Positive impact on visual outcomes through reduction of macular thickness fluctuations with 0.19-mg fluocinolone acetonide implant

Positive impact on visual outcomes through reduction of macular thickness fluctuations with 0.19-mg fluocinolone acetonide implant | 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 Research Article Positive impact on visual outcomes through reduction of macular thickness fluctuations with 0.19-mg fluocinolone acetonide implant Susana Penas, Bernardete Pessoa, Carla Teixeira, Miguel Ruão, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7926202/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Purpose: Retinal thickness fluctuations (RTF) have been associated with best-corrected visual acuity (BCVA). The current study aimed to assess the effectiveness of 0.19-mg fluocinolone acetonide intravitreal (FAc) implant to control RTF and its effect on BCVA. Methods: The RIVER study was a multicenter, retrospective, and non-interventional study that analyzed the data of the Retina.pt Portuguese national registry. Retinal thickness was assessed using the spectral domain optical coherence tomography (SD-OCT). The primary endpoint was the assessment of RTF. Eyes were stratified into quartiles (Q) and median-split according to their retinal thickness amplitude (RTA), retinal thickness standard deviation (RTSD), and central subfield thickness area under the curve (CST-AUC). Results: The mean RTA decreased from 187.6±150.4 µm at baseline to 151.6±126.4 µm after the Fac implant (at the last follow-up visit); p=0.1204. Mean RTSD significantly reduced from 96.3±78.1 µm at baseline to 60.8±57.3 µm at the last follow-up visit (p=0.0032). Compared to pre-FAc implant, BCVA significantly improved in eyes with RTA Q1, Q2, Q3; eyes with RTSD Q1, Q2, and Q3, and eyes with CST-AUC Q1, Q2, and Q3. According to the median split, eyes with RTA and RTSD < to median showed greater BCVA improvement. Conclusions: Regardless of the variable used to assess retinal thickness fluctuation, the FAc implant provided a significant reduction of its variability. Additionally, lower retinal thickness variability was associated with better visual outcomes. Diabetic macular edema macular thickness central retinal thickness fluctuation Fluocinolone acetonide ILUVIEN® Visual acuity Functional outcomes Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The gradual aging of the population, associated with the current lifestyle, has led to an increase in the prevalence of diabetes mellitus (DM) worldwide, which makes diabetes a significant challenge for both the population and Health Care Services [ 1 – 4 ]. Diabetic macular edema (DME) is the most common cause of vision impairment in patients with DM, which is expected to affect 23.5 million people in 2030 [ 4 ]. The pathophysiology of DME is multifactorial and comprises a series of complex events that are regulated by different signaling pathways and mediators related to pro-inflammatory molecules (cytokines, chemokines, and permeating factors), growth factors (vascular endothelial growth factor, VEGF), and other enzymes that regulate the homeostasis of the retina [ 5 – 8 ]. These factors cause a breakdown in the inner blood retinal barrier (BRB), with the subsequent accumulation of intraretinal fluid, primarily in the inner and outer plexiform layers [ 8 , 9 ]. Central macular thickness (CMT) is a relevant clinical parameter for evaluating treatment effectiveness in patients with DME. It has been representative of disease activity and has been used as an outcome parameter in different studies [ 10 – 15 ]. Current evidence suggests a relationship between CMT and visual acuity (VA) in eyes with macular edema [ 16 ], although this relationship has been, at best, moderate [ 17 ]. This moderate relationship might be due to the use of a single CMT measurement along the timeline and could be overcome by repeated CMT measurements over time. There is evidence suggesting that repeated changes in retinal thickness and structural retinal deformations may negatively affect the functionality of photoreceptors [ 18 – 21 ]. In the neuroretina, bipolar cells represent the only connection between photoreceptors and ganglion cells. If the amount of liquid accumulated in the outer plexiform layer exceeds its elasticity limits, then bipolar axons may snap and the transmission pathway may be lost, with a negative impact on visual function [ 18 – 21 ]. Intravitreal injections of VEGF inhibitors (anti-VEGF) and sustained release intravitreal corticosteroid implants are currently considered the Gold-standard treatment for most patients with DME [ 22 ]. Nevertheless, the available anti-VEGF are short-term therapies, requiring multiple monthly injections [ 10 , 11 ]. Additionally, dexamethasone intravitreal implant, despite its effectiveness, has also a limited duration of action (typically 4 to 6 months), as demonstrated by randomized clinical trials (RCTs) and real-world evidence. [ 23 – 26 ]. The time-limited effect of the previously mentioned therapies can lead to retinal fluctuations over time, making long-term retinal control quite challenging. It could be, therefore, hypothesized that using a longer duration treatment, such as, for example, a sustained-delivery intravitreal corticosteroid implant, might provide better retinal thickness fluctuation control. The 0.19-mg fluocinolone acetonide intravitreal (FAc) implant (ILUVIEN®; Alimera Sciences Europe Ltd, Dublin, Ireland) is indicated for treating patients with recurrent and recalcitrant DME [ 27 ]. The effectiveness and safety of the FAc implant have been consistently demonstrated in both RCTs [ 12 , 13 ] and real-life studies [ 14 , 28 – 31 ]. However, as far as we know, only one study evaluated the impact of FAc implant on retinal thickness fluctuations (RTF) control as well as the relationship between such control and VA [ 32 ]. A post hoc analysis of the PALADIN study evaluated the impact of retinal thickness variability control on visual and treatment burden outcomes in patients with DME treated with 0.19 mg FAc implant [ 32 ]. The results of this study showed that this implant significantly reduced the retinal thickness variability at all the time-point measurements for more than 36 months. Additionally, this was associated with a significant visual improvement and reduced supplemental treatments [ 32 ]. The RIVER study was a multicenter, retrospective, non-interventional study that analyzed the data of a Portuguese national registry (Retina.pt) [ 33 ]. This study included patients from 5 hospital centers, who received treatment for persistent or recalcitrant DME, in real-life conditions. This national study had three main purposes. The first was to investigate the standard of care of DME in Portugal during the 12 months prior to the injection of the FAc implant in identified recurrent/recalcitrant DME patients; the second was to evaluate the long-term (up to 36 months) clinical effectiveness and safety of the FAc implant; and third, to assess the long-term impact of the FAc implant on treatment burden in this subset of patients [ 33 ]. This actual study aimed a post-hoc analysis of the RIVER data to assess the long-term effectiveness of the FAc implant in the control of retinal thickness fluctuation (RTF) and its effect on VA. Methods Study Design Secondary analysis of the RIVER data. The Retina.pt national registry included data from five Portuguese public hospitals. Patients included in this database were followed up from April 2014 to April 2021; whereas data was collected from December 2019 to April 2021. The study protocol was approved by the ethics committees of the participating centers in the study (Protocol number GER/002/2019) and was conducted in accordance with the tenants of the Declaration of Helsinki, International Council for Harmonization (ICH) guidelines, guidelines for Good Clinical Practice (GCP), and the Portuguese laws. Written informed consent was provided by the patients before inclusion in Retina.pt database. Study participants This study included both male and female subjects, aged ≥ 18 years, with recurrent or recalcitrant DME despite treatment, [ 34 ] who underwent FAc implantation (unilateral or bilateral) and had available clinical data from 12 months pre to at least 6 months post its administration. Study Outcomes The primary endpoint was the macular RTF assessed with spectral domain optical coherence tomography (SD-OCT). The secondary endpoint was the best corrected visual acuity variation measured with Early Treatment Diabetic Retinopathy Study (ETDRS) charts [ 35 ]. Definitions Retinal Thickness Amplitude (RTA) was calculated as a measure of the variation in Central Subfield Thickness (CST) values over a predefined period of time. RTA represents the difference between the maximum and minimum CST values within this period. Maximum and minimum CST calculations were made as follows: for pre-treatment data, the entire available range of CST values were used; for post-treatment data, CST values were measured from six months up to the last visit. Retinal thickness fluctuations (RTF) refer to variations in retinal thickness. It was calculated as the area under the curve (AUC) of parameters such as retinal thickness amplitude, retinal thickness standard deviation, or central subfield thickness. Retinal Thickness Standard Deviation (RTSD) was computed as a measure of the variability in CST values within a given time frame. The RTSD was determined as the standard deviation of CST values within the predetermined period. The time periods considered were like the ones used for RTA. Central Subfield Thickness Area Under the Curve (CST-AUC) was assessed to capture the cumulative change in CST values over time. The CST-AUC was calculated by plotting the CST values against time, fitting a curve to the data, and deriving the area under the curve. Eyes were stratified into quartiles according to their RTA, RTSD and CST-AUC. The lowest magnitude of variability was associated with quartile 1 (Q1), whilst quartile 4 (Q4) was associated with the highest magnitude variability. Statistical Analysis The current analysis was carried out utilizing SPSS Inc software version 29.0.1.0(171) (PASW Statistics for Windows, Chicago: SPSS Inc. http://www.spss.com.hk/statistics/ ). The Shapiro-Wilk test was used to assess whether variables were normally distributed. Because all quantitative variables followed a normal distribution, the Student's t-test was used for the assessment of RTA, RTSD, and area under the curve (AUC) values, disparities between pre and post-FAc implant measurements. Additionally, the variance in best corrected visual acuity (BCVA) values between the baseline and the last observation, stratified by quartiles of RTA, RTSD, and AUC, was examined through graphical analysis. To compare means, a parametric Student's t-test was applied. CST- Area Under the Curve (CST-AUC) was assessed to capture the cumulative change in CST values over time. The CST-AUC was determined by integrating the curve fitted to the CST data over the specified time interval. The GraphPad software ( https://www.graphpad.com/ ) was employed for plotting, curve fitting, and calculating the area under the curve. Results A total of 222 eyes were included in the RIVER study. Of these, 125 eyes were excluded due to inadequate CST measurements, either because baseline or follow-up data were missing, preventing the assessment of CST changes over time. Consequently, 97 eyes were included in the analysis. The mean age of the study sample was 71.6±8.5 years and 49 (50.1%) patients were female. Mean DME duration was 4.8±2.9 years. At the time of inclusion in the RIVER study, 87 (89.7%) and 94 (96.9%) eyes have been previously treated with anti-VEGF and intravitreal steroids, respectively. At baseline, 25 (25.8%) eyes were taking IOP lowering drops and 4 (4.1%) eyes had undergone glaucoma surgery. Nineteen (19.6%) eyes were phakic, 56 (57.7%) were pseudophakic, and this information was not available in 22 (22.7%) eyes. The main demographic and clinical characteristics are shown in table 1. Retinal Thickness The CST-AUC significantly reduced from 446 µm (pre- FAc) to 349 µm (at the last follow-up visit); p<0.0001 (Figure 1). The mean RTA reduced from 187.6±150.4 µm (pre- FAc) to 151.6±126.4 µm (at the last follow-up visit); p=0.1204 (Figure 2). The pre-FAc implant mean RTSD significantly reduced from 96.3±78.1 µm to 60.8±57.3 µm (p=0.0032) (Figure 3). Best Corrected Visual Acuity To better assess the impact of RTA, RTSD, and CST-AUC on the BCVA from pre-FAc implant injection to the last visit, retinal thickness measurements were split into quartiles. Quartiles were defined as: RTA (Q1: 0 to 34.75 µm; Q2: 34.76 to 114.0 µm; Q3: 114.01 to 225.5 µm; Q4: 225.51 to 519.0 µm); RTSD (Q1: 0 to 14.27 µm; Q2: 14.28 to 43.83 µm; Q3: 43.84 to 90.54; Q4: 90.55 to 355.68 µm); and CST-AUC (Q1: 0 to 262.57 µm; Q2: 262.58 to 336.34 µm; Q3: 336.35 to 389.09 µm; Q4: 389.10 to 1000.38 µm). Compared to pre-FAc implant, BCVA significantly improved in eyes with RTA Q1, Q2, Q3 (Figure 4); eyes with RTSD Q1, Q2, and Q3 (Figure 5), and eyes with CST-AUC Q1, Q2, and Q3 (Figure 6). Regardless of the retinal thickness measurement, the greatest improvements were consistently observed in Q2 and Q3 groups, while the lowest gain was always found in Q4 group (See Table 2 and figures 3, 4, and 5). Additionally, to further investigate the impact of RTA and RTSD on BCVA change, from pre-FAc implant injection to the last visit, retinal thickness measurements were split according to the median of the study sample. The median values of the RTA and RTSD were 114.0 µm and 43.8 µm, respectively. As compared to pre-FAc, mean BCVA significantly improved in both eyes with RTA < median (+11.1±12.6 letters, p<0.0001) and those with RTA ≥ median (+7.7±14.4 letters, p=0.0023). Nevertheless, the BCVA gain was greater in the eyes with RTA < median, although not statistically significant (mean difference: 3.4±13.5 letters; 95%CI: -2.5 to 9.3; p=0.2554). With the sample size included, this analysis had a statistical power of 29% to detect the observed differences. Similarly, there was a significant BCVA gain in both eyes with RTSD < median (+10.3±12.4 letters, P<0.0001) and those with RTSD ≥ median (+8.3±14.8 letters, p=0.0016); although such difference was not significant (mean difference: 2.0±13.6 letters; 95%CI: -4.0 to 8.0; p=0.5061. With the sample size included, this analysis had a statistical power of 11% to detect the observed differences. Discussion This study carried out a secondary analysis of the RIVER study [ 33 ] in which both the effect of the FAc implant on the RTF, as well as its impact on visual outcomes have been analyzed. Over a span of up to 36 months, the FAc implant provided a significant reduction of retinal thickness fluctuation, regardless of the variable used to evaluate it. In addition, better visual outcomes were associated with the reduction of retinal thickness variability. Intravitreal therapies with anti-VEGF and corticosteroids are currently considered the preferred treatment for macular edema in clinical practice [ 22 ]. However, currently available anti-VEGFs require an intensive regimen of injections, often monthly [ 10 , 11 ] as well as frequent examinations, whilst dexamethasone implant has a limited duration of action, requiring frequent retreatments [ 23 – 26 ]. It has been previously reported that the use of these short-acting therapies has been associated with greater RTF, which may lead to irreversible vision loss [ 18 – 21 , 36 – 39 ]. FAc implant has been developed to prolong the effect of fluocinolone acetonide and to reduce the need for repeated injections [ 40 ]. Current evidence shows that the use of FAc implant achieved a progressive and persistent improvement of anatomic and visual outcomes, which is maintained over 36 months [ 12 – 14 , 28 – 32 ]. Previous studies showed that the FAc implant reduced RTF in eyes with DME [ 41 – 43 ]. The results of the ILUVIEN® Clinical Evidence cohort study in the United Kingdom (ICE-UK) [ 42 ] demonstrated that the FAc implant decreased RTA, CST coefficient of variation, and CST standard deviation. Similarly, a small retrospective study reported that FAc implant injection was associated with a significant reduction in the mean CRT amplitude [ 43 ]. Despite this, the subsequent effect of this RTF reduction on visual outcomes still needs to be determined. In fact, the current study observed a significant relationship between the reduction of RTA, RTSD, and CST-AUC and the BCVA improvement. Those eyes with the greatest retinal thickness variability (quartile 4) showed the worse BCVA gains; while those with lower RTF (eyes in quartile 1, 2, and 3) presented greater BCVA improvements. On the other hand, although in our study Q3 showed BCVA improvements in line with Q1 and Q2, the eyes in Q3 and Q4 exhibited larger negative deviations. Previous reports suggested that CST fluctuations were associated with worse VA outcomes and may serve as a more reliable marker of both anatomic and functional treatment response in patients with DME [ 32 , 36 , 41 , 42 ]. The results of a post hoc analysis of the PALADIN study demonstrated that retinal thickness variability was directly and significantly correlated with visual outcomes [ 32 ]. Indeed, the multivariate linear regression analysis showed that the last-reported BCVA was correlated with CST-AUC (R2 = − 0.448), RTA (R2 = − 0.432), and RTSD (R2 = − 0.436) [ 32 ]. In other words, the lower the retinal thickness variability, the greater the BCVA gains, which might be associated with a reduced treatment burden. Additionally, the secondary analysis of the USER study found that VA improvements were correlated with RTA and RTSD reduction, but not with the CST-AUC [ 41 ]. Similarly, Holden et al [ 42 ] reported a significant association between changes in CST variability and the corresponding VA changes. This has been also reported for eyes with neovascular age-related macular degeneration treated with anti-VEGF, where greater RTF was associated with worse visual outcomes, development of fibrosis and macular atrophy [ 37 ]. It has been demonstrated that in macular edema, there is a significant correlation between functional and structural integrity of the retina [ 18 – 21 ]. Pelosini et al [ 18 ] discovered that the integrity of retinal tissue can serve as an indicator of preserved axonal connections and overall visual function. They reported that the strength of this relationship diminishes with increasing distance from the foveal center, as anticipated [ 18 ]. Visual acuity seems to depend on both the presence of fluid in the outer retina and the number of viable bipolar axons [ 18 ]. This suggests that in patients with macular edema, reducing fluctuations in the amount of retinal fluid will preserve cellular integrity and consequently enhance the potential for achieving better visual results. This type of evidence emphasises that drugs promoting less long-term macular thickness fluctuations should be pursued when treating DME patients. Conclusions The findings from this analysis of the RIVER study indicated that the 0.19 mg FAc implant significantly decreased retinal thickness variability, an effect that was sustained throughout a long follow-up period. Moreover, this reduction in retinal thickness fluctuations was consistently correlated with improved visual outcomes. The comprehensive nature of these real-world evidence studies is crucial, as they provide valuable insights into the continuous effects and stability throughout the entire treatment duration, rather than just at the beginning and end of it. Future prospective long-term research studies might help to corroborate our findings and elucidate the value of decreasing RTF in DME treatment strategies. Declarations Acknowledgements Medical writing and Editorial assistant services have been provided by Ciencia y Deporte S.L. Support for this assistance was funded by Alimera Science. Compliance with Ethical Standards Statement of Ethics “All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards”. The study protocol was approved by the ethics committees of the hospitals participating in the study (Protocol number GER/002/2019. Each center Ethics Committe that reviewed and approved this stuty protocol and respective approval numbers are: Comissão de Ética do Centro Hospitalar de Entre Douro e Vouga, EPE, Santa Maria da Feira – approval number – CA-0515/19-0t_MP/AC Comissão de Ética, Serviço de Gestão de Conhecimento - Unidade Local de Saúde de Matosinhos – 198/19 /RS Comissão de Ética CHUP/ ICBAS , Centro Hospitalar do Porto - 2019.258(211-DEFI/221-CE) Comissão de Ética, Centro de Investigação do Centro Hospitalar de Leiria, EPE – 27/2020 Comissão de Ética para a Saúde do CHUSJ, Centro de Investigação da Unidade Local de Saúde São João, Porto - P23-19. Informed Consent Informed consent: “The study protocol was approved by the ethics committees of the hospitals participating in the study (Protocol number GER/002/2019. Written informed consent was provided by the patients before inclusion in Retina.PT database”. Disclosure of potential conflicts of interest Susana Penas has received consulting fees from Alimera Sciences, Bayer, Novartis, and Roche. João Paulo Castro Sousa has received consulting fees from Alimera Sciences, Alcon, Bayer, and Novartis; has received payment or honoraria for lectures, presentations, speakers’ bureaus and educational events from AbbVie, Alimera Sciences, Alcon, Bayer, Novartis, and Roche; was supported for attending meetings and/or travel by Alimera Sciences, Alcon, Bayer, and Novartis; and has participated in Data Safety Monitoring Boards or Advisory Boards for Alimera, Alcon, and Novartis. Ângela Carneiro has participated in Advisory Boards for Alimera Sciences, Allergan, Bayer, Novartis, and Roche. Rufino Silva has participated in Advisory Boards for ABBVIE, Alimera Sciences, Novartis, Bayer, Théa; Novo Nordisk, and Roche. Angelina Meireles has received consulting fees and support for attending meetings and travel from AbbVie; has received payment for presentations from Alcon; has participated in an Advisory Board from Alimera Sciences; and has received support for attending meetings and travel from Alimera Sciences. All the other authors declare no conflicts of interest. Funding Sources Medical writing services has been provided by Alimera Science. Alimera Science did not participate in either data analysis or redaction of the manuscript. Author Contribution SP; BP; CT; MR; JPCS; AC; RS; and AM: Conception and design of the work, interpretation of the data, and revision of the work. SP; BP; CT; MR; JPCS; AC; RS; and AM: Acquisition and interpretation of data for the work. SP and BP: Writing the first draft. All authors were involved in the critical revision of the manuscript. 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Chakravarthy U, Taylor SR, Koch FHJ, Castro de Sousa JP, Bailey C; ILUVIEN Registry Safety Study (IRISS) Investigators Group. (2019) Changes in intraocular pressure after intravitreal fluocinolone acetonide (ILUVIEN): real-world experience in three European countries. Br J Ophthalmol 103(8):1072–1077. doi: 10.1136/bjophthalmol-2018-312284 . Mushtaq B, Bhatnagar A, Palmer H. (2021) Real-world outcomes in diabetic macular edema for the 0.2 µg/day fluocinolone acetonide implant: case series from the Midlands, UK. Clin Ophthalmol 15:2935–2943. doi: 10.2147/OPTH.S283561 . Singer MA, Sheth V, Mansour SE, Coughlin B, Gonzalez VH. (2022) Three-year safety and efficacy of the 0.19-mg fluocinolone acetonide intravitreal implant for diabetic macular edema: the PALADIN study. Ophthalmology 129(6):605–613. doi: 10.1016/j.ophtha.2022.01.015 . Khoramnia R, Peto T, Koch F, Taylor SR, Castro de Sousa JP, Hill L, et al; ILUVIEN Registry Safety Study (IRISS) Investigators Group. (2023) Safety and effectiveness of the fluocinolone acetonide intravitreal implant (ILUVIEN): 3-year results from the European IRISS registry study. Br J Ophthalmol 107(10):1502–1508. doi: 10.1136/bjo-2022-321415 . Ruiz-Moreno JM, Adán A, Lafuente M, Asencio Durán M, Arias Barquet L, García Layana A, et al. (2023) Effectiveness and safety of fluocinolone acetonide intravitreal implant in diabetic macular edema patients considered insufficiently responsive to available therapies (REACT): a prospective, non-randomized, and multicenter study. Int Ophthalmol 43(12):4639–4649. doi: 10.1007/s10792-023-02864-2 . Sheth VS, Singer M, MacCumber M, Cutino A, Kasper J, Coughlin BA, et al. (2023) Long-term control of retinal thickness variability and vision following the 0.19 mg fluocinolone acetonide implant. J Vitreoretin Dis 7(6):490–497. doi: 10.1177/24741264231201314 . Teixeira C, Pessoa B, Ruão M, Sousa JPC, Penas S, Silva R, et al. (2024) ILUVIEN in diabetic macular edema that persists or recurs despite treatment: results from the Retina.pt RIVER audit. Eur J Ophthalmol 34(4):1149–1158. doi: 10.1177/11206721231217525 Panozzo G, Cicinelli MV, Augustin AJ, Battaglia Parodi M, Cunha-Vaz J, Guarnaccia G, et al. (2020) An optical coherence tomography-based grading of diabetic maculopathy proposed by an international expert panel: the European School for Advanced Studies in Ophthalmology classification. Eur J Ophthalmol 30(1):8–18. doi: 10.1177/1120672119880394 . Early Treatment Diabetic Retinopathy Study Research Group. (1985) Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 103:1796–1806. Starr MR, Salabati M, Mahmoudzadeh R, Patel LG, Ammar MJ, Hsu J, et al. (2021) Fluctuations in central subfield thickness associated with worse visual outcomes in patients with diabetic macular edema in clinical trial setting. Am J Ophthalmol 232:90–97. doi: 10.1016/j.ajo.2021.06.030 . Evans RN, Reeves BC, Maguire MG, Martin DF, Muldrew A, Peto T, et al. (2020) Associations of variation in retinal thickness with visual acuity and anatomic outcomes in eyes with neovascular age-related macular degeneration lesions treated with anti-vascular endothelial growth factor agents. JAMA Ophthalmol 138(10):1043–1051. Erratum in: JAMA Ophthalmol. 2020;138(10):1109. doi: 10.1001/jamaophthalmol.2020.3001 . Ciulla TA, Pollack JS, Williams DF. (2021) Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular oedema: a real-world analysis of 28,658 patient eyes. Br J Ophthalmol 105(2):216–221. doi: 10.1136/bjophthalmol-2020-315933 . Sheth V, D'Rozario M, Gune S, Blotner S. (2022) Fluctuations in central foveal thickness and association with vision outcomes with anti-VEGF therapy for nAMD: HARBOR post hoc analysis. BMJ Open Ophthalmol 7(1):e000957. doi: 10.1136/bmjophth-2021-000957 . Nentwich MM, Ulbig MW. (2012) The therapeutic potential of intraocular depot steroid systems: developments aimed at prolonging duration of efficacy. Dtsch Arztebl Int 109(37):584–590. doi: 10.3238/arztebl.2012.0584 . Riemann CD, Eaton AM, Cutino A. (2020) Reduction in retinal thickness fluctuations after treatment with fluocinolone acetonide implant for DME: a post-hoc analysis of the USER study. Ophthalmic Surg Lasers Imaging Retina 51(5):298–306. Erratum in: Ophthalmic Surg Lasers Imaging Retina 51(7):374. doi: 10.3928/23258160-20200501-09 . Holden SE, Habib M, Currie CJ. (2020) Retinal thickness fluctuations in patients receiving fluocinolone acetonide implant for diabetic macular edema. Curr Med Res Opin 36(6):959–965. doi: 10.1080/03007995.2020.1754183 . Schechet SA, Adams OE, Eichenbaum DA, Hariprasad SM. (2019) Macular thickness amplitude changes when switching from discontinuous to continuous therapy for diabetic macular oedema. BMJ Open Ophthalmol 4(1):e000271. doi: 10.1136/bmjophth-2019-000271 . Tables Table 1. Baseline demographic and clinical characteristics of the study sample. Variable N=97 Age, years Mean ± SD 71.6±8.5 Sex, n (%) Women Men 49 (50.5) 48 (49.5) DM Type, n (%) 1 Type 1 Type 2 2 (3.3) 59 (96.7) DR Type, n (%) 3 NPDR PDR 44 (57.1) 33 (42.9) DME duration, years Mean ± SD 4.8±2.9 Lens status, n (%) 2 Phakic Pseudophakic 19 (25.3) 56 (74.7) PRP, n (%) Yes No 86 (88.7) 11 (11.3) Anti-VEGF, n (%) Yes No 87 (89.7) 10 (10.3) IV Steroids, n (%) Yes No 94 (96.9) 3 (3.1) Vitrectomy, n (%) Yes No 14 (14.4) 83 (85.6) BCVA, Letters* Mean ± SD 51.0±17.1 CRT, µm Mean ± SD 469.1±136.6 IOP, mmHg Mean ± SD 15.5±4.3 IOP-LM, n (%) Yes No 25 (25.8) 72 (74.2) Glaucoma surgery, n (%) Yes No 4 (4.1) 93 (95.9) 1 Informacton available in 61 eyes. 2Information available in 75 eyes. 3 Information available in 77 eyes. *ETDRS letters. SD: Standard deviation; DM: Diabetes Mellitus; DR: Diabetic retinopathy; NPDR: Non-proliferative diabetic retinopathy; PDR: Proliferative diabetic retinopathy; PRP: Pan retinal photocoagulation; Anti-VEGF: Vascular endothelial growth factor inhibitors; IV: Intravitreal; BCVA: Best corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; CRT: Central retinal thickness; IOP: Intraocular pressure; IOP-LM: Intraocular pressure lowering medications; Table 2. Overview of the mean best corrected visual acuity (BCVA) change from baseline to the last follow-up visit by Retinal Thickness amplitude (RTA), Thickness Standard Deviation (RTSD), and Central Subfield Thickness Area Under the Curve (CST-AUC) post 0.19 mg fluocinolone acetonide intravitreal (FAc) implant. Mean change in BCVA from baseline* Q1 (n=21) Q2 (n=20) Q3 (n=20) Q4 (n=21) RTA Mean±SD 95%CI Range 9.73±13.08 ⁑ 2.49 to 16.98 -9 to 30 11.82±12.25 ⁑ 5.52 to 18.12 -6 to 44 10.82±15.03 ⁑ 3.10 to 18.55 -21 to 30 5.30±14.12 -1.31 to 11.91 -25 to 29 RTSD Mean±SD 95%CI Range 9.73±13.08 ⁑ 2.49 to 16.98 -9 to 30 10.82±12.11 ⁑ 4.60 to 17.05 -6 to 44 13.21±13.07 ⁑ 6.91 to 19.51 -15 to 30 3.11±15.01 -4.35 to 10.58 -25 to 29 CST-AUC Mean±SD 95%CI Range 8.39±13.49 ⁑ 1.68 to 15.01 -10 to 44 12.41±11.50 ⁑ 6.50 to 18.32 -2 to 30 14.57±9.55 ⁑ 9.18 to 19.76 -2 to 29 3.05±16.44 -4.87 to 10.97 -25 to 30 *ETDRS letters. ⁑ p<0.05 as compared to baseline values. Q: Quartile; BCVA: Best corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; RTA: Retinal thickness amplitude; RTSD: Retinal thickness standard deviation; CST-AUC: Central subfield thickness area under the curve. Additional Declarations Competing interest reported. Susana Penas has received consulting fees from Alimera Sciences, Bayer, Novartis, and Roche. João Paulo Castro Sousa has received consulting fees from Alimera Sciences, Alcon, Bayer, and Novartis; has received payment or honoraria for lectures, presentations, speakers’ bureaus and educational events from AbbVie, Alimera Sciences, Alcon, Bayer, Novartis, and Roche; was supported for attending meetings and/or travel by Alimera Sciences, Alcon, Bayer, and Novartis; and has participated in Data Safety Monitoring Boards or Advisory Boards for Alimera, Alcon, and Novartis. Ângela Carneiro has participated in Advisory Boards for Alimera Sciences, Allergan, Bayer, Novartis, and Roche. Rufino Silva has participated in Advisory Boards for ABBVIE, Alimera Sciences, Novartis, Bayer, Théa; Novo Nordisk, and Roche. Angelina Meireles has received consulting fees and support for attending meetings and travel from AbbVie; has received payment for presentations from Alcon; has participated in an Advisory Board from Alimera Sciences; and has received support for attending meetings and travel from Alimera Sciences. All the other authors declare no conflicts of interest. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 23 Oct, 2025 Editor assigned by journal 23 Oct, 2025 Submission checks completed at journal 23 Oct, 2025 First submitted to journal 22 Oct, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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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-7926202","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":533893034,"identity":"6393d890-1d76-4fb1-951c-f3ded71b07dd","order_by":0,"name":"Susana Penas","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAuUlEQVRIiWNgGAWjYFAC9oMPEgxq6vlJ0MKTbPCg4liCZAOIk0CcHjPJB2eYEwwOEKvF4HZDmkRiG1ue8Y3cA8yFP4jRcufgYYvENplisxt5CcwziLLlRkLiDaAtjNtu5Bgw8xCpxQDoMGbGzTNI0GIkkXCGOXGDBLFaJO+cSTZIqDhmLHHmXcLhGWlEaOG73X7w4Q+DGjn+9tyDjwtsiNDCIAFn8TAcJkYDqhZm4rSMglEwCkbBSAMANCs6n2Ea4QAAAAAASUVORK5CYII=","orcid":"","institution":"Hospital de São João, Porto, Portugal","correspondingAuthor":true,"prefix":"","firstName":"Susana","middleName":"","lastName":"Penas","suffix":""},{"id":533893035,"identity":"507231d4-bb8b-41ee-b849-38434a53992c","order_by":1,"name":"Bernardete Pessoa","email":"","orcid":"","institution":"Centro Hospitalar do Porto","correspondingAuthor":false,"prefix":"","firstName":"Bernardete","middleName":"","lastName":"Pessoa","suffix":""},{"id":533893036,"identity":"f720c540-06bc-4e2e-a9fc-e4c4ed4d95ec","order_by":2,"name":"Carla Teixeira","email":"","orcid":"","institution":"Hospital Pedro Hispano","correspondingAuthor":false,"prefix":"","firstName":"Carla","middleName":"","lastName":"Teixeira","suffix":""},{"id":533893037,"identity":"b816ba8e-9bde-4be6-8913-ccd95988f402","order_by":3,"name":"Miguel Ruão","email":"","orcid":"","institution":"Centro Hospitalar de Entre o Douro e Vouga E.P.E.","correspondingAuthor":false,"prefix":"","firstName":"Miguel","middleName":"","lastName":"Ruão","suffix":""},{"id":533893038,"identity":"99dee8d5-f897-4cb8-989e-be0f26e4c606","order_by":4,"name":"João Paulo Castro Sousa","email":"","orcid":"","institution":"Centro Hospitalar de Leiria","correspondingAuthor":false,"prefix":"","firstName":"João","middleName":"Paulo Castro","lastName":"Sousa","suffix":""},{"id":533893039,"identity":"936c4e73-7760-49f5-bcf3-1494600eac59","order_by":5,"name":"Ângela Carneiro","email":"","orcid":"","institution":"Hospital de São João, Porto, Portugal","correspondingAuthor":false,"prefix":"","firstName":"Ângela","middleName":"","lastName":"Carneiro","suffix":""},{"id":533893040,"identity":"fd256f0f-d2b1-4aaa-89c0-cfc4123b0a89","order_by":6,"name":"Rufino Silva","email":"","orcid":"","institution":"Hospitais da Universidade de Coimbra","correspondingAuthor":false,"prefix":"","firstName":"Rufino","middleName":"","lastName":"Silva","suffix":""},{"id":533893041,"identity":"1951f215-f025-4ddd-9d7b-63b2924077d2","order_by":7,"name":"Angelina Meireles","email":"","orcid":"","institution":"Centro Hospitalar do Porto","correspondingAuthor":false,"prefix":"","firstName":"Angelina","middleName":"","lastName":"Meireles","suffix":""}],"badges":[],"createdAt":"2025-10-22 19:08:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7926202/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7926202/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":97125540,"identity":"75c438f6-9521-42a5-934e-821ed3fce3cf","added_by":"auto","created_at":"2025-12-01 08:19:02","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":955304,"visible":true,"origin":"","legend":"\u003cp\u003eCentral subfield thickness-area under the curve (CST-AU)* from 12 months before until 36 months after the injection of the intravitreal fluocinolone acetonide (FAc) implant.\u003c/p\u003e\n\u003cp\u003e1A. Overview of the evolution of the CST-AU throughout the study follow-up.\u003c/p\u003e\n\u003cp\u003e1B. The mean CST-AUC pre- FAc implant injection (445.55 µm) and at the last follow-up visit (349.21µm), p\u0026lt;0.0001.\u003c/p\u003e\n\u003cp\u003eStatistical significance was calculated by using a two-way paired sample t-test.\u003c/p\u003e\n\u003cp\u003e*CST-AUC is equivalent to degree of retinal dryness over time.\u003c/p\u003e\n\u003cp\u003eCST: Central subfield thickness.\u003c/p\u003e","description":"","filename":"Figure1RIVERCMTFIntOphthalmol1.0.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7926202/v1/94c0200817484432515f1bce.jpg"},{"id":97125541,"identity":"2133f795-b959-4faa-b89e-0925804d6ea8","added_by":"auto","created_at":"2025-12-01 08:19:02","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":960734,"visible":true,"origin":"","legend":"\u003cp\u003eMean retinal thickness amplitude (RTA)* from 12 months before until 36 months after the injection of the intravitreal fluocinolone acetonide (FAc) implant.\u003c/p\u003e\n\u003cp\u003e2A. Overview of the mean RTA over the course of the study.\u003c/p\u003e\n\u003cp\u003e2B. Mean RTA pre- and post of the FAc implant.\u003c/p\u003e\n\u003cp\u003eStatistical significance was calculated by using a two-way paired sample t-test.\u003c/p\u003e\n\u003cp\u003e*RTA is equivalent to the maximum range of retinal fluctuation.\u003c/p\u003e\n\u003cp\u003eCST: Central subfield thickness.\u003c/p\u003e","description":"","filename":"Figure2RIVERCMTFIntOphthalmol1.0.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7926202/v1/a2514c14194271cb23b18396.jpg"},{"id":97125542,"identity":"6e4d9a76-a2a3-44fc-937f-a464d5565eed","added_by":"auto","created_at":"2025-12-01 08:19:02","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":965743,"visible":true,"origin":"","legend":"\u003cp\u003eMean retinal thickness standard deviation (RTSD)* from 12 months before until 36 months after the injection of the intravitreal fluocinolone acetonide (FAc) implant.\u003c/p\u003e\n\u003cp\u003e3A. Overview of the mean RTSD throughout the study follow-up..\u003c/p\u003e\n\u003cp\u003e3B. The mean CST-AUC pre- FAc implant injection (96.3±78.1 µm) and at the last follow-up visit (60.8±57.3 µm), p=0.0032.\u003c/p\u003e\n\u003cp\u003eStatistical significance was calculated by using a two-way paired sample t-test.\u003c/p\u003e\n\u003cp\u003e*RTSD is equivalent to the variations from the mean in retinal thickness over time.\u003c/p\u003e\n\u003cp\u003eCST: Central subfield thickness.\u003c/p\u003e","description":"","filename":"Figure3RIVERCMTFIntOphthalmol1.0.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7926202/v1/164e6fb0a3225f8b34ea20e2.jpg"},{"id":97142356,"identity":"7767511c-16b0-497f-8705-6542d4bebfef","added_by":"auto","created_at":"2025-12-01 10:07:33","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":740745,"visible":true,"origin":"","legend":"\u003cp\u003eMean best corrected visual acuity (BCVA) improvement from baseline to the last follow-up visit by Retinal Thickness Amplitude post 0.19 mg fluocinolone acetonide intravitreal (FAc) implant.\u003c/p\u003e\n\u003cp\u003e*p\u0026lt;0.05 as compared to pre Fac implant injection values.\u003c/p\u003e\n\u003cp\u003eQ: Quartile; BCVA: Best corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; RTA: Retinal thickness amplitude.\u003c/p\u003e","description":"","filename":"Figure4RIVERCMTFIntOphthalmol1.0.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7926202/v1/c5b3ceb0a68500832265418a.jpg"},{"id":97125546,"identity":"aa168bb2-e6e0-420e-9bfe-fb572c520888","added_by":"auto","created_at":"2025-12-01 08:19:02","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":737595,"visible":true,"origin":"","legend":"\u003cp\u003eMean best corrected visual acuity (BCVA) improvement from baseline to the last follow-up visit by Retinal Thickness Standard Deviation post 0.19 mg fluocinolone acetonide intravitreal (FAc) implant.\u003c/p\u003e\n\u003cp\u003e*p\u0026lt;0.05 as compared to pre Fac implant injection values.\u003c/p\u003e\n\u003cp\u003eQ: Quartile; BCVA: Best corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; RTSD: Retinal thickness standard deviation.\u003c/p\u003e","description":"","filename":"Figure5RIVERCMTFIntOphthalmol1.0.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7926202/v1/0e54906180bb424c720070a9.jpg"},{"id":97125543,"identity":"7bd98d48-3db3-4a97-8358-685efb02b82b","added_by":"auto","created_at":"2025-12-01 08:19:02","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":739874,"visible":true,"origin":"","legend":"\u003cp\u003eMean best corrected visual acuity (BCVA) improvement from baseline to the last follow-up visit by Central Subfield Thickness Area Under the Curve (CST-AUC) post 0.19 mg fluocinolone acetonide intravitreal (FAc) implant.\u003c/p\u003e\n\u003cp\u003e*p\u0026lt;0.05 as compared to pre Fac implant injection values.\u003c/p\u003e\n\u003cp\u003eQ: Quartile; BCVA: Best corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; CST-AUC: Central subfield thickness area un\u003c/p\u003e","description":"","filename":"Figure6RIVERCMTFIntOphthalmol1.0.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7926202/v1/7afb6bf8c0d544dfab4b2772.jpg"},{"id":97248558,"identity":"4b6d8cb9-9330-490f-ba19-abf98b5bd8e5","added_by":"auto","created_at":"2025-12-02 13:03:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5773009,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7926202/v1/df29c7c3-c0ba-4f69-9a54-299b5caede63.pdf"}],"financialInterests":"Competing interest reported. Susana Penas has received consulting fees from Alimera Sciences, Bayer, Novartis, and Roche.\nJoão Paulo Castro Sousa has received consulting fees from Alimera Sciences, Alcon, Bayer, and Novartis; has received payment or honoraria for lectures, presentations, speakers’ bureaus and educational events from AbbVie, Alimera Sciences, Alcon, Bayer, Novartis, and Roche; was supported for attending meetings and/or travel by Alimera Sciences, Alcon, Bayer, and Novartis; and has participated in Data Safety Monitoring Boards or Advisory Boards for Alimera, Alcon, and Novartis.\nÂngela Carneiro has participated in Advisory Boards for Alimera Sciences, Allergan, Bayer, Novartis, and Roche.\nRufino Silva has participated in Advisory Boards for ABBVIE, Alimera Sciences, Novartis, Bayer, Théa; Novo Nordisk, and Roche.\nAngelina Meireles has received consulting fees and support for attending meetings and travel from AbbVie; has received payment for presentations from Alcon; has participated in an Advisory Board from Alimera Sciences; and has received support for attending meetings and travel from Alimera Sciences.\nAll the other authors declare no conflicts of interest.","formattedTitle":"Positive impact on visual outcomes through reduction of macular thickness fluctuations with 0.19-mg fluocinolone acetonide implant","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe gradual aging of the population, associated with the current lifestyle, has led to an increase in the prevalence of diabetes mellitus (DM) worldwide, which makes diabetes a significant challenge for both the population and Health Care Services [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Diabetic macular edema (DME) is the most common cause of vision impairment in patients with DM, which is expected to affect 23.5\u0026nbsp;million people in 2030 [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe pathophysiology of DME is multifactorial and comprises a series of complex events that are regulated by different signaling pathways and mediators related to pro-inflammatory molecules (cytokines, chemokines, and permeating factors), growth factors (vascular endothelial growth factor, VEGF), and other enzymes that regulate the homeostasis of the retina [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. These factors cause a breakdown in the inner blood retinal barrier (BRB), with the subsequent accumulation of intraretinal fluid, primarily in the inner and outer plexiform layers [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCentral macular thickness (CMT) is a relevant clinical parameter for evaluating treatment effectiveness in patients with DME. It has been representative of disease activity and has been used as an outcome parameter in different studies [\u003cspan additionalcitationids=\"CR11 CR12 CR13 CR14\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCurrent evidence suggests a relationship between CMT and visual acuity (VA) in eyes with macular edema [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e], although this relationship has been, at best, moderate [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis moderate relationship might be due to the use of a single CMT measurement along the timeline and could be overcome by repeated CMT measurements over time.\u003c/p\u003e\u003cp\u003eThere is evidence suggesting that repeated changes in retinal thickness and structural retinal deformations may negatively affect the functionality of photoreceptors [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In the neuroretina, bipolar cells represent the only connection between photoreceptors and ganglion cells. If the amount of liquid accumulated in the outer plexiform layer exceeds its elasticity limits, then bipolar axons may snap and the transmission pathway may be lost, with a negative impact on visual function [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIntravitreal injections of VEGF inhibitors (anti-VEGF) and sustained release intravitreal corticosteroid implants are currently considered the Gold-standard treatment for most patients with DME [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Nevertheless, the available anti-VEGF are short-term therapies, requiring multiple monthly injections [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Additionally, dexamethasone intravitreal implant, despite its effectiveness, has also a limited duration of action (typically 4 to 6 months), as demonstrated by randomized clinical trials (RCTs) and real-world evidence. [\u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The time-limited effect of the previously mentioned therapies can lead to retinal fluctuations over time, making long-term retinal control quite challenging. It could be, therefore, hypothesized that using a longer duration treatment, such as, for example, a sustained-delivery intravitreal corticosteroid implant, might provide better retinal thickness fluctuation control.\u003c/p\u003e\u003cp\u003eThe 0.19-mg fluocinolone acetonide intravitreal (FAc) implant (ILUVIEN\u0026reg;; Alimera Sciences Europe Ltd, Dublin, Ireland) is indicated for treating patients with recurrent and recalcitrant DME [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. The effectiveness and safety of the FAc implant have been consistently demonstrated in both RCTs [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e] and real-life studies [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. However, as far as we know, only one study evaluated the impact of FAc implant on retinal thickness fluctuations (RTF) control as well as the relationship between such control and VA [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. A post hoc analysis of the PALADIN study evaluated the impact of retinal thickness variability control on visual and treatment burden outcomes in patients with DME treated with 0.19 mg FAc implant [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The results of this study showed that this implant significantly reduced the retinal thickness variability at all the time-point measurements for more than 36 months. Additionally, this was associated with a significant visual improvement and reduced supplemental treatments [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe RIVER study was a multicenter, retrospective, non-interventional study that analyzed the data of a Portuguese national registry (Retina.pt) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. This study included patients from 5 hospital centers, who received treatment for persistent or recalcitrant DME, in real-life conditions. This national study had three main purposes. The first was to investigate the standard of care of DME in Portugal during the 12 months prior to the injection of the FAc implant in identified recurrent/recalcitrant DME patients; the second was to evaluate the long-term (up to 36 months) clinical effectiveness and safety of the FAc implant; and third, to assess the long-term impact of the FAc implant on treatment burden in this subset of patients [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis actual study aimed a post-hoc analysis of the RIVER data to assess the long-term effectiveness of the FAc implant in the control of retinal thickness fluctuation (RTF) and its effect on VA.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy Design\u003c/h2\u003e\u003cp\u003eSecondary analysis of the RIVER data. The Retina.pt national registry included data from five Portuguese public hospitals. Patients included in this database were followed up from April 2014 to April 2021; whereas data was collected from December 2019 to April 2021.\u003c/p\u003e\u003cp\u003e The study protocol was approved by the ethics committees of the participating centers in the study (Protocol number GER/002/2019) and was conducted in accordance with the tenants of the Declaration of Helsinki, International Council for Harmonization (ICH) guidelines, guidelines for Good Clinical Practice (GCP), and the Portuguese laws.\u003c/p\u003e\u003cp\u003eWritten informed consent was provided by the patients before inclusion in Retina.pt database.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eStudy participants\u003c/h3\u003e\n\u003cp\u003eThis study included both male and female subjects, aged\u0026thinsp;\u0026ge;\u0026thinsp;18 years, with recurrent or recalcitrant DME despite treatment, [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e] who underwent FAc implantation (unilateral or bilateral) and had available clinical data from 12 months pre to at least 6 months post its administration.\u003c/p\u003e\n\u003ch3\u003eStudy Outcomes\u003c/h3\u003e\n\u003cp\u003eThe primary endpoint was the macular RTF assessed with spectral domain optical coherence tomography (SD-OCT). The secondary endpoint was the best corrected visual acuity variation measured with Early Treatment Diabetic Retinopathy Study (ETDRS) charts [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eDefinitions\u003c/h3\u003e\n\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eRetinal Thickness Amplitude (RTA)\u003c/span\u003e was calculated as a measure of the variation in Central Subfield Thickness (CST) values over a predefined period of time. RTA represents the difference between the maximum and minimum CST values within this period. Maximum and minimum CST calculations were made as follows: for pre-treatment data, the entire available range of CST values were used; for post-treatment data, CST values were measured from six months up to the last visit.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eRetinal thickness fluctuations (RTF)\u003c/span\u003e refer to variations in retinal thickness. It was calculated as the area under the curve (AUC) of parameters such as retinal thickness amplitude, retinal thickness standard deviation, or central subfield thickness.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eRetinal Thickness Standard Deviation (RTSD)\u003c/span\u003e was computed as a measure of the variability in CST values within a given time frame. The RTSD was determined as the standard deviation of CST values within the predetermined period. The time periods considered were like the ones used for RTA.\u003c/p\u003e\u003cp\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003eCentral Subfield Thickness Area Under the Curve (CST-AUC)\u003c/span\u003e was assessed to capture the cumulative change in CST values over time. The CST-AUC was calculated by plotting the CST values against time, fitting a curve to the data, and deriving the area\u003c/p\u003e\u003cp\u003eunder the curve.\u003c/p\u003e\u003cp\u003eEyes were stratified into quartiles according to their RTA, RTSD and CST-AUC. The lowest magnitude of variability was associated with quartile 1 (Q1), whilst quartile 4 (Q4) was associated with the highest magnitude variability.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eThe current analysis was carried out utilizing SPSS Inc software version 29.0.1.0(171) (PASW Statistics for Windows, Chicago: SPSS Inc. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.spss.com.hk/statistics/\u003c/span\u003e\u003cspan address=\"http://www.spss.com.hk/statistics/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). The Shapiro-Wilk test was used to assess whether variables were normally distributed. Because all quantitative variables followed a normal distribution, the Student's t-test was used for the assessment of RTA, RTSD, and area under the curve (AUC) values, disparities between pre and post-FAc implant measurements. Additionally, the variance in best corrected visual acuity (BCVA) values between the baseline and the last observation, stratified by quartiles of RTA, RTSD, and AUC, was examined through graphical analysis. To compare means, a parametric Student's t-test was applied.\u003c/p\u003e\u003cp\u003eCST- Area Under the Curve (CST-AUC) was assessed to capture the cumulative change in CST values over time. The CST-AUC was determined by integrating the curve fitted to the CST data over the specified time interval. The GraphPad software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.graphpad.com/\u003c/span\u003e\u003cspan address=\"https://www.graphpad.com/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) was employed for plotting, curve fitting, and calculating the area under the curve.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 222 eyes were included in the RIVER study. Of these, 125 eyes were excluded due to inadequate CST measurements, either because baseline or follow-up data were missing, preventing the assessment of CST changes over time. Consequently, 97 eyes were included in the analysis.\u003c/p\u003e\n\u003cp\u003eThe mean age of the study sample\u0026nbsp;was 71.6\u0026plusmn;8.5 years and 49 (50.1%) patients were female. Mean DME duration was 4.8\u0026plusmn;2.9 years. At the time of inclusion in the RIVER study, 87 (89.7%) and 94 (96.9%) eyes have been previously treated with anti-VEGF and intravitreal steroids, respectively.\u003c/p\u003e\n\u003cp\u003eAt baseline, 25 (25.8%) eyes were taking IOP lowering drops and 4 (4.1%) eyes had undergone glaucoma surgery. Nineteen (19.6%) eyes were phakic, 56 (57.7%) were pseudophakic, and this information was not available in 22 (22.7%) eyes.\u003c/p\u003e\n\u003cp\u003eThe main demographic and clinical characteristics are shown in table 1.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eRetinal Thickness\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe CST-AUC significantly reduced from 446 \u0026micro;m (pre- FAc) to 349 \u0026micro;m (at the last follow-up visit); p\u0026lt;0.0001 (Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe mean RTA reduced from 187.6\u0026plusmn;150.4 \u0026micro;m (pre- FAc) to 151.6\u0026plusmn;126.4 \u0026micro;m (at the last follow-up visit); p=0.1204 (Figure 2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe pre-FAc implant mean RTSD significantly reduced from 96.3\u0026plusmn;78.1 \u0026micro;m to 60.8\u0026plusmn;57.3 \u0026micro;m (p=0.0032) (Figure 3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBest Corrected Visual Acuity\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eTo better assess the impact of RTA, RTSD, and CST-AUC on the BCVA from pre-FAc implant injection to the last visit, retinal thickness measurements were split into quartiles. Quartiles were defined as: RTA (Q1: 0 to 34.75 \u0026micro;m; Q2: 34.76 to 114.0 \u0026micro;m; Q3: 114.01 to 225.5 \u0026micro;m; Q4: 225.51 to 519.0 \u0026micro;m); RTSD (Q1: 0 to 14.27 \u0026micro;m; Q2: 14.28 to 43.83 \u0026micro;m; Q3: 43.84 to 90.54; Q4: 90.55 to 355.68 \u0026micro;m); and CST-AUC (Q1: 0 to 262.57 \u0026micro;m; Q2: 262.58 to 336.34 \u0026micro;m; Q3: 336.35 to 389.09 \u0026micro;m; Q4: 389.10 to 1000.38 \u0026micro;m).\u003c/p\u003e\n\u003cp\u003eCompared to pre-FAc implant, BCVA significantly improved in eyes with RTA Q1, Q2, Q3 (Figure 4); eyes with RTSD Q1, Q2, and Q3 (Figure 5), and eyes with CST-AUC Q1, Q2, and Q3 (Figure 6). Regardless of the retinal thickness measurement, the greatest improvements were consistently observed in Q2 and Q3 groups, while the lowest gain was always found in Q4 group (See Table 2 and figures 3, 4, and 5).\u003c/p\u003e\n\u003cp\u003eAdditionally, to further investigate the impact of RTA and RTSD on BCVA change, from pre-FAc implant injection to the last visit, retinal thickness measurements were split according to the median of the study sample. The median values of the RTA and RTSD were 114.0 \u0026micro;m and 43.8 \u0026micro;m, respectively. As compared to pre-FAc, mean BCVA significantly improved in both eyes with RTA \u0026lt; median (+11.1\u0026plusmn;12.6 letters, p\u0026lt;0.0001) and those with RTA \u0026ge; median (+7.7\u0026plusmn;14.4 letters, p=0.0023). Nevertheless, the BCVA gain was greater in the eyes with RTA \u0026lt; median, although not statistically significant (mean difference: 3.4\u0026plusmn;13.5 letters; 95%CI: -2.5 to 9.3; p=0.2554). With the sample size included, this analysis had a statistical power of 29% to detect the observed differences. Similarly, there was a significant BCVA gain in both eyes with RTSD \u0026lt; median (+10.3\u0026plusmn;12.4 letters, P\u0026lt;0.0001) and those with RTSD \u0026ge; median (+8.3\u0026plusmn;14.8 letters, p=0.0016); although such difference was not significant (mean difference: 2.0\u0026plusmn;13.6 letters; 95%CI: -4.0 to 8.0; p=0.5061. With the sample size included, this analysis had a statistical power of 11% to detect the observed differences.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study carried out a secondary analysis of the RIVER study [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] in which both the effect of the FAc implant on the RTF, as well as its impact on visual outcomes have been analyzed. Over a span of up to 36 months, the FAc implant provided a significant reduction of retinal thickness fluctuation, regardless of the variable used to evaluate it. In addition, better visual outcomes were associated with the reduction of retinal thickness variability.\u003c/p\u003e\u003cp\u003eIntravitreal therapies with anti-VEGF and corticosteroids are currently considered the preferred treatment for macular edema in clinical practice [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, currently available anti-VEGFs require an intensive regimen of injections, often monthly [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] as well as frequent examinations, whilst dexamethasone implant has a limited duration of action, requiring frequent retreatments [\u003cspan additionalcitationids=\"CR24 CR25\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. It has been previously reported that the use of these short-acting therapies has been associated with greater RTF, which may lead to irreversible vision loss [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR37 CR38\" citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eFAc implant has been developed to prolong the effect of fluocinolone acetonide and to reduce the need for repeated injections [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Current evidence shows that the use of FAc implant achieved a progressive and persistent improvement of anatomic and visual outcomes, which is maintained over 36 months [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29 CR30 CR31\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePrevious studies showed that the FAc implant reduced RTF in eyes with DME [\u003cspan additionalcitationids=\"CR42\" citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. The results of the ILUVIEN\u0026reg; Clinical Evidence cohort study in the United Kingdom (ICE-UK) [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] demonstrated that the FAc implant decreased RTA, CST coefficient of variation, and CST standard deviation. Similarly, a small retrospective study reported that FAc implant injection was associated with a significant reduction in the mean CRT amplitude [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Despite this, the subsequent effect of this RTF reduction on visual outcomes still needs to be determined. In fact, the current study observed a significant relationship between the reduction of RTA, RTSD, and CST-AUC and the BCVA improvement. Those eyes with the greatest retinal thickness variability (quartile 4) showed the worse BCVA gains; while those with lower RTF (eyes in quartile 1, 2, and 3) presented greater BCVA improvements. On the other hand, although in our study Q3 showed BCVA improvements in line with Q1 and Q2, the eyes in Q3 and Q4 exhibited larger negative deviations.\u003c/p\u003e\u003cp\u003ePrevious reports suggested that CST fluctuations were associated with worse VA outcomes and may serve as a more reliable marker of both anatomic and functional treatment response in patients with DME [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. The results of a post hoc analysis of the PALADIN study demonstrated that retinal thickness variability was directly and significantly correlated with visual outcomes [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Indeed, the multivariate linear regression analysis showed that the last-reported BCVA was correlated with CST-AUC (R2\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.448), RTA (R2\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.432), and RTSD (R2\u0026thinsp;=\u0026thinsp;\u0026minus;\u0026thinsp;0.436) [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In other words, the lower the retinal thickness variability, the greater the BCVA gains, which might be associated with a reduced treatment burden. Additionally, the secondary analysis of the USER study found that VA improvements were correlated with RTA and RTSD reduction, but not with the CST-AUC [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Similarly, Holden \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] reported a significant association between changes in CST variability and the corresponding VA changes. This has been also reported for eyes with neovascular age-related macular degeneration treated with anti-VEGF, where greater RTF was associated with worse visual outcomes, development of fibrosis and macular atrophy [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIt has been demonstrated that in macular edema, there is a significant correlation between functional and structural integrity of the retina [\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Pelosini \u003cem\u003eet al\u003c/em\u003e [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] discovered that the integrity of retinal tissue can serve as an indicator of preserved axonal connections and overall visual function. They reported that the strength of this relationship diminishes with increasing distance from the foveal center, as anticipated [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Visual acuity seems to depend on both the presence of fluid in the outer retina and the number of viable bipolar axons [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. This suggests that in patients with macular edema, reducing fluctuations in the amount of retinal fluid will preserve cellular integrity and consequently enhance the potential for achieving better visual results. This type of evidence emphasises that drugs promoting less long-term macular thickness fluctuations should be pursued when treating DME patients.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe findings from this analysis of the RIVER study indicated that the 0.19 mg FAc implant significantly decreased retinal thickness variability, an effect that was sustained throughout a long follow-up period. Moreover, this reduction in retinal thickness fluctuations was consistently correlated with improved visual outcomes.\u003c/p\u003e\u003cp\u003eThe comprehensive nature of these real-world evidence studies is crucial, as they provide valuable insights into the continuous effects and stability throughout the entire treatment duration, rather than just at the beginning and end of it. Future prospective long-term research studies might help to corroborate our findings and elucidate the value of decreasing RTF in DME treatment strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedical writing and Editorial assistant services have been provided by Ciencia y Deporte S.L. Support for this assistance was funded by Alimera Science.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of Ethics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e“All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards”. The study protocol was approved by the ethics committees of the hospitals participating in the study (Protocol number GER/002/2019. Each center Ethics Committe that reviewed and approved this stuty protocol and respective approval numbers are:\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eComissão de Ética do Centro Hospitalar de Entre Douro e Vouga, EPE, Santa Maria da Feira – approval number – CA-0515/19-0t_MP/AC\u003c/p\u003e\n\u003cp\u003eComissão de Ética, Serviço de Gestão de Conhecimento - Unidade Local de Saúde de Matosinhos – 198/19 /RS\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eComissão de Ética CHUP/ ICBAS , Centro Hospitalar do Porto - 2019.258(211-DEFI/221-CE)\u003c/p\u003e\n\u003cp\u003eComissão de Ética, Centro de Investigação do Centro Hospitalar de Leiria, EPE – 27/2020\u003c/p\u003e\n\u003cp\u003eComissão de Ética para a Saúde do CHUSJ, Centro de Investigação da Unidade Local de Saúde São João, Porto \u0026nbsp;- P23-19.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent:\u003c/strong\u003e “The study protocol was approved by the ethics committees of the hospitals participating in the study (Protocol number GER/002/2019. Written informed consent was provided by the patients before inclusion in Retina.PT database”.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure of potential conflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSusana Penas has received consulting fees from Alimera Sciences, Bayer, Novartis, and Roche.\u003c/p\u003e\n\u003cp\u003eJoão Paulo Castro Sousa has received consulting fees from Alimera Sciences, Alcon, Bayer, and Novartis; has received payment or honoraria for lectures, presentations, speakers’ bureaus and educational events from AbbVie, Alimera Sciences, Alcon, Bayer, Novartis, and Roche; was supported for attending meetings and/or travel by Alimera Sciences, Alcon, Bayer, and Novartis; and has participated in Data Safety Monitoring Boards or Advisory Boards for Alimera, Alcon, and Novartis.\u003c/p\u003e\n\u003cp\u003eÂngela Carneiro has participated in Advisory Boards for Alimera Sciences, Allergan, Bayer, Novartis, and Roche.\u003c/p\u003e\n\u003cp\u003eRufino Silva has participated in Advisory Boards for ABBVIE, Alimera Sciences, Novartis, Bayer, Théa; Novo Nordisk, and Roche.\u003c/p\u003e\n\u003cp\u003eAngelina Meireles has received consulting fees and support for attending meetings and travel from AbbVie; has received payment for presentations from Alcon; has participated in an Advisory Board from Alimera Sciences; and has received support for attending meetings and travel from Alimera Sciences.\u003c/p\u003e\n\u003cp\u003eAll the other authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;Sources\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMedical writing services has been provided by Alimera Science. Alimera Science did not participate in either data analysis or redaction of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSP; BP; CT; MR; JPCS; AC; RS; and AM: Conception and design of the work, interpretation of the data, and revision of the work.\u0026nbsp;\u003cbr\u003e\u0026nbsp;SP; BP; CT; MR; JPCS; AC; RS; and AM: Acquisition and interpretation of data for the work.\u003cbr\u003e\u0026nbsp;SP and BP: Writing the first draft.\u003c/p\u003e\n\u003cp\u003eAll authors were involved in the critical revision of the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final version of the manuscript and take responsibility for the accuracy of integrity of any part of the work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this article. Further enquiries can be directed to the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLi JQ, Welchowski T, Schmid M, Letow J, Wolpers AC, et al. (2021) Retinal diseases in Europe: prevalence, incidence and healthcare needs. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://miloftalmica.it/wp-content/uploads/2021/07/Euretina-Retinal-Diseases.pdf\u003c/span\u003e\u003cspan address=\"https://miloftalmica.it/wp-content/uploads/2021/07/Euretina-Retinal-Diseases.pdf\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Accessed September 29, 2025.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSun H, Saeedi P, Karuranga S, Pinkepank M, Ogurtsova K, Duncan BB, et al. 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Int Ophthalmol 43(12):4639\u0026ndash;4649. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1007/s10792-023-02864-2\u003c/span\u003e\u003cspan address=\"10.1007/s10792-023-02864-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSheth VS, Singer M, MacCumber M, Cutino A, Kasper J, Coughlin BA, et al. (2023) Long-term control of retinal thickness variability and vision following the 0.19 mg fluocinolone acetonide implant. J Vitreoretin Dis 7(6):490\u0026ndash;497. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/24741264231201314\u003c/span\u003e\u003cspan address=\"10.1177/24741264231201314\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTeixeira C, Pessoa B, Ru\u0026atilde;o M, Sousa JPC, Penas S, Silva R, et al. 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Eur J Ophthalmol 30(1):8\u0026ndash;18. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/1120672119880394\u003c/span\u003e\u003cspan address=\"10.1177/1120672119880394\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEarly Treatment Diabetic Retinopathy Study Research Group. (1985) Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol 103:1796\u0026ndash;1806.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStarr MR, Salabati M, Mahmoudzadeh R, Patel LG, Ammar MJ, Hsu J, et al. (2021) Fluctuations in central subfield thickness associated with worse visual outcomes in patients with diabetic macular edema in clinical trial setting. 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Erratum in: JAMA Ophthalmol. 2020;138(10):1109. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1001/jamaophthalmol.2020.3001\u003c/span\u003e\u003cspan address=\"10.1001/jamaophthalmol.2020.3001\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCiulla TA, Pollack JS, Williams DF. (2021) Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular oedema: a real-world analysis of 28,658 patient eyes. Br J Ophthalmol 105(2):216\u0026ndash;221. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bjophthalmol-2020-315933\u003c/span\u003e\u003cspan address=\"10.1136/bjophthalmol-2020-315933\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSheth V, D'Rozario M, Gune S, Blotner S. (2022) Fluctuations in central foveal thickness and association with vision outcomes with anti-VEGF therapy for nAMD: HARBOR post hoc analysis. BMJ Open Ophthalmol 7(1):e000957. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmjophth-2021-000957\u003c/span\u003e\u003cspan address=\"10.1136/bmjophth-2021-000957\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNentwich MM, Ulbig MW. (2012) The therapeutic potential of intraocular depot steroid systems: developments aimed at prolonging duration of efficacy. Dtsch Arztebl Int 109(37):584\u0026ndash;590. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3238/arztebl.2012.0584\u003c/span\u003e\u003cspan address=\"10.3238/arztebl.2012.0584\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRiemann CD, Eaton AM, Cutino A. (2020) Reduction in retinal thickness fluctuations after treatment with fluocinolone acetonide implant for DME: a post-hoc analysis of the USER study. Ophthalmic Surg Lasers Imaging Retina 51(5):298\u0026ndash;306. Erratum in: Ophthalmic Surg Lasers Imaging Retina 51(7):374. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3928/23258160-20200501-09\u003c/span\u003e\u003cspan address=\"10.3928/23258160-20200501-09\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHolden SE, Habib M, Currie CJ. (2020) Retinal thickness fluctuations in patients receiving fluocinolone acetonide implant for diabetic macular edema. Curr Med Res Opin 36(6):959\u0026ndash;965. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1080/03007995.2020.1754183\u003c/span\u003e\u003cspan address=\"10.1080/03007995.2020.1754183\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchechet SA, Adams OE, Eichenbaum DA, Hariprasad SM. (2019) Macular thickness amplitude changes when switching from discontinuous to continuous therapy for diabetic macular oedema. BMJ Open Ophthalmol 4(1):e000271. doi: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmjophth-2019-000271\u003c/span\u003e\u003cspan address=\"10.1136/bmjophth-2019-000271\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Baseline demographic and clinical characteristics of the study sample.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN=97\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge, years\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e71.6\u0026plusmn;8.5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eSex, n (%)\u003c/p\u003e\n \u003cp\u003eWomen\u003c/p\u003e\n \u003cp\u003eMen\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e49 (50.5)\u003c/p\u003e\n \u003cp\u003e48 (49.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDM Type, n (%)\u003csup\u003e1\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eType 1\u003c/p\u003e\n \u003cp\u003eType 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (3.3)\u003c/p\u003e\n \u003cp\u003e59 (96.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDR Type, n (%)\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eNPDR\u003c/p\u003e\n \u003cp\u003ePDR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e44 (57.1)\u003c/p\u003e\n \u003cp\u003e33 (42.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eDME duration, years\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4.8\u0026plusmn;2.9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eLens status, n (%)\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003ePhakic\u003c/p\u003e\n \u003cp\u003ePseudophakic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e19 (25.3)\u003c/p\u003e\n \u003cp\u003e56 (74.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePRP, n (%)\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e86 (88.7)\u003c/p\u003e\n \u003cp\u003e11 (11.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAnti-VEGF, n (%)\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e87 (89.7)\u003c/p\u003e\n \u003cp\u003e10 (10.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIV Steroids, n (%)\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e94 (96.9)\u003c/p\u003e\n \u003cp\u003e3 (3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eVitrectomy, n (%)\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14 (14.4)\u003c/p\u003e\n \u003cp\u003e83 (85.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBCVA, Letters*\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e51.0\u0026plusmn;17.1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eCRT, \u0026micro;m\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e469.1\u0026plusmn;136.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIOP, mmHg\u003c/p\u003e\n \u003cp\u003eMean \u0026plusmn; SD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e15.5\u0026plusmn;4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eIOP-LM, n (%)\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e25 (25.8)\u003c/p\u003e\n \u003cp\u003e72 (74.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eGlaucoma surgery, n (%)\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (4.1)\u003c/p\u003e\n \u003cp\u003e93 (95.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003csup\u003e1\u003c/sup\u003eInformacton available in 61 eyes.\u003c/p\u003e\n\u003cp\u003e2Information available in 75 eyes.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e3\u003c/sup\u003eInformation available in 77 eyes.\u003c/p\u003e\n\u003cp\u003e*ETDRS letters.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSD: Standard deviation; DM: Diabetes Mellitus; DR: Diabetic retinopathy; NPDR: Non-proliferative diabetic retinopathy; PDR: Proliferative diabetic retinopathy; PRP: Pan retinal photocoagulation; Anti-VEGF: Vascular endothelial growth factor inhibitors; IV: Intravitreal; BCVA: Best corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; CRT: Central retinal thickness; IOP: Intraocular pressure; IOP-LM: Intraocular pressure lowering medications;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2. Overview of the mean best corrected visual acuity (BCVA) change from baseline to the last follow-up visit by Retinal Thickness amplitude (RTA), Thickness Standard Deviation (RTSD), and Central Subfield Thickness Area Under the Curve (CST-AUC) post 0.19 mg fluocinolone acetonide intravitreal (FAc) implant.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean change in BCVA from baseline*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ1\u003c/strong\u003e (n=21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ2\u003c/strong\u003e (n=20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ3\u003c/strong\u003e (n=20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eQ4\u003c/strong\u003e (n=21)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTA\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9.73\u0026plusmn;13.08\u003csup\u003e⁑\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e2.49 to 16.98\u003c/p\u003e\n \u003cp\u003e-9 to 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e11.82\u0026plusmn;12.25\u003csup\u003e⁑\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e5.52 to 18.12\u003c/p\u003e\n \u003cp\u003e-6 to 44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10.82\u0026plusmn;15.03\u003csup\u003e⁑\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e3.10 to 18.55\u003c/p\u003e\n \u003cp\u003e-21 to 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e5.30\u0026plusmn;14.12\u003c/p\u003e\n \u003cp\u003e-1.31 to 11.91\u003c/p\u003e\n \u003cp\u003e-25 to 29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRTSD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e9.73\u0026plusmn;13.08\u003csup\u003e⁑\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e2.49 to 16.98\u003c/p\u003e\n \u003cp\u003e-9 to 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e10.82\u0026plusmn;12.11\u003csup\u003e⁑\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e4.60 to 17.05\u003c/p\u003e\n \u003cp\u003e-6 to 44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13.21\u0026plusmn;13.07\u003csup\u003e⁑\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e6.91 to 19.51\u003c/p\u003e\n \u003cp\u003e-15 to 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.11\u0026plusmn;15.01\u003c/p\u003e\n \u003cp\u003e-4.35 to 10.58\u003c/p\u003e\n \u003cp\u003e-25 to 29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCST-AUC\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003eMean\u0026plusmn;SD\u003c/p\u003e\n \u003cp\u003e95%CI\u003c/p\u003e\n \u003cp\u003eRange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e8.39\u0026plusmn;13.49\u003csup\u003e⁑\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e1.68 to 15.01\u003c/p\u003e\n \u003cp\u003e-10 to 44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e12.41\u0026plusmn;11.50\u003csup\u003e⁑\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e6.50 to 18.32\u003c/p\u003e\n \u003cp\u003e-2 to 30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e14.57\u0026plusmn;9.55\u003csup\u003e⁑\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003e9.18 to 19.76\u003c/p\u003e\n \u003cp\u003e-2 to 29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3.05\u0026plusmn;16.44\u003c/p\u003e\n \u003cp\u003e-4.87 to 10.97\u003c/p\u003e\n \u003cp\u003e-25 to 30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*ETDRS letters.\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e⁑\u003c/sup\u003ep\u0026lt;0.05 as compared to baseline values.\u003c/p\u003e\n\u003cp\u003eQ: Quartile; BCVA: Best corrected visual acuity; ETDRS: Early Treatment Diabetic Retinopathy Study; RTA: Retinal thickness amplitude; RTSD: Retinal thickness standard deviation; CST-AUC: Central subfield thickness area under the curve.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"inte","sideBox":"Learn more about [International Ophthalmology](https://www.springer.com/journal/10792)","snPcode":"10792","submissionUrl":"https://submission.nature.com/new-submission/10792/3","title":"International Ophthalmology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Diabetic macular edema, macular thickness, central retinal thickness fluctuation, Fluocinolone acetonide, ILUVIEN®, Visual acuity, Functional outcomes","lastPublishedDoi":"10.21203/rs.3.rs-7926202/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7926202/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose: Retinal thickness fluctuations (RTF) have been associated with best-corrected visual acuity (BCVA). The current study aimed to assess the effectiveness of 0.19-mg fluocinolone acetonide intravitreal (FAc) implant to control RTF and its effect on BCVA.\u003c/p\u003e\n\u003cp\u003eMethods: The RIVER study was a multicenter, retrospective, and non-interventional study that analyzed the data of the Retina.pt Portuguese national registry. Retinal thickness was assessed using the spectral domain optical coherence tomography (SD-OCT). The primary endpoint was the assessment of RTF. Eyes were stratified into quartiles (Q) and median-split according to their retinal thickness amplitude (RTA), retinal thickness standard deviation (RTSD), and central subfield thickness area under the curve (CST-AUC).\u003c/p\u003e\n\u003cp\u003eResults: The mean RTA decreased from 187.6±150.4 µm at baseline to 151.6±126.4 µm after the Fac implant (at the last follow-up visit); p=0.1204. Mean RTSD significantly reduced from 96.3±78.1 µm at baseline to 60.8±57.3 µm at the last follow-up visit (p=0.0032). Compared to pre-FAc implant, BCVA significantly improved in eyes with RTA Q1, Q2, Q3; eyes with RTSD Q1, Q2, and Q3, and eyes with CST-AUC Q1, Q2, and Q3. According to the median split, eyes with RTA and RTSD \u0026lt; to median showed greater BCVA improvement.\u003c/p\u003e\n\u003cp\u003eConclusions: Regardless of the variable used to assess retinal thickness fluctuation, the FAc implant provided a significant reduction of its variability. Additionally, lower retinal thickness variability was associated with better visual outcomes.\u003c/p\u003e","manuscriptTitle":"Positive impact on visual outcomes through reduction of macular thickness fluctuations with 0.19-mg fluocinolone acetonide implant","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 08:18:58","doi":"10.21203/rs.3.rs-7926202/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-23T10:13:09+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-23T07:53:39+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-23T07:52:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Ophthalmology","date":"2025-10-22T18:54:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"inte","sideBox":"Learn more about [International Ophthalmology](https://www.springer.com/journal/10792)","snPcode":"10792","submissionUrl":"https://submission.nature.com/new-submission/10792/3","title":"International Ophthalmology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"05962731-5b14-43c8-872d-8b8c42567c1f","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-06T00:53:13+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 08:18:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7926202","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7926202","identity":"rs-7926202","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}