The clinical efficacy of different treatments for macular edema secondary to BRVO

doi:10.21203/rs.3.rs-1404239/v1

PDF

Research Article

The clinical efficacy of different treatments for macular edema secondary to BRVO

https://doi.org/10.21203/rs.3.rs-1404239/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted 07 Apr, 2022

You are reading this latest preprint version

Objective: To assess the clinical efficacy of sustained-release dexamethasone (DEX) , conbercept and laser photocoagulation on macular edema （ME） secondary to BRVO.

Methods: 159 ischemic BRVO eyes were enrolled and randomly divided into sustained-release DEX group (30 eyes), CBC group (51 eyes), combination group (DEX+CBC, 29 eyes), and laser group (49 eyes). and received single intravitreal injection of sustained-release DEX (0.7 mg), CBC (0.05 ml) [3+PRN], sustained-release DEX (0.7 mg) combined with CBC (0.05 ml), and laser photocoagulation therapy respectively. The changes of the central foveal thickness (CFT) and best-corrected visual acuity (BCVA) were observed. Additionally, the number of HRD was calculated.

Results: After treatment, CFT significantly decreased and BCVA significantly increased in DEX, CBC and combination groups (all P<0.01). Moreover, the number of HRD in three intravitreal injection groups was significantly reduced compared with pre-treatment (all P<0.01).

Conclusion: Intravitreal injection of sustained-release DEX, CBC and combined treatment could alleviate BRVO-related ME, reduce CFT , and improve patients’ visual acuity . The retinal HRD number decreased after all intravitreal injections . In addition, there were non-responders in all intravitreal treatment groups, and the mean baseline HRD number of non-responder group was higher than that of responder group.

branch retinal vein occlusion (BRVO)

hyper reflective dots (HRD)

macular edema（ME)

sustained-release dexamethasone(DEX)

conbercept(CBC)

Retinal vein occlusion (RVO) is the second leading retinal vascular disease after diabetic retinopathy (DR). Macular edema (ME) secondary to RVO is an important cause of visual loss, but the pathogenesis of this disease still remains unclear. Previous studies [1] have shown that RVO is closely associated with hypertension, hematological diseases, dyslipidemia, diabetes, immunity, and inflammatory responses, all of which are potential pathogenic factors of RVO. RVO can be divided into central retinal vein occlusion (CRVO) and branch retinal vein occlusion（BRVO） based on the site of disease onset. According to the severity of ischemia, it can be divided into ischemic and non-ischemic RVO. Without active and effective treatment, RVO may induce ME, which will seriously affect the visual acuity of the patients [2].

The treatments for RVO-ME in clinical practices mainly include drug therapy and laser photocoagulation，while drug therapy includes glucocorticoid treatment and anti- vascular endothelial growth factor (VEGF) treatment.Sustained-release DEX is a water-soluble drug that can effectively enter the vitreous body. Previous studies have demonstrated that intravitreal injection of sustained-release DEX in RVO patients could alleviate ME and increase the visual acuity [14]. Conbercept (KH902; Chengdu Kanghong Biotech Co., Ltd., Sichuan, China,CBC) could competitively bind to VEGFA, VEGFB and PIGF to antagonize the effects of VEGF on promoting the proliferation of vascular endothelial cells, thereby inhibiting angiogenesis and reducing vascular leakage. Photocoagulation could help reconstruct the internal and external blood-retinal barrier, and reduce macular capillary leakage, thereby reducing or preventing cystoid macular edema. This study aimed to assess the clinical efficacy of sustained-release DEX, conbercept (CBC), and laser photocoagulation therapy in the treatment of ME secondary to ischemic BRVO, as well as the change of retinal hyper reflective dots (HRD) number in BRVO patients after treatments.

Patients

This is a retrospective study approved by the Medical Ethics Committee of Qilu Hospital，China. The study adhered to the tenets of the Declaration of Helsinki.A total of 159 ischemic BRVO patients (159 eyes diagnosed) who were treated in Qilu hospital ,Cheeloo College of Medicine,Shandong University,between January 2018 and January 2020 were included in this study. According to the treatment the patients were divided into sustained-release DEX group (30 eyes), CBC group (51 eyes), combination group (DEX+CBC, 29 eyes), and laser group (49 eyes) . All patients were diagnosed as ischemic BRVO by fluorescein angiography. The inclusion criteria were as follows: 1) patients diagnosed with BRVO-ME with general stable condition; 2) ME suggested by optical coherence tomography (OCT); 3) for patients with both eyes affected, only one eye was randomly selected and included in this study. The exclusion criteria were : 1) eyes with poor imaging qualities due to turbid refractive media such as vitreous hemorrhage and cataract; 2) patients received anti-VEGF treatment or retinal laser photocoagulation before; 3) patients with certain diseases of the ocular fundus, such as diabetic ME and exudative age-related macular degeneration.

Methods

For DEX group, the eyes received intravitreal injection of sustained-release DEX (0.7 mg) once. The eyes in the CBC group received intravitreal CBC injection(0.05 ml) using 3+PRN method, and the eyes in the combination group received intravitreal injection of sustained-release DEX (0.7 mg) combined with CBC (0.05 ml). Laser photocoagulation therapy was performed on eye lesions in laser group. The BCVA results were transformed into LogMAR for statistical analysis. The CFT referred to the mean thickness between the inner limiting membrane and retinal pigment epithelium measured by OCT (Heidelberg Engineering, Heidelberg, Germany) scanning of the central fovea of the macula. The measurement was repeated 3 times by the same experienced technician, and the mean value was calculated. For HRD calculation, OCT 5 line raster scanning mode was adopted. Centered on the central foveal, the linear scanning with a line length of 6 mm and a spacing of 0.25 mm was performed. The HRD was manually counted, then the HRD number on the 5 scanning lines was added. Patients with the central subfield thickness (CST) <300μm or a reduction of CST >50μm after intravitreal drug injection were classified as responding patients .

Endpoints

The endpoints in this study included the BCVA, CFT and HRD of the eyes in each group at baseline and the BCVA, CFT and HRD of the eyes in each group after 12 months of treatment.

Statistical analysis

SPSS21.0 software was used for the statistical analysis. The quantitative data, including BCVA during the treatment and changes of CFT and HRD, were described with means and standard divisions (x ±s). T test was used to compare the quantitative data between two groups.

Changes of CFT after treatments in the 4 groups

Before treatment, the CFT of DEX, CBC and the combination group was (497.34±121.26) μm, (503.27±119.85) μm and (512.91±117.39) μm, respectively, after 12 months of treatment, dropping to (299.17±112.30) μm, (304.56±109.38) μm and (251.63±101.43) μm, and the difference was statistically significant (all P<0.01). Moreover, the CFT of the laser group was (499.72±120.48) μm before treatment, and decreased to (461.21±114.78) μm after treatment, but the difference was not statistically significant (P>0.05)(Figure 1, Table 1).

Comparison of BCVA before and after treatments in the 4 groups

The BCVA in DEX, CBC and the combination group before treatment was 0.76±0.21, 0.74±0.2 and0.77±0.21, respectively, and increased to 0.50±0.18, 0.51±0.17 and 0.43±0.16 at 12 months after treatment. Therefore, the BCVA of these 3 groups were improved significantly after treatment(all P<0.01). In contrast, the BCVA in the laser group was 0.73±0.19 before treatment and 0.71±0.17 at 12 months after treatment, and the difference was not statistically significant (P>0.05)(Figure 2, Table 2).

Comparison of HRD before and after treatments in 3 intravitreal treatment groups

The number of HRD in DEX, CBC and the combination group before treatment was 30.34±15.42, 27.8±15.73 and 29.61±14.66, respectively, which was significantly reduced to 16.81±12.32, 18.93±13.45 and 15.74±13.64 at 12 months after treatment(Figure 3, Table 3).

Stratified comparison of HRD before and after treatment in 3 intravitreal treatment groups

For the patients in the DEX group, the number of HRD in the responsive subgroup was 26.71±14.83 before treatment, which significantly reduced to 10.03±10.11 at 12 months after treatment (P<0.01). In contrast, the HRD number in the non-responsive subgroup was 36.92±16.49 before treatment, which reduced to 29.10±16.33 at 12 months after treatment. However, the difference was not statistically significant (P>0.05). For patients in the CBC group, the number of HRD in the responsive subgroup was 25.22±15.24 before treatment, and significantly reduced to 11.12±10.86 at 12 months after treatment (P<0.01). However, there was no significant difference of HRD number in the non-responsive subgroup between pre-treatment（31.41±16.62）and treatment for 12 months (29.23±16.86) (P>0.05). Similarly, for patients in the combination group, the HRD number in the responsive subgroup significantly reduced to 9.26±10.99 at 12 months after treatment, compared to pre-treatment (25.96±14.08) (P<0.01), while that in the non-responsive subgroup did not change significantly comparing pre-treatment (36.23±15.71) to treatment (25.46±17.62) (P>0.05)(Figure 4, Table 4).

The CFT in DEX, CBC, and the combination groups significantly decreased after treatments (all P<0.01). In contrast, there was no significant change of CFT in the laser group (P>0.05). Similarly, the BCVA in the DEX, CBC, and combination groups significantly increased after the treatments (all P<0.01). There was also no significant change of BCVA in the laser group (P>0.05). In addition, the HRD number in the three intravitreal treatment groups significantly reduced after treatment (all P<0.01).

RVO is the second leading retinal vascular disease that can induce visual loss behind DR. According to the manifestations of retinal ischemia, RVO can be divided into ischemic and non-ischemic types. ME secondary to RVO is the major cause of visual loss, while long-term ME could induce visual cells apoptosis, consequently leading to permanent visual loss. Therefore, active application of effective methods to treat RVO-ME has important clinical significance for improving patients' visual acuity.

Currently, the treatments for RVO-ME in clinical practices mainly include drug therapy and laser photocoagulation. Sustained-release DEX is a water-soluble drug that can effectively enter the vitreous body. Previous studies have demonstrated that intravitreal injection of sustained-release DEX in RVO patients could alleviate ME and increase the visual acuity [13]. VEGF has various homologous isoforms, such as VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor (PLGF). Among them, VEGF-A played an important role in angiogenesis and increasing vascular permeability [11], mainly by binding to vascular endothelial growth factor receptor (VEGFR). CBC is the fusion protein of the extracellular region of human VEGF receptor-1 (VEGFR-1), VEGFR-2, and human IgGFc fragment. It could competitively bind to VEGFA, VEGFB and PIGF to antagonize the effects of VEGF on promoting the proliferation of vascular endothelial cells, thereby inhibiting angiogenesis and reducing vascular leakage. Photocoagulation, which aims to reduce retinal edema and improve visual acuity, could destroy the photoreceptors in the retinal anoxic region and consequently reduce the retinal oxygen demand. In addition, photocoagulation could also reduce the release of angiogenic factors induced by anoxia, thereby preventing or reducing angiogenesis. Furthermore, photocoagulation could help reconstruct the internal and external blood-retinal barrier, and reduce macular capillary leakage, thereby reducing or preventing cystoid macular edema. In this study, the BRVO eyes were divided into DEX group (30 eyes), CBC group (51 eyes), combination group (29 eyes), and laser group (49 eyes)according to the treatment, respectively, then the BCVA, CFT, and HRD changes were assessed at 12 months after treatment. Our findings showed that intravitreal injection of CBC, sustained-release DEX or both drugs in patients with ME secondary to BRVO could effectively alleviate ME, reduce CFT (P<0.01), and increase the patient’s visual acuity (P<0.01).

The pathogeneses of ME have been mainly associated with the high expression of VEGF and the release of inflammatory mediators after retinal occlusion, retinal ischemia and hypoxia. Previous studies have demonstrated that there was already an imbalance between pro- and anti- inflammatory factors in the retina, and inflammatory reactions already occurred even before the appearance of microangiopathy [12]. HRD has been considered as a sign of active inflammation [7], which refers to the small (diameters ≤30 μm) diffused dotty lesions with clear boundaries and the signal intensity equal to or higher than the retinal pigment epithelium shown by SD-OCT [3,4]. HDR could be found in patients with various diseases of the ocular fundus, such as RVO, AMD, DR/DME, Stargardt disease, and retinitis pigmentosa. They could also be found in the whole retina but were mainly clustered in the external layer. Professor Coscas firstly reported HRD in 2009 [5,6] and described it as dotty hyper-reflective material with small volumes distributed throughout the entire retina, but mainly in the exterior layer, and in the cystoid macular edema between retinal layers of AMD patients. Numerous studies in wAMD, DR, and DME have shown that HRD could be activated microglial cells [3,8,9], which is a marker of active retinal inflammation. During RVO, microglia can migrate from the interior retinal layer to the external retinal layer and release IL-6, TNF, NO, VEGF, and MCP-1 to promote inflammatory responses, disrupt the blood-retinal barrier, and induce macular edema [10]. Our findings showed that HRD was found in the retina of all RVO patients before treatment, suggesting that inflammatory responses participated in the ME in RVO, while intravitreal injection of both sustained-release DEX and CBC significantly reduced the number of HRD in the retina (P<0.01). Further analysis showed that all three groups, including the DEX group, CBC group, and combination group, could be divided into responsive and non-responsive subgroups, while the HRD numbers were significantly higher in the non-responsive subgroups compared to responsive subgroups, thus suggesting that patients with higher baseline HRD numbers responded poorly to the treatment, and also had poorer visual outcomes.

In summary, all chronic retinal stresses could induce various sub-clinical molecular changes and cellular inflammatory responses, which consequently induced the development and progression of ME and seriously affected the vision of patients. Inflammatory factors participated in the development of ME secondary to RVO, while HRD could be used to identify inflammatory factors. Intravitreal injection of sustained-release DEX, CBC, or combined treatment could reduce the number of HRD in the retina, alleviate ME, and increase patients' visual acuity. The patients with higher baseline HRD numbers had a poorer response to the treatment, the treatment efficacy was suboptimal, and the visual prognosis were also poor.

Conflict of interest: The author(s) declare no competing interests.

Acknowledgments: None.

Author contributions

YL H, H W and Y T conducted the research conception and design, and drafted the research manuscript. MR K and JY L participated in the data collection. L G ，Y Z and X Y carried out the Analysis and interpretation of data. YL H ,H W and Y T participated in the design and perfomed statistical analysis. All authors reviewed the fnal manuscript.

Funding

None.

Data availability The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Compliance with ethical standards

Conflict of interest The author(s) declare no competing interests.

Ethical approval This study was approved by the Ethics Review Committee of Qilu Hospital, Shandong University and adhered to the tenets of the Declaration of Helsinki.Due to the retrospective nature of the study, informed consent was not required.

Consent to participate and publish Informed consent was obtained from all participants and their legal guardians and informed consent was obtained to publish the information in an online open access publication.

Singer MA, Cohen SR, Groth SL, et al. Comparing bevacizumab and ranibizumab for initial reduction of central macular thickness in patients with retinal vein occlusions[J]. Clinical Ophthalmology, 2013, (7):1377–1383.
Donati S, Barosi P, Bianchi M, et al. Combined intravitreal bevacizumab and grid laser photocoagulation for macular edema secondary to branch retinal vein occlusion[J].Eur J Ophthalmol, 2012, 22(4):607–614.
Vujosevic S, et al. Hyperreflective Intraretinal Spots in Diabetics without and with Nonproliferative Diabetic Retinopathy: An In Vivo Study Using Spectral Domain OCT[J]. Journal of Diabetes Research, 2013, 2013:1–5.
Mo B, et al. Evaluation of hyperreflective foci as a prognostic factor of visual outcome in retinal vein occlusion[J]. International Journal of Ophthalmology, 2017(04):111–118.
Coscas G, Coscas F, Vismara S, Zourdani A, Li Calzi CI: Clinical features and natural history of AMD; in Coscas G, Coscas F, Vismara S, Zourdani A, Li Calzi CI (eds): Optical Coherence Tomography in Age-Related Macular Degeneration. Heidelberg, Sprin- ger, 2009, pp 171–174.
G. Coscas, U. de Benedetto, F. Coscas et al., “Hyperreflective dots: a new spectral-domain optical coherence tomography entity for follow-up and prognosis in exudative age-related macular degeneration,” Ophthalmologica, vol. 229, pp. 32–37, 2013.
7.. Coscas G, Loewenstein A, Augustin A, et al. Management of retinal vein occlusion–consensus document. Ophthalmologica 2011; 226(1): 4–28.
Coscas G, et al. Hyperreflective Dots: A New Spectral-Domain Optical Coherence Tomography Entity for Follow-Up and Prognosis in Exudative Age-Related Macular Degeneration[J]. Ophthalmologica, 2013, 229(1):32–37.
Li M, et al. Clinicopathologic Correlation of Anti–Vascular Endothelial Growth Factor–Treated Type 3 Neovascularization in Age-Related Macular Degeneration[J]. Ophthalmology, 2017, 125(2):1–12.
Andreas E, Despina K, Nadia S, et al. Microglia Activation and Recruitment of Circulating Macrophages During Ischemic Experimental Branch Retinal Vein Occlusion[J]. Investigative Opthalmology & Visual Science, 2017, 58(2):944-.
Bhisitkul RB. Vascular endothelial growth factor biology: clinical implications for ocular treatments[J].Br J Ophthalmol, 2006,90(12):1542–1547.
Sfikakis PP et al. Diab Care 2010;33:1523–28; 3. Funatsu H. Ophthalmology 2009;116:73–9; 4. Dong N et al. Mol Vis 2013;19:1734–46.
WJ Mayer, A Wolf, M Kernt, D Kook, A Kampik,M Ulbig and C Haritoglou.Twelve-month experience with Ozurdex for the treatment of macular edema associated with retinal vein occlusion.Eye (Lond). 2013 Jul;27(7):816–22.

Table 1 Comparison of CFT between 4 groups Pre-treatment and 12 months post-treatment

	Pre-treatment CFT	CFT at 12 months post-treatment	t	P
DEX group (n=30)	497.34±121.26	299.17±112.30	6.5674	0.0000
CBC group (n=51)	503.27±119.85	304.56±109.38	8.7457	0.0000
Combination group (n=29)	512.91±117.39	251.63±101.43	9.0695	0.0000
Laser group (n=49)	499.72±120.48	461.21±114.78	1.6200	0.1085

Table 2.Comparison of BCVA between 4 groups Pre-treatment and 12 months post-treatment

	Pre-treatment BCVA	BCVA at 12 months post-treatment	t	P
DEX group (n=30)	0.76±0.21	0.50±0.18	5.1488	0.0000
CBC group (n=51)	0.74±0.2	0.51±0.17	6.2575	0.0000
Combination group (n=29)	0.77±0.21	0.43±0.16	6.9352	0.0000
Laser group (n=49)	0.73±0.19	0.71±0.17	0.5522	0.5821

Table 3.Comparison of HRD between 3 intravitreal treatment groups Pre-treatment and 12 months post-treatment

	Pre-treatment HRD	HRD at 12 months post-treatment	t	P
DEX group (n=30)	30.34±15.42	16.81±12.32	3.7547	0.0004
CBC group (n=51)	27.8±15.73	18.93±13.45	3.0917	0.0026
Combination group (n=29)	29.61±14.66	15.74±13.64	3.7301	0.0004

Table 4 Stratifie Comparison of HRD between 3 intravitreal treatment groups Pre-treatment and 12 months post-treatment

Subgroup	Pre-treatment HRD	HRD at 12 months post-treatment	t	P
DEX responsive subgroup (n=19)	26.71±14.83	10.03±10.11	4.0509	0.0003
DEX non-responsive subgroup (n=11)	36.92±16.49	29.10±16.33	1.1176	0.2770
CBC responsive subgroup (n=29)	25.22±15.24	11.12±10.86	4.0575	0.0002
CBC non-responsive subgroup (n=22)	31.41±16.62	29.23±16.86	0.4319	0.6680
Combination responsive subgroup (n=17)	25.96±14.08	9.26±10.99	3.8550	0.0005
Combination non-responsive subgroup (n=12)	36.23±15.71	25.46±17.62	1.5804	0.1283

No competing interests reported.

PDF

Version 1

posted 07 Apr, 2022

You are reading this latest preprint version

The clinical efficacy of different treatments for macular edema secondary to BRVO

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Results

Discussion

Statements And Declarations

References

Tables

Competing Interests

Status:

Version 1