Long-term Recovery of Retinal Structure and Function in Vogt-Koyanagi-Harada Disease: A 5-Year Follow-up Study Using Adaptive Optics Imaging and Fundus Microperimetry

Long-term Recovery of Retinal Structure and Function in Vogt-Koyanagi-Harada Disease: A 5-Year Follow-up Study Using Adaptive Optics Imaging and Fundus Microperimetry | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Long-term Recovery of Retinal Structure and Function in Vogt-Koyanagi-Harada Disease: A 5-Year Follow-up Study Using Adaptive Optics Imaging and Fundus Microperimetry Tomoko Nakamura, Shinya Abe, Toshihiko Oiwake, Atsushi Hayashi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6175565/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Jan, 2026 Read the published version in Scientific Reports → Version 1 posted 11 You are reading this latest preprint version Abstract Vogt-Koyanagi-Harada (VKH) disease recovery patterns remain inadequately characterized over extended periods. This study evaluated retinal changes in VKH patients across 5 years using adaptive optics imaging and microperimetry. Twenty-five eyes from 13 patients were monitored longitudinally. Macular cone density gradually increased throughout the observation period but remained below healthy control levels. Eyes with pretreatment cystoid spaces initially showed lower cone density values, but this disparity disappeared after 3 years. Average threshold values improved consistently from baseline, while macular integrity values significantly decreased after 2 years. Cone density correlated significantly with retinal sensitivity. These findings indicate that with appropriate treatment, VKH disease demonstrates progressive improvement in both retinal structure and function over time, though complete structural recovery may not occur. Pretreatment cystoid spaces influence early outcomes but do not significantly affect long-term recovery. Biological sciences/Neuroscience/Visual system/Retina Health sciences/Diseases/Eye diseases/Uveal diseases Vogt-Koyanagi-Harada disease cone density adaptive optics photoreceptor retinal sensitivity microperimetry Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Vogt-Koyanagi-Harada (VKH) disease is a systemic inflammatory disorder characterized by autoimmune reactions that target melanocytes 1 , 2 . It affects multiple organs including the eyes, inner ear, meninges, and skin, with ocular manifestations typically presenting as bilateral uveitis accompanied by serous retinal detachment and optic disc edema 3 , 4 . As a characteristic finding of serous retinal detachment (SRD) in VKH disease, multilobular cysts with reflective septae in subretinal fluid have been shown to be a useful diagnostic feature of VKH disease in early-stage patients 5 , 6 . While VKH disease generally demonstrates favorable visual outcomes with appropriate treatment 7 , the long-term impact of these cystic spaces on the prognosis regarding visual function, changes in the retinal microstructure, and qualitative aspects of visual recovery remain inadequately understood. In a structural retinal assessment, advances in adaptive optics (AO) technology have enabled the high-resolution imaging of cone photoreceptors in vivo, facilitating temporal evaluations of the relationship between the retinal microstructure and visual function 8 , 9 . Using AO and optical coherence tomography (OCT), Zhang et al. demonstrated a correlation between the reflective point distribution in C-scans at the inner segment/outer segment junction and the cone spacing, establishing that AO imaging can monitor patients' outer segment status over time 10 . In addition, Litts et al. comprehensively demonstrated that cone mosaic reflectivity reflects outer segment health 11 . For a functional assessment, macular integrity assessment (MAIA) microperimetry provides enhanced reproducibility and a detailed sensitivity evaluation compared to conventional microperimetry. MAIA microperimetry enables the real-time tracking of minute eye movements, providing accurate measurements of sensitivity changes at identical retinal locations, which makes it particularly suitable for long-term functional monitoring. MAIA microperimetry also provides a macular integrity index, allowing quantitative evaluations of retinal functional integrity 12 , 13 . In this study, we observed patients with VKH disease over a 5-year period to comprehensively understand the structural and functional recovery process in this disease. By combining cone density measurements using AO imaging with a retinal sensitivity assessment using MAIA, we focused on elucidating the influence of initial cystic spaces on long-term outcomes and the temporal correlation between structural and functional indices. Methods Study design and patients This retrospective study included consecutive patients diagnosed with acute-phase VKH at Toyama University Hospital between 2012 and 2018. Diagnosis was based on international criteria 1 . Only eyes with foveal SRD before steroid treatment and ≥ 5 years follow-up were included. Thirty eyes from 30 healthy volunteers served as controls. The study was approved by the Research Ethics Committee of Toyama University Hospital (approval no. R2024039), with informed consent waiver and opt-out option provided. All methods were performed in accordance with relevant guidelines and regulations. Ophthalmologic assessments and treatment All patients underwent comprehensive ocular examinations at baseline, including BCVA, fundus examination, standard spectral domain OCT examination along with enhanced depth imaging-OCT (RS-3000 Advance; Nidek, Aichi, Japan) or Swept Source OCT (Triton; Topcon, Tokyo), and fluorescein and indocyanine green angiography. OCT was performed every 2–3 days for 2 weeks, then biweekly until SRD resolution, and monthly thereafter. Following treatment completion, patients were examined every 3–6 months. Treatment consisted of intravenous methylprednisolone (1000 mg/day for 3 days) followed by tapering oral prednisolone. Two patients received additional cyclosporine, and one received both cyclosporine and adalimumab. Thirty eyes from 30 healthy volunteers served as controls for AO cone density analysis. Adaptive optics imaging and the measurement of cone density Macular AO images were captured using the rtx1™ AO fundus camera (Imagine Eyes; Orsay, France). High-resolution images were obtained at the fovea and four surrounding regions (nasal, temporal, superior, and inferior). The image alignment and the creation of multi-image mosaics were accomplished using i2k Retina software (DualAlign™, Clifton Park, NY). Cone density measurements were performed using AO Detect Mosaic V2.0b17 (Imagine Eyes), with axial length measurements from OA-2000 biometer (Tomey, Nagoya, Japan). Measurements were taken in all quadrants at 0.75 mm from the foveal center, using 80-µm2 regions to avoid retinal capillaries. The same areas were identified using retinal capillary patterns. Baseline was defined as initial OCT confirmation of SRD resolution. Cone density was evaluated at baseline, 6 months, and 1, 2, 3, and 5 years post-resolution. For microperimetry correlation analysis, mean cone density values from all four locations were used. Fundus microperimetry procedure For microperimetric assessments, we used MAIA system (CenterVue, Padova, Italy). Examinations were conducted using the Expert Protocol, administered monocularly at specific intervals, i.e., upon the resolution of the patient's SRD (baseline) and then at 6 months and 1, 2, 3, and 5 years post-resolution. The protocol used Goldmann III white stimuli and a 4 − 2 threshold strategy. The stimulus luminance ranged from 0 to 36 decibels (dB), with a peak intensity of 318 cd/m². The test grid comprised 37 points within a 10° central macular area, arranged in three concentric rings (2°, 6°, and 10°) of 12 points each, plus a central point. We analyzed two primary metrics: the macular integrity (a value normalized against age-adjusted data) and the average threshold. These parameters provided comprehensive insights into the patients' macular function and sensitivity across the 5-year follow-up period. Cystoid space detection on pretreatment OCT We investigated the correlations among the patients' pretreatment OCT findings, mean cone density, macular integrity, and average threshold. At the initial pretreatment visit for each patient, we assessed the OCT images for the presence/absence of cystoid spaces at 0.75 mm from the foveal center, which corresponded to the location of the cone density measurements. Based on these findings, the patients were categorized into two groups: those without cystoid spaces on pretreatment OCT and those with cystoid spaces. Data collection and analysis The patients' MAIA and AO imaging data were collected and analyzed using JMP® 17 software (SAS Institute, Cary, NC). Paired t-tests and Spearman's correlation coefficients were used to compare the MAIA data and cone density at various time points after the resolution of SRD. Data are presented as mean ± standard deviation. Results Thirteen patients (25 eyes) with acute VKH disease were examined. The mean age of the VKH patient group (mean ± standard deviation) was 44.4 ± 11.0 years (range 27–58 years), and that of the healthy control group was 34.5 ± 9.4 years (range 22–50 years). The mean BCVA values in logMAR units for all 25 eyes are presented in Table 1 . Significant improvements in BCVA were observed from baseline through 5 years compared to the pre-steroid treatment values (p < 0.001 for all comparisons). In all cases, the SRD improved after the initial systemic steroid treatment, and no SRD recurrence was observed during the 5-year follow-up period. Table 1 Mean BCVA values in LogMAR units over time (n = 25 eyes) Time Point Mean ± SD Range p-value* Pre-steroid Treatment 0.21 ± 0.28 -0.18 to 0.82 − Baseline (SRD resolution) -0.05 ± 0.15 -0.18 to 0.40 p < 0.001 6 months -0.13 ± 0.08 -0.18 to 0.15 p < 0.001 1 year -0.15 ± 0.06 -0.18 to 0.05 p < 0.001 2 years -0.15 ± 0.07 -0.18 to 0.05 p < 0.001 3 years -0.14 ± 0.08 -0.18 to 0.15 p < 0.001 5 years -0.14 ± 0.10 -0.30 to 0.15 p < 0.001 * Statistical significance was calculated in comparison to pre-steroid treatment values. Abbreviations : BCVA, best-corrected visual acuity; LogMAR, logarithm of the minimum angle of resolution; SD, standard deviation; SRD, serous retinal detachment. Changes in mean cone density Cone densities at 0.75 mm from the foveal center were analyzed over the 5-year follow-up period. Mean cone densities in VKH eyes showed significant increases from baseline at all time points (p < 0.001) (Fig. 1 a). At 5 years, the mean cone density in VKH eyes remained significantly lower than that of healthy control eyes (24496 ± 3220 cones/mm 2 ) (p = 0.004) (Fig. 1 b). Eyes with cystoid spaces showed significantly lower cone densities compared to those without from baseline to 2 years (p < 0.001–0.045), but no significant differences were observed from years 3 to 5 (Fig. 1 c). Detailed statistical analyses and complete datasets are provided in Supplementary Table S1 and S2. MAIA analysis of Macular Integrity and Average Threshold values Macular integrity and average threshold were analyzed over the 5-year follow-up period, with detailed data provided in Supplementary Table S3. Mean macular integrity values showed a significant decrease from baseline at 2, 3, and 5 years (p = 0.042, p = 0.027, and p = 0.018, respectively) (Fig. 2 a), while average threshold values showed significant increases at all time points compared to baseline (p < 0.001–0.022) (Fig. 2 b). Macular integrity and average threshold values were compared between eyes with and without cystoid spaces on pretreatment OCT, with detailed data provided in Supplementary Table S4. While eyes with cystoid spaces showed a trend toward higher macular integrity values at baseline and 6 months, there were no significant differences between groups throughout the 5-year follow-up period (Fig. 2 c). The average threshold values were significantly lower in eyes with cystoid spaces at baseline, 6 months, and 1 year (p = 0.014, p = 0.043 and p = 0.045, respectively), but no significant differences were observed after 2 years (Fig. 2 d). The correlations between the mean cone density and the MAIA parameters The relationship between the mean cone density and each of the MAIA parameters was analyzed. The distribution of mean cone density and MAIA parameters at each measurement point is illustrated in Fig. 3 . The Spearman correlation coefficient between the mean cone density and the macular integrity value was ρ = −0.4993 (p < 0.0001). The Spearman correlation coefficient between the mean cone density and the average threshold value was ρ = 0.6070 (p < 0.0001), indicating a significant correlation. Figure 4 shows the temporal changes in both AO and MAIA findings over 5 years in a representative case. Supplementary video S1 demonstrates the sequential changes in cone mosaic patterns observed by AO imaging. Discussion This 5-year study revealed two key findings: ( i ) the cone density in patients with VKH gradually increased over time, with early recovery influenced by pretreatment cystoid spaces, although differences resolved after 3 years; and ( ii ) the patients' retinal function showed continuous improvement in threshold values and macular integrity. Notably, despite the treatment and improvement, the cone density remained lower than that in the healthy eyes throughout the study period, indicating long-lasting effects of VKH disease on the outer retinal layer. One of our research group's previous studies revealed a gradual recovery of cone density during a 12-month follow-up period after the resolution of the patients' SRD, although the recovery did not reach healthy eye levels 14 . This incomplete recovery likely involves two mechanisms: inflammatory damage to photoreceptor outer segments and damage from the SRD itself 15 – 17 . In addition, the correlation between the reflective point distribution in C-scans at the inner segment/outer segment junction and cone spacing observed by Zhang et al. with the use of adaptive optics SD-OCT 10 supports our direct observations of outer-segment damage through AO imaging. Interestingly, the maintenance of good visual acuity despite lower cone density compared to healthy eyes might be explained by Doi et al.'s theory of cone photoreceptor redundancy relative to retinal ganglion cells 18 . The second key finding of our present investigation concerns the structural and functional impact of cystoid spaces and their temporal changes. It has been established that VKH disease is characterized by multilobular cysts with reflective septae in subretinal fluid, occurring in 61.5% of untreated cases, particularly in young, early-stage patients 5 , 6 . In the present study, the cases with cystoid spaces showed not only a significantly reduced initial cone density but also significantly lower mean retinal sensitivity up to 1 year after the initiation of treatment. This correlation between morphology and function is supported by several studies. Lee et al. demonstrated that cystoid spaces caused a separation of inner and outer segments, correlating with initial visual decline 19 , and Bae et al. showed that VKH cases with a high fibrin index demonstrated a reduced photoreceptor outer segment volume after the resolution of their SRD 20 . Notably, our present findings demonstrated that the impact of cystoid spaces lessened over time, with differences in cone photoreceptor density disappearing after 3 years. Regarding the relationship between OCT morphological changes and visual function, Zhou et al. reported that the integrity of the ellipsoid zone and the interdigitation zone strongly correlated with visual function 21 . That finding suggested that early appropriate therapeutic intervention may improve initial structural and functional photoreceptor layer damage, leading to long-term recovery. We evaluated long-term retinal functional changes in the macula of VKH patients by using MAIA microperimetry, and we examined their correlation with cone density. The results revealed the following findings. The MAIA evaluation revealed that the average threshold significantly improved after 6 months of treatment and continued to show gradual improvement. This aligns with the report by Abu El-Asrar et al. concerning the pattern of retinal sensitivity improvement up to 12 months post-treatment 22 . Regarding macular integrity parameters, a significant score reduction was observed in that study after treatment, indicating long-term improvement in retinal function. The significant correlation between cone density and MAIA parameters in VKH eyes is a noteworthy finding. In particular, the positive correlation with mean retinal sensitivity and the negative correlation with macular integrity directly demonstrate the relationship between morphological and functional changes. These results support Zhou et al.'s findings regarding the correlation between photoreceptor layer integrity observed on OCT and macular function 23 . Our results emphasize the importance of comprehensive structural and functional monitoring in VKH disease. As Abu El-Asrar et al. noted, an assessment of visual acuity alone may underestimate a patient's retinal impairment, highlighting microperimetry's value 22 . Our present 5-year study demonstrates that early treatment provides good outcomes despite the presence of initial cystoid spaces, and adaptive optics with a MAIA analysis provides valuable cellular-level insights that are applicable to other retinal disorders. This study has several limitations, including the small sample size and restricted cone density measurement points. Due to its relatively small scale, caution is required in generalizing the results. Future research should examine larger patient groups, broader retinal regions, and more factors that may affect the treatment response. Understanding the molecular mechanisms behind recovery processes could advance personalized treatment approaches for VKH disease. Declarations Competing interests All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. Author Contribution TN and SA designed the study. TN and TO analyzed the data. TN and AH interpreted results and wrote the manuscript. TO and AH critically revised the content. TN and AH coordinated the research planning and execution. Acknowledgements: This work was supported by a grant from the Japan Society for the Promotion of Science (JSPS) KAKENHI, no. JP24K19785. Data Availability The datasets used and/or analysed during the current study available from the corresponding author on reasonable request. References Read, R. W. et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am. J. Ophthalmol. 131 , 647–652. 10.1016/s0002-9394(01)00925-4 (2001). Sugita, S. et al. Ocular infiltrating CD4 + T cells from patients with Vogt-Koyanagi-Harada disease recognize human melanocyte antigens. Invest. Ophthalmol. Vis. Sci. 47 , 2547–2554. 10.1167/iovs.05-1547 (2006). Moorthy, R. S., Inomata, H. & Rao, N. A. Vogt-Koyanagi-Harada syndrome. Surv. Ophthalmol. 39 , 265–292. 10.1016/s0039-6257(05)80105-5 (1995). O'Keefe, G. A. & Rao, N. A. Vogt-Koyanagi-Harada disease. Surv. Ophthalmol. 62 , 1–25. 10.1016/j.survophthal.2016.05.002 (2017). Tsujikawa, A. et al. Retinal cystoid spaces in acute Vogt-Koyanagi-Harada syndrome. Am. J. Ophthalmol. 139 , 670–677. 10.1016/j.ajo.2004.11.053 (2005). Yamaguchi, Y., Otani, T. & Kishi, S. Tomographic features of serous retinal detachment with multilobular dye pooling in acute Vogt-Koyanagi-Harada disease. Am. J. Ophthalmol. 144 , 260–265. 10.1016/j.ajo.2007.04.007 (2007). Nakayama, M., Keino, H., Watanabe, T. & Okada, A. A. Clinical features and visual outcomes of 111 patients with new-onset acute Vogt-Koyanagi-Harada disease treated with pulse intravenous corticosteroids. Br. J. Ophthalmol. 103 , 274–278. 10.1136/bjophthalmol-2017-311691 (2019). Roorda, A. & Duncan, J. L. Adaptive optics ophthalmoscopy. Annu. Rev. Vis. Sci. 1 , 19–50. 10.1146/annurev-vision-082114-035357 (2015). Pircher, M. & Zawadzki, R. J. Review of adaptive optics OCT (AO-OCT): principles and applications for retinal imaging [Invited]. Biomed. Opt. Express . 8 , 2536–2562. 10.1364/BOE.8.002536 (2017). Zhang, Y. & Roorda, A. Evaluating the lateral resolution of the adaptive optics scanning laser ophthalmoscope. J. Biomed. Opt. 11 , 014002. 10.1117/1.2166434 (2006). Litts, K. M., Cooper, R. F., Duncan, J. L. & Carroll, J. Photoreceptor-Based Biomarkers in AOSLO Retinal Imaging. Invest. Ophthalmol. Vis. Sci. 58 , BIO255–BIO267. 10.1167/iovs.17-21868 (2017). Molina-Martin, A., Pinero, D. P. & Perez-Cambrodi, R. J. Normal values for microperimetry with the MAIA microperimeter: sensitivity and fixation analysis in healthy adults and children. Eur. J. Ophthalmol. 27 , 607–613. 10.5301/ejo.5000930 (2017). Parodi, M. B. et al. Mp1 and Maia Fundus Perimetry in Healthy Subjects and Patients Affected by Retinal Dystrophies. Retina 35 , 1662–1669. 10.1097/IAE.0000000000000504 (2015). Nakamura, T., Hayashi, A. & Oiwake, T. Recovery of macular cone photoreceptors in Vogt-Koyanagi-Harada disease. Graefes Arch. Clin. Exp. Ophthalmol. 256 , 387–394. 10.1007/s00417-017-3869-5 (2018). Yamaki, K. et al. Ocular and extraocular inflammation induced by immunization of tyrosinase related protein 1 and 2 in Lewis rats. Exp. Eye Res. 71 , 361–369. 10.1006/exer.2000.0893 (2000). Hayakawa, K., Ishikawa, M. & Yamaki, K. Ultrastructural changes in rat eyes with experimental Vogt-Koyanagi-Harada disease. Jpn J. Ophthalmol. 48 , 222–227. 10.1007/s10384-003-0061-8 (2004). Sakai, T. et al. Cone photoreceptor recovery after experimental detachment and reattachment: an immunocytochemical, morphological, and electrophysiological study. Invest. Ophthalmol. Vis. Sci. 44 , 416–425. 10.1167/iovs.02-0633 (2003). Doi, E. et al. Efficient coding of spatial information in the primate retina. J. Neurosci. 32 , 16256–16264. 10.1523/JNEUROSCI.4036-12.2012 (2012). Lee, J. E. et al. Edema of the photoreceptor layer in Vogt-Koyanagi-Harada disease observed using high-resolution optical coherence tomography. Korean J. Ophthalmol. 23 , 74–79. 10.3341/kjo.2009.23.2.74 (2009). Bae, S. S. & Forooghian, F. Optical Coherence Tomography-Based Quantification of Photoreceptor Injury and Recovery in Vogt-Koyanagi-Harada Uveitis. Ocul Immunol. Inflamm. 25 , 338–343. 10.3109/09273948.2015.1125510 (2017). Zhou, M. et al. Differences in photoreceptor recovery among patients and between different parts of the posterior pole in Vogt-Koyanagi-Harada disease. Eye (Lond) . 32 , 572–578. 10.1038/eye.2017.250 (2018). Abu El-Asrar, A. M., Al-Mezaine, H. S., Hemachandran, S., Hariz, R. & Kangave, D. Retinal functional changes measured by microperimetry after immunosuppressive therapy in patients with Vogt-Koyanagi-Harada disease. Eur. J. Ophthalmol. 22 , 368–375. 10.5301/ejo.5000035 (2012). Zhou, M. et al. Correlation between Retinal Changes and Visual Function in Late-Stage Vogt-Koyanagi-Harada Disease: An Optical Coherence Tomography Study. J Ophthalmol 916485, (2015). 10.1155/2015/916485 (2015). Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6175565","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":432126734,"identity":"00f6529d-32f1-4abe-917f-d806dd373667","order_by":0,"name":"Tomoko Nakamura","email":"data:image/png;base64,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","orcid":"","institution":"University of Toyama","correspondingAuthor":true,"prefix":"","firstName":"Tomoko","middleName":"","lastName":"Nakamura","suffix":""},{"id":432126735,"identity":"8c71c0f4-a7dd-4be8-bff0-c26a5b2f76c8","order_by":1,"name":"Shinya Abe","email":"","orcid":"","institution":"University of Toyama","correspondingAuthor":false,"prefix":"","firstName":"Shinya","middleName":"","lastName":"Abe","suffix":""},{"id":432126736,"identity":"6b71fe18-6204-4b9e-861c-f36cde058eb9","order_by":2,"name":"Toshihiko Oiwake","email":"","orcid":"","institution":"University of Toyama","correspondingAuthor":false,"prefix":"","firstName":"Toshihiko","middleName":"","lastName":"Oiwake","suffix":""},{"id":432126737,"identity":"d6734c9d-3c93-460f-8eab-95d7efa390a9","order_by":3,"name":"Atsushi Hayashi","email":"","orcid":"","institution":"University of Toyama","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Hayashi","suffix":""}],"badges":[],"createdAt":"2025-03-07 06:38:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6175565/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6175565/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-34652-6","type":"published","date":"2026-01-20T15:57:40+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":79174611,"identity":"56ab6a1b-99b6-4fcd-a527-63fd5e4240b5","added_by":"auto","created_at":"2025-03-25 09:53:26","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":4387716,"visible":true,"origin":"","legend":"\u003cp\u003eCone density analysis in the 13 patients with VKH, over a 5-year period.\u003cstrong\u003e (a)\u003c/strong\u003eTemporal changes in mean cone density (cones/mm²) at 0.75 mm from the foveal center in VKH eyes (n=25) from baseline (when the patient's serous retinal detachment [SRD] was resolved) through the 5-year follow-up. \u003cstrong\u003e(b)\u003c/strong\u003eComparison of cone density between the VKH patients at 5 years (n=25) and the healthy controls (n=30). Centerlines show the medians; box limits indicate the 25th and 75th percentiles; whiskers extend to 1.5 times the interquartile range from the 25th and 75th percentiles. \u003cstrong\u003e(c)\u003c/strong\u003e Comparison of cone density between the eyes with cystoid spaces (\u003cem\u003ewhite diamonds\u003c/em\u003e) (n=12) and those without cystoid spaces (\u003cem\u003eblack diamonds\u003c/em\u003e) (n=13) on pretreatment OCT. *p\u0026lt;0.05, **p\u0026lt;0.01. M: months, VKH: Vogt-Koyanagi-Harada disease, Y: years.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6175565/v1/0a3b5be75365f09bf349c9cf.png"},{"id":79174648,"identity":"ef23876f-e8c5-47a3-ab7e-2839552f2c83","added_by":"auto","created_at":"2025-03-25 09:53:28","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":10875558,"visible":true,"origin":"","legend":"\u003cp\u003eAnalysis of macular integrity and average threshold values using a macular integrity assessment (MAIA) in the VKH patients over the 5-year period. \u003cstrong\u003e(a)\u003c/strong\u003e The changes over time in macular integrity values from baseline through the 5 years of follow-up. \u003cstrong\u003e(b)\u003c/strong\u003eThe changes over time in the average threshold (dB) from baseline through 5 years of follow-up. \u003cstrong\u003e(c)\u003c/strong\u003e The comparison of macular integrity between the eyes without cystoid spaces (\u003cem\u003eblack bars\u003c/em\u003e) and those with cystoid spaces (\u003cem\u003egray bars\u003c/em\u003e) on pretreatment OCT. \u003cstrong\u003e(d)\u003c/strong\u003e The comparison of the average threshold between the eyes without cystoid spaces (\u003cem\u003eblack bars\u003c/em\u003e) and those with cystoid space (\u003cem\u003egray bars\u003c/em\u003e) on pretreatment OCT. Numbers in parentheses: the number of eyes analyzed at each time point. *p\u0026lt;0.05, **p\u0026lt;0.01. M: months, Y: years.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6175565/v1/0712ed17519d187790f2a669.png"},{"id":79174650,"identity":"a0df124f-d2cf-4f04-aeab-24cf39fda2e7","added_by":"auto","created_at":"2025-03-25 09:53:28","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3348003,"visible":true,"origin":"","legend":"\u003cp\u003eThe correlation analysis between cone density and the macular function parameters. \u003cstrong\u003e(a)\u003c/strong\u003eThe correlation between the mean cone density and macular integrity. A significant negative correlation was observed (Spearman's ρ = −0.4993, p\u0026lt;0.0001). \u003cem\u003eSolid line:\u003c/em\u003e the regression line. \u003cem\u003eDotted lines:\u003c/em\u003e the 95% confidence interval (n=136). \u003cstrong\u003e(b)\u003c/strong\u003e The correlation between the mean cone density and the average threshold. A significant positive correlation was observed (Spearman's ρ = 0.6070, p\u0026lt;0.0001\u003cem\u003e Solid line:\u003c/em\u003e the regression line. \u003cem\u003eDotted lines: \u003c/em\u003ethe 95% confidence interval (n=136).\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6175565/v1/43d49f435f08a0d6d83caf09.png"},{"id":79174757,"identity":"150c68c6-8170-4f43-b8de-d9d54f726a87","added_by":"auto","created_at":"2025-03-25 09:53:32","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":77480516,"visible":true,"origin":"","legend":"\u003cp\u003eClinical findings in the left eye of a 48-year-old male patient. \u003cstrong\u003e(a)\u003c/strong\u003e At initial presentation: Fundus photograph and vertical optical coherence tomography (OCT) scan showing serous retinal detachment with cystoid spaces. \u003cstrong\u003e(b) \u003c/strong\u003eAfter steroid therapy: Fundus photograph and vertical OCT scan at the time of complete resolution of serous retinal detachment (defined as baseline). \u003cstrong\u003e(c)\u003c/strong\u003eBaseline adaptive optics (AO) panoramic image. Asterisk indicates the foveal center. Scale bar = 200 μm. \u003cstrong\u003e(d) \u003c/strong\u003eLongitudinal AO images (1.2 × 1.2 mm) at 2 degrees superior to fovea. At baseline, cone mosaic beneath dotted line appears blurred, showing progressive improvement during follow-up. \u003cstrong\u003e(e) \u003c/strong\u003eLongitudinal retinal sensitivity maps from fundus microperimetry. Color bar indicates sensitivity in dB.\u003c/p\u003e","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-6175565/v1/9f0d14a568b08b48a136b6c2.png"},{"id":101152063,"identity":"65acfc27-5d26-4b1b-897d-5a60bafae22d","added_by":"auto","created_at":"2026-01-26 16:09:37","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":77284012,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6175565/v1/9586d71b-34b8-4743-9c42-5c8ddecdebd3.pdf"},{"id":79174750,"identity":"3e5e9e88-16b5-49e3-a897-b274b6a3e505","added_by":"auto","created_at":"2025-03-25 09:53:31","extension":"mov","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4751390,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalVideoS1.mov","url":"https://assets-eu.researchsquare.com/files/rs-6175565/v1/654300e14a9d337058288309.mov"},{"id":79174657,"identity":"6683d455-35bb-49ab-a820-60bbb4ec0705","added_by":"auto","created_at":"2025-03-25 09:53:29","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":24359,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-6175565/v1/dc62952eeedc98bd81fd7f2b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Long-term Recovery of Retinal Structure and Function in Vogt-Koyanagi-Harada Disease: A 5-Year Follow-up Study Using Adaptive Optics Imaging and Fundus Microperimetry","fulltext":[{"header":"Introduction","content":"\u003cp\u003eVogt-Koyanagi-Harada (VKH) disease is a systemic inflammatory disorder characterized by autoimmune reactions that target melanocytes\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. It affects multiple organs including the eyes, inner ear, meninges, and skin, with ocular manifestations typically presenting as bilateral uveitis accompanied by serous retinal detachment and optic disc edema\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. As a characteristic finding of serous retinal detachment (SRD) in VKH disease, multilobular cysts with reflective septae in subretinal fluid have been shown to be a useful diagnostic feature of VKH disease in early-stage patients\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. While VKH disease generally demonstrates favorable visual outcomes with appropriate treatment \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, the long-term impact of these cystic spaces on the prognosis regarding visual function, changes in the retinal microstructure, and qualitative aspects of visual recovery remain inadequately understood.\u003c/p\u003e \u003cp\u003eIn a structural retinal assessment, advances in adaptive optics (AO) technology have enabled the high-resolution imaging of cone photoreceptors in vivo, facilitating temporal evaluations of the relationship between the retinal microstructure and visual function \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Using AO and optical coherence tomography (OCT), Zhang et al. demonstrated a correlation between the reflective point distribution in C-scans at the inner segment/outer segment junction and the cone spacing, establishing that AO imaging can monitor patients' outer segment status over time \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. In addition, Litts et al. comprehensively demonstrated that cone mosaic reflectivity reflects outer segment health \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFor a functional assessment, macular integrity assessment (MAIA) microperimetry provides enhanced reproducibility and a detailed sensitivity evaluation compared to conventional microperimetry. MAIA microperimetry enables the real-time tracking of minute eye movements, providing accurate measurements of sensitivity changes at identical retinal locations, which makes it particularly suitable for long-term functional monitoring. MAIA microperimetry also provides a macular integrity index, allowing quantitative evaluations of retinal functional integrity \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn this study, we observed patients with VKH disease over a 5-year period to comprehensively understand the structural and functional recovery process in this disease. By combining cone density measurements using AO imaging with a retinal sensitivity assessment using MAIA, we focused on elucidating the influence of initial cystic spaces on long-term outcomes and the temporal correlation between structural and functional indices.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and patients\u003c/h2\u003e \u003cp\u003eThis retrospective study included consecutive patients diagnosed with acute-phase VKH at Toyama University Hospital between 2012 and 2018. Diagnosis was based on international criteria\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Only eyes with foveal SRD before steroid treatment and \u0026ge;\u0026thinsp;5 years follow-up were included. Thirty eyes from 30 healthy volunteers served as controls. The study was approved by the Research Ethics Committee of Toyama University Hospital (approval no. R2024039), with informed consent waiver and opt-out option provided. All methods were performed in accordance with relevant guidelines and regulations.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eOphthalmologic assessments and treatment\u003c/h3\u003e\n\u003cp\u003eAll patients underwent comprehensive ocular examinations at baseline, including BCVA, fundus examination, standard spectral domain OCT examination along with enhanced depth imaging-OCT (RS-3000 Advance; Nidek, Aichi, Japan) or Swept Source OCT (Triton; Topcon, Tokyo), and fluorescein and indocyanine green angiography. OCT was performed every 2\u0026ndash;3 days for 2 weeks, then biweekly until SRD resolution, and monthly thereafter. Following treatment completion, patients were examined every 3\u0026ndash;6 months. Treatment consisted of intravenous methylprednisolone (1000 mg/day for 3 days) followed by tapering oral prednisolone. Two patients received additional cyclosporine, and one received both cyclosporine and adalimumab. Thirty eyes from 30 healthy volunteers served as controls for AO cone density analysis.\u003c/p\u003e\n\u003ch3\u003eAdaptive optics imaging and the measurement of cone density\u003c/h3\u003e\n\u003cp\u003eMacular AO images were captured using the rtx1\u0026trade; AO fundus camera (Imagine Eyes; Orsay, France). High-resolution images were obtained at the fovea and four surrounding regions (nasal, temporal, superior, and inferior). The image alignment and the creation of multi-image mosaics were accomplished using i2k Retina software (DualAlign\u0026trade;, Clifton Park, NY). Cone density measurements were performed using AO Detect Mosaic V2.0b17 (Imagine Eyes), with axial length measurements from OA-2000 biometer (Tomey, Nagoya, Japan). Measurements were taken in all quadrants at 0.75 mm from the foveal center, using 80-\u0026micro;m2 regions to avoid retinal capillaries. The same areas were identified using retinal capillary patterns. Baseline was defined as initial OCT confirmation of SRD resolution. Cone density was evaluated at baseline, 6 months, and 1, 2, 3, and 5 years post-resolution. For microperimetry correlation analysis, mean cone density values from all four locations were used.\u003c/p\u003e\n\u003ch3\u003eFundus microperimetry procedure\u003c/h3\u003e\n\u003cp\u003eFor microperimetric assessments, we used MAIA system (CenterVue, Padova, Italy). Examinations were conducted using the Expert Protocol, administered monocularly at specific intervals, i.e., upon the resolution of the patient's SRD (baseline) and then at 6 months and 1, 2, 3, and 5 years post-resolution. The protocol used Goldmann III white stimuli and a 4\u0026thinsp;\u0026minus;\u0026thinsp;2 threshold strategy. The stimulus luminance ranged from 0 to 36 decibels (dB), with a peak intensity of 318 cd/m\u0026sup2;. The test grid comprised 37 points within a 10\u0026deg; central macular area, arranged in three concentric rings (2\u0026deg;, 6\u0026deg;, and 10\u0026deg;) of 12 points each, plus a central point. We analyzed two primary metrics: the macular integrity (a value normalized against age-adjusted data) and the average threshold. These parameters provided comprehensive insights into the patients' macular function and sensitivity across the 5-year follow-up period.\u003c/p\u003e\n\u003ch3\u003eCystoid space detection on pretreatment OCT\u003c/h3\u003e\n\u003cp\u003eWe investigated the correlations among the patients' pretreatment OCT findings, mean cone density, macular integrity, and average threshold. At the initial pretreatment visit for each patient, we assessed the OCT images for the presence/absence of cystoid spaces at 0.75 mm from the foveal center, which corresponded to the location of the cone density measurements. Based on these findings, the patients were categorized into two groups: those without cystoid spaces on pretreatment OCT and those with cystoid spaces.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eData collection and analysis\u003c/h2\u003e \u003cp\u003eThe patients' MAIA and AO imaging data were collected and analyzed using JMP\u0026reg; 17 software (SAS Institute, Cary, NC). Paired t-tests and Spearman's correlation coefficients were used to compare the MAIA data and cone density at various time points after the resolution of SRD. Data are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eThirteen patients (25 eyes) with acute VKH disease were examined. The mean age of the VKH patient group (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation) was 44.4\u0026thinsp;\u0026plusmn;\u0026thinsp;11.0 years (range 27\u0026ndash;58 years), and that of the healthy control group was 34.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.4 years (range 22\u0026ndash;50 years). The mean BCVA values in logMAR units for all 25 eyes are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Significant improvements in BCVA were observed from baseline through 5 years compared to the pre-steroid treatment values (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for all comparisons). In all cases, the SRD improved after the initial systemic steroid treatment, and no SRD recurrence was observed during the 5-year follow-up period.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMean BCVA values in LogMAR units over time (n\u0026thinsp;=\u0026thinsp;25 eyes)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime Point\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value*\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre-steroid Treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.18 to 0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026minus;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBaseline (SRD resolution)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.18 to 0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.18 to 0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1 year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.18 to 0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.18 to 0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.18 to 0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5 years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.30 to 0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e* Statistical significance was calculated in comparison to pre-steroid treatment values. \u003cb\u003eAbbreviations\u003c/b\u003e: BCVA, best-corrected visual acuity; LogMAR, logarithm of the minimum angle of resolution; SD, standard deviation; SRD, serous retinal detachment.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eChanges in mean cone density\u003c/h3\u003e\n\u003cp\u003eCone densities at 0.75 mm from the foveal center were analyzed over the 5-year follow-up period. Mean cone densities in VKH eyes showed significant increases from baseline at all time points (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). At 5 years, the mean cone density in VKH eyes remained significantly lower than that of healthy control eyes (24496\u0026thinsp;\u0026plusmn;\u0026thinsp;3220 cones/mm\u003csup\u003e2\u003c/sup\u003e) (p\u0026thinsp;=\u0026thinsp;0.004) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Eyes with cystoid spaces showed significantly lower cone densities compared to those without from baseline to 2 years (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u0026ndash;0.045), but no significant differences were observed from years 3 to 5 (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). Detailed statistical analyses and complete datasets are provided in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e and S2.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eMAIA analysis of Macular Integrity and Average Threshold values\u003c/h2\u003e \u003cp\u003eMacular integrity and average threshold were analyzed over the 5-year follow-up period, with detailed data provided in Supplementary Table S3. Mean macular integrity values showed a significant decrease from baseline at 2, 3, and 5 years (p\u0026thinsp;=\u0026thinsp;0.042, p\u0026thinsp;=\u0026thinsp;0.027, and p\u0026thinsp;=\u0026thinsp;0.018, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea), while average threshold values showed significant increases at all time points compared to baseline (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u0026ndash;0.022) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMacular integrity and average threshold values were compared between eyes with and without cystoid spaces on pretreatment OCT, with detailed data provided in Supplementary Table S4. While eyes with cystoid spaces showed a trend toward higher macular integrity values at baseline and 6 months, there were no significant differences between groups throughout the 5-year follow-up period (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). The average threshold values were significantly lower in eyes with cystoid spaces at baseline, 6 months, and 1 year (p\u0026thinsp;=\u0026thinsp;0.014, p\u0026thinsp;=\u0026thinsp;0.043 and p\u0026thinsp;=\u0026thinsp;0.045, respectively), but no significant differences were observed after 2 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eThe correlations between the mean cone density and the MAIA parameters\u003c/h2\u003e \u003cp\u003eThe relationship between the mean cone density and each of the MAIA parameters was analyzed. The distribution of mean cone density and MAIA parameters at each measurement point is illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The Spearman correlation coefficient between the mean cone density and the macular integrity value was ρ = \u0026minus;0.4993 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). The Spearman correlation coefficient between the mean cone density and the average threshold value was ρ\u0026thinsp;=\u0026thinsp;0.6070 (p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), indicating a significant correlation.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the temporal changes in both AO and MAIA findings over 5 years in a representative case. Supplementary video S1 demonstrates the sequential changes in cone mosaic patterns observed by AO imaging.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis 5-year study revealed two key findings: (\u003cem\u003ei\u003c/em\u003e) the cone density in patients with VKH gradually increased over time, with early recovery influenced by pretreatment cystoid spaces, although differences resolved after 3 years; and (\u003cem\u003eii\u003c/em\u003e) the patients' retinal function showed continuous improvement in threshold values and macular integrity. Notably, despite the treatment and improvement, the cone density remained lower than that in the healthy eyes throughout the study period, indicating long-lasting effects of VKH disease on the outer retinal layer.\u003c/p\u003e \u003cp\u003eOne of our research group's previous studies revealed a gradual recovery of cone density during a 12-month follow-up period after the resolution of the patients' SRD, although the recovery did not reach healthy eye levels \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. This incomplete recovery likely involves two mechanisms: inflammatory damage to photoreceptor outer segments and damage from the SRD itself \u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. In addition, the correlation between the reflective point distribution in C-scans at the inner segment/outer segment junction and cone spacing observed by Zhang et al. with the use of adaptive optics SD-OCT \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e supports our direct observations of outer-segment damage through AO imaging. Interestingly, the maintenance of good visual acuity despite lower cone density compared to healthy eyes might be explained by Doi et al.'s theory of cone photoreceptor redundancy relative to retinal ganglion cells \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe second key finding of our present investigation concerns the structural and functional impact of cystoid spaces and their temporal changes. It has been established that VKH disease is characterized by multilobular cysts with reflective septae in subretinal fluid, occurring in 61.5% of untreated cases, particularly in young, early-stage patients \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. In the present study, the cases with cystoid spaces showed not only a significantly reduced initial cone density but also significantly lower mean retinal sensitivity up to 1 year after the initiation of treatment. This correlation between morphology and function is supported by several studies. Lee et al. demonstrated that cystoid spaces caused a separation of inner and outer segments, correlating with initial visual decline \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e, and Bae et al. showed that VKH cases with a high fibrin index demonstrated a reduced photoreceptor outer segment volume after the resolution of their SRD \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Notably, our present findings demonstrated that the impact of cystoid spaces lessened over time, with differences in cone photoreceptor density disappearing after 3 years.\u003c/p\u003e \u003cp\u003eRegarding the relationship between OCT morphological changes and visual function, Zhou et al. reported that the integrity of the ellipsoid zone and the interdigitation zone strongly correlated with visual function \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. That finding suggested that early appropriate therapeutic intervention may improve initial structural and functional photoreceptor layer damage, leading to long-term recovery.\u003c/p\u003e \u003cp\u003eWe evaluated long-term retinal functional changes in the macula of VKH patients by using MAIA microperimetry, and we examined their correlation with cone density. The results revealed the following findings. The MAIA evaluation revealed that the average threshold significantly improved after 6 months of treatment and continued to show gradual improvement. This aligns with the report by Abu El-Asrar et al. concerning the pattern of retinal sensitivity improvement up to 12 months post-treatment \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Regarding macular integrity parameters, a significant score reduction was observed in that study after treatment, indicating long-term improvement in retinal function. The significant correlation between cone density and MAIA parameters in VKH eyes is a noteworthy finding. In particular, the positive correlation with mean retinal sensitivity and the negative correlation with macular integrity directly demonstrate the relationship between morphological and functional changes. These results support Zhou et al.'s findings regarding the correlation between photoreceptor layer integrity observed on OCT and macular function \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur results emphasize the importance of comprehensive structural and functional monitoring in VKH disease. As Abu El-Asrar et al. noted, an assessment of visual acuity alone may underestimate a patient's retinal impairment, highlighting microperimetry's value \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Our present 5-year study demonstrates that early treatment provides good outcomes despite the presence of initial cystoid spaces, and adaptive optics with a MAIA analysis provides valuable cellular-level insights that are applicable to other retinal disorders.\u003c/p\u003e \u003cp\u003eThis study has several limitations, including the small sample size and restricted cone density measurement points. Due to its relatively small scale, caution is required in generalizing the results. Future research should examine larger patient groups, broader retinal regions, and more factors that may affect the treatment response. Understanding the molecular mechanisms behind recovery processes could advance personalized treatment approaches for VKH disease.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eTN and SA designed the study. TN and TO analyzed the data. TN and AH interpreted results and wrote the manuscript. TO and AH critically revised the content. TN and AH coordinated the research planning and execution.\u003c/p\u003e\u003ch2\u003eAcknowledgements:\u003c/h2\u003e \u003cp\u003eThis work was supported by a grant from the Japan Society for the Promotion of Science (JSPS) KAKENHI, no. JP24K19785.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets used and/or analysed during the current study available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRead, R. W. et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e \u003cb\u003e131\u003c/b\u003e, 647\u0026ndash;652. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0002-9394(01)00925-4\u003c/span\u003e\u003cspan address=\"10.1016/s0002-9394(01)00925-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2001).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSugita, S. et al. Ocular infiltrating CD4\u0026thinsp;+\u0026thinsp;T cells from patients with Vogt-Koyanagi-Harada disease recognize human melanocyte antigens. \u003cem\u003eInvest. Ophthalmol. Vis. Sci.\u003c/em\u003e \u003cb\u003e47\u003c/b\u003e, 2547\u0026ndash;2554. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1167/iovs.05-1547\u003c/span\u003e\u003cspan address=\"10.1167/iovs.05-1547\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoorthy, R. S., Inomata, H. \u0026amp; Rao, N. A. Vogt-Koyanagi-Harada syndrome. \u003cem\u003eSurv. Ophthalmol.\u003c/em\u003e \u003cb\u003e39\u003c/b\u003e, 265\u0026ndash;292. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/s0039-6257(05)80105-5\u003c/span\u003e\u003cspan address=\"10.1016/s0039-6257(05)80105-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (1995).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eO'Keefe, G. A. \u0026amp; Rao, N. A. Vogt-Koyanagi-Harada disease. \u003cem\u003eSurv. Ophthalmol.\u003c/em\u003e \u003cb\u003e62\u003c/b\u003e, 1\u0026ndash;25. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.survophthal.2016.05.002\u003c/span\u003e\u003cspan address=\"10.1016/j.survophthal.2016.05.002\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTsujikawa, A. et al. Retinal cystoid spaces in acute Vogt-Koyanagi-Harada syndrome. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e \u003cb\u003e139\u003c/b\u003e, 670\u0026ndash;677. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ajo.2004.11.053\u003c/span\u003e\u003cspan address=\"10.1016/j.ajo.2004.11.053\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2005).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamaguchi, Y., Otani, T. \u0026amp; Kishi, S. Tomographic features of serous retinal detachment with multilobular dye pooling in acute Vogt-Koyanagi-Harada disease. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e \u003cb\u003e144\u003c/b\u003e, 260\u0026ndash;265. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ajo.2007.04.007\u003c/span\u003e\u003cspan address=\"10.1016/j.ajo.2007.04.007\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2007).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakayama, M., Keino, H., Watanabe, T. \u0026amp; Okada, A. A. Clinical features and visual outcomes of 111 patients with new-onset acute Vogt-Koyanagi-Harada disease treated with pulse intravenous corticosteroids. \u003cem\u003eBr. J. Ophthalmol.\u003c/em\u003e \u003cb\u003e103\u003c/b\u003e, 274\u0026ndash;278. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bjophthalmol-2017-311691\u003c/span\u003e\u003cspan address=\"10.1136/bjophthalmol-2017-311691\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2019).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoorda, A. \u0026amp; Duncan, J. L. Adaptive optics ophthalmoscopy. \u003cem\u003eAnnu. Rev. Vis. Sci.\u003c/em\u003e \u003cb\u003e1\u003c/b\u003e, 19\u0026ndash;50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1146/annurev-vision-082114-035357\u003c/span\u003e\u003cspan address=\"10.1146/annurev-vision-082114-035357\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePircher, M. \u0026amp; Zawadzki, R. J. Review of adaptive optics OCT (AO-OCT): principles and applications for retinal imaging [Invited]. \u003cem\u003eBiomed. Opt. Express\u003c/em\u003e. \u003cb\u003e8\u003c/b\u003e, 2536\u0026ndash;2562. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1364/BOE.8.002536\u003c/span\u003e\u003cspan address=\"10.1364/BOE.8.002536\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang, Y. \u0026amp; Roorda, A. Evaluating the lateral resolution of the adaptive optics scanning laser ophthalmoscope. \u003cem\u003eJ. Biomed. Opt.\u003c/em\u003e \u003cb\u003e11\u003c/b\u003e, 014002. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1117/1.2166434\u003c/span\u003e\u003cspan address=\"10.1117/1.2166434\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2006).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLitts, K. M., Cooper, R. F., Duncan, J. L. \u0026amp; Carroll, J. Photoreceptor-Based Biomarkers in AOSLO Retinal Imaging. \u003cem\u003eInvest. Ophthalmol. Vis. Sci.\u003c/em\u003e \u003cb\u003e58\u003c/b\u003e, BIO255\u0026ndash;BIO267. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1167/iovs.17-21868\u003c/span\u003e\u003cspan address=\"10.1167/iovs.17-21868\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMolina-Martin, A., Pinero, D. P. \u0026amp; Perez-Cambrodi, R. J. Normal values for microperimetry with the MAIA microperimeter: sensitivity and fixation analysis in healthy adults and children. \u003cem\u003eEur. J. Ophthalmol.\u003c/em\u003e \u003cb\u003e27\u003c/b\u003e, 607\u0026ndash;613. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5301/ejo.5000930\u003c/span\u003e\u003cspan address=\"10.5301/ejo.5000930\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParodi, M. B. et al. Mp1 and Maia Fundus Perimetry in Healthy Subjects and Patients Affected by Retinal Dystrophies. \u003cem\u003eRetina\u003c/em\u003e \u003cb\u003e35\u003c/b\u003e, 1662\u0026ndash;1669. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/IAE.0000000000000504\u003c/span\u003e\u003cspan address=\"10.1097/IAE.0000000000000504\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakamura, T., Hayashi, A. \u0026amp; Oiwake, T. Recovery of macular cone photoreceptors in Vogt-Koyanagi-Harada disease. \u003cem\u003eGraefes Arch. Clin. Exp. Ophthalmol.\u003c/em\u003e \u003cb\u003e256\u003c/b\u003e, 387\u0026ndash;394. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s00417-017-3869-5\u003c/span\u003e\u003cspan address=\"10.1007/s00417-017-3869-5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamaki, K. et al. Ocular and extraocular inflammation induced by immunization of tyrosinase related protein 1 and 2 in Lewis rats. \u003cem\u003eExp. Eye Res.\u003c/em\u003e \u003cb\u003e71\u003c/b\u003e, 361\u0026ndash;369. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1006/exer.2000.0893\u003c/span\u003e\u003cspan address=\"10.1006/exer.2000.0893\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2000).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHayakawa, K., Ishikawa, M. \u0026amp; Yamaki, K. Ultrastructural changes in rat eyes with experimental Vogt-Koyanagi-Harada disease. \u003cem\u003eJpn J. Ophthalmol.\u003c/em\u003e \u003cb\u003e48\u003c/b\u003e, 222\u0026ndash;227. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10384-003-0061-8\u003c/span\u003e\u003cspan address=\"10.1007/s10384-003-0061-8\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2004).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSakai, T. et al. Cone photoreceptor recovery after experimental detachment and reattachment: an immunocytochemical, morphological, and electrophysiological study. \u003cem\u003eInvest. Ophthalmol. Vis. Sci.\u003c/em\u003e \u003cb\u003e44\u003c/b\u003e, 416\u0026ndash;425. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1167/iovs.02-0633\u003c/span\u003e\u003cspan address=\"10.1167/iovs.02-0633\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2003).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDoi, E. et al. Efficient coding of spatial information in the primate retina. \u003cem\u003eJ. Neurosci.\u003c/em\u003e \u003cb\u003e32\u003c/b\u003e, 16256\u0026ndash;16264. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1523/JNEUROSCI.4036-12.2012\u003c/span\u003e\u003cspan address=\"10.1523/JNEUROSCI.4036-12.2012\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee, J. E. et al. Edema of the photoreceptor layer in Vogt-Koyanagi-Harada disease observed using high-resolution optical coherence tomography. \u003cem\u003eKorean J. Ophthalmol.\u003c/em\u003e \u003cb\u003e23\u003c/b\u003e, 74\u0026ndash;79. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3341/kjo.2009.23.2.74\u003c/span\u003e\u003cspan address=\"10.3341/kjo.2009.23.2.74\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2009).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBae, S. S. \u0026amp; Forooghian, F. Optical Coherence Tomography-Based Quantification of Photoreceptor Injury and Recovery in Vogt-Koyanagi-Harada Uveitis. \u003cem\u003eOcul Immunol. Inflamm.\u003c/em\u003e \u003cb\u003e25\u003c/b\u003e, 338\u0026ndash;343. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3109/09273948.2015.1125510\u003c/span\u003e\u003cspan address=\"10.3109/09273948.2015.1125510\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2017).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou, M. et al. Differences in photoreceptor recovery among patients and between different parts of the posterior pole in Vogt-Koyanagi-Harada disease. \u003cem\u003eEye (Lond)\u003c/em\u003e. \u003cb\u003e32\u003c/b\u003e, 572\u0026ndash;578. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1038/eye.2017.250\u003c/span\u003e\u003cspan address=\"10.1038/eye.2017.250\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2018).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbu El-Asrar, A. M., Al-Mezaine, H. S., Hemachandran, S., Hariz, R. \u0026amp; Kangave, D. Retinal functional changes measured by microperimetry after immunosuppressive therapy in patients with Vogt-Koyanagi-Harada disease. \u003cem\u003eEur. J. Ophthalmol.\u003c/em\u003e \u003cb\u003e22\u003c/b\u003e, 368\u0026ndash;375. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5301/ejo.5000035\u003c/span\u003e\u003cspan address=\"10.5301/ejo.5000035\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2012).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou, M. et al. Correlation between Retinal Changes and Visual Function in Late-Stage Vogt-Koyanagi-Harada Disease: An Optical Coherence Tomography Study. \u003cem\u003eJ Ophthalmol\u003c/em\u003e 916485, (2015). \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1155/2015/916485\u003c/span\u003e\u003cspan address=\"10.1155/2015/916485\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2015).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Vogt-Koyanagi-Harada disease, cone density, adaptive optics, photoreceptor, retinal sensitivity, microperimetry","lastPublishedDoi":"10.21203/rs.3.rs-6175565/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6175565/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eVogt-Koyanagi-Harada (VKH) disease recovery patterns remain inadequately characterized over extended periods. This study evaluated retinal changes in VKH patients across 5 years using adaptive optics imaging and microperimetry. Twenty-five eyes from 13 patients were monitored longitudinally. Macular cone density gradually increased throughout the observation period but remained below healthy control levels. Eyes with pretreatment cystoid spaces initially showed lower cone density values, but this disparity disappeared after 3 years. Average threshold values improved consistently from baseline, while macular integrity values significantly decreased after 2 years. Cone density correlated significantly with retinal sensitivity. These findings indicate that with appropriate treatment, VKH disease demonstrates progressive improvement in both retinal structure and function over time, though complete structural recovery may not occur. Pretreatment cystoid spaces influence early outcomes but do not significantly affect long-term recovery.\u003c/p\u003e","manuscriptTitle":"Long-term Recovery of Retinal Structure and Function in Vogt-Koyanagi-Harada Disease: A 5-Year Follow-up Study Using Adaptive Optics Imaging and Fundus Microperimetry","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-25 09:53:10","doi":"10.21203/rs.3.rs-6175565/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-11T07:36:46+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-05T23:19:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"290854884770555713697329472230927770033","date":"2025-08-26T13:22:23+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-07-02T14:48:51+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"221440146733838063813214218053292142123","date":"2025-06-10T03:39:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"337252576400741630305238781319118574749","date":"2025-03-21T13:25:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-03-21T00:23:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-03-21T00:22:15+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-03-17T16:03:51+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-03-15T05:25:44+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-03-07T06:35:11+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"64315b28-8757-4f68-a29f-7fede72706d2","owner":[],"postedDate":"March 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":46100821,"name":"Biological sciences/Neuroscience/Visual system/Retina"},{"id":46100822,"name":"Health sciences/Diseases/Eye diseases/Uveal diseases"}],"tags":[],"updatedAt":"2026-01-26T16:05:36+00:00","versionOfRecord":{"articleIdentity":"rs-6175565","link":"https://doi.org/10.1038/s41598-025-34652-6","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2026-01-20 15:57:40","publishedOnDateReadable":"January 20th, 2026"},"versionCreatedAt":"2025-03-25 09:53:10","video":"","vorDoi":"10.1038/s41598-025-34652-6","vorDoiUrl":"https://doi.org/10.1038/s41598-025-34652-6","workflowStages":[]},"version":"v1","identity":"rs-6175565","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6175565","identity":"rs-6175565","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}