
Neovascular age-related macular degeneration (nAMD) is one of the major causes of acquired irreversible vision loss in elderly populations in developed countries [1,2]. In addition to typical wet AMD, variants of nAMD, such as polypoidal choroidal vasculopathy (PCV) and retinal angiomatous proliferation, also exist [1]. PCV has a prevalence of just 8%-13% in Caucasian patients [3] but is a more common subtype of nAMD in Asian populations, where the prevalence varies between 23% and 54% [4-6]. Dr. Yannuzzi reported that PCV patients have peculiar polypoidal subretinal vascular lesions associated with serous and hemorrhagic detachments of the retinal pigment epithelium [7]. In the present study, PCV was diagnosed based on the presence of polypoidal lesions with or without a branched vascular network on indocyanine green angiography (ICGA), according to diagnostic criteria from a PCV workgroup [8].
Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents suppress fluid accumulation caused by choroidal neovascularization in nAMD and have become the mainstay of treatment for this condition [9]. Currently, brolucizumab (Beovu®; Novartis AG and Genentech, Inc.), an effective and longer-lasting anti-VEGF agent, was recently approved in South Korea as a new treatment for nAMD, including PCV [10]. Brolucizumab is a humanized single-chain antibody fragment consisting of the tips of the Fab region of the antibody that inhibits VEGF-A alone. Additionally, brolucizumab has a low molecular weight of 26 kDa, which enables better tissue penetration along with high stability and solubility. Brolucizumab is highly concentrated, with molar doses 12 times that of aflibercept (Eylea®; Regeneron Pharmaceuticals and Bayer HealthCare) and 22 times that of ranibizumab (Lucentis®; Genentech) [11].
The primary function of VEGF is to promote angiogenesis, vasodilation, and increased vascular permeability, which play critical roles in the pathogenesis of nAMD [12,13]. However, VEGF, especially VEGF-A, is also essential for survival of retinal ganglion cells (RGCs) and retinal nerve fiber layer. It has neuroprotective properties and plays a significant role in glaucoma prevention [12,13]. Therefore, theoretically, the use of anti-VEGF agents could lead to RGC and the retinal nerve fiber layer loss.
Existing studies have analyzed the effect of anti-VEGF agents on peripapillary retinal nerve fiber layer (RNFL) thickness in both typical wet AMD and PCV patients [14,15], but no such studies have limited their patient population solely to PCV patients. Further, Jun and Hwang reported that the effect of brolucizumab on RNFL thickness was not significant for a 3-month period [14], and no longer-term results have yet been reported. Therefore, the present study was conducted to analyze the long-term effect of intravitreal brolucizumab (IVB) injections on RNFL thickness in patients with PCV.
A retrospective consecutive case series study was performed. Patients who previously received another anti-VEGF therapy for PCV, including bevacizumab, ranibizumab, and/or aflibercept, but who continued to show fluid accumulation on spectral-domain optical coherence tomography (SD-OCT) due to poor response to the treatment were potential participants. Of a total of 56 PCV patients, 45 were excluded based on the study exclusion criteria, leaving 11 eyes in 11 patients who ultimately switched to IVB (6 mg/0.05 mL) therapy at our hospital from April 2021 to February 2023 and who were eligible for analysis. Baseline was defined as the initiation of brolucizumab therapy. The pro-re-nata protocol was used as an IVB dosing regimen, which is a treatment protocol where decisions to carry out an injection were based on the anatomic findings at each follow-up visit. Exclusion criteria were as follows: (1) Patients with other ocular diseases such as retinal vascular disease, uveitis, glaucoma, or optic nerve disease (4 patients). Prior to enrollment, the presence of glaucoma was assessed in all patients. Both eyes underwent evaluation using Cirrus high-definition optical coherence tomography (OCT) (Carl Zeiss Meditec) and standard automated perimetry with the 24-2 Swedish interactive threshold algorithm visual field test (Humphrey Visual Field Analyzer; Carl Zeiss Meditec); (2) Patients with intraocular inflammation following IVB injection (7 patients); (3) Patients whose contralateral eye had nAMD or had previously received anti-VEGF treatment (14 patients); (4) Patients with a follow-up period <12 months or those who did not have at least one measurement of RNFL thickness between baseline and 12 months (18 patients); (5) Patients with diffuse subretinal or intraretinal fluid causing auto-segmentation layer errors on the spectral-domain OCT (SD-OCT) program (2 patients). Medical records and SD-OCT (Spectralis OCT system; Heidelberg Engineering) data at baseline and 1, 3, 6, 9, and 12 months after IVB injection were retrospectively reviewed. PCV was diagnosed based on the presence of polypoidal lesions with or without a branched vascular network in ICGA [16,17]. As a control group, 11 normal contralateral eyes of these patients were selected. Eyes diagnosed with nAMD or administered any anti-VEGF injection treatment were excluded from the control group.
All patients enrolled in this study underwent fluorescein angiography and ICGA at baseline or before IVB injection. At 1, 3, 6, 9, and 12 months after IVB therapy, BCVA and intraocular pressure (IOP) were assessed by slit-lamp biomicroscopy, fundus photography, and SD-OCT. RNFL thickness was automatically measured by the SD-OCT program (Spectralis Nsite Axonal Analytics Software; Heidelberg Engineering). The total 360° RNFL was divided into six sectors, as follows: temporal (315°-45°), superior temporal (45°-90°), superior nasal (90°-135°), nasal (135°-225°), inferior nasal (225°-270°), and inferior temporal (270°-315°). The measured RNFL thickness values of these six sectors were averaged to obtain the global RNFL thickness.
In this study, RNFL OCT results with poor quality were excluded when the automatic real-time score was <16 points and the signal-to-noise ratio was ≥15 dB. The central macular thickness (CMT) was defined as the average retinal thickness at the central 1-mm diameter, and macular thickness was determined using a volume scan of 30° centered on the fovea with a central fixation assist and a 250-μm distance between scans.
This study was conducted in accordance with the principles of the Declaration of Helsinki. The Institutional Review Board (IRB) of Hangil Eye Hospital approved this study and waived the requirement for informed consent from the study participants due to the retrospective nature of the study (IRB number: IRB-23006).
The R program version 4.3.1 for Windows (R Foundation for Statistical Computing) was used to conduct statistical analysis. Data were expressed as “median with interquartile range” or “mean ± standard deviation” values. The Mann–Whitney U test was used to compare the IVB-treated eyes to the control eyes. The Wilcoxon signed-rank test was used to examine longitudinal changes in values from the baseline assessment to each follow-up visit. Statistical significance was considered when the p-value was <0.05.
Demographics and baseline characteristics of patients are summarized in Table 1. The median age of the patients was 67 years, and there were eight men (72.7%). The median number of other anti-VEGF therapies administered before switching to IVB was seven. The median logarithm of the minimum angle of resolution (logMAR) of BCVA was 0.30, and the median IOP was 16 mmHg. The median logMAR of BCVA in the fellow eyes group was 0.00, and these eyes showed statistically significantly better visual acuity compared to the IVB-treated eyes (p-value < 0.001).
In both groups of the IVB-treated eyes and the fellow eyes, there were no significant differences in BCVA between baseline and all follow-up visits. At all follow-up visits, the BCVA of the fellow eye was significantly better than that of the IVB group (Fig. 1, p-value < 0.001).
In both groups, no significant change in IOP was observed at 12 months in the treated and fellow eyes, and no significant difference was observed between the treated and fellow eyes at any visit.
Table 2 summarizes the RNFL thickness in the superior temporal, temporal, inferior temporal, inferior nasal, nasal, superior nasal, and global sectors. In the IVB-treated eyes group, at 1 month after IVB treatment, only the inferior temporal sector RNFL thickness had decreased significantly compared to baseline (mean ± standard deviation: 151.0 ± 19.1, p-value = 0.029). However, from 3 to 12 months after IVB treatment, the change in inferior temporal sector RNFL thickness compared to baseline was not significant. Meanwhile, in the IVB-treated eyes group, the RNFL thickness of other sectors did not show a significant change compared to baseline.
In the fellow eyes, there were no significant longitudinal changes in RNFL thickness of all sectors between baseline and all follow-up visits. At all follow-up visits, the RNFL thickness of all sectors in the fellow eyes group did not show the significant differences from the comparable measurement in the IVB group (Table 2).
CMT at baseline before switching to brolucizumab was statistically significantly thicker than that of fellow eyes that did not receive injections (p-value = 0.030, Table 3). In the IVB-treated eyes group, CMT decreased statistically significantly from 1 month to 12 months after IVB treatment compared to baseline (p-value: 0.006, 0.009, 0.009, 0.032, and 0.033, respectively; Table 3). There were no significant differences between CMT in the IVB-treated eyes group and that in the fellow eyes group from 1 month to 12 months after IVB treatment (p-value: 0.282, 0.101, 0.168, 0.414, and 0.131, respectively; Table 3).
We evaluated the effect of brolucizumab on RNFL thickness in patients with nAMD who previously had an incomplete response to other anti-VEGF agents. The CMT significantly decreased after IVB injection, while BCVA did not show an improvement compared to baseline. We found no statistically significant differences in IOP or peripapillary RNFL thickness between the treated and fellow eyes at any visit. Additionally, no significant long-term changes were noted in the global RNFL thickness or other sectors compared to baseline in the IVB-treated eyes.
Conflicting reports exist regarding changes in RNFL thickness over time with anti-VEGF treatment in nAMD patients. Valverde-Megías et al. [18] and Martinez-de-la-Casa et al. [19] both reported a significant decrease in RNFL thickness across all sectors, including the global sector, at 12 months following intravitreal ranibizumab injection. In patients with nAMD treated with aflibercept, global sector RNFL thickness was significantly decreased compared to baseline at the 10-month follow-up [20]. Some reports have indicated that significant longitudinal changes in RNFL thickness were observed only in specific sectors or at intermediate follow-up visits; for example, Jo et al. [21] found no significant change in global sector RNFL thickness compared to baseline at 12 months after intravitreal ranibizumab injection, though a significant decrease was observed in the temporal segment. Jun and Hwang [14] reported that the temporal sector RNFL thickness showed a significant decrease compared to baseline only at 1 month after IVB injection, and significance was lost by the 3-month follow-up. However, several studies have reported no significant change in RNFL thickness compared to baseline in any sector or at any follow-up point after anti-VEGF injections in nAMD patients. For instance, Shah et al. [22] observed 707 eyes for 24 months following intravitreal injection of pegaptanib or bevacizumab and/or ranibizumab, and Horsley et al. [23] observed 41 eyes for 27 months, both reporting no significant changes in RNFL thickness. Similarly, Gunay and Esenulku [24] reported no significant differences in RNFL thickness up to 12 months following intravitreal aflibercept injection in 34 eyes diagnosed with nAMD. Lee et al. [25] found no significant change in RNFL thickness over time in 16 eyes treated with bevacizumab, ranibizumab, or aflibercept for up to 24 months.
In the present study, there was no significant long-term change in global sector RNFL thickness compared to baseline after IVB injection. However, RNFL thickness in the inferior temporal sector decreased significantly at 1 month. The peripapillary inferior temporal quadrant is close to the macula, and, prior to IVB injection, RNFL thickness may have been increased due to macular edema and elevated CMT. It is hypothesized that anti-VEGF injections reduce CMT and enhanced RNFL thickness in the temporal region as nAMD activity decreases. Additionally, no significant differences in RNFL thickness were observed in any sector compared to in the control group of untreated fellow eyes at all follow-up visits. Similar findings have been reported in other studies, where no significant differences in RNFL thickness were seen compared to control groups of normal fellow eyes or age-matched healthy patients [14,15,18,21].
CMT showed a significant decrease compared to baseline at all follow-up points up to 12 months after IVB injection (Table 3). Although CMT was significantly thicker before IVB injection than that in the control group, this statistical significance was lost at all follow-up visits after IVB injections (Table 3). However, significant anatomical changes in CMT did not lead to significant functional changes in BCVA; in fact, BCVA showed no significant change compared to baseline at any follow-up point up to 12 months after IVB injection (Fig. 1A). In our study, only refractory PCV patients who switched to brolucizumab were included. Studies analyzing the long-term effects of switching to brolucizumab have reported only anatomical improvement and decreased disease activity without significant improvements in BCVA [26-28]. It is presumed that BCVA did not improve despite anatomical improvement because the damage to the photoreceptor cells had already progressed irreversibly.
This study has some limitations. The study design was retrospective, and it included a small number of patients. In addition, all subjects were Korean; therefore, the results may not be generalizable to other racial or ethnic groups. Despite these limitations, however, this study provides valuable data regarding the effect of brolucizumab injection on RNFL thickness in non-naïve patients with PCV.
In summary, when treating PCV patients with persistent fluid accumulations on OCT by switching to brolucizumab, RNFL thickness did not show significant changes compared to baseline or the control group. These findings suggest that IVB treatment for PCV has no detrimental effects on RNFL thickness for 1 year post-injection.
The authors declare no conflicts of interest relevant to this article.
Conception (D.D.H.); Design (D.D.H.); Data acquisition (G.H.); Analysis (G.H.); interpretation (G.H.); writing (G.H., D.D.H.); review (G.H., D.D.H.); Final approval of the article (All authors)
![]() |
![]() |