Outcome of navigated laser photocoagulation for persistent macular edema in branch retinal vein occlusion

Abstract

To evaluate the clinical efficacy of navigated laser photocoagulation (Navilas®) for persistent macular edema (ME) secondary to branch retinal vein occlusion (BRVO), and to determine whether angiographic microaneurysm (MA) morphology, including clustered MAs, telangiectatic capillaries (TelCaps), and MAs within collateral vessels, is associated with successful discontinuation of anti-vascular endothelial growth factor (VEGF) therapy. This retrospective observational study included eyes with persistent BRVO-associated ME treated with Navilas® at Nagoya City University Hospital between June 2014 and February 2022 and followed for at least 3 months. Clinical data and multimodal imaging findings were retrospectively reviewed. Outcomes included changes in best-corrected visual acuity and central subfield thickness, changes in anti-VEGF injection frequency, and successful discontinuation of anti-VEGF therapy. Angiographic MA morphology was assessed using fluorescein angiography and indocyanine green angiography. Logistic regression analysis was performed to identify morphological predictors of treatment discontinuation. Best-corrected visual acuity remained stable throughout follow-up after Navilas®. Approximately 60% of eyes achieved successful discontinuation of anti-VEGF therapy. Discontinuation was achieved in 63% (5 out of 8) of eyes with TelCaps, 33% (2 out of 6) of eyes with MAs within collateral vessels, and 27% (3 out of 11) of eyes with clustered MAs. In eyes that required continued anti-VEGF therapy, the injection frequency was significantly reduced compared with the pretreatment period. Logistic regression analysis demonstrated that the presence of clustered MAs was significantly associated with failure to discontinue anti-VEGF therapy. Navilas® appears to be an effective adjunctive treatment for persistent BRVO-associated ME, maintaining visual function while reducing the burden of anti-VEGF therapy. The presence of clustered MAs may serve as a useful angiographic biomarker of suboptimal response to navigated laser treatment, potentially reflecting severe localized hyperpermeability and extensive capillary nonperfusion. Angiographic assessment of MA morphology may therefore help refine patient selection and guide individualized treatment strategies.

1. Introduction

Branch retinal vein occlusion (BRVO) is a prevalent retinal vascular disorder and a major cause of visual impairment, particularly among older individuals with systemic vascular risk factors. Macular edema (ME) represents the principal cause of vision loss in BRVO and arises from a complex interplay of venous congestion, capillary nonperfusion, and disruption of the blood–retina barrier. Vascular endothelial growth factor (VEGF), along with inflammatory mediators such as interleukin-6, has been implicated in the pathogenesis of BRVO-associated ME.^[1]

Anti-VEGF therapy has substantially improved short-term visual and anatomical outcomes and is currently regarded as the first-line treatment for BRVO-related ME. Randomized clinical trials have demonstrated that intravitreal administration of ranibizumab and aflibercept leads to significant improvements in best-corrected visual acuity and reductions in retinal thickness.^[2,3] However, a considerable proportion of eyes exhibit persistent or recurrent edema, necessitating repeated intravitreal injections over prolonged periods.^[2,3]

In the chronic phase of BRVO, microvascular structural abnormalities – including microaneurysms (MAs), TelCaps, and collateral vessel formation – become increasingly prominent. Previous studies have suggested that these lesions may serve as focal sources of leakage that are not adequately suppressed by VEGF inhibition.^[4-9] In particular, MAs have been associated with refractory ME in BRVO, and their morphological characteristics and spatial distribution may have clinical relevance.^[5,7,8] Furthermore, collateral vessels may harbor leaking MAs, indicating that collateral-associated vascular remodeling may contribute to the persistence of edema.^[4,5]

These focal vascular abnormalities may therefore represent potential therapeutic targets for focal laser photocoagulation. Prior to the advent of anti-VEGF therapy, focal or grid laser photocoagulation was an established treatment modality for BRVO-associated ME.^[10] However, conventional slit-lamp–based laser photocoagulation has several inherent limitations, including reliance on manual targeting, limited precision in treating small parafoveal lesions, and the potential risk of inadvertent foveal damage.^[11,12]

Navigated laser photocoagulation (Navilas®) has been developed to address these limitations by integrating fundus imaging, multimodal image registration, eye-tracking technology, and preplanned laser delivery.^[9,11-13] Previous studies in diabetic ME and other macular disorders have demonstrated that navigated laser systems may enhance treatment accuracy and reproducibility, while potentially reducing the need for retreatment.^[9,11-13]

Nevertheless, evidence regarding the efficacy of navigated laser specifically in BRVO remains limited, and the angiographic predictors of treatment response have yet to be fully elucidated. In particular, the impact of MA multiplicity, the presence of TelCaps, and MAs located within collateral vessels on edema resolution and the discontinuation of anti-VEGF therapy remains unclear.

Accordingly, the present study aimed to evaluate the clinical outcomes of Navilas® photocoagulation in eyes with persistent BRVO-associated ME and to investigate the relationship between angiographic MA morphology and the likelihood of anti-VEGF discontinuation. Identification of morphological predictors of therapeutic response may facilitate more appropriate patient selection for navigated laser treatment and contribute to reducing the long-term burden associated with repeated intravitreal injections.

2. Materials and methods

2.1. Study design and setting

This retrospective observational study was conducted at Nagoya City University Hospital. The study protocol was approved by the Institutional Review Board of Nagoya City University Graduate School of Medical Sciences (approval No. 60-25-0194), and all procedures adhered to the tenets of the Declaration of Helsinki. Patients who presented to Nagoya City University Hospital on or after February 2008 were screened for eligibility. Inclusion criteria were as follows: eyes with BRVO complicated by persistent ME that underwent Navilas® between June 2014 and February 2022, with a minimum follow-up of 3 months. Eyes with coexisting retinal diseases were excluded.

2.2. Observational procedures

All patients underwent comprehensive ophthalmic evaluation, including measurement of best-corrected visual acuity (BCVA), indirect ophthalmoscopy, color fundus photography, and optical coherence tomography (OCT; Cirrus HD-OCT, Carl Zeiss Meditec, Dublin), as well as fluorescein angiography (FA), indocyanine green angiography (ICGA), and/or OCT angiography (OCTA; RTVue XR Avanti, AngioVue, Optovue Inc., Fremont). FA and ICGA were performed using a wide-field scanning laser ophthalmoscope (Optos California; Optos PLC, Dunfermline, UK) and a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2; Heidelberg Engineering, Heidelberg, Germany). BCVA, indirect ophthalmoscopy, and OCT were conducted at baseline and at monthly intervals following Navilas® treatment. FA and ICGA were performed to identify and characterize MAs.

2.3. Treatment protocol

All eyes received Navilas® for persistent ME. Treatments were performed using the Navilas® 577+ system (OD-OS GmbH, Teltow, Germany). Yellow-wavelength (577 nm) laser photocoagulation was applied to target leaking MAs. Treatment planning was conducted by retinal specialists using static images obtained from FA, ICGA, and/or OCTA. FA and ICGA were performed to identify and characterize MAs. Although BRVO is primarily a retinal vascular disease, ICGA was utilized in addition to FA because the longer infrared wavelength of ICGA provides superior penetration through overlying retinal hemorrhage and marked diffuse fluorescein leakage, allowing clearer visualization and precise localization of leaking MAs for laser treatment planning, as previously described.^[14] These images were subsequently registered and overlaid onto live fundus images to enable precise, real-time guidance of laser spot delivery. Following photocoagulation, color fundus imaging was performed to confirm concordance between planned and delivered laser spots. During follow-up, additional treatments – including anti- VEGF therapy – were administered in cases of insufficient reduction in central subfield thickness (CST) or recurrence of ME.

2.4. Outcome measures

BCVA was measured using Landolt C charts and converted to the logarithm of the minimal angle of resolution (logMAR) for statistical analysis. CST was automatically quantified using the OCT device. Three angiographic morphological parameters of MAs were evaluated in each eye. “Multiple MAs” were defined as the presence of 5 or more MAs within an area equivalent to 1 optic disc diameter. TelCaps were defined as MAs exceeding the diameter of adjacent retinal vessels. MAs located within collateral vessels were classified as “MAs in collateral vessels.”

Clinical outcomes included logMAR visual acuity, CST, the requirement for additional treatment following Navilas® photocoagulation, and the rate of discontinuation of anti-VEGF therapy.

2.5. Statistical analysis

Statistical analyses were performed using Easy R (EZR), version 1.40, a graphical user interface for R (The R Foundation for Statistical Computing, Vienna, Austria).^[15] EZR is a modified version of R Commander designed to incorporate statistical functions frequently used in biostatistics.^[15] Repeated-measures analysis of variance (ANOVA) was employed to compare logMAR visual acuity and CST at baseline and at 1, 3, and 6 months after Navilas® treatment, as well as at the final visit. The paired t-test was used to compare the number of anti-VEGF injections before and after Navilas® treatment, both in the overall cohort and in the subgroup requiring continued injections. Logistic regression analysis was conducted to evaluate whether the presence of multiple MAs, TelCaps, or MAs within collateral vessels was associated with failure to discontinue anti-VEGF therapy. A P value < .05 was considered statistically significant.

3. Results

3.1. Patients

A total of 26 eyes from 26 patients (8 men and 18 women) were included in this study. The mean age was 70.8 ± 8.8 years. Baseline demographic and clinical characteristics are summarized in Table 1. The mean interval from the initial visit to Navilas® laser treatment was 25.8 ± 29.9 months.

Table 1.

Demographics of the study population with branch retinal vein occlusion.

Number of cases	26 cases with 26 eyes
Gender (male/female)	8 cases with 8 eyes in males and 18 eyes in 18 females
Average age	70.8 years old (SD:8.8)
Subtype of BRVO (major/macular, ischemic/nonischemic)	Major: 16 cases, macular: 10 cases, ischemic: 14 cases, nonischemic: 12 cases
DM (yes/no/unknown)	Yes: 4 cases, no: 19 cases, unknown: 3 cases
HT (yes/no/unknown)	Yes: 14 cases, no: 7 cases, unknown: 5 cases
Lens status (phakia/pseudophakia)	Phakia: 9 cases, phakia→pseudophakia: 6 cases, pseudophakia: 11 cases
Pretreatment – (IVA/IVR/IVB/TA/scatter/direct PHC/grid; there are duplicates)	IVA: 10 cases, IVR: 17 cases, IVB: 2 cases, TA: 10 cases, scatter PHC: 7 cases, direct PHC: 5 cases, grid: 1 case
STTA (yes/no)	Yes: 3 cases. no: 23 cases
The rate of discontinuation of anti-VEGF injections	16 cases/26 cases (62%)
Navilas® Laser application time (average from the date of first visit)	25.8 (SD: 29.9) months
Navilas® Type of Guide (FA/ICGA/OCT.)	FA: 7 cases, ICGA: 18 cases, OCT: 1 case
The number of MAs (10 or more)	10 or more: 9 cases, <10: 17cases
MA capability: 5 or more in the range of 1 papillary diameter	5 or more: 11 cases, <5: 15 cases
MA size: greater than retinal vessel diameter (TelCaps)	Yes: 8 cases, no: 18 cases
Whether the MA is in the collateral vessels	Yes: 6 cases, no: 20 cases
The rate of discontinuation of anti-VEGF injections by angiographic MA morphology	TelCaps: 5 cases/8 cases (63%) MAs in collateral vessels: 2 cases/6 cases (33%) Clustered MAs: 3 cases/11cases (27%)

BRVO = branch retinal vein occlusion, DM = diabetes mellitus, FA = fluorescein angiography, HT = hypertension, ICGA = indocyanine green angiography, IVA = intravitreal injection of aflibercept, IVB = intravitreal injection of bevacizumab, IVR = intravitreal injection of ranibizumab, MA = microaneurysm, OCT = optical coherence tomography, PHC = retinal laser photocoagulation, SD = standard deviation, STTA = sub-tenon’s capsule injection of TA, TA = triamcinolone acetonide, TelCaps = telangiectatic capillaries, VEGF = vascular endothelial growth factor.

Navilas® laser photocoagulation was performed under FA guidance in 7 eyes, ICGA guidance in 18 eyes, and alternative imaging guidance (specifically, high-resolution OCTA) in 1 eye. Angiographic characteristics of MAs are also summarized in Table 1. All eyes exhibited angiographically detectable MAs prior to Navilas® treatment. Based on morphological classification, some eyes demonstrated clustered MAs, others exhibited TelCaps, and in several cases, MAs were located within collateral vessels.

3.2. Changes in visual acuity

Overall, logMAR VA was maintained or showed a mild tendency toward improvement following Navilas® treatment. Temporal changes in BCVA are illustrated in Figure 1 for the entire cohort and stratified according to discontinuation of anti-VEGF therapy.

Figure 1.

Temporal changes in BCVA (logMAR). (A) All cases. In the analysis of all cases, no statistically significant improvement in best-corrected visual acuity (BCVA) was observed at the post-navigated laser photocoagulation (Navilas®) time point compared with baseline. (B) Analysis stratified by the discontinuation of anti-vascular endothelial growth factor (VEGF) therapy. Similarly, in the analysis stratified by the discontinuation status of anti-VEGF therapy after Navilas treatment, no significant improvement in BCVA was observed compared with baseline. BCVA = best-corrected visual acuity, logMAR = logarithm of the minimal angle of resolution, VEGF = vascular endothelial growth factor.

In the overall cohort, mean logMAR VA did not show significant changes at any posttreatment time point compared with baseline, indicating stable visual function throughout the follow-up period. Given that many eyes had already achieved visual improvement with prior anti-VEGF therapy, further gains after Navilas® were limited, and maintenance of vision was the predominant outcome.

In the cases in which anti-VEGF therapy was no longer required, the mean logMAR VA demonstrated a gradual trend toward improvement; however, this did not reach statistical significance, likely due to the limited sample size. As for cases in which anti-VEGF therapy was continued, the mean logMAR VA showed minimal change from baseline, with a visual course distinct from that of the discontinuation group.

3.3. Changes in central subfield thickness

As shown in Figure 2, mean CST did not differ significantly at 1, 3, or 6 months after Navilas® treatment compared with baseline (P > .05, repeated-measures ANOVA). This likely reflects the chronic nature of the enrolled cases, many of which had long-standing ME prior to treatment.

Figure 2.

Temporal changes in CST. (A) All eyes. In the analysis of all cases, no statistically significant improvement in BCVA was observed at 1, 3, 6 months after Navilas treatment compared with baseline; however, a significant difference was observed at the final follow-up (P = .0039**). (B) Analysis stratified by the discontinuation of anti-vascular endothelial growth factor (VEGF) therapy. In the analysis stratified by the discontinuation status of anti-VEGF therapy after Navilas treatment, neither group showed a statistically significant improvement in central subfield thickness (CST) compared with baseline. ANOVA = analysis of variance, BCVA = best-corrected visual acuity, CST = central subfield thickness, VEGF = vascular endothelial growth factor.

However, at the final visit, CST was significantly reduced compared with baseline (P = .0039, repeated-measures ANOVA). This pattern was consistently observed in both the discontinuation and non-discontinuation groups.

3.4. Additional treatments after Navilas® photocoagulation

Additional treatments administered after Navilas® photocoagulation are summarized in Figure 3. Over an approximate 2-year follow-up period, the mean number of anti-VEGF injections was 1.3 ± 2.4. The mean number of sub-Tenon triamcinolone acetonide injections was 0.7 ± 1.2, and the mean number of additional laser treatments was 1.4 ± 1.7.

Figure 3.

Additional treatments after Navilas® laser treatment. Additional treatments after the initial navigated laser photocoagulation (Navilas®). The mean follow-up period after Navilas® treatment was 28.5 (standard deviation: SD 20.5) months. Over a follow-up period of more than 2 years, the mean number of anti-vascular endothelial growth factor (VEGF) injections was only 1.3 (SD 2.4). PHC = retinal laser photocoagulation, SD = standard deviation, STTA = sub-tenon’s capsule injection of triamcinolone acetonide, VEGF = vascular endothelial growth factor.

Figure 4A, B compare the number of anti-VEGF injections before and after Navilas® treatment in the overall cohort (n = 26) and in eyes that did not achieve discontinuation of anti-VEGF therapy (n = 10). In the overall cohort, the mean number of injections during comparable pre- and posttreatment periods decreased significantly from 5.5 ± 4.1 to 1.3 ± 2.4 (P < .001, paired t-test).

Figure 4.

Comparison of the number of anti-VEGF agents injection before and after Navilas® laser treatment. (A) All cases (n = 26). The number of anti-vascular endothelial growth factor (VEGF) injections was significantly reduced after navigated laser photocoagulation (Navilas®) laser treatment (P < .001***). (B) Cases without discontinuation of anti-VEGF therapy (n = 10). Even in cases where anti-VEGF therapy could not be discontinued, the number of injections was significantly reduced after Navilas® treatment (P = .0070**). SD = standard deviation, VEGF = vascular endothelial growth factor.

Notably, even among eyes that required continued anti-VEGF therapy, the number of injections was significantly reduced following Navilas® treatment (P = .0070, paired t-test).

3.5. Predictors of discontinuation of anti-VEGF therapy (logistic regression analysis)

Sixteen of 26 eyes (62%) successfully discontinued anti-VEGF therapy following Navilas® treatment. Stratified by angiographic MA morphology, successful discontinuation of anti-VEGF therapy was achieved in 63% (5 of 8 eyes) of eyes with TelCaps, 33% (2 of 6 eyes) with MAs within collateral vessels, and 27% (3 of 11 eyes) with clustered MAs (Table 1). As summarized in Table 2, logistic regression analysis demonstrated that, among the evaluated morphological parameters, the presence of clustered MAs within an area equivalent to 1 optic disc diameter was the only factor significantly associated with failure to discontinue anti-VEGF therapy (P = .0154).

Table 2.

Predictive factors associated with discontinuation of anti-VEGF therapy after Navilas laser treatment (logistic regression analysis).

Factor	OR	95% CI	P
Clustered MAs	0.0672	0.00756–0.597	.0154*
MA size (TelCaps)	2.46	0.176–34.5	.504
MAs in collateral vessels	0.432	0.0231–8.05	.574

Cl = confidence Interval, MA = microaneurysm, OR = odds ratio, TelCaps = telangiectatic capillaries, VEGF = vascular endothelial growth factor.

^*P < .05.

Although TelCaps and MAs located within collateral vessels showed trends toward poorer outcomes, these associations did not reach statistical significance in this cohort. These findings suggest that MA clustering may serve as a clinically relevant morphological marker influencing therapeutic response.

3.6. Representative cases

Figure 5 illustrates a representative case with a limited number of well-demarcated MAs identified on ICGA. Targeted Navilas® photocoagulation of these lesions resulted in resolution of ME, a marked reduction in CST (from 466 to 282 μm), and improvement in BCVA (from 0.7 to 1.0 in decimal notation). Anti-VEGF therapy was subsequently discontinued in this case.

Figure 5.

Representative case in which treatment was completed with Navilas® laser treatment. (A) Late-phase fluorescein angiogram. Diffuse hyperfluorescence is observed at the macula. (B) Late-phase indocyanine green angiogram (ICGA). Hyperfluorescent spots, thought to be caused by capillary microaneurysms (yellow circle) underlying persistent macular edema, are clearly identified in the late-phase of ICGA. (C–H) Optical coherence tomography (OCT) findings. (C–E) Before targeting laser by navigated laser photocoagulation (Navilas®) at leaky microaneurysms. The best-corrected visual acuity (BCVA) in decimal units was 0.7, and the central subfield thickness (CST) measured 466 µm. (F–H) After Navilas®. (C, F) OCT color maps. (D, G) OCT horizontal scans. (E, H) OCT vertical scans. (F–H) Macular edema was almost resolved after Navilas®. The BCVA in decimal unit improved to 1.0, and the CST decreased to 282 µm. BCVA = best-corrected visual acuity, CST = central subfield thickness, ICGA = indocyanine green angiography, OCT = optical coherence tomography.

In contrast, Figure 6 presents a case with numerous MAs diffusely distributed across the temporal macula. Baseline BCVA was 0.3 (decimal notation), and CST was 248 μm. Despite ICGA-guided laser treatment targeting multiple lesions, BCVA showed minimal change (0.4), while ME worsened, with CST increasing to 438 μm. This case highlights the limited efficacy of Navilas® photocoagulation in eyes with extensive MA clustering.

Figure 6.

Representative case with repeated recurrences after Navilas® laser treatment. (A) Late-phase fluorescein angiogram. Multiple diffuse hyperfluorescent spots are observed at the macula. (B) Late-phase indocyanine green angiogram (ICGA). Hyperfluorescent spots, thought to be caused by capillary microaneurysms (yellow circle) underlying persistent macular edema, are clearly identified on the late-phase of ICGA. (C–H) Optical coherence tomography (OCT) findings. (C–E) Before targeting laser by navigated laser photocoagulation (Navilas®) at leaky microaneurysms. The best-corrected visual acuity (BCVA) in decimal unit was 0.3, and the central subfield thickness (CST) measured 248 µm. (F–H) After Navilas®. (C, F) OCT color maps. (D, G) OCT horizontal scans. (E, H) OCT vertical scans. (F–H) The BCVA in decimal unit remained relatively unchanged at 0.4; however, the macular edema worsened, with the CST increasing to 438 µm. BCVA = best-corrected visual acuity, CST = central subfield thickness, ICGA = indocyanine green angiography, OCT = optical coherence tomography.

4. Discussion

In this retrospective case series of eyes with persistent ME secondary to BRVO, Navilas® resulted in structural improvement and a reduction in the treatment burden associated with anti- VEGF therapy. More than half of the treated eyes were able to discontinue intravitreal injections during follow-up, and CST demonstrated a gradual decrease over time. These findings support the role of Navilas® as an adjunctive therapeutic modality in chronic BRVO, particularly in cases where angiographically identifiable focal leakage contributes to persistent edema.^[9,11-13]

A principal finding of the present study is the significant association between MA morphology and treatment outcomes. Specifically, eyes exhibiting clustered MAs within a confined retinal region were significantly less likely to achieve discontinuation of anti-VEGF therapy. This observation suggests that MA multiplicity may reflect more advanced or diffuse microvascular damage, in which focal laser treatment alone is insufficient to fully suppress leakage. This interpretation is consistent with previous reports indicating that MAs are associated with refractory edema in BRVO and that their morphology and spatial distribution are clinically relevant determinants of disease behavior.^[5,7,8] In contrast, eyes with a limited number of discrete MAs demonstrated more favorable responses to Navilas® treatment, supporting the concept that focal photocoagulation is most effective when leakage originates from well-defined and localized lesions.^[5,7]

One possible explanation for these findings is that clustered MAs represent a more advanced stage of microvascular remodeling in chronic BRVO. Prior studies have suggested that MA-associated structural alterations may persist despite anti-VEGF therapy and contribute to treatment resistance.^[5,8] Under such conditions, VEGF blockade alone may be insufficient, as structural abnormalities of the vessel wall itself may become a dominant source of fluid exudation, independent of VEGF-mediated permeability.^[1,5] By directly targeting these structural sources of leakage, focal laser photocoagulation may effectively reduce exudation from abnormal vascular lesions in BRVO-related ME.^[5,9]

TelCaps and MAs located within collateral vessels also demonstrated trends toward poorer outcomes, although these associations did not reach statistical significance in the present cohort. TelCaps have been described as aneurysmal capillary dilations detectable on multimodal imaging and have been associated with persistent exudative changes in retinal vascular disorders.^[16] Additionally, collateral vessels that develop following venous occlusion may harbor MAs and contribute to chronic leakage.^[4,5] Although the sample size in this study was limited, the observed trends are consistent with prior imaging studies suggesting that complex microvascular abnormalities play a role in refractory edema in retinal vein occlusion.^[4-8,16]

Another important aspect of this study is the application of multimodal angiographic imaging, particularly ICGA, to identify leakage sources. ICGA may be especially valuable in chronic cases where diffuse fluorescein leakage obscures precise lesion localization on FA. Previous studies have demonstrated that ICGA can reveal vascular abnormalities not readily detectable on FA and may facilitate more accurate identification of responsible lesions in BRVO-related ME.^[16,17] Accurate localization of leakage sources is critical for successful focal photocoagulation, and the use of ICGA may therefore enhance the precision of treatment planning in navigated laser therapy.^[17]

Navigated laser systems offer several technical advantages over conventional slit-lamp–based laser photocoagulation. By integrating multimodal imaging, treatment planning software, and real-time eye-tracking technology, the Navilas® system enables highly accurate delivery of preplanned laser spots to targeted retinal regions. Previous studies have shown that navigated laser improves treatment accuracy and reproducibility compared with conventional techniques.^[9,11-13] These advantages are particularly relevant in BRVO-related ME, where precise targeting of small parafoveal leakage sources is essential. Enhanced targeting accuracy may facilitate more effective closure of focal leakage sites while minimizing the risk of inadvertent foveal damage.^[9,11-13]

The observed reduction in anti-VEGF injection frequency is also of considerable clinical significance. Although intravitreal anti-VEGF therapy has markedly improved visual outcomes in retinal vein occlusion, many patients require frequent injections over extended periods.^[2,3] This imposes a substantial burden on both patients and healthcare systems. In real-world clinical settings, repeated clinic visits and procedures may be particularly challenging for elderly patients, who constitute a large proportion of those affected by BRVO. Furthermore, repeated intravitreal injections carry cumulative risks, including endophthalmitis and intraocular inflammation. Adjunctive therapies that stabilize ME while reducing injection frequency are therefore of substantial clinical value. Notably, in the present study, even eyes requiring continued anti-VEGF therapy demonstrated a significant reduction in injection frequency following navigated laser treatment.

Collectively, these findings support the concept of morphology-guided management of BRVO-related ME. Anti-VEGF monotherapy is effective in many cases, particularly in earlier disease stages where VEGF-mediated vascular permeability predominates.^[1-3 However, in chronic cases characterized by structural vascular abnormalities – such as MAs, TelCaps, and collateral vessel–associated lesions – focal laser photocoagulation targeting leakage sources may provide additional therapeutic benefit.^[4-8,16,17] Careful evaluation of angiographic features using multimodal imaging may therefore facilitate the identification of patients most likely to benefit from adjunctive navigated laser therapy.

Several limitations of this study should be acknowledged. First, the retrospective design and relatively small sample size may have limited statistical power, particularly in detecting associations with certain morphological parameters. Second, follow-up intervals and retreatment decisions were not strictly standardized, as treatments were administered in routine clinical practice. Additionally, the timing of Navilas® intervention varied among patients, potentially introducing selection bias. Third, MA morphology was primarily assessed using angiographic methods, and quantitative evaluation using newer imaging modalities, such as optical coherence tomography angiography (OCTA), was not performed.

Future prospective studies with larger cohorts are warranted to validate the predictive value of MA morphology in determining treatment response. Advances in imaging technologies, including OCTA and automated lesion quantification, may further enhance the characterization of microvascular abnormalities in retinal vein occlusion.^[4-8,16] Such approaches may facilitate the development of robust morphological biomarkers to guide individualized treatment strategies. Ultimately, improved identification of focal leakage sources may enable more targeted adjunctive laser therapy and reduce the long-term burden associated with repeated intravitreal injections.

Author contributions

Conceptualization: Yoshio Hirano.

Data curation: Toshihiro Hojo.

Formal analysis: Yoshio Hirano.

Funding acquisition: Tsutomu Yasukawa, Yoshio Hirano.

Investigation: Toshihiro Hojo, Yukie Kamiya, Takaaki Yuguchi, Soichiro Kuwayama.

Methodology: Toshihiro Hojo, Yoshio Hirano.

Project administration: Yoshio Hirano.

Resources: Tsutomu Yasukawa, Yoshio Hirano.

Software: Toshihiro Hojo, Yoshio Hirano.

Supervision: Tsutomu Yasukawa, Yoshio Hirano.

Validation: Toshihiro Hojo, Tsutomu Yasukawa, Yoshio Hirano.

Visualization: Toshihiro Hojo, Yoshio Hirano.

Writing – original draft: Toshihiro Hojo.

Writing – review & editing: Yoshio Hirano.