We included the eyes that experienced at least 1 episode of ON and were followed for at least 2 years after the first attack of ON in patients with AQP4-IgG–positive NMOSD. We performed a retrospective review of clinical data, including ophthalmological examination and orbital MRI, of 34 eyes of 22 patients. Functional outcomes were measured as final visual acuity, visual field index, and mean deviation and structural outcomes as final retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layer (GCIPL) thickness. Results: The mean age at onset of the first ON was 42.7 ± 13.7, and all patients were female. The poor visual acuity was significantly associated with the worse final visual acuity and thinner RNFL and GCIPL. Older age also showed a negative correlation with RNFL thickness. The number of attacks was not statistically significant for functional and structural outcomes. The lesion involving the intracanalicular optic nerve to the chiasm on orbital MRI showed worse visual acuity and a thinner GCIPL. Rapid high-dose intravenous methylprednisolone pulse therapy within 3 days was statistically significant, with better visual acuity and more preserved GCIPL thickness. Conclusions: Our results indicate that the severity of ON rather than the number of recurrences might be critical for the visual prognosis of patients with AQP4-IgG–positive NMOSD. Rapid treatment within 3 days may improve Department of Ophthalmology (YM, S-JK, JHJ), Seoul National University Hospital, Seoul, Republic of Korea; Department of Ophthalmology (YJ), Eulji Medical Center, Eulji University School of Medicine, Uijeongbu, South Korea; Department of Ophthalmology (H-JL), Jeonbuk National University Hospital, Jeonju, Republic of Korea; Department of Neurology (S-MK), Seoul National University Hospital, Seoul, Republic of Korea; and Department of Ophthalmology (S-JK, JHJ), Seoul National University College of Medicine, Seoul, Republic of Korea. The authors report no conflicts of interest. Address correspondence to: Jae Ho Jung, MD, PhD, 101, Daehak-ro Jongno-gu, Seoul 03080, South Korea; E-mail: [e-mail] Moon et al: J Neuro-Ophthalmol 2022; 42: 303-309 visual outcomes, and a younger age at onset may have better visual outcomes. Journal of Neuro-Ophthalmology 2022;42:303–309 doi: 10.1097/WNO.0000000000001554 © 2022 by North American Neuro-Ophthalmology Society N euromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating autoimmune disease of the central nervous system (CNS), characterized by recurrent attacks of optic neuritis (ON), transverse myelitis, area postrema syndrome, and brainstem symptoms (1,2). It is well-known that aquaporin-4immunoglobulin (AQP4-IgG) is a sensitive and specific serum marker for NMOSD that primarily causes astrocytic damage (3,4). The introduction of AQP4-IgG has improved our understanding of CNS demyelinating disease and expanded the recognition of the clinical phenotype (5). Furthermore, AQP4-IgG provides the diagnostic criteria; AQP4-IgG positivity in NMOSD implies poor visual prognosis after ON as compared with multiple sclerosis and myelin oligodendrocyte glycoprotein antibody–associated disorders (6–12). Because ON occurs in over 60% of NMOSD cases and causes more severe visual disability than other demyelinating ONs, several studies have previously identified prognostic factors for visual outcomes in patients with NMOSD; these factors include age of disease onset, relapsing course, severity of the attacks, length of lesion on MRI, and time from the onset to treatment (13–20). However, these studies did not include serologic test data or they included both AQP4-IgG–positive and AQP4-IgG– negative NMOSD. In addition, they have only assessed the visual acuity as a main outcome, without assessing structural outcomes, such as retinal nerve fiber layer (RNFL) or ganglion cell–inner plexiform layer (GCIPL) thickness. 303 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Therefore, in this study, we aimed to identify the factors associated with long-term visual prognosis for functional and structural outcomes of ON in patients with AQP4IgG–positive NMOSD. METHODS This retrospective study included patients diagnosed with AQP4-IgG–positive NMOSD at Seoul National University Hospital. The study protocol was reviewed and approved by the Institutional Review Board of Seoul National University Hospital. The study procedures were conducted in accordance with the tenets of the Declaration of Helsinki. Study Subjects We screened the patients who were older than 15 years by searching for the serum testing results for AQP4-IgG between February 2010 and December 2018. Serum samples were tested for the presence of AQP4-IgG using a live cell–based assay. The diagnosis of NMOSD with AQP4-IgG based on the 2015 International Panel NMO Diagnostic criteria for NMOSD (7) and contrast-enhanced orbital MRI were performed to make an accurate diagnosis. We included the eyes that experienced at least 1 episode of ON. The exclusion criteria were as follows: (1) history of malignancy, (2) systemic or other ophthalmological diseases that affect visual acuity or visual field (VF) test results, (3) follow-up period of less than 2 years after the first ON attack, and (4) poor quality of data on final visual outcomes (Fig. 1). We reviewed patient medical records for basic demographic data such as age, sex, medical history, and results of ophthalmological examination. To evaluate disease severity, we collected data on the best-corrected visual acuity (BCVA) and logarithm of the minimum angle of resolution (logMAR) at nadir throughout the disease course. In addition, low vision measured as count finger, hand motion, and light perception were converted to logMAR 1.7, 2.0, and 2.3, respectively (21). We also reviewed the data on the time from initial ocular symptoms (pain and/or visual disturbance) to intravenous methylprednisolone administration for each attack. When the patient had undergone recurrent ON during the follow-up period, the longest period from initial symptoms to treatment was selected for the final data analysis. In addition, we evaluated the results of orbital MRI performed within 1 month after the onset of symptoms. The anterior visual pathway was divided into 5 segments and semiquantitatively measured the length of lesions: the anterior/posterior intraorbital optic nerve, intracanalicular optic nerve, intracranial optic nerve, and optic chiasm. Optic nerve segments with gadolinium contrast on fatsuppressed T1 imaging or with a high signal on T2 imaging were regarded as acute ON lesions, and the number of involved segments was measured. The interpretations of the 304 orbital MRI were performed independently and blinded to the clinical information by a neuro-ophthalmologist (Y.M.), with reference to the reports of the neuroradiologist. Finally, when the patients had undergone recurrent ON during the follow-up period, the longest extent of involvement was selected for the final data. Statistical Analysis The following data were collected as final visual outcomes for our observation of more than 2 years after the first ON: (1) functional outcomes: the best visual acuity and the best results of the VF test using a automated perimeter (Swedish interactive threshold algorithm 30-2, Carl Zeiss Meditec, Dublin, CA) after the final ON and (2) structural outcomes: the mean RNFL thickness and the mean ganglion cell–inner plexiform layer (GCIPL) thickness on optical coherence tomography (OCT) using a Cirrus HDOCT device (Carl Zeiss Meditec, Inc). Continuous data were summarized and presented as mean ± SD and range while categorical data were presented as proportions and percentages. Owing to the nonnormal distribution of the data, we tested the correlation between clinical characteristics and visual outcomes using the Spearman rank-order correlation coefficient. In addition, we classified the subjects into 2 groups according to clinical characteristics and compared the visual outcomes between the 2 groups using the Mann–Whitney U test to clarify the factors associated with visual outcomes. All statistical analyses were performed using SPSS version 23.0 (SPSS, Inc, Chicago, IL). RESULTS The study cohort consisted of 34 eyes of 22 patients, all of whom were women. The mean age at the first ON onset was 42.7 ± 13.7; they were followed for an average of 8.5 ± 5.1 years. The mean number of attacks per eye was 1.6 ± 1.5, with 11 eyes (32.4%) exhibiting recurrent ON. We obtained data on the visual acuity at nadir from 19 eyes; the mean visual acuity at nadir was logMAR 1.56 ± 1.17. Of them, 12 eyes (63.2%) showed visual acuity worse than logMAR 1.0 at nadir. Orbital MRI analysis was performed for 19 affected eyes. The intraorbital optic nerve, involved in 17 eyes (89.5%), was the most affected segment. Nine eyes (47.4%) showed ON involvement in segments other than the intraorbital optic nerve with or without intraorbital optic nerve involvement (Table 1). The mean of the final visual acuity in our observation period was logMAR 0.45 ± 0.74, with 5 eyes (14.7%) showing a final visual acuity worse than logMAR 1.0. The mean RNFL and GCIPL thickness was 64.5 ± 13.6 mm and 58.5 ± 9.4 mm, respectively. In correlation analysis, age at the first ON was negatively correlated with RNFL thickness (Spearman r = 20.425, P = 0.012). Older patients also showed thinner GCIPL and poor Moon et al: J Neuro-Ophthalmol 2022; 42: 303-309 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Flow diagram for inclusion and exclusion for the analysis. final visual acuity with borderline significance. The number of ON attacks showed no significant correlation with visual outcomes, whereas the poor visual acuity at nadir showed poor visual outcomes in both functional (visual acuity, Spearman r = 0.658; VF index, Spearman r = 20.529; mean deviation in the VF test, Spearman r = 20.596, and all P , 0.05) and structural (RNFL thickness, Spearman r = 0.556; GCIPL thickness, Spearman r = 20.827, and all P , 0.05) aspects. Longer lesions in MRI were correlated with thinner GCIPL (Spearman r = 20.488, P = 0.034). It also showed correlation with the poor visual acuity and thinner RNFL; however, it did not reach statistical significance (Table 2). In addition, we classified the subjects into 2 groups according to the number of ON attacks (1 vs $ 2), visual acuity at nadir (#logMAR 1.0 vs .logMAR 1.0), and extent of involvement on orbital MRI (not involved in intracanalicular optic nerve chiasm vs involved in intracanalicular optic nerve chiasm) (Table 3). The number of attacks was not significantly correlated with the functional and structural outcomes. When ON was involved in the intracanalicular optic nerve to the chiasm, the final visual acuity and GCIPL were worse and thinner than otherwise, respectively. We obtained data on treatment at acute stage ON for 18 eyes; all were treated with high-dose intravenous methylprednisolone pulse therapy in the acute stage. We analyzed the visual outcomes according to the time from the onset of ON to treatment. In correlation analysis, shorter duration between the onset and the treatment showed better visual acuity (Spearman r = 0.485, P = 0.041), whereas it had no correlation with the results of OCT or VF tests. When the subjects Moon et al: J Neuro-Ophthalmol 2022; 42: 303-309 were classified by the time from the ON onset to treatment at 1 week, there was no significant difference between the 2 groups. However, when the subjects were classified by the time from the onset to treatment as 3 days, the rapid treatment group showed significantly better visual acuity and more preserved GCIPL thickness (Table 4). Of 18 eyes above, 10 eyes were treated with additional plasmapheresis. They showed no significant difference in visual outcomes compared with the eyes without plasmapheresis (Table 5). TABLE 1. Baseline demographic and clinical characteristics of the study population Demographic Characteristics Mean ± SD (Range) Age at 1st optic neuritis, yr Sex (male:female)* Bilaterality (right:left:both)* Follow-up period, yrs No. of attacks (/person) No. of attacks (/eye) VA at nadir (n = 19 eyes)† Extent of involvement on MRI (n = 19 eyes)† Intraorbital optic nerve Intracanalicular optic nerve Intracranial optic nerve Optic chiasm 42.7 ± 13.7 (17.7–67.9) 0:22 6:4:12 8.5 ± 5.1 2.2 ± 2.0 (1–10) 1.6 ± 1.5 (1–9) 1.56 ± 1.17 (0.0–3.0) 17 (89.5%) 9 (47.4%) 7 (36.8%) 1 (5.3%) *Values are presented as the ratio of the number of patients. † Data on visual acuity at nadir and MRI within 1 month after the onset of symptom were obtained for 19 eyes. 305 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Correlation between clinical characteristics and visual outcomes Functional Outcomes VA VFI MD RNFL Thickness GCIPL Thickness 0.313 0.072 0.265 0.130 0.658 0.002 0.429 0.067 20.321 0.110 20.056 0.786 20.529 0.043 20.354 0.179 20.316 0.116 20.019 0.927 20.596 0.019 20.316 0.233 20.425 0.012 20.268 0.126 20.556 0.013 20.438 0.060 20.336 0.060 20.255 0.158 20.827 ,0.001 20.488 0.034 Clinical Characteristics Age at 1st optic neuritis No. of attacks VA at nadir Length of lesions Spearman P Spearman P Spearman P Spearman P r r r r Structural Outcomes Bold font indicates statistical significance with P , 0.05. GCIPL, ganglion cell–inner plexiform layer; MD, mean deviation; RNFL, retinal nerve fiber layer; VA, visual acuity; VFI, visual field index. In our study, younger patients showed more favorable outcomes than older patients. There have been conflicting results on the correlation between age at onset and visual outcomes among previous studies, mainly because of genetic factors (16–18,22). Akaishi et al included Asian patients with AQP4-IgG–positive NMOSD aged from 15 to 70 years, which is similar to the study population in this study. They also found that younger patients had better visual prognosis. CONCLUSIONS In this study, we found that younger age at the first ON, better visual acuity at nadir, ON confined to the intraorbital optic nerve, and rapid treatment with intravenous methylprednisolone within 3 days were statistically significant with better functional and/or structural outcomes in patients with AQP4-IgG–positive NMOSD. The number of recurrences showed no significant correlation with visual outcomes. TABLE 3. Comparison of functional and structural outcomes according to (A) number of optic neuritis attacks, (B) VA at nadir, and (C) extent of involvement on magnetic resonance imaging Functional Outcomes Structural Outcomes RNFL Thickness, mm GCIPL Thickness, mm 28.6 ± 9.2 66.5 ± 15.1 60.1 ± 9.5 62.0 ± 44.4 212.2 ± 13.7 60.2 ± 9.0 55.0 ± 8.6 .0.999 0.866 0.164 0.204 (A) Group VA, logMAR VFI (%) No. of attacks = 1 (n = 23) No. of attacks $2 (n = 11) P 0.33 ± 0.62 77.6 ± 29.1 0.70 ± 0.94 0.153 MD, dB Functional Outcomes (B) Group VA at nadir #logMAR 1.0 (n = 7) VA at nadir .logMAR 1.0 (n = 12) P Structural Outcomes RNFL Thickness, mm GCIPL Thickness, mm 23.1 ± 2.5 72.4 ± 12.5 65.7 ± 7.1 58.8 ± 42.4 214.3 ± 13.0 56.8 ± 10.5 52.6 ± 5.5 0.272 0.224 0.020 0.003 VA, logMAR VFI (%) 20.03 ± 0.11 93.3 ± 4.3 0.72 ± 0.82 0.017 MD, dB Functional Outcomes (C) Group Not involved in intracanalicular optic nerve w chiasm (n = 9) Involved in intracanalicular optic nerve w chiasm (n = 10) P Structural Outcomes RNFL Thickness, mm GCIPL Thickness, mm VA, logMAR VFI (%) MD, dB 20.03 ± 0.12 91.8 ± 10.1 23.8 ± 4.8 71.2 ± 13.8 64.3 ± 8.7 0.26 ± 0.40 82.0 ± 26.8 27.0 ± 8.0 59.8 ± 9.2 53.7 ± 7.2 0.043 0.645 0.505 0.095 0.010 GCIPL, ganglion cell–inner plexiform layer; MD, mean deviation; RNFL, retinal nerve fiber layer; VA, visual acuity; VFI, visual field index. 306 Moon et al: J Neuro-Ophthalmol 2022; 42: 303-309 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 4. Comparison of functional and structural outcomes according to time from the optic neuritis onset to treatment as (A) 1 week and (B) 3 days Functional Outcomes Structural Outcomes (A) Group VA, logMAR VFI (%) MD, dB #1 week (n = 6) .1 week (n = 12) P 0.00 ± 0.12 0.41 ± 0.66 0.315 94.6 ± 4.0 62.5 ± 43.7 0.272 22.7 ± 1.9 213.0 ± 13.8 0.272 RNFL Thickness, mm GCIPL Thickness, mm 69.3 ± 9.3 61.3 ± 15.8 0.122 60.4 ± 8.7 59.8 ± 11.6 0.792 Functional Outcomes (B) Group #3 days (n = 6) .3 days (n = 12) P Structural Outcomes VA, logMAR VFI (%) MD, dB 20.07 ± 0.10 0.31 ± 0.55 0.024 92.5 ± 3.0 74.6 ± 39.0 0.529 23.6 ± 1.5 29.0 ± 12.5 0.776 RNFL Thickness, mm GCIPL Thickness, mm 71.3 ± 10.9 62.9 ± 13.2 0.111 65.7 ± 4.8 56.9 ± 10.3 0.044 Data on treatment at acute stage were obtained for 18 eyes. GCIPL, ganglion cell–inner plexiform layer; MD, mean deviation; RNFL, retinal nerve fiber layer; VA, visual acuity; VFI, visual field index. Thongmee et al reported that BCVA at nadir better than count finger was significantly associated with better visual outcomes after the first episode of ON in patients with NMOSD (22). They included AQP4-IgG–positive and AQP4-IgG–negative NMOSD and analyzed the final visual acuity at 1 year after the first ON without recurrence. In contrast to the previous study, we only included patients with AQP4-IgG–positive ON and analyzed long-term visual outcomes more than 2 years after the first ON. We also found that patients with better BCVA at nadir had better final visual function and optic nerve structure. BCVA at nadir might reflect the severity of inflammation and its effects on functional and structural damage; consequently, the severity of inflammation might be associated with visual prognosis. The lesion length of ON was previously reported as a prognostic factor for visual function in patients with NMOSD (18,20). Similarly, we measured semiquantitatively the length of lesions, which showed the correlation between longer lesions and poor outcomes. In addition, based on the results that the intraorbital optic nerve was affected in 90% of the subjects, it can be inferred that the length of the lesion would be longer in patients with involvement of the extraorbital visual pathway. It indicates that the severity of attack represented as the extent of inflammation on MRI would be associated with the visual outcomes. However, it should be noted that we did not exactly measure the lesion length of ON in this study. Interestingly, all patients with extraorbital visual pathway involvement had lesions in the intracanalicular portion of the optic nerve and so did all patients with longer than 3 segments involvement. It means that the longer extent was correlated with the involvement of intracanalicular optic nerve. Intracanalicular optic nerves are surrounded by bony structures; even a small amount of swelling of the tissue may cause optic nerve compression because of vulnerability to compression, owing to space limitations in the canal (23,24). Therefore, further studies should be needed to certify the effect of lengths and location of lesions, separately. Interestingly, we found that the number of attacks did not correlate with the visual outcomes. Some retrospective studies reported that a relapsing course of NMO had a poor visual prognosis (14,15,25). However, multivariable analysis was not conducted in those studies, and in one of them, the visual acuity at nadir was worse in the relapsing group. Therefore, we can infer that the relapsing group has a higher chance of experiencing any severe attack of ON, which causes severe visual disability. Recurrence of ON is TABLE 5. Comparison of functional and structural outcomes according to the plasmapheresis Functional Outcomes Group VA, logMAR VFI (%) With additional plasmapheresis (n = 10) Without plasmapheresis (n = 8) P 0.11 ± 0.32 93.5 ± 3.4 0.28 ± 0.64 0.965 68.3 ± 42.6 0.955 Structural Outcomes RNFL Thickness, mm GCIPL Thickness, mm 23.5 ± 1.6 63.1 ± 11.4 57.4 ± 7.9 210.6 ± 13.9 0.955 71.3 ± 16.1 0.237 66.8 ± 10.8 0.073 MD, dB Data on treatment at acute stage were obtained for 18 eyes. GCIPL, ganglion cell–inner plexiform layer; MD, mean deviation; RNFL, retinal nerve fiber layer; VA, visual acuity; VFI, visual field index. Moon et al: J Neuro-Ophthalmol 2022; 42: 303-309 307 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution considered to be indirectly related to visual prognosis because it increases the probability of exposure to severe ON rather than the number of attacks correlating with visual outcomes. Another point that requires attention is the time from the onset of ON to treatment. Previously, several studies have reported that the rapid administration of high-dose intravenous methylprednisolone improves the final visual function and retinal nerve fiber structure in patients with NMOSD (22,25,26). In addition, Kleiter and colleagues have emphasized early therapeutic intervention, particularly in AQP4-IgG–seropositive patients. These studies reported a different cut-off duration between the onset of ON and the start of treatment because of the disparity of statistical methods for analysis and distribution of the study population. In our study, we found that rapid treatment within 3 days was associated with a better visual acuity and more preserved GCIPL. Considering this rapid deterioration in visual function, only hyperacute treatment may cause a significant change in disease severity and consequently improve visual outcomes. Our study has several limitations. First, the number of subjects was relatively small, and the median of the number of ON attacks was 1 in this study. It could make a lack of correlation between the recurrence and visual outcomes. In addition, some data on clinical course and MRI could not be obtained, and study subjects in our study had a lower percentage of poor visual outcomes than has been reported in the literature because of the retrospective nature of this study. Owing to the aforementioned reasons, a multivariable analysis could not be performed in this study, which may limit the statistical strength. It should be noted that the visual acuity at nadir and length of lesions on MRI had a significant correlation (Spearman r = 0.679, and all P = 0.005), although the number of attacks showed no significant correlation with age at onset, visual acuity at nadir, length of lesions, or the time from the onset to treatment. Further studies using a multivariable model to identify the relative risk of parameters are needed when we include more subjects in the near future. Second, all subjects in this study were women because their predominance in NMOSD is well known (27). Thus, we were not able to assess the effect of sex on visual prognosis. In addition, the association between age and visual prognosis remains controversial, although our results from 34 eyes showed poor visual prognosis in older patients. Therefore, further studies with larger sample sizes are needed to confirm the effect of age and sex on visual outcomes in patients with APQ4-IgG–positive NMOSD. Finally, the maintenance therapy for recurrence prevention was various in our cohort according to individual clinical and socioeconomic factors. Thus, we were not able to investigate the effect of maintenance therapy on the visual outcomes. Although the number of recurrence was correlated with visual outcomes in this study, recurrence prevention is required to avoid further severe acute optic 308 nerve inflammation. Therefore, well-designed prospective studies should be needed to evaluate the effect of maintenance regimen. In conclusion, the visual acuity at the nadir and extent of involvement of optic nerve inflammation are associated with visual prognosis. Our results indicate that the severity of ON, rather than the number of recurrences, might be critical for the visual prognosis in patients with AQP4-IgG– positive NMOSD. Rapid treatment with intravenous methylprednisolone may improve visual outcomes. Younger age at onset is also significantly correlated with better visual outcomes. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: S.-M. Kim, S.-J. Kim, and Jae Ho Jung; b. Acquisition of data: Y. Moon, Y. Jang, H.-J. Lee, S.-M. Kim, S.-J. Kim, and J. H. Jung; c. Analysis and interpretation of data: Y. 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