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 Table of Contents  
Year : 2022  |  Volume : 34  |  Issue : 2  |  Page : 98-103

Update on imaging and anti-VEGF therapy for diabetic retinopathy

1 Department of Retina, Aravind Eye Hospital, Madurai, Tamil Nadu, India
2 Department of Retina, Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom

Date of Submission08-May-2022
Date of Decision11-May-2022
Date of Acceptance16-May-2022
Date of Web Publication30-Aug-2022

Correspondence Address:
Prof. Sobha Sivaprasad
Moorfields Eye Hospital NHS Foundation Trust, 162, City Road, London
United Kingdom
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/kjo.kjo_65_22

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The classification of diabetic retinopathy has been based on 7-field photographs. With advances in retinal imaging, there is an unmet need to reclassify this condition as new predictive factors have been identified in the peripheral retina. In addition, we have transitioned from an era of laser treatment for vision-threatening complications to robust evidence that anti-VEGF therapy can modulate the diabetic retinopathy scores. In this review, the literature on both retinal imaging and role of anti-VEGF on diabetic retinopathy highlights both the merits and shortcomings of available evidence in this area.

Keywords: Anti-VEGF, diabetic retinopathy, widefield retinal imaging

How to cite this article:
Sen S, Sivaprasad S. Update on imaging and anti-VEGF therapy for diabetic retinopathy. Kerala J Ophthalmol 2022;34:98-103

How to cite this URL:
Sen S, Sivaprasad S. Update on imaging and anti-VEGF therapy for diabetic retinopathy. Kerala J Ophthalmol [serial online] 2022 [cited 2023 Feb 2];34:98-103. Available from: http://www.kjophthal.com/text.asp?2022/34/2/98/355041

  Introduction Top

The worldwide prevalence of diabetes mellitus (DM) has increased from 1.2% in 1971 to 9.3% in 2019 and the overall projected numbers of people with diabetes are 700 million in 2045.[1],[2] Diabetic retinopathy (DR) is one of the most significant microvascular complications of DM. Vision-threatening DR, comprising of diabetic macular edema (DME) and proliferative DR (PDR), needs to be detected at an early stage to prevent its progression to advanced stages.[3],[4],[5],[6],[7] The progression of DR can be documented using clinical photographs at regular screening intervals.

DR is characterized by endothelial injury, loss of pericytes and breakdown of blood retinal barrier, and major pathogenetic biochemical pathways have been discovered related to chronic hyperglycemia.[8] Of the several factors driving the pathways, the most well established is that of the vascular endothelial growth factor (VEGF).[9],[10]

Since the 1960s, panretinal photocoagulation has been the mainstay of treatment of eyes with PDR, supported by data from the DRS study.[11] However, DRS study also showed that 50% of eyes with PDR would still progress to severe vision loss even after Pan Retinal Photocoagulation (PRP).[11] VEGF levels in the vitreous have been shown to reduce after PRP, with a clinical regression of neovascularisation, reduction of vitreous hemorrhage and chance of future tractional retinal detachment.[12] Nevertheless, PRP has several limitations, including permanent loss of peripheral field of vision, night blindness, worsening of macular edema, vitreous hemorrhage, uveal effusion and transient loss of central vision.[13] Furthermore, it requires a clear media and good patient cooperation. Intravitreal anti-VEGF therapy has become the standard of care for eyes with DME, with multiple randomised clinical trials demonstrating its effect on visual outcome in DME.[14],[15]

Decades of research has shown that Non-Proliferative Diabetic Retinopathy (NPDR) may be prevented from progressing to PDR by appropriate control of modifiable risk factors. There is, however, no specific treatment for NPDR, except for close observation. Recent literature on anti-VEGF in DME has shown that NPDR may be reversible and this may prevent development of vision-threatening complications.

The purpose of this review is to summarise the evidence of anti-VEGF use in DR and to explore into imaging modalities examining the peripheral retina, which may improve the detection rate of DR and improve treatment and follow-up. The authors performed a literature search using Pubmed/Medline and Google Scholar up to February 2021 using keywords “wide-field imaging,” “diabetic retinopathy,” “proliferative diabetic retinopathy,” non-proliferative diabetic retinopathy,” “DRSS” and “anti-VEGF.”

  Retinal Imaging for DR Top

Conventional color fundus photography

The Early Treatment Diabetic Retinopathy Study (ETDRS) group was the first to classify DR eyes as having mild, moderate, severe, very severe NPDR and early and high-risk PDR.[16],[17],[18] This was done using seven 30-degree field stereoscopic photography which could capture around 35% of the whole retina[13],[19],[20],[21] The ETDRS-Diabetic Retinopathy Severity Score (DRSS) was developed that scored each eye from 10 (no retinopathy) to 85 (advanced PDR), with a progression of DR defined as 2- or 3-step change in the DRSS.[22],[23],[24] Recently, the Diabetic Retinopathy Clinical Research Network (DRCR.net) has evaluated 200° ultra-wide field imaging (UWFI) for DR grading as against ETDRS 7-field photography and found them to be equivalent.[25]

Ultra-wide field imaging

UWFI of the retina captures 82% of the total area, which may be more relevant in evaluation of the peripheral retina in PDR eyes.[26],[27],[28] UWFI has helped to identify predominantly peripheral lesions (PPL), namely, hemorrhages, microaneurysms, intraretinal microvascular abnormalities, venous beading and neovascularization, which are more severe outside the ETDRS 7 standard photographic fields.[29] These PPLs can identify at-risk DR eyes independent of the ETDRS-DRSS level, because these eyes have larger areas of capillary non-perfusion (CNP) on angiography.[29] Furthermore, DRSS grades have been found comparable to UWFI in the protocol AA, and the inclusion of PPL to ETDRS grades may improve the identification of eyes at risk for PDR.[25] The incorporation of UWFI in the existing classification of DR has been proposed.

  Retinal Perfusion Top

Fundus fluorescein angiography was not a part of the original ETDRS classification for severity of DR and has not played much role in classification of the disease, albeit its importance in identifying high-risk lesions.[30] CNP is generally measured manually in disc areas or by binarization techniques.[31],[32],[33],[34] More recent studies are aiming for automated detection of non-perfusion.[32]

Optical coherence tomography angiography (OCTA)

OCTA has made the visualization of retinal vasculature possible without dye injection. The superficial and deep retinal capillary plexuses and choriocapillaris can be imaged individually in high resolution, along with measurement of other vascular parameters, such as vessel density, perfusion index, foveal avascular zone area, fractal dimension, etc.[35],[36],[37] OCTA may detect vascular abnormalities, such as microaneurysms in the deep capillary plexus that is not visible on FA, and help in detecting DR in patients who have normal fundus on ophthalmoscopy.[38],[39] OCTA may also be used to characterise diabetic macular ischemia.[40]

Ultra-wide field angiography (UWFA)

UWFA is a more practical alternative to standard field Fluorescein Angiogram (FA) by nullifying the need for repeated imaging for peripheries and has become the investigation of choice for understanding the extent of CNP areas. But it is also invasive. In this regard, wide-field OCTA has emerged as a comparable platform to UWFA for evaluation of peripheral ischemia in DR as a non-invasive modality.[41]

Wide-field OCTA, apart extensive characterisation of neovascularisation in DR eyes, can detect peripheral non-perfusion superior to FA, with segmentation of individual layers, and needs to be evaluated further in this regard.[42] With improvements in scanning speed, resolution and field of view, OCTA has the potential to replace FA for characterisation of retinal microvasculature in DR.[43]

  Automated Detection of DR Progression Top

Artificial intelligence (AI) based platforms have been used for DR grading with significant efficiency and accuracy. AI can grade DR as referable or non-referable DR. Deep learning-based AI can grade DR into ETDRS or similar stages, along with presence or absence of DME.[44],[45] There is a lot of scope in automated detection and analysis of PPLs with UWFI for the prediction of DR severity and progression.[29],[46] Automated detection of CNP areas may also be a very reliable method of detecting PDR risk.[47],[48],[49],[50] UWFA images have been used for automated analysis and has been found comparable to human graders.[51],[52],[53]

  Impact of Anti-VEGFs on Retinal Non-Perfusion and DR Progression Top

CNP correlated with DR and DME severity, however, the threshold at which the complications begin, is less well understood.[54],[55] A recent study found that eyes with more than 107.3-disc area of CNP were at highest risk of developing PDR.[56] The RECOVERY study suggests that aflibercept therapy in PDR eyes without DME may show reduced progression of CNP in addition to an improvement of DRSS scores.[57] However, more reports suggest no improvement of non-perfusion with anti-VEGF therapy. Other reports also indicate that anti-VEGF therapy may reduce leakage.[32],[58],[59],[60] Anti-VEGF therapy may also improve DRSS scores.[15],[21],[31],[32],[61],[62],[63],[64] The post-hoc analysis of DRCR.net Protocol T[65] found that the DRSS scores improved with all available anti-VEGF drugs, similar to previous studies.[14],[15],[66],[67],[68],[69],[70],[71],[72],[73] This improvement was sustained in around 70% of PDR eyes.[65] The RISE and RIDE trials also found improvement of DRSS scores in PDR eyes with ranibizumab and needed PRP less frequently.[74] In the PRN dosing phase of RISE/RIDE studies, almost 70% patients maintained their improvement of DR severity, along with visual improvement with repeated injections.[68] A delayed progression of CNP was also observed. Therefore, patients may require continued treatment with anti-VEGFs. In the VISTA and VIVID trials, aflibercept improved the DRSS scores for a maintenance period of 148 weeks.[73]

Prospective clinical trials of anti-VEGFs in PDR

DRCR.net Protocol S was designed to evaluate intravitreal ranibizumab as a monotherapy for treatment naïve PDR eyes, against PRP.[75] Ranibizumab showed equivalent efficacy for regression of PDR when compared to PRP, and even had better visual outcomes. This trial suggested that aggressive anti-VEGF therapy in PDR is more beneficial than PRP alone.[76]

In eyes with PDR along with vitreous hemorrhage, anti-VEGF treatment may be used to treat the underlying DR, although DRCR Protocol H did not show any significant difference in vitrectomy rates between ranibizumab-injected and sham-treated eyes.[77]

The CLARITY trial compared monotherapy with aflibercept and PRP for treatment naïve PDR eyes.[78] After 2 years of follow-up, higher proportion of eyes getting aflibercept showed neovascularization regression compared to PRP-treated eyes. Aflibercept also led to higher improvements in DRSS and less chances of developing newer complications.

The PROTEUS trial was a randomised trial for comparing PRP against PRP with additional ranibizumab for regression of high-risk PDR features.[74] The study found that combined treatment showed higher chances of complete regression of neovascularization compared to PRP alone. Thus, a combined approach may have more sustained effect.

The PRIDE study is an ongoing clinical trial that compares the effects of PRP alone versus ranibizumab alone versus PRP-ranibizumab combined therapy in PDR in terms of change of neovascularization area over 12 months.[79]

Prospective clinical trials of anti-VEGFs in NPDR

In the DRCR.net Protocol W trial, moderate to severe NPDR eyes without DME received aflibercept and it was found that over 2 years, aflibercept reduced the the risk of developing vision-threatening complications, both PDR and DME.[80] The ongoing PANORAMA trial will evaluate the role of aflibercept injections versus sham in severe NPDR without DME, towards DRSS improvement during a 2-year period.[81] Over 100 weeks, the rate of development of vision-threatening complications, DME, PRP requirement and change in BCVA also will be measured. The dosing schedule has been kept as 2 mg every 16 weeks for 2 years or every 8 weeks in the first year followed by PRN dosing in the second year. After 24 weeks, almost 60% of eyes getting aflibercept have achieved 2-step or more improvement in DRSS compared to sham, irrespective of the dosing schedule, and they also had reduction in chances of development of vision-threatening complications.[82]

  Reclassification of DR Top

The DRSS was initially developed with 7-field photography system, however, we have additional imaging tools at hand, namely, UWFI, OCTA and UWFA. Because peripheral retinopathy changes may be identified in a significant number of eyes outside the ETDRS fields, modalities, such as UWFA may increase the DRSS severity.[26],[27] These eyes may also have higher progression rates of DR.[29],[83] Because the DRSS was standardised for treatment naïve eyes, the utility of the same scoring system in monitoring eyes that have received treatment in the form of PRP or anti-VEGF has been long debated. The only factor significantly associated with 2-step or more DRSS improvement with antiVEGF therapy is baseline DRSS.[84] In addition, an eye with moderate to severe NPDR may be more responsive to DRSS improvement than an eye with mild NPDR at baseline, despite being more unstable. Hence, when the moderate to severe NPDR eye improves to mild NPDR stage, this “induced” state is quite different from a “treatment naïve” mild NPDR eye of the same DRSS.[85],[86] Hence, the DRSS fails to adequately describe this post-treatment underlying state in DR eyes. On the contrary, a UWFA at this point might help in evaluating the peripheral ischemia, which in turn might help predict the natural course and further treatment response in the “induced” and “treatment naïve” eyes. AI-based standardization of UWF images may further help in achieving a uniform criterion for treatment purposes and for monitoring eyes in clinical trials.

Literature regarding UWFA or wide-field OCTA for documentation of peripheral ischemia in DR and effects of anti-VEGF is scarce. Patients requiring long-term maintenance therapies with follow-up might be more compliant towards non-invasive imaging techniques, such as UW-OCTA.[87],[88]

  Current Recommendations Top

The American Academy of Ophthalmology Preferred Practice Pattern committee has recommended that anti-VEGF drugs may be advised in PDR patients in place of PRP only in patients who can be followed up regularly and in the presence of DME. It is also advised in eyes where a PRP is not possible, namely, presence of media opacity or vitreous hemorrhage.[89] There is growing evidence on anti-VEGFs in severe NPDR eyes that would normally not be considered for PRP. A significant proportion of these NPDR eyes may be at a risk of progressing to PDR but prediction of rate of progression remains challenging. Furthermore, considering the cost of treatment with anti-VEGF drugs, optimal selection of high-risk and highly motivated patients are required.

Financial support and sponsorship

This study was part of the ORNATE India project which was funded by the GCRF UKRI (MR/P207881/1).

Conflicts of interest

There are no conflicts of interest.

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