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ORIGINAL ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 1  |  Page : 276-281

Vitreoretinal interface after intravitreal injection of aflibercept for patients with diabetic macular edema and edema due to branch retinal vein occlusion


1 Department of Ophthalmology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Ophthalmology, Sohag Teaching Hospital, Sohag, Egypt

Date of Submission07-Apr-2021
Date of Decision05-May-2021
Date of Acceptance17-May-2021
Date of Web Publication18-Apr-2022

Correspondence Address:
Mohammed A. A. Ibrahim
Sohag
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_82_21

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  Abstract 


Objective
The aim of this study was to demonstrate the occurrence of vitreoretinal interface changes in patients with macular edema secondary to branch retinal vein occlusion (BRVO) and diabetic macular edema (DME) after intravitreal injection (IVI) of aflibercept (anti-vascular endothelial growth factor).
Background
IVI of aflibercept is an effective treatment for macular edema (ME) secondary to BRVO and DME.
Patients and methods
This prospective comparative case series study was carried out on 50 eyes of 30 patients coming to the Ophthalmology Department of Menoufia University Hospitals. Patients included had ME secondary to BRVO and DME. Patients were randomly enrolled into two groups. Group A included 16 eyes which had ME secondary to BRVO. Group B included 34 eyes which had ME secondary to DME.
Results
The results revealed that there was no significant difference between the studied groups regarding postoperative visual outcome and central macular thickness. However, there was a significant increase in epiretinal membrane complication in BRVO group than DME group postoperatively.
Conclusion
After IVI of aflibercept for ME, there was a significant improvement in visual acuity, all over the period of follow-up. Moreover, the optical coherence tomography improved significantly. The rate of complications was higher in the BRVO group than the DM group. The presence of vitreoretinal interface abnormalities affected the effectiveness of anti-vascular endothelial growth factor and final visual outcome.

Keywords: aflibercept, intravitreal injection, macular edema


How to cite this article:
Ahmed KE, Mandour SS, Ibrahim MA. Vitreoretinal interface after intravitreal injection of aflibercept for patients with diabetic macular edema and edema due to branch retinal vein occlusion. Menoufia Med J 2022;35:276-81

How to cite this URL:
Ahmed KE, Mandour SS, Ibrahim MA. Vitreoretinal interface after intravitreal injection of aflibercept for patients with diabetic macular edema and edema due to branch retinal vein occlusion. Menoufia Med J [serial online] 2022 [cited 2024 Mar 29];35:276-81. Available from: http://www.mmj.eg.net/text.asp?2022/35/1/276/343137




  Introduction Top


Macular edema (ME) is the leading cause of deteriorated visual acuity in patients with diabetic macular edema (DME) and branch retinal vein occlusion (BRVO) [1]. The discovery of vascular endothelial growth factor (VEGF) and the subsequent development of new agents targeting VEGF pathway have made a pathogenesis-oriented approach possible for DME therapy [2].

DME is a consequence of diabetic retinopathy in the macular area and is secondary to retinal barrier rupture, which is in turn secondary to a range of metabolic changes brought about by hyperglycemia. The most important molecule in retinal barrier rupture is the VEGF [2].

The pathogenesis of ME in BRVO is believed to be a result of multiple inflammatory cascades. Analysis of vitreous samples from patients with BRVO has established the increased levels of VEGF, interleukin-6, interleukin-8, and monocyte chemoattractant protein-1 compared with controls [3].

Excessive VEGF is produced from retinal epithelial cells, endothelial cells, and Muller cells in the setting of BRVO, resulting in vascular permeability and contributing to macular edema. Moreover, retinal ischemia results in elevated secretion of VEGF, leading to increased vascular permeability and vasodilation [4].

Currently, intravitreal anti-VEGF injections (IVIs) are considered to be the first-line therapy for treatment of DME [5].

Aflibercept (Eylea; Bayer Plc, Leverkusen, Germany) was approved by European Medicines Agency (EMA) for treatment of DMO in June 2014 [6].

It is a 115-kDa recombinant fusion protein molecule made up of a constant region (Fc) of human immunoglobulin G1 merged with two VEGF receptors (1 and 2). It has a higher binding capacity to VEGF-A in relation to bevacizumab and ranibizumab, with the advantage of additional binding to VEGF-B and placental growth factor, all molecules of which are involved in angiogenesis [7].

It is supposed that anti-VEGF therapy may switch angiogenesis to fibrosis and thus increase retinal traction [8].

Some mechanisms suggest that the extreme fluctuations in intraocular pressure and deformation of the globe during IVI result in vitreoretinal traction. Another possible mechanism is the angio-fibrotic switch of VEGF and connective tissue growth factor in PDR. The anti-VEGF IVI reduces intravitreal unbound, active VEGF levels. This can cause rising connective tissue growth factor levels and thus promote a switch from angiogenesis to fibrosis [9].

Hypoxia promotes VEGF transcription, so it upregulates angiogenesis to restore oxygen and nutrition supply for tissues. However, VEGF not only plays the role in the angiogenesis and vascular barrier breakdown but also leads to leukocyte adhesion to vascular walls and increases expression of vascular cell adhesion molecule-1 in the retina and the brain; thus, it plays a role in inflammation activation [10].

In the normal state, the vitreous firmly adheres to the vitreous base, optic disc, and macula at birth. The posterior vitreous cortex is 100 μm thick. It consists of densely packed collagen fibrils, which insert superficially into the internal limiting membrane of the retina, and attach to the internal limiting membrane by glue-like macromolecules, such as laminin, fibronectin, chondroitin, and heparin sulfate proteoglycans [11].

Spectral-domain optical coherence tomography (SD-OCT) is a noninvasive, quantitative method of imaging that is widely used in clinical practice. Spectral-domain-OCT has been used in clinical trials to measure retinal thickness of the macula and document the presence of anatomic changes in retinal diseases [12].

One of the common complications of eye in diabetes was vitreoretinal interface abnormalities [13].

Vitreoretinal interface abnormalities include epiretinal membrane (ERM), vitreomacular adhesion, vitreomacular traction (VMT), macular cysts or ME, partial-thickness macular hole, full-thickness macular hole, and posterior vitreous detachment [14].

The aim of this study was to demonstrate the occurrence of vitreoretinal interface changes in patients with macular edema secondary to BRVO and DME after IVI of aflibercept (anti-VEGF).


  Patients and methods Top


Study design

This was a prospective case series that included 50 eyes of 30 patients attending the outpatient clinic of Menoufia University Hospitals in the period from January 2019 to August 2020.

Group A included 16 eyes which had ME secondary to BRVO.

Group B included 34 eyes which had ME secondary to with DME.

Exclusion criteria were patients with ME (DME and BRVO) with vitreoretinal interface disorders, and ME owing to inflammatory causes (uveitis and Irvine–Gass).

Preoperative assessment of all patients included in the study was done, such as detailed ophthalmologic examination, including visual acuity, intraocular pressure measured by Goldmann applanation tonometer, cornea, pupillary response, AC death, crystalline lens, sclera examined by slit-lamp, and fundus examination by slit-lamp biomicroscopy with 78 D indirect lens.

Surgical technique

Each eye underwent IVI of aflibercept once a month for three consecutive months.

Postoperative visits were scheduled at postoperative day 1, 1 week, and 2 weeks. Detailed ophthalmic examination was done in these visits.

Postoperative care and follow-up: patients were given topical antibiotics, topical antiglaucoma drugs, and systemic carbonic anhydrase inhibitors.

Postoperative assessment was by doing OCT 1 month after the third injection and biomicroscope 6 months after the third injection.

This study included the following follow-up visits:

  1. Baseline (before injection).
  2. 1 month after the third injection.
  3. 6 months after the third injection.


Statistical analysis

  1. Data were collected and entered to the computer using IBM SPSS software package, version 20.0 (IBM Corp., Armonk, New York, USA). Qualitative data were described using number and percent. Comparison between different groups regarding categorical variables was tested using χ2 test.
  2. Quantitative data were described using mean and SD for normally distributed data, whereas abnormally distributed data were expressed using median, minimum, and maximum. Analytical statistics was done using χ2 test and unpaired t test. P value was considered statistically significant when it was less than 0.05. χ2 test was used to assess the association between qualitative nominal variables. It was performed mainly on frequencies. It determines whether the observed frequencies differ significantly from expected frequencies.



  Results Top


This study included 50 eyes of 30 patients. They were enrolled into two groups. Group A (BRVO) included 16 (32%) eyes and group B (DME) included 34 (68%) eyes [Table 1].
Table 1: Distribution of the studied patients regarding the diagnosis

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Patients' ages ranged from 45 to 77 years, and the mean age was 62.10 ± 811 years.

There was a statistically significant difference between baseline and both 3 and 6 months in both groups (P1 < 0.05), whereas there was no statistically significant difference between the two groups at the same time (P2 > 0.05) regarding visual outcome [Table 2].
Table 2: Visual outcome between two groups

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The visual acuity in group A (BRVO) ranged from 0.03 to 0.13, with a mean value of 0.091 ± 0.037 at baseline, whereas after 3 months, it ranged from 0.10 to 0.25, with a mean value of 0.166 ± 0.040, and after 6 months, it ranged from 0.16 to 0.40, with a mean value of 0.235 ± 0.090. There was a statistically significant difference between baseline and both 3 and 6 months ((P1 < 0.05).

The visual acuity in group B (DME) ranged from 0.03 to 0.13, with a mean value of 0.096 ± 0.032 at baseline, whereas after 3 months, it ranged from 0.10 to 0.25, with a mean value of 0.171 ± 0.045, and after 6 months, it ranged from 0.13 to 0.50, with a mean value of 0.276 ± 0.103. There was a statistically significant difference between baseline and both 3 and 6 months (P1 < 0.05).

There was a statistically significant difference between baseline and both 3 and 6 months postoperatively in both groups (P1 < 0.05), whereas there was no statistically significant difference between the two groups at the same time (P2 > 0.05) regarding central macular thickness (CMT) [Table 3].
Table 3: Comparison between two groups as regard to central macular thickness

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The CMT in group A (BRVO) ranged from 490 to 580, with a mean value of 519.4 ± 22.9 at baseline; after 3 months, it ranged from 379 to 387, with a mean value of 383.45 ± 4.3; and after 6 months, it ranged from 367 to 382, with a mean value of 369.9 ± 1.7.

The CMT in group B (DME) ranged from 490 to 540, with a mean value of 510.6 ± 18.9 at baseline; after 3 months, it ranged from 385 to 397, with a mean value of 390.47 ± 3.49; and after 6 months, it ranged from 377 to 382, with a mean value of 379.09 ± 1.56.

There was a significant increase in ERM complication in the BRVO group than DME [Table 4].
Table 4: Comparison between two groups as regard to complications

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In group A (BRVO), three (18.8%) cases developed ERM complication after 3 months (1 month after the third injection). This occurred, despite the risk factors being controlled. This complication was noticed in follow-up visits after three injections. These cases had normal vitreoretinal interface before injection.

In group B (DME), only one (2.9%) case developed ERM and one (2.9%) case developed VMT. These complications occurred after 3 months despite controlling blood sugar. These cases had normal vitreoretinal interface before injection [Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5].
Figure 1: OCT of normal macula. OCT, optical coherence tomography.

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,
Figure 2: Image of ERM (OCT). ERM, epiretinal membrane; OCT, optical coherence tomography.

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,
Figure 3: TOPCON 3D OCT-2000 Topcon (Tokyo, Japan). OCT, optical coherence tomography.

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,
Figure 4: Case of BRVO after three injections, with ERM. BROV, branch retinal vein occlusion; ERM, epiretinal membrane.

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,
Figure 5: Case of DME after three injections (VMT). DME, diabetic macular edema; VMT, vitreomacular traction.

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  Discussion Top


DME, one of the major complications of diabetic retinopathy, is also one of the leading causes of visual impairment in the working-age population [15].

In our study, the visual acuity (decimal) shows a statistically significant improvement after 3 months and after 6 months (P < 0.05) in comparison with baseline measurements.

Cetin et al.[16] studied the assessment of macular traction and vitreoretinal interface alterations in DME treated with IVIs. they found that the visual acuity significantly improved, and the two eyes showed progression in visual acuity in comparison with baseline stage.

Bressler et al.[17] reported that the number of patients who experienced at least 10 or 15 letter gains in visual acuity after having ranibizumab for DME was lower in the presence of mild surface wrinkling when compared with those not having surface wrinkling.

In other study carried out by Chang et al. [18],[19] on the incidence and risk factors for the development of vitreomacular interface abnormality in DME treated with IVI of anti-VEGF, they noticed an improvement of best-corrected visual acuity (BCVA) and central macular thickness (CRT) at the final visit compared with baseline in eyes treated with IVI; the differences were statistically significant for BCVA as expected (BCVA: P = 0.027). These results were not surprising, as there have been many studies reporting that IVI is effective for both short-term and long-term treatment of DME. However, this study also revealed that anti-VEGF was less effective in improving the BCVA after the formation of vitreomacular interface abnormality (VMIA). The improvement in BCVA was no longer significant in the group with VMIA formation (P = 0.088) compared with the group without VMIA formation (P = 0.001).

In our study, the results of CMT (DME) at baseline ranged from 490 to 540, with a mean of 510.60 ± 18.90; CMT after 3 months ranged from 385 to 397, with a mean value of 390.47 ± 3.49; and after 6 months, it ranged from 377 to 382, with a mean value of 379.09 ± 1.56. There was a statistically significant decrease after 3 and 6 months (P < 0.05).

On the contrary, in BRVO, with discovery of the role of VEGF in development of ME, IVI of aflibercept is the drug of choice in treatment of ME [20].

In our study, the visual acuity in BRVO shows a statistically significant improvement after 3 months and after 6 months (P < 0.05) in comparison with baseline measurements.

In our study, the results of CMT in the group of BRVO at baseline ranged from 490 to 580, with a mean of 519.40 ± 22.90; CMT after 3 months ranged from 379 to 387, with a mean value of 383.45 ± 4.30; and after 6 months, it ranged from 367 to 382, with a mean value of 369.9 ± 1.70. There was a statistically significant decrease after 3 and 6 months (P < 0.05).

In the study carried out by Campochiaro et al. [21], they found monthly IVI of aflibercept provided significant improvement in visual benefit and reduction in CMT with ME after BRVO.

In our study, only three eyes from 16 eyes of BRVO had developed ERM after three injections (1 month after the third injection), with percentage of 18.8%. In the other diagnosis, only one case had developed ERM, with percentage of 2.9%, and only one case had developed VMT, with percentage of 2.9%.

In agreement with our study, Sadiq et al.[19] reported that eight (8.33%) eyes developed VMIA during the follow-up period, of which seven eyes were classified as ERM and one eye was classified as anomalous vitreomacular adhesion on OCT.

In our study, the occurrence of VMA vitromacular traction VRAs had affected the visual outcome. We found deterioration in vision in two (5.88%) cases from 34 cases of DME in cases of VRAs, improvement in 27 (79.41%) cases in cases of normal VRI, and stabilization of vision in five (14.71%) cases in cases of normal VRI.

In agreement with our study, Campochiaro et al.[21] reported that presence of ERM, EZ elastic zone (EZ) irregularity, and Disorganization of Retinal Inner Layers (DRIL) were associated with significantly lower final visual acuity (P < 0.0001).


  Conclusion Top


After IVI of aflibercept for ME, there was a significant improvement in visual acuity. All over the period of follow up, and also the OCT improved significantly. The rate of complications was higher in BRVO group than DM group, and the presence of vitreoretinal interface abnormalities affected the effectiveness of anti-VEGF and final visual outcome.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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