Research Article
Retinal Function and Structure after Intravitreal Injections in Patients with Macular Edema Following Central Retinal Vein Occlusion in Clinical Practice
Elisabeth Wittström*, Monika Meinert and Daniel Samuelsson
Corresponding Author: Elisabeth Wittström, Department of Ophthalmology, Skane University Hospital, Lund University, SE-221 85 Lund, Sweden
Received: April 20, 2019; Revised: April 28, 2019; Accepted: April 27, 2019
Citation: Wittström E, Meinert M & Samuelsson D. (2019) Retinal Function and Structure after Intravitreal Injections in Patients with Macular Edema Following Central Retinal Vein Occlusion in Clinical Practice. Ophthalmol Clin Res, 2(1): 48-63.
Copyrights: ©2019 Wittström E, Meinert M & Samuelsson D. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Purpose: To investigate the clinical and electrophysiological effects of serial intravitreal injections of dexamethasone implant and aflibercept for macular edema after central retinal vein occlusion (CRVO).

Methods: Fifteen patients with macular edema after CRVO were examined with full-field electroretinography (ERG) within 1 month of symptom onset and 2 and 12 months after the start of treatment. They were divided into a non-ischemic and an ischemic CRVO group. All the CRVO patients had undergone clinical ophthalmological examination at the CRVO debut, monthly for 6 months and then every second month for 18 months.

The primary outcome measures were the change in the retinal function 2 and 12 months after treatment. Secondary outcome measures included best corrected visual acuity, intraocular pressure, central foveal thickness (CFT) and the presence of neovascular glaucoma (NVG).

Results: Of the 15 patients, 4 (27%) had non-ischemic and 11 (73%) had ischemic CRVO. A significant reduction in CFT, compared with baseline values, was observed in the whole group of CRVO patients at 2, 12 and 24 months (p=0.001, 0.017 and 0.022, respectively). A significant decrease in b-wave amplitudes of combined rod-cone response and of single-flash cone response of the full-field ERG was observed 12 months after treatment, while the reduction in the b-wave amplitudes of 30 Hz flicker response of the full-field ERG was significant compared with baseline values in all studied CRVO patients at both 2 and 12 months (p=0.046, 0.008, 0.021 and 0.030, respectively). Three of the eleven patients with ischemic CRVO (27%) developed NVG, on average, 18 months after CRVO debut.

Conclusion: This study revealed a decrease in retinal function at 12 months in CRVO patients undergoing serial intravitreal injections for macular edema after CRVO. The treatment did not prevent the development of NVG in ischemic CRVO.

 

Keywords: Central retinal vein occlusion, Intravitreal injections, Full-field electroretinography, Retinal function


INTRODUCTION

Central retinal vein occlusion (CRVO) is a common sight-threatening retinal vascular disease in the elderly. CRVO affects 0.8 per 1000 persons and the incidence increases significantly with age [1]. Systemic hypertension and vascular disease are important risk factors for CRVO in patients older than 50 years [2]. Further risk factors for CRVO have been found to be diabetes mellitus, hyperlipidemia, black race, male sex, diagnosis of stroke, blood hyper viscosity and thrombophilia. Ophthalmic risk factors for CRVO have also been reported, including ocular hypertension, glaucoma and changes in the retinal arteries [2,3].                

Studies on the natural visual outcome of CRVO have shown the major causes of vision loss to be macular edema and neovascularization with secondary neovascular glaucoma (NVG) and/or vitreous hemorrhages [4-6]. CRVO can be divided into non-ischemic and ischemic types. The risk of neovascular complications in patients with CRVO is related to the extent of retinal capillary non-perfusion, which can be evaluated with fluorescein angiography (FA) [7-9] and full-field electroretinography (full-field ERG). The cone b-wave implicit times, in both photopic and scotopic 30 Hz flicker ERG have been found to be significantly correlated with the degree of retinal ischemia [10-14], as well as with the concentration of vascular endothelial growth factor (VEGF) in the aqueous humor of CRVO eyes [15].

An evidence-based systemic study on clinical course of CRVO showed that untreated CRVO eyes, including non-ischemic CRVO, had poor visual acuity, which declined further over time. One third of eyes with non-ischemic CRVO became ischemic over a 3 year period, while in 30% of the non-ischemic CRVO eyes macular edema resolved and NVG was rare. In ischemic CRVO eyes, NVG developed in at least 23% of the eyes within 10 months and ischemic CRVO cases had poor baseline and final vision [16].

VEGF is a hypoxia-inducible angiogenic peptide; a potent growth factor for vascular endothelial cells, which promotes neovascularization and increases vascular permeability in patients with ischemic retinal diseases [17-21]. Anti-VEGF therapy at an early stage of retinal disease has been shown to be beneficial for visual recovery [19-21]. Retinal ischemia and vascular damage in CRVO eyes result in a breakdown of the inner blood-retinal barrier and disruption of this barrier is associated with complex cellular processes that lead to the release of angiogenic and inflammatory cytokines [22]. These cytokines have been found to be overexpressed in the aqueous humor or vitreous fluid of CRVO eyes [23-27]. Both anti-VEGF-therapy and treatment with intravitreal corticosteroid-based agents have been found to be effective in reducing the intraocular level of cytokines and in the reduction of macular edema due to CRVO [25-27].

Since 2010, intravitreal anti-VEGF agents, such as ranibizumab, bevacizumab and recently aflibercept and corticosteroid-based agents, such as dexamethasone and preservative-free triamcinolone, have been used for the treatment of macular edema-associated with CRVO and replaced the recommendations of the Central Retinal Vein Occlusion Study (CVOS) [28,29]. Three large prospective randomized controlled studies on the treatment of macular edema after CRVO (CRUISE, GALILEO and COPERNICUS) have demonstrated that repeated intravitreal injections of ranibizumab (in the CRUISE study) and aflibercept (in the GALILEO and COPERNICUS studies) improved visual and anatomic outcomes at follow-up compared to observation [30-33].

Anti-VEGF intravitreal injections were generally well tolerated and their use quickly replaced standard of care for CRVO-associated macular edema recommended by CVOS [28,29,34-36]. However, long-term results from the extension studies for CRUISE, COPERNICUS and GALILEO demonstrated a decline in visual and anatomic improvements in CRVO eyes when CRVO patients were monitored at least every 3 months and treated with fewer anti-VEGF injections [37-39]. Corticosteroid-based intravitreal injections for the treatment of macular edema-associated with CRVO, including the dexamethasone implant and triamcinolone acetonide used as off-label agent, decrease macular edema in CRVO eyes in the same way as anti-VEGF agents, by reducing vascular permeability, downregulating inflammatory mediators and inhibiting VEGF [40,41]. In the SCORE and GENEVA studies it has been found that intravitreal injections of corticosteroids for the treatment of macular edema associated with CRVO were superior to observation regarding visual and anatomical improvements in CRVO eyes [40-42]. Long-term visual and anatomical outcomes have been reported to be similar to those with dexamethasone implants and anti-VEGF agents in CRVO eyes treated for macular edema [43]. However, intravitreal corticosteroid treatment has been associated with a higher frequency of adverse effects, including the elevation of intraocular pressure (IOP) and cataract formation or progression [35,40,43-47].

It has been suggested that anti-VEGF therapy may not only reduce macular edema in CRVO eyes and improve vision, but may also prevent the deterioration of retinal perfusion and promote reperfusion [48-51]. In contrast, the SCORE study and post hoc analysis of the pooled data from the GENEVA study showed that intravitreal corticosteroid treatment was not associated with lower incidences of neovascular events or less global (peripheral and macular) non-perfusion compared with observation. The area of global non-perfusion increased from baseline to the end of the studies and was similar in treated and untreated eyes [52,53]. Using wide-field FA (WFFA), it has been shown that the area of peripheral retinal non-perfusion may vary in CRVO eyes and may affect the clinical course and the response to treatment of these eyes [54]. Wykoff et al. [55] performed serial WFFA on 12 ischemic CRVO eyes over a period of 3 years. All eyes demonstrated extensive areas of retinal peripheral non-perfusion at baseline, and the area of retinal non-perfusion increased in all eyes during treatment with ranibizumab, with a mean loss of approximately 8.1% of the perfused retinal area per year.

The Rubeosis Anti-VEGF (RAVE) study [56] and two retrospective studies [57,58] on neovascular events in eyes with CRVO treated with anti-VEGF showed that anti-VEGF therapy could improve retinal anatomy and vision in eyes with ischemic CRVO, but it did not prevent ocular neovascularization.

Quantifying the extent of global retinal non-perfusion in patients with CRVO using FA or WFFA is very difficult and very subjective and an electrophysiological method such as full-field ERG may be a more appropriate, objective method for the evaluation of the total retinal function before and after anti-VEGF or intravitreal corticosteroid therapy for macular edema associated with CRVO. Only a few studies have been performed to evaluate the retinal function before and after intravitreal treatment of CRVO patients using full-field ERG [59,60].

The aim of this prospective study was thus to evaluate the retinal function and structure in patients with macular edema due to non-ischemic and ischemic CRVO, using full-field ERG and optical coherence tomography (OCT), before and after serial intravitreal injections.

PATIENTS AND METHODS

The study was approved by the Ethics Committee of Lund University and all participants gave their written informed consent according to the principles outlined in the Universal Declaration of Helsinki.

Fifteen patients with macular edema secondary to CRVO who were examined with full-field ERG within 1 month of symptom onset and treated with intravitreal injections (dexamethasone implant and aflibercept) were included in this study. They were also examined with full-field ERG 2 and 12 months after the start of the intravitreal treatment. Patients with glaucoma, ocular inflammation or cloudy media due to cataract, keratopathy or vitreous hemorrhage were excluded. The patients were divided into two groups: a non-ischemic (n=4) and an ischemic CRVO group (n=11). Two patients in the ischemic CRVO group did not undergo full-field ERG at 12 months; one because of death (not related to the intravitreal treatment) and the other refused to undergo full-field ERG but completed all other tests at 12 months. All 15 patients received one intravitreal dexamethasone implant injection at the beginning of the study, after which they had the possibility to switch to aflibercept or continue with dexamethasone. Only three patients continued with dexamethasone treatment (two of them had two intravitreal dexamethasone implant injections and one of them had five intravitreal dexamethasone implant injections before changing to aflibercept).

CRVO was classified as non-ischemic if the cone b-wave implicit time in the 30 Hz flicker ERG was ≤ 37 ms and as ischemic if the cone b-wave implicit time was >37 ms [11]. Visual and ophthalmoscopic findings and capillary non perfusion findings on FA were also used to classify CRVO in the present study [7-10]. Macular edema was retreated if the best corrected visual acuity (BCVA) decreased by more than five ETDRS-letters and/or the central foveal thickness in OCT increased by more than 100 µm. Patients with 2 clock hours’ iris neovascularization or any angle neovascularization and IOP greater than 22 mm Hg were defined as having NVG.

Ocular examination

All the CRVO patients had undergone clinical ophthalmological examination including BCVA, Early Treatment Diabetic Retunopathy Study (ETDRS-letters), measurement of IOP (Goldman applanation tonometry), slit-lamp examination, biomicroscopy, gonioscopy and OCT examination at the debut of CRVO and then monthly for 6 months, and thereafter every two months for 18 months.

Full-field electroretinography

Full-field electroretinograms were recorded with an Espion E2 analysis system (Diagnosys, LLC, Lowell, MA, USA) after the pupil had been dilated with topical 1% cyclopentolate and 10% phenylephrine, and the subject’s eyes had been dark-adapted for 40 min. After topical anesthesia of the eye, a Burian-Allen bipolar contact lens was applied to the cornea, and the ground electrode to the forehead. Responses were obtained with a wide-band filter (-3 dB at 1 Hz and 500 Hz), while stimulating with brief (30 µs) full-field flashes of dim blue light (0.0045 cd•s/m2) to elicit rod response and with white light (3 cd•s/m2) to elicit the combined rod-cone response. Cone responses were obtained with 30 Hz flickering white light (3 cd•s/m2) averaged over 20 sweeps and single-flash white light (3 cd•s/m2). The background luminance was 30 cd/m2. The recording procedures were the same as those prescribed in the standard protocol for clinical electroretinography recommended by the International Society for Clinical Electrophysiology of Vision (ISCEV) [61].

Optical coherence tomography

OCT was performed using the spectral domain 3D OCT-1000, version 3.00 software (Topcon, Tokyo, Japan). The 3D macular scan option was used in all scans in this study, centered on the fovea, covering 6 × 6 mm, with a resolution of 512 × 128, creating an image of the whole macular area. The fast macular thickness scan protocol was used. The central foveal thickness (CFT) was used in the analysis. The macular thickness measurements are given as numerical values (μm).

The primary outcome measures were the change in the total retinal function at 2 and 12 months after treatment, as demonstrated by full-field ERG and the secondary outcome measures were BCVA, IOP, CFT and presence of NVG.

Treatment procedure

All 15 patients received the initial intravitreal dexamethasone implant injections (Ozurdex, Allergan; Inc., Irvine, CA, USA) via the pars plana under sterile conditions. The patients were then allowed to change to 2 mg intravitreal aflibercept injections (Bayer, Healthcare Pharmaceuticals, Berlin, Germany) or continue with dexamethasone implant injections as needed.

STATISTICAL ANALYSIS

The data were analyzed using SPSS version 21 (SPSS Inc., Chicago, IL, USA). The Wilcoxon signed-rank test was used to determine whether significant changes had occurred between baseline, 2 and 12 months and the final examination within each CRVO group and the Mann-Whitney U-test was used to compare ordinal parameters between the two study groups. Categorical variables were compared between the two study groups using Fisher’s exact test. Values of p ≤ 0.05 were considered to show statistical significance.

RESULTS

Of the 15 patients studied 4 (27%) had non-ischemic CRVO and 11 (73%) had ischemic CRVO. No significant difference was observed between the non-ischemic and ischemic CRVO groups regarding sex, age, time from CRVO debut to treatment, follow-up period, number of dexamethasone implant or aflibercept injections, ocular complications or lens status (Table 1).

Analysis of the whole group of CRVO patients

A significant improvement in BCVA (ETDRS-letters) was observed, from 46.0 ± 17.0 letters to 60.0 ± 20.4 letters (p=0.001) 2 months after the intravitreal injections. The mean BCVA decreased at 12 months to 45.0 ± 28 letters (p=0.789) and was almost unchanged, 45.0 ± 27.0 letters, 24 months after retreatments, compared with baseline (p=0.972) (Figure 1 and Table 2). A significant increase in IOP was observed, from 19.0 ± 6.0 mm Hg at baseline to 23.0 ± 8.0 mm Hg (p=0.045) 2 months after the intravitreal injection. The mean IOP decreased both 12 and 24 months after treatment and there was no significant difference compared with baseline (p=0.893 and 0.953, respectively) (Figure 2 and Table 2). The mean CFT decreased significantly, from 679.0 ± 166.2 µm at baseline to 284.0 ± 107.1 µm (p=0.001) 2 months after the intravitreal injection. A different but still significant improvement in CFT was also observed both 12 and 24 months after treatment, compared with baseline (p=0.017 and 0.022, respectively) (Figure 3 and Table 2).

The changes in full-field ERG response for the whole group of CRVO patients during the study period are given in Table 3. The a- and b-wave amplitudes of combined rod-cone and single-flash response and the b-wave of rod and 30 Hz flicker response of the full-field ERG decreased both 2 and 12 months after treatment, compared with baseline values (Figures 4-6 and Table 3). The b-wave amplitudes of combined rod-cone response and of single-flash cone response were significantly decreased 12 months after treatment, compared with baseline (p=0.046 and 0.008, respectively) (Figures 4 and 5 and Table 3). The b-wave amplitudes of 30 Hz flicker response (cone response) decreased significantly in all CRVO patients studied, both 2 and 12 months after treatment, compared with baseline (p=0.021 and 0.030, respectively) (Figure 6 and Table 3).

Analysis of the group with non-ischemic CRVO

No significant improvement in BCVA was observed 2 months after treatment (73.3 ± 4.0 letters) compared with baseline values (58.0 ± 10.0 letters) (p=0.068) and the mean BCVA decreased slightly 12 and 24 months after treatment, compared with baseline values (p=0.066 and 0.144) (Figure 1 and Table 2). No significant changes in IOP were observed during the whole study period, compared with baseline (Figure 2 and Table 2). The mean CFT decreased from 641.0 ± 70 µm at baseline to 221.3 ± 49.0 µm 2 months after treatment and increased slightly at 12 and 24 months after treatment, compared with baseline values (p=0.068, 0.068 and 0.068, respectively) (Figure 3 and Table 2).

The b-wave amplitudes of rod, combined rod-cone and 30 Hz flicker response of the full-field ERG increased 2 months after treatment, compared with baseline, but the increase did not reach statistical significance (p=0.460, 0.465 and 0.465, respectively) (Table 4). In contrast, the b-wave amplitudes of rod, combined rod-cone and 30 Hz flicker response of the full-field ERG showed a decrease 12 months after treatment, compared with baseline, but the decrease did not reach statistical significance (p=0.099, 0.465 and 0.465, respectively) (Table 4).

Analysis of the group with ischemic CRVO

A significant improvement was observed in BCVA, from 44.4 ± 17.0 letters at baseline to 55.1 ± 22.0 letters 2 months after the intravitreal injection, compared with baseline values (p=0.007) (Table 2). No significant changes in IOP were observed at any point in time during the study, compared with baseline values (Table 2). The mean BCVA decreased from 44.4 ± 17.0 letters at baseline to 35.0 ± 26.4 letters at 12 months and to 37.4 ± 27.0 letters at 24 months (p=0.236 and 0.514, respectively) (Table 2).

The mean CFT decreased significantly, from 692 ± 191.0 µm at baseline to 307.0 ± 115.0 µm 2 months after the intravitreal injection (p=0.003). No significant improvement in CFT was observed after 12 or 24 months of treatment, compared with baseline (0.083 and 0.114, respectively) (Table 2).

The a-wave and b-wave amplitudes of rod, combined rod-cone, single-flash and the b-wave amplitudes of 30 Hz flicker response of the full-field ERG decreased both 2 and 12 months after treatment, compared with baseline, but the decrease was only statistically significant for b-wave amplitudes of single-flash response 12 months after treatment, compared with baseline values (p=0.008) and for b-wave amplitudes of 30 Hz flicker response both 2 and 12 months after treatment, compared with baseline (p=0.006 and 0.033, respectively) (Table 5).

Three of 11 (27%) patients with ischemic CRVO developed NVG (8, 19 and 29 months after CRVO debut or after 18 months, on average). There were no incidents of endophtalmitis, retinal tears or retinal detachment. No serious non-ocular adverse events occurred.

DISCUSSION

Intravitreal injections of dexamethasone implant and aflibercept were effective in bringing about a significant reduction of CFT, compared with baseline values, in the whole group of CRVO patients during the treatment period in the present study. Patients with non-ischemic CRVO showed a more marked reduction in CFT than those with ischemic CRVO. A significant reduction in CFT, compared with baseline values, has been reported 6 months after anti-VEGF therapy, which was maintained 12 months after repeated ranibizumab injections for macular edema following CRVO in the CRUISE study [30,31] and after repeated aflibercept injections in the COPERNICUS study [32] and the GALILEO study [33].

The mean BCVA improved significantly 2 months after the treatment in the whole group of CRVO patients, compared with baseline values, but the visual gains were diminished 12 and 24 months after treatment, despite the monitoring every two months and repeated aflibercept or dexamethasone implant injections as needed. Patients with ischemic CRVO exhibited the greatest visual loss, nearly 20 letters, both at 12 and 24 months, while patients with non-ischemic CRVO showed insignificant visual loss, ≤ 3 letters, 12 and 24 months after treatment. These findings are in contrast to the results of several previous studies, where it was reported that visual gains achieved with 6 monthly injections of ranibizumab, bevacizumab or aflibercept in patients with macular edema after CRVO were maintained 12 months after treatment [30,31,59,62].

The reason for the poorer worse visual results observed after 12 months in the present study could be the high percentage of patients with ischemic CRVO. In the present study 73% of the patients had ischemic CRVO, while in the COPERNICUS study [32] only 30% of the patients had ischemic CRVO, 14% in the GALILEO study [33], 0.5% in the CRUISE study [31], while all the CRVO patients in the study by Mayer et al. [62] had non-ischemic CRVO. The deterioration in the visual acuity 12 months after treatment in the present study was unchanged up to 24 months in both ischemic and non-ischemic CRVO patients. It has been reported in other studies that neither the improvements in visual acuity nor the reductions in the CFT were maintained after the first year of anti-VEGF and dexamethasone therapy for macular edema after CRVO [37-39,63,64].

To the best of our knowledge, the present study is the first clinical pilot study on the treatment of CRVO patients with both repeated dexamethasone implant and aflibercept injections using full-field ERG to evaluate the total retinal function 2 and 12 months after treatment. A significant decrease in the b-wave amplitudes of combined rod-cone and of single-flash cone response was observed 12 months after treatment, compared with baseline values in all studied CRVO patients, while the reduction in b-wave amplitudes of 30 Hz flicker response was significant compared with baseline values in all studied CRVO patients of this study both 2 and 12 months after treatment. All patients with ischemic CRVO also showed a significant reduction in b-wave amplitudes for single-flash response 12 months after treatment and for b-wave amplitudes of 30 Hz flicker response 2 and 12 months after treatment.

The findings of the current study indicate a decrease in retinal function in the whole group of CRVO patients studied, especially in patients with ischemic CRVO, 12 months after treatment with repeated intravitreal injections as needed. Previous electrophysiological studies on retinal function after anti-VEGF treatment have revealed no significant changes in the scotopic or the photopic full-field ERG amplitudes or implicit times at the end of the follow-up period, compared with baseline values [65-68]. However, other studies also showed a non-significant reduction in the b-wave amplitudes of the rod, combined rod-cone and 30 Hz flicker response in scotopic full-field ERG at the end of the follow-up period, compared with baseline values, indicating long-term deterioration of photoreceptor function [69,70].

We have previously found a more marked reduction in retinal function in patients with ischemic CRVO treated with bevacizumab and PRP than in those treated with PRP only, 6 months after treatment [60]. In contrast, Topčić et al. [59] reported significantly improved retinal function 6 and 12 months after bevacizumab treatment of macular edema resulting from CRVO. After separating ischemic from non-ischemic CRVO, the authors of the above study found no improvement in the retinal function of patients with ischemic CRVO 12 months after treatment.

There are two possible reasons for the decrease in retinal function in CRVO patients after intravitreal injections in this study. The first could be progressive ischemia associated with the natural development of CRVO. Hayreh et al. [6] and McIntosh et al. [16] have reported that progressive ischemia develop when CRVO is untreated. It has also been reported that up to 34% of eyes with non-ischemic CRVO become ischemic CRVO over a 3 year period and that 23% of eyes with ischemic CRVO developed NVG within 15 months [16]. In the present study, 3 of 11 of the patients with ischemic CRVO (27%) developed NVG an average of 18 months after CRVO debut, and treatment with intravitreal injections did not prevent the progression of retinal ischemia in the eyes of these patients.

The second factor that could contribute to the decrease in retinal function could be direct effects of the dexamethasone or aflibercept on the function of the photoreceptors through damage to the choriocapillaris or the photoreceptors, especially in patients with ischemic CRVO. A significant reduction in choriocapillaris endothelial cell fenestration and segmental occlusion by thrombocytes and leukocytes, which influenced circulation and impaired nutritional provision to the photoreceptors, has been found in primate eyes treated with bevacizumab [71].

Marneros et al. [72] have also shown that VEGF was essential for the development and maintenance of the choriocapillaris. Mutant mice that lack VEGF expression in the retinal pigment epithelium showed morphologic abnormalities in the retinal pigment epithelium and photoreceptors. Furthermore, both a and b wave amplitudes of scotopic full-field ERG response were significantly reduced in these mice compared to the full-field ERG response of control mice [72]. VEGF-A has been recognized as an important survival factor for the retinal neurons and a critical neuroprotectant during ischemic injury by increasing the blood flow to the retina and decreasing the number of apoptotic retinal cells. Chronic inhibition of VEGF-A by anti-VEGF agents reduces macular edema and the neovascularization, but also simultaneously reduces the neuro protective effect of VEGF-A [73]. Anti-VEGF injections have been associated with increased apoptosis in retinal photoreceptor cells, reduced retinal thickness of the inner and outer layer of the retina and a significant reduction in both a and b wave amplitudes of full-field ERG response [74,75]. VEGF blocking may increase the progression of retinal non perfusion and, secondarily, decrease retinal function as measured by full-field ERG. However, it was not possible to ascertain this it in the present study as we did not evaluate untreated CRVO eyes longitudinally. Leaving patients untreated would be unethical.

Although a significant reduction in CFT was seen in CRVO patients undergoing serial intravitreal injections in this study, the retinal function was not improved at 12 months and the treatment did not prevent the development of NVG in ischemic CRVO. NVG occurred in 27% of patients with ischemic CRVO undergoing anti-VEGF therapy in this study an average of 18 months after CRVO debut. Our findings concerning NVG are similar to those in previous studies on CRVO patients undergoing serial anti-VEGF injections [56-58].

Ryu et al. [57] reported that NVG occurred at 19.7 months after CRVO debut and they concluded that although anti-VEGF therapy for macular edema, especially in patients with ischemic CRVO, does not prevent the development of ocular neovascularization, it may be delayed compared to the natural development of CRVO-associated neovascularization. The RAVE study [56] has also shown that anti-VEGF therapy can improve retinal anatomy and vision in eyes with ischemic CRVO, but neurovascular complications were not prevented by VEGF inhibition, only delayed. The SCORE-study [52] has also shown that triamcinolone treatment was not associated with lower incidences of neurovascular events or non-perfusion status, compared with observation. In a more recent study by Wykoff et al. [55] using WFFA, a progressive loss of the retinal perfusion was observed in ischemic CRVO eyes undergoing anti-VEGF therapy. However, Campochiaro et al. [48] reported anti-VEGF therapy to have a protective effect on retinal vascular perfusion.

Our study has several limitations, including the small number of patients in each group, the lack of a control group to evaluate untreated CRVO eyes longitudinally and a short follow-up period.

CONCLUSION

This study revealed a decrease in total retinal function, measured by full-field ERG, at 12 months in patients undergoing repeated intravitreal injections of dexamethasone implant and aflibercept using as needed dosing. The treatment did not prevent the development of NVG in ischemic CRVO. Further electrophysiological studies with longer follow-up periods and a control group consisting of untreated CRVO eyes are needed to clarify the long-term effects of anti-VEGF therapy on the retinal photoreceptor cells, especially in retinal diseases with severe retinal ischemia.

ACKNOWLEDGEMENT

This study was supported by Stiftelsen för synskadade I f.d. Malmöhus län and Skane University Hospital.

DISCLOSURE

The authors report no conflicts of interest in this work.

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