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Long-Term Effect of Intravitreal Brolucizumab Injections on Peripapillary Retinal Nerve Fiber Layer Thickness in Patients with Refractory Polypoidal Choroidal Vasculopathy
J Retin 2024;9(2):169-176
Published online November 30, 2024
© 2024 The Korean Retina Society.

Gyudeok Hwang1, Daniel Duck-Jin Hwang1,2

1Department of Ophthalmology, Hangil Eye Hospital, Incheon, Korea
2Department of Ophthalmology, Catholic Kwandong University College of Medicine, Incheon, Korea
Correspondence to: Daniel Duck-Jin Hwang, MD, PhD
Department of Ophthalmology, Hangil Eye Hospital, #35 Bupyeong-daero, Bupyeong-gu, Incheon 21388, Korea
Tel: 82-32-503-3322, Fax: 82-32-504-3322
E-mail: daniel.dj.hwang@gmail.com
Received October 4, 2024; Revised October 14, 2024; Accepted October 18, 2024.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Purpose: This study aimed to evaluate the long-term effects of intravitreal brolucizumab (IVB) injections on peripapillary retinal nerve fiber layer (RNFL) thickness in patients with polypoidal choroidal vasculopathy (PCV).
Methods: This retrospective case series included 11 eyes from 11 patients with PCV who were switched to IVB treatment due to persistent fluid accumulation despite prior anti-vascular endothelial growth factor (VEGF) therapy. RNFL thickness was measured using spectral-domain optical coherence tomography at baseline and 1, 3, 6, 9, and 12 months post-IVB injection. The data were compared to baseline data of treated eyes and untreated fellow eyes.
Results: A significant decrease in RNFL thickness was observed in the inferior temporal sector of the treated eyes at 1 month post-IVB injection compared to baseline (p = 0.029). However, this difference was not significant at subsequent follow-up points. No significant long-term changes were noted in global RNFL thickness or other RNFL sectors compared to baseline. Additionally, there were no significant differences in RNFL thickness between IVB-treated and -untreated fellow eyes at any follow-up visit. Central macular thickness decreased significantly from baseline over the 12-month study period, but BCVA did not significantly differ from baseline at any time point.
Conclusions: Long-term use of IVB in PCV patients does not lead to significant changes in RNFL thickness in treated eyes relative to untreated fellow eyes. The initial decrease in RNFL thickness in the inferior temporal sector may be due to a reduction in macular edema rather than neurotoxicity caused by anti-VEGF treatment. These findings suggest that IVB treatment for PCV does not have a detrimental impact on RNFL thickness over 12 months.
Keywords : Brolucizumab; Polypoidal choroidal vasculopathy; Retinal nerve fiber layer; Vascular endothelial growth factor
Introduction

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.

Materials and Methods

Patients

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.

Ophthalmic examinations

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.

Ethics statement

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).

Statistical analysis

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.

Results

Baseline characteristics

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).

Baseline characteristics of study eyes with polypoidal choroidal vasculopathy and the numbers that received intravitreal brolucizumab injection for the study period

Characteristic Value
No. of patients 11
Age (years) 67 (65.5–70.5)
Sex (male/female) 8/3
Systemic disease
Hypertension (n) 0
Diabetes (n) 1
Laterality (OD/OS) 6/5
No. of previous anti-VEGF injections [min, max] 7 (4–17) [3, 38]
No. of brolucizumab injections for 12 months [min, max] 4 (3–5) [1, 6]
Corrected visual acuity (logMAR) 0.30 (0.26–0.61)
Refractive error (SE) 0.38 (-0.31–0.75)
IOP (mmHg) 16.0 (14.0–17.0)

Values are presented as number, median (interquartile range).

IOP = intraocular pressure; logMAR = logarithm of the minimum angle of resolution; max = maximum; min = minimum; n = number; nAMD = neovascular age-related macular degeneration; OD = right eye; OS = left eye; PCV = polypoidal choroidal vasculopathy; SE = spherical equivalent; VEGF = vascular endothelial growth factor.



Changes in BCVA and IOP

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).

Fig. 1. Changes in best-corrected visual acuity (BCVA) and intraocular pressure (IOP). (A) Mean BCVA in the intravitreal brolucizumab (IVB)-treated and -untreated fellow eye groups. (B) Mean IOP in the IVB-treated and -untreated fellow eye groups. The differences between baseline and the follow-up visits for each value are analyzed using the Wilcoxon signed-rank test, and there was no significant longitudinal change at any follow-up visit in the IVB-treated and fellow eye groups. At all follow-up visits, the BCVA of the fellow eyes group was significantly better than that of the IVB group (p-value < 0.05 using the Mann–Whitney U test). Statistically significant differences (p < 0.05) between the values for the treated and fellow eyes are represented with asterisks. Error bars represent standard errors.

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.

Change in RNFL thickness

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.

Longitudinal changes in retinal nerve fiber layer thickness in the group administered intravitreal brolucizumab injections and the untreated fellow eyes

RNFL sector Treated eyes with brolucizumab (μm) p-value* Fellow eyes (μm) p-value* p-value
Global sector RNFL
Baseline 104.3 ± 11.6 - 101.1 ± 11.3 - 0.717
1 month 102.6 ± 9.7 0.280 99.9 ± 10.2 0.685 0.357
3 months 103.4 ± 10.0 0.551 100.2 ± 10.0 0.834 0.356
6 months 104.5 ± 11.7 0.999 100.5 ± 9.8 0.865 0.356
9 months 106.3 ± 13.6 0.305 100.6 ± 10.4 0.779 0.308
12 months 107.7 ± 14.9 0.113 100.3 ± 11.3 0.999 0.199
Superior temporal sector RNFL
Baseline 143.4 ± 16.2 - 145.4 ± 8.5 - 0.212
1 month 141.0 ± 14.5 0.397 143.7 ± 8.8 0.282 0.533
3 months 144.5 ± 12.8 0.759 144.2 ± 8.5 0.199 0.869
6 months 141.9 ± 21.0 0.999 144.8 ± 10.2 0.999 0.094
9 months 143.2 ± 21.5 0.999 143.7 ± 13.1 0.717 0.308
12 months 149.5 ± 21.9 0.114 144.5 ± 10.3 0.765 0.999
Temporal sector RNFL
Baseline 78.8 ± 15.9 - 78.3 ± 12.1 - 0.999
1 month 75.7 ± 10.2 0.161 78.2 ± 12.1 0.861 0.576
3 months 77.7 ± 11.9 0.755 77.9 ± 11.8 0.526 0.999
6 months 80.0 ± 14.5 0.503 78.7 ± 10.8 0.892 0.793
9 months 80.6 ± 13.9 0.181 75.5 ± 13.5 0.362 0.411
12 months 82.5 ± 14.3 0.119 78.5 ± 11.8 0.999 0.430
Inferior temporal sector RNFL
Baseline 156.9 ± 23.5 - 148.5 ± 24.6 - 0.393
1 month 151.0 ± 19.1 0.029 149.0 ± 23.3 0.750 0.599
3 months 151.1 ± 15.8 0.202 149.9 ± 22.8 0.360 0.974
6 months 155.3 ± 17.9 0.306 149.8 ± 24.1 0.469 0.532
9 months 154.8 ± 19.6 0.414 149.6 ± 23.8 0.681 0.693
12 months 155.7 ± 24.3 0.221 151.3 ± 25.1 0.443 0.694
Inferior nasal sector RNFL
Baseline 115.3 ± 17.7 - 109.6 ± 14.6 - 0.430
1 month 111.9 ± 16.9 0.172 109.5 ± 13.3 0.672 0.554
3 months 111.0 ± 17.1 0.123 109.6 ± 12.8 0.952 0.645
6 months 114.0 ± 13.8 0.999 112.4 ± 12.7 0.838 0.645
9 months 117.8 ± 19.5 0.236 110.5 ± 12.8 0.755 0.449
12 months 116.6 ± 22.0 0.965 111.4 ± 15.5 0.342 0.793
Nasal sector RNFL
Baseline 69.8 ± 12.3 - 67.8 ± 17.6 - 0.490
1 month 69.8 ± 13.4 0.999 66.0 ± 15.7 0.348 0.324
3 months 69.5 ± 13.7 0.999 66.3 ± 15.6 0.763 0.531
6 months 69.7 ± 12.4 0.953 66.5 ± 15.6 0.905 0.411
9 months 72.9 ± 14.7 0.103 66.9 ± 14.6 0.677 0.358
12 months 75.3 ± 17.5 0.153 66.5 ± 16.8 0.952 0.224
Superior nasal sector RNFL
Baseline 122.8 ± 22.5 - 113.2 ± 13.7 - 0.430
1 month 118.6 ± 22.4 0.446 109.5 ± 11.1 0.051 0.307
3 months 123.5 ± 24.3 0.999 110.3 ± 11.4 0.351 0.177
6 months 122.9 ± 30.3 0.799 109.2 ± 12.0 0.141 0.411
9 months 123.1 ± 27.8 0.999 111.4 ± 14.2 0.518 0.393
12 months 123.8 ± 30.5 0.726 110.3 ± 12.8 0.504 0.263

Values are presented as mean ± standard deviation.

RNFL = retinal nerve fiber layer.

*Comparison between the baseline and follow-up visits for each value (Wilcoxon signed-rank test). Comparison between treated eyes with brolucizumab and untreated fellow eyes (Mann–Whitney U test). Significant p-values are shown in‡.



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

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).

Central macular thickness before and after intravitreal brolucizumab injection

Follow-up visit Treated eyes with brolucizumab (μm) p-value* Fellow eyes (μm) p-value* p-value
Baseline 373.4 ± 113.0 285.9 ± 37.4 0.030
1 month 262.0 ± 83.7 0.006 286.5 ± 37.7 0.341 0.282
3 months 264.3 ± 83.9 0.009 283.7 ± 38.3 0.553 0.101
6 months 267.3 ± 84.0 0.009 286.8 ± 39.4 0.593 0.168
9 months 285.7 ± 93.5 0.032 285.0 ± 40.6 0.905 0.414
12 months 270.1 ± 94.5 0.033 288.8 ± 42.8 0.593 0.131

Values are presented as mean ± standard deviation.

*Comparison values between baseline and follow-up visits for each value (Wilcoxon signed-rank test). Comparison between treated eyes with brolucizumab and untreated fellow eyes in each period (Mann–Whitney U test). Values are presented as median (interquartile range).

The significant p-values are shown in‡.


Discussion

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.

Conflicts of Interest

The authors declare no conflicts of interest relevant to this article.

Author Contribution

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)

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