Serial Aqueous VEGF Analysis for Predicting Anti-VEGF Treatment Outcomes in Neovascular Glaucoma from Diabetic Retinopathy: a prospective analysis

Serial Aqueous VEGF Analysis for Predicting Anti-VEGF Treatment Outcomes in Neovascular Glaucoma from Diabetic Retinopathy: a prospective analysis | 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 Serial Aqueous VEGF Analysis for Predicting Anti-VEGF Treatment Outcomes in Neovascular Glaucoma from Diabetic Retinopathy: a prospective analysis Taesung Joo, Jin-Ho Joo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8711380/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 29 Apr, 2026 Read the published version in BMC Ophthalmology → Version 1 posted 10 You are reading this latest preprint version Abstract This study evaluated the effectiveness of intravitreal bevacizumab (IVB) in neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy (PDR). It assessed outcomes of three bi-weekly IVB injections and analyzed the correlation between serial aqueous VEGF levels and clinical parameters to predict treatment efficacy. A prospective study was conducted on 17 NVG patients due to PDR. Each received three bi-weekly IVB injections. Aqueous VEGF levels, intraocular pressure (IOP), and best-corrected visual acuity (BCVA) were measured before and after treatment. Follow-up continued for three years, with additional injections given as needed. After three injections, VEGF levels significantly dropped from 4681.46 pg/mL to 104.55 pg/mL. BCVA improved from 1.27 to 0.91 (LogMAR), and IOP decreased from 32.71 mmHg to 25.29 mmHg. Higher initial VEGF levels were linked to worse BCVA, elevated IOP, and more frequent injections. Patients needing six or more injections had significantly worse baseline VEGF, BCVA, and IOP. Three bi-weekly IVB injections effectively reduced VEGF levels, improved IOP, and enhanced BCVA. Serial VEGF monitoring helps predict outcomes, as higher initial VEGF levels indicate more severe disease and increased treatment needs. Aqueous VEGF serves as a valuable biomarker for NVG management. neovascular glaucoma bevacizumab (Avastin®) vascular endothelial growth factor aqueous humor diabetic retinopathy Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Glaucoma is a chronic eye disease that damages the optic nerve and causes permanent blindness. The global prevalence of glaucoma has increased from 64.3 million cases in 2013 and is projected to exceed 111 million by 2040 1 . Neovascular glaucoma (NVG) is a vision-threatening secondary glaucoma characterized by neovascularization of the iris and increased intraocular pressure (IOP). NVG accounts for 3.9% of all glaucoma cases and 9–14.7% of all secondary glaucoma, with a higher prevalence among individuals with underlying conditions causing retinal ischemia and chronic hypoxia, such as proliferative diabetic retinopathy (PDR), central retinal vein occlusion (CRVO), and ocular ischemic syndrome (OIS) 2 , 3 . Retinal ischemia triggers the release of vascular endothelial growth factor (VEGF), which induces angiogenesis. In NVG, excessive VEGF enters the anterior chamber of the eye from the posterior pole, promoting the formation of pathological blood vessels in the iris and iridocorneal angle 4 . Tripathi et al. 5 demonstrated through competitive enzyme immunoassay that patients with NVG exhibit a significantly increased levels of VEGF in the aqueous humor. Similarly, Sun et al. 6 found that the concentration of aqueous VEGF-A was higher in the NVG group than that in the PDR group, with notably higher concentrations in the aqueous humor than that in the vitreous. Kim et al. 7 reported that elevated aqueous humor VEGF levels were associated with failure following Ahmed glaucoma implantation. Therefore, VEGF, an endothelial cell-specific angiogenic factor, plays a central role in iris neovascularization and NVG. Based on these findings, anti-VEGF therapies have been employed for the treatment of ocular neovascularization. Bevacizumab (Avastin, Genentech, South San Francisco, CA), a humanized monoclonal antibody targeting all VEGF isoforms, shows promise in treating iris neovascularization and NVG 8 . The off-label use of intravitreal bevacizumab (IVB) stabilizes neovascular activity and controls IOP in patients with iris and/or iridocorneal angle neovascularization particularly in early stage NVG without angle closure, although repeated injections maybe necessary in some cases. In advanced NVG, IVB alone may not stabilize elevated IOP but can be used as a preoperative adjunct to improve the quality and safety of surgery 9 . Although these encouraging results may suggest that bevacizumab should be the first treatment of choice for NVG, the optimal dosage and injection intervals for IVB to treat NVG has not yet been established. A few studies identified through a MEDLINE search quantitatively evaluated IVB-induced changes in VEGF concentrations in fluid from patients with advanced NVG and found that bevacizumab reduced VEGF levels in the aqueous humor 10 , 11 . Sasamoto et al. showed a significant decrease in aqueous humor VEGF levels one week after the initial injection, with a notable correlation between VEGF levels and IOP 12 . While previous studies have measured VEGF concentrations before and after treatment, these evaluations were typically conducted only once. No studies have yet serially measured VEGF levels following multiple injections. Therefore, this study investigated the effects of three consecutive bi-weekly intravitreal anti-VEGF injections in a group of patients with PDR-induced NVG. VEGF concentrations in the aqueous humor were measured and analyzed after each injection to predict IOP control and the prognosis of IVB treatment. Methods Subjects, method, and data analysis This was a prospective, comparative study approved by the Institutional Review Board of Kyung Hee University Hospital at Gangdong (KHNMC 2016-12-021) and adhered to the provisions of the Declaration of Helsinki for research involving human subjects. Written informed consent was obtained from all the participants. Between 2016 and 2022, patients with NVG secondary to PDR, who exhibited uncontrolled IOP despite maximum antiglaucomatous medications (topical β-blockers, topical carbonic anhydrase inhibitors (CAIs), topical α2-adrenergic agonists, and systemic medications) and demonstrated neovascularization of the iris and/or iridocorneal angle, were included in this study. Eligible patients were treated with three IVB injections at 2-week intervals. All patients received panretinal photocoagulation (PRP) to control neovascularization, particularly in cases with angle closure due to peripheral anterior synechia. Aqueous humor samples from the anterior chamber were collected before each injection, and VEGF concentrations (pg/mL) were measured by enzyme-linked immunosorbent assay. After receiving three injections, patients were observed for 1 month. If IOP was > 21 mm Hg or neovascularization was identified, they were treated with additional IVB injections on a pro re nata (PRN) regimen. Conversely, if IOP was normal or neovascularization was not present at this time, patients were followed-up two months later. At subsequent 2-month follow-up, those required further injections were monitored 1 month after treatment, while those who did not requiring further injections were observed 3 months later. The maximum observation period was 3 months. The end point of the study was set at 3 years following the first injection. Patients were withdrawn from the study if they opted for surgery to control their IOP or declined to continue participation (Fig. 1 ). Best-corrected visual acuity (BCVA, LogMAR), IOP, and VEGF concentrations before injections were analyzed using the Wilcoxon signed-rank test, and the correlation between initial VEGF concentration and BCVA or IOP after three injections was evaluated using Spearman correlation analysis. The correlation between the initial VEGF concentration in aqueous humor and the interval to the first PRN injection after three consecutive injections, as well as the average number of PRN injections per year, was analyzed using Spearman correlation analysis. Patients were divided into two groups for subgroup analysis based on the number of injections received: those who received five or fewer anti-VEGF injections and those who received six or more anti-VEGF injections. BCVA and IOP results were compared between these groups using the Mann-Whitney test. Data were processed and statistically analyzed using SPSS for Windows (Version 27.0; SPSS, Chicago, IL). For all tests, P < 0.05 was considered statistically significant. Anti-VEGF injection All NVG patients received intravitreal injections of 0.05 mL of 1.25 mg IVB via a 30-gauge needle in the inferior temporal quadrant, positioned 3.5 mm to 4 mm posterior to the limbus. Antiglaucomatous medications and anti-inflammatory and anti-infective eye drops (prednisolone acetate ophthalmic suspension, United States Pharmacopoeia; Allergan, Inc., Irvine, CA and levofloxacin hydrate ophthalmic solution, Japan Pharmacopoeia; Santen pharmaceutical CO., LTD., Ishikawa) were administered as necessary to manage IOP and address inflammatory and/or infectious response. Aqueous humor sampling Aqueous humor samples were collected during each IVB treatment (pre-IVB). A 200 µL sample of undiluted aqueous humor was obtained via anterior chamber paracentesis using a 30-gauge needle. Each aqueous humor sample was placed in an Eppendorf tube, rapidly frozen at -80°C and protected from light until the VEGF concentration was measured. Measurement of aqueous humor VEGF concentration VEGF concentrations in aqueous humor were measured using an enzyme-linked immunosorbent assay (Quantikine®, Human VEGF immunoassay, R&D System Inc., Minneapolis, MN). According to the protocol provided by the manufacturer. For each assay, 100 µL per sample was used. The mean of two readings was utilized for quantitative analysis. The limit of the detectable VEGF concentration was 15.6 pg/mL. Result Demographic data of the patients A total of 20 NVG patients who met the inclusion criteria were included in the study. However, three patients were excluded: two eyes required glaucoma surgery due to uncontrolled IOP, and one patient voluntarily withdrew from the study. All measurements were performed successfully, with no failures resulting from insufficient sampling in VEGF determination. The mean age of patients with NVG was 63.47 ± 9.25 years, comprising 14 men and 3 women. The average diabetes duration was 11.12 ± 7.13 years, and the mean HbA1c was 9.12 ± 1.30%. The mean number of injection treatments received was 8.76 ± 5.77. All data are summarized in Table 1 . Table 1 Clinical demographics of the participants Variables Participants (n = 17) Age mean (range), year 63.47 ± 9.25 (52–86) Sex Male 14 (82%) Female 3 (18%) Duration of diabetes mean (range), years 11.12 ± 7.13 (0–22) HbA1c mean (range), % 9.12 ± 1.30 (7.4–11.3) Number of injections mean (range) 8.76 ± 5.77 (3–21) Table 2 provides detailed case-by-case data, including BCVA (LogMAR) and IOP measured before the first injection and after the third injection, as well as aqueous humor VEGF concentrations measured before the first injection and prior to the third injection. Additionally, the table includes the total number of injections, final BCVA (LogMAR), and final IOP. For patients receiving PRN injections, further details such as the interval between the first PRN injection after the initial three injections (in months), and average annual PRN injections are also provided. Table 2 Data from 17 patients with neovascular glaucoma who participated in the study Case DM duration (Years) Hb1Ac (%) Initial BCVA (LogMAR) After 3 injections BCVA (LogMAR) Initial IOP (mmHg) After 3 injections IOP (mmHg) Initial VEGF (pg/mL) Before 3rd injections VEGF (pg/mL) Total number of injections Interval between first PRN injection after 3 injections (months) Average number of PRN injections per year Final BCVA (LogMAR) Final IOP (mmHg) 1 2 8.7 1.10 0.30 23 11 441.2 40.5 3 - - 0.30 11 2 12 8.4 1.40 1.40 22 25 6593.0 46.6 13 1 3.33 2.00 21 3 21 9.8 0.70 0.70 35 20 653.5 72.5 5 6 0.67 0.52 16 4 20 11.0 3.70 2.70 80 39 29540.0 298.0 10 1 2.33 3.70 23 5 0 9.9 0.70 0.70 47 25 1366.0 129.6 6 3 1 0.52 19 6 20 11.3 2.70 2.70 41 27 5477.0 150.0 8 1 1.67 2.70 25 7 10 8.1 0.30 0.15 15 19 220.9 62.0 5 3 0.67 0.30 20 8 9 7.6 1.70 0.22 13 15 99.1 52.2 4 6 0.33 0.40 12 9 16 7.4 0.70 0.40 28 22 391.6 53.0 5 3 0.67 0.30 19 10 14 7.5 1.10 1.10 35 40 824.0 157.2 21 2 6 0.52 19 11 0 9.1 0.30 0.52 21 15 8329.0 42.1 11 1 2.67 0.30 22 12 3 9.0 0.30 0.22 33 21 307.8 25.4 5 2 0.67 0.22 21 13 10 8.6 0.70 0.82 16 33 268.1 130.5 18 1 5 0.82 22 14 10 11.3 0.82 0.30 23 20 508.6 21.0 19 1 5.33 0.30 21 15 22 7.7 1.30 0.40 60 28 420.2 35.0 5 2 0.67 0.30 18 16 10 10.1 0.30 0.15 25 21 554.8 63.8 3 - - 0.15 17 17 10 9.6 3.70 2.70 39 49 23590.0 398.0 8 1 1.67 2.70 18 11.1 9.12 1.27 0.91 32.7 25.3 4681.5 104.5 8.76 2.00 1.92 0.95 19.1 BCVA: best corrected visual acuity, DM: diabetes mellitus, IOP: intraocular pressure, VEGF: vascular endothelial growth factor Change in parameters before (pre-IVB) and after bi-weekly three consecutive IVB injections (post-IVB) Compared to pre-IVB values, the mean BCVA (LogMAR) (1.27 ± 1.10) significantly improved after three IVB injections (0.91 ± 0.92, P < 0.001). The mean IOP (32.71 ± 17.33 mmHg) significantly decreased after three IVB injections (25.29 ± 9.99mmHg, P = 0.031). The mean VEGF concentration (4681.46 ± 8673.42 pg/mL) significantly decreased before the third IVB injection (104.55 ± 102.78 pg/mL, P < 0.001) (Fig. 2 ). Correlation between initial VEGF concentration and parameters A significant positive correlation was observed between initial VEGF concentration and post-IVB BCVA (LogMAR) (r = 0.737, P < 0.001) (Fig. 3 A), pre-IVB IOP (r = 0.535, P = 0.027) (Fig. 3 B), and post-IVB IOP (r = 0.636, P = 0.006) (Fig. 3 C), except for pre-IVB BCVA (LogMAR) (r = 0.401, P = 0.110). Correlation of PRN injections with initial VEGF concentration In 15 out of 17 eyes, PRN injections were performed as follow-ups after three consecutive bi-weekly IVB injections. On average, the first PRN injection occurred two months after the initial three injections, with an average of 1.92 PRN injections per year. When examining these parameters in relation to the initial VGEF concentration, the interval between the first PRN injection after three consecutive injections showed a statistically significant correlation with the initial VEGF concentration (r = -0.587, P = 0.021) (Fig. 4 ). Average number of PRN injections per year did not show a statistically significant correlation with initial VEGF concentration, although a P value of 0.069 was noted (r = 0.482). Comparison of subgroups according to number of injections For subgroup comparative analysis, we defined group 1 as those who received 5 or fewer injections (n = 8) and group 2 as those who received 6 or more injections (n = 9). The BCVA (LogMAR) showed no statistical difference between groups at pre-IVB (0.80 ± 0.52 vs 1.68 ± 1.33, P = 0.095). However, after three injections, a statistically significant difference was noted (0.32 ± 0.18 vs 1.44 ± 0.99, P = 0.010) (Fig. 5 A). The IOP showed no statistical difference between groups at pre-IVB (29.0 ± 14.7 mmHg vs 36.0 ± 19.6 mmHg, P = 0.416) or after one injection (20.5 ± 5.2 mmHg vs 26.3 ± 9.3 mmHg, P = 0.129), but a statistically significant difference was observed after three injections (19.6 ± 5.0 mmHg vs 30.3 ± 10.8 mmHg, P = 0.021) (Fig. 5 B). The VEGF concentrations showed statistically significant difference at pre-IVB (386.1 ± 177.3 pg/mL vs 8499.5 ± 10750.8 pg/mL, P = 0.049), before second injection (52.2 ± 15.6 pg/mL vs 131.4 ± 102.1 pg/mL, P = 0.048), and before third injections (50.5 ± 15.9 pg/mL vs 152.5 ± 124.1 pg/mL, P = 0.036) (Fig. 5 C). Discussion The results demonstrated that anti-VEGF therapy significantly reduced aqueous VEGF concentrations in patients with NVG, leading to improvements in BCVA and IOP after three consecutive bi-weekly IVB injection. However, some patients experienced poor IOP control or persistent or recurrent neovascularization of the iris and/or iridocorneal angle, requiring repeated injections. Statistically significant correlations were found between initial aqueous VEGF concentrations and BCVA and IOP after three injections, indicating that higher initial VEGF concentrations were associated with poorer visual outcomes and less effective IOP control. Furthermore, a correlation between initial aqueous VEGF concentration and the interval between first PRN injections following three IVB treatment was observed. Comparative analysis between patients receiving five or fewer injections and six or more injections showed statistically significant higher initial VEGF concentrations in the latter group, along with worse BCVA and IOP outcomes after three injections. NVG is challenging to treat, often requiring the use of multiple treatment modalities simultaneously, and may require the cooperation of both retina and glaucoma specialist. According to the European Glaucoma Society, NVG management relies on two primary principles: (1) the treatment of retinal ischemia by performing PRP or intravitreal anti-VEGF injections and (2) controlling high IOP by topical and systemic pharmacological medications or surgical interventions to avoid damage to the optic nerve 13 . The most common conditions leading to NVG are ischemic eye diseases such as PDR, CRVO, and OIS, with PRP serving as the primary treatment to alleviate retinal ischemia. The goal of PRP is to reduce the ischemic areas in the retina by increasing the oxygen supply and suppressing the secretion of VEGF 14 . In addition, there are pharmacologic and surgical treatments to control IOP. Topical anti-glaucoma drugs such as topical β-blockers, α-agonists, and CAIs, may be beneficial in reducing IOP. Systemic CAIs can also be effective for temporary short-term IOP reduction but must be used carefully in patients with renal impairment 15 . However, pharmacological treatment does not provide an adequate response for elevated IOP; approximately 50% of NVG cases require surgical IOP control such as drainage valve implantation, trabeculectomy with mitomycin C or 5-fluorouracil, and cyclodestructive procedures are usually required 16 . Patients with NVG exhibit elevated VEGF concentrations, which can be reduced through intravitreal injection treatment of anti-VEGF inhibitors, the focus of this study. Bevacizumab, a full-length humanized, is a recombinant monoclonal IgG antibody that inactivates all VEGF isoforms 17 . Several studies have demonstrated the efficacy of bevacizumab in NVG management. Ghanem et al. reported significant regression of iris neovascularization and IOP reduction one week after IVB 18 . Wakabayashi et al. also reported that IVB stabilizes neovascular activity and controls IOP in patients with iris and/or iridocorneal angle neovascularization alone and in early-stage NVG without angle closure 9 . Matsuyama et al. reported that IVB significantly decreased the free VEGF in the aqueous humor within seven days 11 . Additionally, Sasamoto et al. found that the rate of improved or unchanged visual acuity after IVB was higher than the rate of worsening visual acuity 12 . Costagliola et al reported significant improvement in visual acuity in all patients after three IVBs administered at four-week intervals 19 . While other studies have shown improvement in IOP control and neovascularization after three IVBs within four weeks, visual acuity changes were not statistically significant 20 . These findings indicate that bevacizumab shows clinical benefits in patients with NVG, suggesting it as a potential first-line treatment. However, its effects are transient due to the short half-life of the drug 12 . Several studies have investigated the pharmacokinetics of bevacizumab in rabbits and humans following intravitreal injection. In rabbits, bevacizumab reaches its peak concentration in the vitreous humor one day after injection and in the aqueous humor three days after injection, with half-lives of 4.32 and 4.88 days, respectively 21 . Another study reported peak concentration in the vitreous and aqueous humor one day after injection, with half-life of 6.61 and 6.51 days, respectively 22 . In humans, Moisseiev et al. reported a mean vitreal half-life of 4.9 days in non-vitrectomized eyes and 0.66 days in previously vitrectomized eye 23 . Csaky et al. reported that peak IVB concentrations were detected at 2–5 days post-injection, with a half-life of approximately 10 days 24 . Krohne et al. reported that concentration of bevacizumab in aqueous humor peaked on the first day after injection and a half-life was 9.82 days in non-vitrectomized eyes 25 . These findings indicate that the time to peak concentration and the half-life of bevacizumab in rabbit and human aqueous and vitreous humor are short. This study was designed to administer three consecutive bi-weekly IVB injections in patients with PDR-induced NVG, recognizing the short intraocular half-life of bevacizumab which is less than one week. Considering the higher aqueous VEGF concentrations in patients with NVG compared to that in patients with PDR, and the elevated VEGF levels in aqueous humor relative to vitreous humor, it was hypothesized that maintaining consistent intraocular anti-VEGF levels would achieve better IOP control. In fact, several studies have shown the benefit of reducing the interval between injections in patients with refractory neovascular age-related macular degeneration (nAMD) 26 . Bi-weekly injections have been shown to significantly increase binding activity, suggesting that administration of anti-VEGF drugs every two weeks may benefit patients who respond poorly to monthly therapy 27 . In this study, NVG was considered a refractory glaucoma caused by increased VEGF levels in the anterior chamber. The results confirmed that three consecutive bi-weekly IVB injections significantly improve visual acuity, controlling IOP, and reducing aqueous VEGF concentration. A review of bi-weekly injection safety showed no issues in rabbit eyes 28 . Other studies have reported subretinal fibrosis with bi-weekly injections in patients with nAMD 29 , but no retinal fibrosis was observed in the current study. This study further established that higher initial VEGF concentration was associated with increased IOP, decreased visual acuity, and a relatively greater number of injections required for treatment. While previous studies only found a correlation between VEGF concentration and IOP, they did not demonstrate associations with visual acuity or number of injections. Consistent with earlier findings, this study confirmed a positive correlation between VEGF concentration and IOP 12 . Additionally, it provided novel evidence linking VEGF concentration to visual acuity and the frequency of IVB injections, marking a significant contribution to the field. Based on the study design, it would have been more precise to measure VEGF concentrations by collecting fluid two weeks after the three consecutive injections. However, ethical constraints prevented the collection of aqueous humor samples following the treatment regimen. Another limitation of this study was the small sample size, as it was conducted prospectively. The elevated VEGF concentrations observed in PDR-induced NVG confirm the critical role of VEGF in NVG progression and IVB administered at the initial two-week interval effectively reduces these concentrations. Furthermore, this study found that initial VEGF concentration could not only predict the prognosis of visual acuity and IOP, but also the severity of NVG and the number of injections required for effective treatment. Higher initial VEGF concentrations were associated with a greater number of injections and poorer visual acuity and IOP outcomes. These findings suggest that measuring VEGF concentration in the anterior chamber may help predict the effectiveness of anti-VEGF treatment in patients with NVG. Declarations Competing interests The authors declare no competing financial interests. Ethics declarations The current research followed the tenets of the Declaration of Helsinki, and all patients provided informed consent after an explanation of the study protocol. The Institutional Review Board at Kyung Hee University Hospital at Gangdong (KHNMC 2016-12-021) approved this retrospective study. Consent for publication Not Applicable. Funding This research was supported by the Chung-Ang University Research Grants in 2024. Author Contribution T.J. contributed acquisition of data, and drafting the article. J.H.J. contributed the conception and design of the study, analysis and interpretation of data, and final approval of the version to be submitted. Acknowledgement We would like to thank Editage (www.editage.co.kr) for English language editing. Data Availability The datasets generated in the current study are available from the corresponding author upon reasonable request. References Tham YC, et al. 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Cite Share Download PDF Status: Published Journal Publication published 29 Apr, 2026 Read the published version in BMC Ophthalmology → Version 1 posted Editorial decision: Revision requested 20 Mar, 2026 Reviews received at journal 08 Mar, 2026 Reviews received at journal 06 Mar, 2026 Reviewers agreed at journal 24 Feb, 2026 Reviewers agreed at journal 24 Feb, 2026 Reviewers invited by journal 24 Feb, 2026 Editor assigned by journal 23 Feb, 2026 Editor invited by journal 01 Feb, 2026 Submission checks completed at journal 01 Feb, 2026 First submitted to journal 01 Feb, 2026 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-8711380","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":596659726,"identity":"a9055024-49f8-4c2a-bea4-d7b8a0a8682c","order_by":0,"name":"Taesung Joo","email":"","orcid":"","institution":"HanGil Eye Hospital","correspondingAuthor":false,"prefix":"","firstName":"Taesung","middleName":"","lastName":"Joo","suffix":""},{"id":596659729,"identity":"3c5b20ef-6fb6-436c-bf40-59978c2fbbb3","order_by":1,"name":"Jin-Ho Joo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2ElEQVRIiWNgGAWjYFACHgYGyQY2Bgb2BiDHwIIULTwHQFokiNTCCLJAIgHEI0ILv3TvAQbLHXxy/JLPr274USDBwN/enYBXi+SccwkMkmfYjCVn55Td7AE6TOLM2Q14tRjcyDFgkGxjS9xwOyftBg9Qi4FELrFabp5Ju/mHNC032I/dJsoWyTlnDA4AtRhL9uSw3ZYxkOAh6Bd+6R7Dx5Jtx+T42Y8/u/nmj40cf3svfi2giDgswXAMyOIxAPF58CuHamH8wFADZLE/IKx6FIyCUTAKRiQAADS1Q856V0rQAAAAAElFTkSuQmCC","orcid":"","institution":"Chung-Ang University","correspondingAuthor":true,"prefix":"","firstName":"Jin-Ho","middleName":"","lastName":"Joo","suffix":""}],"badges":[],"createdAt":"2026-01-27 14:08:59","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8711380/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8711380/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12886-026-04852-3","type":"published","date":"2026-04-29T15:57:38+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":103587303,"identity":"cc269525-94c8-4f92-82ae-4c683de0105b","added_by":"auto","created_at":"2026-02-27 11:27:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":152871,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart illustrating the intravitreal bevacizumab (IVB) treatment and observation inpatients with neovascular glaucoma (NVG) with uncontrolled intraocular pressure (IOP).\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8711380/v1/53122f587086e9b0be4321e5.jpg"},{"id":103587368,"identity":"cffcdd48-0492-4a5e-9da8-04de8e610fd4","added_by":"auto","created_at":"2026-02-27 11:27:49","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":130240,"visible":true,"origin":"","legend":"\u003cp\u003ePlot graphs showing changes in parameters: (A) best corrected visual acuity (BCVA), (B) intraocular pressure (IOP) at baseline, after intravitreal bevacizumab (IVB) treatment, and at the 3-year follow-up, and (C) vascular endothelial growth factor (VEGF) concentrations at baseline and after IVB treatment.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8711380/v1/7fd94b5c9b51a851a6fbf7ec.jpg"},{"id":103587294,"identity":"1bc6a9f1-e4c2-4c84-8e1e-7325fbd362a0","added_by":"auto","created_at":"2026-02-27 11:27:40","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":96480,"visible":true,"origin":"","legend":"\u003cp\u003eGraphs showing correlations between initial vascular endothelial growth factor (VEGF) concentration and parameters: (A) best corrected visual acuity (BCVA) after three intravitreal bevacizumab (IVB) injection (r = 0.737, P \u0026lt; 0.001), (B) initial intraocular pressure (IOP) (r = 0.535, P \u0026lt; 0.027). (C) IOP after three IVB injection (r = 0.636, P = 0.006)\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8711380/v1/4a27705126aaa7c96d883d35.jpg"},{"id":103587305,"identity":"5999e339-1876-4c0d-83b2-3e5239f79446","added_by":"auto","created_at":"2026-02-27 11:27:43","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":47320,"visible":true,"origin":"","legend":"\u003cp\u003eGraph showing the correlation between initial vascular endothelial growth factor (VEGF) concentration and the interval to the first PRN injection following three intravitreal bevacizumab (IVB) injections (r = -0.587, P = 0.021).\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8711380/v1/6c7e19677d31192ea9372559.jpg"},{"id":103587296,"identity":"cabbaa09-eeb9-4c62-90d6-39b2794b56be","added_by":"auto","created_at":"2026-02-27 11:27:40","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":154173,"visible":true,"origin":"","legend":"\u003cp\u003eComparison of clinical parameters between subgroups based on the number of injections. Subgroups are divided into patients receiving five or fewer injections and those requiring six or more injections, with comparisons made for (A) best corrected visual acuity (BCVA), (B) intraocular pressure (IOP), and (C) vascular endothelial growth factor (VEGF) concentrations. BCVA and IOP were recorded before the first injection, after three injections, and at the 3-year follow-up, while VEGF levels were recorded prior to each of the three injections.\u003c/p\u003e","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8711380/v1/6fbc3f05ce916259da128f9a.jpg"},{"id":108438072,"identity":"6f102e84-5e8d-444c-b8bf-c9dad797a36f","added_by":"auto","created_at":"2026-05-04 16:06:55","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":934473,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8711380/v1/ef5dd8e9-801c-4be1-881c-b3970ad05206.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Serial Aqueous VEGF Analysis for Predicting Anti-VEGF Treatment Outcomes in Neovascular Glaucoma from Diabetic Retinopathy: a prospective analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGlaucoma is a chronic eye disease that damages the optic nerve and causes permanent blindness. The global prevalence of glaucoma has increased from 64.3\u0026nbsp;million cases in 2013 and is projected to exceed 111\u0026nbsp;million by 2040 \u003csup\u003e1\u003c/sup\u003e. Neovascular glaucoma (NVG) is a vision-threatening secondary glaucoma characterized by neovascularization of the iris and increased intraocular pressure (IOP). NVG accounts for 3.9% of all glaucoma cases and 9\u0026ndash;14.7% of all secondary glaucoma, with a higher prevalence among individuals with underlying conditions causing retinal ischemia and chronic hypoxia, such as proliferative diabetic retinopathy (PDR), central retinal vein occlusion (CRVO), and ocular ischemic syndrome (OIS) \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRetinal ischemia triggers the release of vascular endothelial growth factor (VEGF), which induces angiogenesis. In NVG, excessive VEGF enters the anterior chamber of the eye from the posterior pole, promoting the formation of pathological blood vessels in the iris and iridocorneal angle \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Tripathi et al. \u003csup\u003e5\u003c/sup\u003e demonstrated through competitive enzyme immunoassay that patients with NVG exhibit a significantly increased levels of VEGF in the aqueous humor. Similarly, Sun et al. \u003csup\u003e6\u003c/sup\u003e found that the concentration of aqueous VEGF-A was higher in the NVG group than that in the PDR group, with notably higher concentrations in the aqueous humor than that in the vitreous. Kim et al. \u003csup\u003e7\u003c/sup\u003e reported that elevated aqueous humor VEGF levels were associated with failure following Ahmed glaucoma implantation. Therefore, VEGF, an endothelial cell-specific angiogenic factor, plays a central role in iris neovascularization and NVG.\u003c/p\u003e \u003cp\u003eBased on these findings, anti-VEGF therapies have been employed for the treatment of ocular neovascularization. Bevacizumab (Avastin, Genentech, South San Francisco, CA), a humanized monoclonal antibody targeting all VEGF isoforms, shows promise in treating iris neovascularization and NVG \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The off-label use of intravitreal bevacizumab (IVB) stabilizes neovascular activity and controls IOP in patients with iris and/or iridocorneal angle neovascularization particularly in early stage NVG without angle closure, although repeated injections maybe necessary in some cases. In advanced NVG, IVB alone may not stabilize elevated IOP but can be used as a preoperative adjunct to improve the quality and safety of surgery \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Although these encouraging results may suggest that bevacizumab should be the first treatment of choice for NVG, the optimal dosage and injection intervals for IVB to treat NVG has not yet been established.\u003c/p\u003e \u003cp\u003eA few studies identified through a MEDLINE search quantitatively evaluated IVB-induced changes in VEGF concentrations in fluid from patients with advanced NVG and found that bevacizumab reduced VEGF levels in the aqueous humor \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Sasamoto et al. showed a significant decrease in aqueous humor VEGF levels one week after the initial injection, with a notable correlation between VEGF levels and IOP \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWhile previous studies have measured VEGF concentrations before and after treatment, these evaluations were typically conducted only once. No studies have yet serially measured VEGF levels following multiple injections. Therefore, this study investigated the effects of three consecutive bi-weekly intravitreal anti-VEGF injections in a group of patients with PDR-induced NVG. VEGF concentrations in the aqueous humor were measured and analyzed after each injection to predict IOP control and the prognosis of IVB treatment.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects, method, and data analysis\u003c/h2\u003e \u003cp\u003e This was a prospective, comparative study approved by the Institutional Review Board of Kyung Hee University Hospital at Gangdong (KHNMC 2016-12-021) and adhered to the provisions of the Declaration of Helsinki for research involving human subjects. Written informed consent was obtained from all the participants.\u003c/p\u003e \u003cp\u003eBetween 2016 and 2022, patients with NVG secondary to PDR, who exhibited uncontrolled IOP despite maximum antiglaucomatous medications (topical β-blockers, topical carbonic anhydrase inhibitors (CAIs), topical α2-adrenergic agonists, and systemic medications) and demonstrated neovascularization of the iris and/or iridocorneal angle, were included in this study. Eligible patients were treated with three IVB injections at 2-week intervals.\u003c/p\u003e \u003cp\u003eAll patients received panretinal photocoagulation (PRP) to control neovascularization, particularly in cases with angle closure due to peripheral anterior synechia. Aqueous humor samples from the anterior chamber were collected before each injection, and VEGF concentrations (pg/mL) were measured by enzyme-linked immunosorbent assay.\u003c/p\u003e \u003cp\u003eAfter receiving three injections, patients were observed for 1 month. If IOP was \u0026gt;\u0026thinsp;21 mm Hg or neovascularization was identified, they were treated with additional IVB injections on a pro re nata (PRN) regimen. Conversely, if IOP was normal or neovascularization was not present at this time, patients were followed-up two months later. At subsequent 2-month follow-up, those required further injections were monitored 1 month after treatment, while those who did not requiring further injections were observed 3 months later. The maximum observation period was 3 months. The end point of the study was set at 3 years following the first injection. Patients were withdrawn from the study if they opted for surgery to control their IOP or declined to continue participation (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eBest-corrected visual acuity (BCVA, LogMAR), IOP, and VEGF concentrations before injections were analyzed using the Wilcoxon signed-rank test, and the correlation between initial VEGF concentration and BCVA or IOP after three injections was evaluated using Spearman correlation analysis. The correlation between the initial VEGF concentration in aqueous humor and the interval to the first PRN injection after three consecutive injections, as well as the average number of PRN injections per year, was analyzed using Spearman correlation analysis. Patients were divided into two groups for subgroup analysis based on the number of injections received: those who received five or fewer anti-VEGF injections and those who received six or more anti-VEGF injections. BCVA and IOP results were compared between these groups using the Mann-Whitney test.\u003c/p\u003e \u003cp\u003eData were processed and statistically analyzed using SPSS for Windows (Version 27.0; SPSS, Chicago, IL). For all tests, P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eAnti-VEGF injection\u003c/h3\u003e\n\u003cp\u003eAll NVG patients received intravitreal injections of 0.05 mL of 1.25 mg IVB via a 30-gauge needle in the inferior temporal quadrant, positioned 3.5 mm to 4 mm posterior to the limbus. Antiglaucomatous medications and anti-inflammatory and anti-infective eye drops (prednisolone acetate ophthalmic suspension, United States Pharmacopoeia; Allergan, Inc., Irvine, CA and levofloxacin hydrate ophthalmic solution, Japan Pharmacopoeia; Santen pharmaceutical CO., LTD., Ishikawa) were administered as necessary to manage IOP and address inflammatory and/or infectious response.\u003c/p\u003e\n\u003ch3\u003eAqueous humor sampling\u003c/h3\u003e\n\u003cp\u003eAqueous humor samples were collected during each IVB treatment (pre-IVB). A 200 \u0026micro;L sample of undiluted aqueous humor was obtained via anterior chamber paracentesis using a 30-gauge needle. Each aqueous humor sample was placed in an Eppendorf tube, rapidly frozen at -80\u0026deg;C and protected from light until the VEGF concentration was measured.\u003c/p\u003e\n\u003ch3\u003eMeasurement of aqueous humor VEGF concentration\u003c/h3\u003e\n\u003cp\u003eVEGF concentrations in aqueous humor were measured using an enzyme-linked immunosorbent assay (Quantikine\u0026reg;, Human VEGF immunoassay, R\u0026amp;D System Inc., Minneapolis, MN). According to the protocol provided by the manufacturer. For each assay, 100 \u0026micro;L per sample was used. The mean of two readings was utilized for quantitative analysis. The limit of the detectable VEGF concentration was 15.6 pg/mL.\u003c/p\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eDemographic data of the patients\u003c/h2\u003e \u003cp\u003eA total of 20 NVG patients who met the inclusion criteria were included in the study. However, three patients were excluded: two eyes required glaucoma surgery due to uncontrolled IOP, and one patient voluntarily withdrew from the study. All measurements were performed successfully, with no failures resulting from insufficient sampling in VEGF determination.\u003c/p\u003e \u003cp\u003eThe mean age of patients with NVG was 63.47\u0026thinsp;\u0026plusmn;\u0026thinsp;9.25 years, comprising 14 men and 3 women. The average diabetes duration was 11.12\u0026thinsp;\u0026plusmn;\u0026thinsp;7.13 years, and the mean HbA1c was 9.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30%. The mean number of injection treatments received was 8.76\u0026thinsp;\u0026plusmn;\u0026thinsp;5.77. All data are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical demographics of the participants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParticipants\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge \u003c/p\u003e \u003cp\u003emean (range), year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63.47\u0026thinsp;\u0026plusmn;\u0026thinsp;9.25 (52\u0026ndash;86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (82%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (18%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of diabetes\u003c/p\u003e \u003cp\u003emean (range), years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.12\u0026thinsp;\u0026plusmn;\u0026thinsp;7.13 (0\u0026ndash;22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHbA1c\u003c/p\u003e \u003cp\u003emean (range), %\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.30 (7.4\u0026ndash;11.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of injections\u003c/p\u003e \u003cp\u003emean (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.76\u0026thinsp;\u0026plusmn;\u0026thinsp;5.77 (3\u0026ndash;21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e provides detailed case-by-case data, including BCVA (LogMAR) and IOP measured before the first injection and after the third injection, as well as aqueous humor VEGF concentrations measured before the first injection and prior to the third injection. Additionally, the table includes the total number of injections, final BCVA (LogMAR), and final IOP. For patients receiving PRN injections, further details such as the interval between the first PRN injection after the initial three injections (in months), and average annual PRN injections are also provided.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eData from 17 patients with neovascular glaucoma who participated in the study\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"15\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDM duration (Years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHb1Ac\u003c/p\u003e \u003cp\u003e(%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eInitial BCVA (LogMAR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eAfter 3 injections BCVA (LogMAR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eInitial IOP (mmHg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAfter 3 injections IOP (mmHg)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eInitial VEGF (pg/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eBefore 3rd injections VEGF (pg/mL)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eTotal number of injections\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eInterval between first PRN injection after 3 injections\u003c/p\u003e \u003cp\u003e(months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c13\" namest=\"c12\"\u003e \u003cp\u003eAverage number of PRN injections per year\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003eFinal BCVA (LogMAR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c15\"\u003e \u003cp\u003eFinal IOP (mmHg)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e441.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e40.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6593.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e46.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e3.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e653.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e72.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e29540.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e298.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1366.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e129.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5477.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e150.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e220.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e62.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e99.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e52.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e391.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e53.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e824.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e157.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.52\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e8329.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e42.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e307.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e25.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e268.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e130.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e508.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e21.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e5.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e420.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e35.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e554.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e63.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e23590.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e398.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e2.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e11.1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e9.12\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e1.27\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.91\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e32.7\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e25.3\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u003cb\u003e4681.5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u003cb\u003e104.5\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e\u003cb\u003e8.76\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c12\" namest=\"c11\"\u003e \u003cp\u003e\u003cb\u003e2.00\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e\u003cb\u003e1.92\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e\u003cb\u003e0.95\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e\u003cb\u003e19.1\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"15\"\u003eBCVA: best corrected visual acuity, DM: diabetes mellitus, IOP: intraocular pressure, VEGF: vascular endothelial growth factor\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eChange in parameters before (pre-IVB) and after bi-weekly three consecutive IVB injections (post-IVB)\u003c/h3\u003e\n\u003cp\u003eCompared to pre-IVB values, the mean BCVA (LogMAR) (1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10) significantly improved after three IVB injections (0.91\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The mean IOP (32.71\u0026thinsp;\u0026plusmn;\u0026thinsp;17.33 mmHg) significantly decreased after three IVB injections (25.29\u0026thinsp;\u0026plusmn;\u0026thinsp;9.99mmHg, P\u0026thinsp;=\u0026thinsp;0.031). The mean VEGF concentration (4681.46\u0026thinsp;\u0026plusmn;\u0026thinsp;8673.42 pg/mL) significantly decreased before the third IVB injection (104.55\u0026thinsp;\u0026plusmn;\u0026thinsp;102.78 pg/mL, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e\n\u003ch3\u003eCorrelation between initial VEGF concentration and parameters\u003c/h3\u003e\n\u003cp\u003eA significant positive correlation was observed between initial VEGF concentration and post-IVB BCVA (LogMAR) (r\u0026thinsp;=\u0026thinsp;0.737, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA), pre-IVB IOP (r\u0026thinsp;=\u0026thinsp;0.535, P\u0026thinsp;=\u0026thinsp;0.027) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB), and post-IVB IOP (r\u0026thinsp;=\u0026thinsp;0.636, P\u0026thinsp;=\u0026thinsp;0.006) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC), except for pre-IVB BCVA (LogMAR) (r\u0026thinsp;=\u0026thinsp;0.401, P\u0026thinsp;=\u0026thinsp;0.110).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation of PRN injections with initial VEGF concentration\u003c/h2\u003e \u003cp\u003eIn 15 out of 17 eyes, PRN injections were performed as follow-ups after three consecutive bi-weekly IVB injections. On average, the first PRN injection occurred two months after the initial three injections, with an average of 1.92 PRN injections per year. When examining these parameters in relation to the initial VGEF concentration, the interval between the first PRN injection after three consecutive injections showed a statistically significant correlation with the initial VEGF concentration (r = -0.587, P\u0026thinsp;=\u0026thinsp;0.021) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Average number of PRN injections per year did not show a statistically significant correlation with initial VEGF concentration, although a P value of 0.069 was noted (r\u0026thinsp;=\u0026thinsp;0.482).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eComparison of subgroups according to number of injections\u003c/h2\u003e \u003cp\u003eFor subgroup comparative analysis, we defined group 1 as those who received 5 or fewer injections (n\u0026thinsp;=\u0026thinsp;8) and group 2 as those who received 6 or more injections (n\u0026thinsp;=\u0026thinsp;9). The BCVA (LogMAR) showed no statistical difference between groups at pre-IVB (0.80\u0026thinsp;\u0026plusmn;\u0026thinsp;0.52 vs 1.68\u0026thinsp;\u0026plusmn;\u0026thinsp;1.33, P\u0026thinsp;=\u0026thinsp;0.095). However, after three injections, a statistically significant difference was noted (0.32\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18 vs 1.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.99, P\u0026thinsp;=\u0026thinsp;0.010) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). The IOP showed no statistical difference between groups at pre-IVB (29.0\u0026thinsp;\u0026plusmn;\u0026thinsp;14.7 mmHg vs 36.0\u0026thinsp;\u0026plusmn;\u0026thinsp;19.6 mmHg, P\u0026thinsp;=\u0026thinsp;0.416) or after one injection (20.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.2 mmHg vs 26.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9.3 mmHg, P\u0026thinsp;=\u0026thinsp;0.129), but a statistically significant difference was observed after three injections (19.6\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0 mmHg vs 30.3\u0026thinsp;\u0026plusmn;\u0026thinsp;10.8 mmHg, P\u0026thinsp;=\u0026thinsp;0.021) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB). The VEGF concentrations showed statistically significant difference at pre-IVB (386.1\u0026thinsp;\u0026plusmn;\u0026thinsp;177.3 pg/mL vs 8499.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10750.8 pg/mL, P\u0026thinsp;=\u0026thinsp;0.049), before second injection (52.2\u0026thinsp;\u0026plusmn;\u0026thinsp;15.6 pg/mL vs 131.4\u0026thinsp;\u0026plusmn;\u0026thinsp;102.1 pg/mL, P\u0026thinsp;=\u0026thinsp;0.048), and before third injections (50.5\u0026thinsp;\u0026plusmn;\u0026thinsp;15.9 pg/mL vs 152.5\u0026thinsp;\u0026plusmn;\u0026thinsp;124.1 pg/mL, P\u0026thinsp;=\u0026thinsp;0.036) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe results demonstrated that anti-VEGF therapy significantly reduced aqueous VEGF concentrations in patients with NVG, leading to improvements in BCVA and IOP after three consecutive bi-weekly IVB injection. However, some patients experienced poor IOP control or persistent or recurrent neovascularization of the iris and/or iridocorneal angle, requiring repeated injections. Statistically significant correlations were found between initial aqueous VEGF concentrations and BCVA and IOP after three injections, indicating that higher initial VEGF concentrations were associated with poorer visual outcomes and less effective IOP control. Furthermore, a correlation between initial aqueous VEGF concentration and the interval between first PRN injections following three IVB treatment was observed. Comparative analysis between patients receiving five or fewer injections and six or more injections showed statistically significant higher initial VEGF concentrations in the latter group, along with worse BCVA and IOP outcomes after three injections.\u003c/p\u003e \u003cp\u003eNVG is challenging to treat, often requiring the use of multiple treatment modalities simultaneously, and may require the cooperation of both retina and glaucoma specialist. According to the European Glaucoma Society, NVG management relies on two primary principles: (1) the treatment of retinal ischemia by performing PRP or intravitreal anti-VEGF injections and (2) controlling high IOP by topical and systemic pharmacological medications or surgical interventions to avoid damage to the optic nerve \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. The most common conditions leading to NVG are ischemic eye diseases such as PDR, CRVO, and OIS, with PRP serving as the primary treatment to alleviate retinal ischemia. The goal of PRP is to reduce the ischemic areas in the retina by increasing the oxygen supply and suppressing the secretion of VEGF \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. In addition, there are pharmacologic and surgical treatments to control IOP. Topical anti-glaucoma drugs such as topical β-blockers, α-agonists, and CAIs, may be beneficial in reducing IOP. Systemic CAIs can also be effective for temporary short-term IOP reduction but must be used carefully in patients with renal impairment \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. However, pharmacological treatment does not provide an adequate response for elevated IOP; approximately 50% of NVG cases require surgical IOP control such as drainage valve implantation, trabeculectomy with mitomycin C or 5-fluorouracil, and cyclodestructive procedures are usually required \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePatients with NVG exhibit elevated VEGF concentrations, which can be reduced through intravitreal injection treatment of anti-VEGF inhibitors, the focus of this study. Bevacizumab, a full-length humanized, is a recombinant monoclonal IgG antibody that inactivates all VEGF isoforms \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Several studies have demonstrated the efficacy of bevacizumab in NVG management. Ghanem et al. reported significant regression of iris neovascularization and IOP reduction one week after IVB \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. Wakabayashi et al. also reported that IVB stabilizes neovascular activity and controls IOP in patients with iris and/or iridocorneal angle neovascularization alone and in early-stage NVG without angle closure \u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Matsuyama et al. reported that IVB significantly decreased the free VEGF in the aqueous humor within seven days \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Additionally, Sasamoto et al. found that the rate of improved or unchanged visual acuity after IVB was higher than the rate of worsening visual acuity \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Costagliola et al reported significant improvement in visual acuity in all patients after three IVBs administered at four-week intervals \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. While other studies have shown improvement in IOP control and neovascularization after three IVBs within four weeks, visual acuity changes were not statistically significant \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThese findings indicate that bevacizumab shows clinical benefits in patients with NVG, suggesting it as a potential first-line treatment. However, its effects are transient due to the short half-life of the drug \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Several studies have investigated the pharmacokinetics of bevacizumab in rabbits and humans following intravitreal injection. In rabbits, bevacizumab reaches its peak concentration in the vitreous humor one day after injection and in the aqueous humor three days after injection, with half-lives of 4.32 and 4.88 days, respectively \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Another study reported peak concentration in the vitreous and aqueous humor one day after injection, with half-life of 6.61 and 6.51 days, respectively \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. In humans, Moisseiev et al. reported a mean vitreal half-life of 4.9 days in non-vitrectomized eyes and 0.66 days in previously vitrectomized eye \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Csaky et al. reported that peak IVB concentrations were detected at 2\u0026ndash;5 days post-injection, with a half-life of approximately 10 days \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Krohne et al. reported that concentration of bevacizumab in aqueous humor peaked on the first day after injection and a half-life was 9.82 days in non-vitrectomized eyes \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. These findings indicate that the time to peak concentration and the half-life of bevacizumab in rabbit and human aqueous and vitreous humor are short.\u003c/p\u003e \u003cp\u003eThis study was designed to administer three consecutive bi-weekly IVB injections in patients with PDR-induced NVG, recognizing the short intraocular half-life of bevacizumab which is less than one week. Considering the higher aqueous VEGF concentrations in patients with NVG compared to that in patients with PDR, and the elevated VEGF levels in aqueous humor relative to vitreous humor, it was hypothesized that maintaining consistent intraocular anti-VEGF levels would achieve better IOP control. In fact, several studies have shown the benefit of reducing the interval between injections in patients with refractory neovascular age-related macular degeneration (nAMD) \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Bi-weekly injections have been shown to significantly increase binding activity, suggesting that administration of anti-VEGF drugs every two weeks may benefit patients who respond poorly to monthly therapy \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. In this study, NVG was considered a refractory glaucoma caused by increased VEGF levels in the anterior chamber. The results confirmed that three consecutive bi-weekly IVB injections significantly improve visual acuity, controlling IOP, and reducing aqueous VEGF concentration. A review of bi-weekly injection safety showed no issues in rabbit eyes \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Other studies have reported subretinal fibrosis with bi-weekly injections in patients with nAMD \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e, but no retinal fibrosis was observed in the current study.\u003c/p\u003e \u003cp\u003eThis study further established that higher initial VEGF concentration was associated with increased IOP, decreased visual acuity, and a relatively greater number of injections required for treatment. While previous studies only found a correlation between VEGF concentration and IOP, they did not demonstrate associations with visual acuity or number of injections. Consistent with earlier findings, this study confirmed a positive correlation between VEGF concentration and IOP \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Additionally, it provided novel evidence linking VEGF concentration to visual acuity and the frequency of IVB injections, marking a significant contribution to the field.\u003c/p\u003e \u003cp\u003eBased on the study design, it would have been more precise to measure VEGF concentrations by collecting fluid two weeks after the three consecutive injections. However, ethical constraints prevented the collection of aqueous humor samples following the treatment regimen. Another limitation of this study was the small sample size, as it was conducted prospectively.\u003c/p\u003e \u003cp\u003eThe elevated VEGF concentrations observed in PDR-induced NVG confirm the critical role of VEGF in NVG progression and IVB administered at the initial two-week interval effectively reduces these concentrations. Furthermore, this study found that initial VEGF concentration could not only predict the prognosis of visual acuity and IOP, but also the severity of NVG and the number of injections required for effective treatment. Higher initial VEGF concentrations were associated with a greater number of injections and poorer visual acuity and IOP outcomes. These findings suggest that measuring VEGF concentration in the anterior chamber may help predict the effectiveness of anti-VEGF treatment in patients with NVG.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing financial interests.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics declarations\u003c/h2\u003e \u003cp\u003e The current research followed the tenets of the Declaration of Helsinki, and all patients provided informed consent after an explanation of the study protocol. The Institutional Review Board at Kyung Hee University Hospital at Gangdong (KHNMC 2016-12-021) approved this retrospective study.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eConsent for publication\u003c/h2\u003e \u003cp\u003eNot Applicable.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research was supported by the Chung-Ang University Research Grants in 2024.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eT.J. contributed acquisition of data, and drafting the article. J.H.J. contributed the conception and design of the study, analysis and interpretation of data, and final approval of the version to be submitted.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe would like to thank Editage (www.editage.co.kr) for English language editing.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated in the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eTham YC, et al. Global prevalence of glaucoma and projections of glaucoma burden through 2040: a systematic review and meta-analysis. 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Can J Ophthalmol. 2010;45:386\u0026ndash;92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3129/i10-024\u003c/span\u003e\u003cspan address=\"10.3129/i10-024\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarikian A, Mahfoud Z, Abdulaal M, Safar A, Bashshur ZF. Induction with intravitreal bevacizumab every two weeks in the management of neovascular age-related macular degeneration. Am J Ophthalmol. 2015;159:131\u0026ndash;7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ajo.2014.10.005\u003c/span\u003e\u003cspan address=\"10.1016/j.ajo.2014.10.005\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"neovascular glaucoma, bevacizumab (Avastin®), vascular endothelial growth factor, aqueous humor, diabetic retinopathy","lastPublishedDoi":"10.21203/rs.3.rs-8711380/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8711380/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study evaluated the effectiveness of intravitreal bevacizumab (IVB) in neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy (PDR). It assessed outcomes of three bi-weekly IVB injections and analyzed the correlation between serial aqueous VEGF levels and clinical parameters to predict treatment efficacy. A prospective study was conducted on 17 NVG patients due to PDR. Each received three bi-weekly IVB injections. Aqueous VEGF levels, intraocular pressure (IOP), and best-corrected visual acuity (BCVA) were measured before and after treatment. Follow-up continued for three years, with additional injections given as needed. After three injections, VEGF levels significantly dropped from 4681.46 pg/mL to 104.55 pg/mL. BCVA improved from 1.27 to 0.91 (LogMAR), and IOP decreased from 32.71 mmHg to 25.29 mmHg. Higher initial VEGF levels were linked to worse BCVA, elevated IOP, and more frequent injections. Patients needing six or more injections had significantly worse baseline VEGF, BCVA, and IOP. Three bi-weekly IVB injections effectively reduced VEGF levels, improved IOP, and enhanced BCVA. Serial VEGF monitoring helps predict outcomes, as higher initial VEGF levels indicate more severe disease and increased treatment needs. Aqueous VEGF serves as a valuable biomarker for NVG management.\u003c/p\u003e","manuscriptTitle":"Serial Aqueous VEGF Analysis for Predicting Anti-VEGF Treatment Outcomes in Neovascular Glaucoma from Diabetic Retinopathy: a prospective analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-27 11:26:44","doi":"10.21203/rs.3.rs-8711380/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-03-20T08:46:32+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-09T01:09:18+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-03-07T01:25:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"301616758251190626346370289808903142067","date":"2026-02-25T04:43:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"192217309125108384006789256280659407142","date":"2026-02-25T00:55:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-24T09:55:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-23T11:55:52+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-02-02T04:32:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-01T15:56:30+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2026-02-01T13:59:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a2a515dc-f96c-493c-b7b1-ceb395f159db","owner":[],"postedDate":"February 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-05-04T16:06:50+00:00","versionOfRecord":{"articleIdentity":"rs-8711380","link":"https://doi.org/10.1186/s12886-026-04852-3","journal":{"identity":"bmc-ophthalmology","isVorOnly":false,"title":"BMC Ophthalmology"},"publishedOn":"2026-04-29 15:57:38","publishedOnDateReadable":"April 29th, 2026"},"versionCreatedAt":"2026-02-27 11:26:44","video":"","vorDoi":"10.1186/s12886-026-04852-3","vorDoiUrl":"https://doi.org/10.1186/s12886-026-04852-3","workflowStages":[]},"version":"v1","identity":"rs-8711380","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8711380","identity":"rs-8711380","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}