Kerala Journal of Ophthalmology

: 2022  |  Volume : 34  |  Issue : 2  |  Page : 98--103

Update on imaging and anti-VEGF therapy for diabetic retinopathy

Sagnik Sen1, Sobha Sivaprasad2,  
1 Department of Retina, Aravind Eye Hospital, Madurai, Tamil Nadu, India
2 Department of Retina, Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom

Correspondence Address:
Prof. Sobha Sivaprasad
Moorfields Eye Hospital NHS Foundation Trust, 162, City Road, London
United Kingdom


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.

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 2022 Sep 25 ];34:98-103
Available from:

Full Text


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

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 ( 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

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

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

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 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 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 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

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

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.


1International Diabetes Federation. IDF Diabetes Atlas teB. Belgium: International Diabetes Federation; 2019. Available from: [Last accessed date on 2021 Apr 19].
2Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract 2019;157:107843. doi: 10.1016/j.diabres. 2019.107843.
3Stratton IM, Kohner EM, Aldington SJ, Turner RC, Holman RR, Manley SE, et al. UKPDS 50: Risk factors for incidence and progression of retinopathy in Type II diabetes over 6 years from diagnosis. Diabetologia 2001;44:156-63.
4Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. IX. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1989;107:237-43.
5Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. X. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more. Arch Ophthalmol 1989;107:244-9.
6Cikamatana L, Mitchell P, Rochtchina E, Foran S, Wang JJ. Five-year incidence and progression of diabetic retinopathy in a defined older population: The blue mountains eye study. Eye 2007;21:465-71.
7Moshfeghi A, Garmo V, Sheinson D, Ghanekar A, Abbass I. Five-year patterns of diabetic retinopathy progression in US clinical practice. Clin Ophthalmol 2020;14:3651-9.
8Frank RN. Diabetic retinopathy. N Engl J Med 2004;350:48-58.
9Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 1983;219:983-5.
10Witmer AN, Vrensen GF, Van Noorden CJ, Schlingemann RO. Vascular endothelial growth factors and angiogenesis in eye disease. Prog Retin Eye Res 2003;22:1-29. doi: 10.1016/s1350-9462(02)00043-5.
11Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of diabetic retinopathy study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology 1981;88:583-600.
12Aiello LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, Shah ST, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480-7.
13Flynn HW Jr, Chew EY, Simons BD, Barton FB, Remaley NA, Ferris FL 3rd. Pars plana vitrectomy in the early treatment diabetic retinopathy study. ETDRS report number 17. The Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1992;99:1351-7.
14Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Ranibizumab for diabetic macular edema: Results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology 2012;119:789-801.
15Korobelnik JF, Do DV, Schmidt-Erfurth U, Boyer DS, Holz FG, Heier JS, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology 2014;121:2247-54.
16Zhang X, Saaddine JB, Chou CF, Cotch MF, Cheng YJ, Geiss LS, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA 2010;304:649-56.
17Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35:556-64.
18Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991;98(5 Suppl):766-85.
19Grading diabetic retinopathy from stereoscopic color fundus photographs--an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991;98(5 Suppl):786-806.
20Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 1991;98(5 Suppl):823-33.
21Wilkinson CP, Ferris FL 3rd, Klein RE, Lee PP, Agardh CD, Davis M, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003;110:1677-82.
22Slakter J S,Schneebaum J W, Shah S A. Digital Algorithmic Diabetic Retinopathy Severity Scoring System (An American Ophthalmological Society Thesis) Trans Am Ophthalmol Soc. 2015;113: T9.
23Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Lachin JM, Genuth S, Cleary P, Davis MD, Nathan DM. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med 2000;342:381-9.
24UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317:703-13.
25Aiello LP, Odia I, Glassman AR, Melia M, Jampol LM, Bressler NM, et al. Comparison of early treatment diabetic retinopathy study standard 7-field imaging with ultrawide-field imaging for determining severity of diabetic retinopathy. JAMA Ophthalmol 2019;137:65-73.
26Ashraf M, Shokrollahi S, Salongcay RP, Aiello LP, Silva PS. Diabetic retinopathy and ultrawide field imaging. Semin Ophthalmol 2020;35:56-65.
27Wessel MM, Aaker GD, Parlitsis G, Cho M, D'Amico DJ, Kiss S. Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina 2012;32:785-91.
28Choudhry N, Duker JS, Freund KB, Kiss S, Querques G, Rosen R, et al. Classification and guidelines for widefield imaging: Recommendations from the International Widefield Imaging Study Group. Ophthalmol Retina 2019;3:843-9.
29Silva PS, Cavallerano JD, Haddad NM, Kwak H, Dyer KH, Omar AF, et al. Peripheral lesions identified on ultrawide field imaging predict increased risk of diabetic retinopathy progression over 4 years. Ophthalmology 2015;122:949-56.
30Rabbani H, Allingham MJ, Mettu PS, Cousins SW, Farsiu S. Fully automatic segmentation of fluorescein leakage in subjects with diabetic macular edema. Investig Ophthalmol Vis Sci 2015;56:1482-92.
31Chandra S, Sheth J, Anantharaman G, Gopalakrishnan M. Ranibizumab-induced retinal reperfusion and regression of neovascularization in diabetic retinopathy: An angiographic illustration. Am J Ophthalmol Case Rep 2018;9:41-4.
32Levin AM, Rusu I, Orlin A, Gupta MP, Coombs P, D'Amico DJ, et al. Retinal reperfusion in diabetic retinopathy following treatment with anti-VEGF intravitreal injections. Clin Ophthalmol 2017;11:193-200.
33Reddy RK, Pieramici DJ, Gune S, Ghanekar A, Lu N, Quezada-Ruiz C, et al. Efficacy of ranibizumab in eyes with diabetic macular edema and macular nonperfusion in RIDE and RISE. Ophthalmology 2018;125:1568-74.
34Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology 2014;121:1783-9.
35Agemy SA, Scripsema NK, Shah CM, Chui T, Garcia PM, Lee JG, et al. Retinal vascular perfusion density mapping using optical coherence tomography angiography in normals and diabetic retinopathy patients. Retina 2015;35:2353-63.
36Matsunaga DR, Yi JJ, De Koo LO, Ameri H, Puliafito CA, Kashani AH. Optical coherence tomography angiography of diabetic retinopathy in human subjects. Ophthalmic Surg Lasers Imaging Retina 2015;46:796-805.
37Ishibazawa A, Nagaoka T, Takahashi A, Omae T, Tani T, Sogawa K, et al. Optical coherence tomography angiography in diabetic retinopathy: A prospective pilot study. Am J Ophthalmol 2015;160:35-44 e1.
38Yang JY, Wang Q, Yan YN, Zhou WJ, Wang YX, Wu SL, et al. Microvascular retinal changes in pre-clinical diabetic retinopathy as detected by optical coherence tomographic angiography. Graefe's Arch Clin and Exp Ophthalmol 2020;258:513-20.
39Russell JF, Shi Y, Hinkle JW, Scott NL, Fan KC, Lyu C, et al. Longitudinal wide-field swept-source OCT angiography of neovascularization in proliferative diabetic retinopathy after panretinal photocoagulation. Ophthalmology Retina 2019;3:350-61.
40Garcia JM, Lima TT, Louzada RN, Rassi AT, Isaac DL, Avila M. Diabetic macular ischemia diagnosis: Comparison between optical coherence tomography angiography and fluorescein angiography. J Ophthalmol 2016;2016:3989310. doi: 10.1155/2016/3989310.
41Russell JF, Flynn HW Jr, Sridhar J, Townsend JH, Shi Y, Fan KC, et al. Distribution of diabetic neovascularization on ultra-widefield fluorescein angiography and on simulated widefield OCT angiography. Am J Ophthalmol 2019;207:110-20.
42Couturier A, Rey PA, Erginay A, Lavia C, Bonnin S, Dupas B, et al. Widefield OCT-angiography and fluorescein angiography assessments of nonperfusion in diabetic retinopathy and edema treated with anti-vascular endothelial growth factor. Ophthalmology 2019;126:1685-94.
43Or C, Sabrosa AS, Sorour O, Arya M, Waheed N. Use of OCTA, FA, and ultra-widefield imaging in quantifying retinal ischemia: A review. Asia Pac J Ophthalmol 2018;7:46-51.
44Abramoff MD, Lou Y, Erginay A, Clarida W, Amelon R, Folk JC, et al. Improved automated detection of diabetic retinopathy on a publicly available dataset through integration of deep learning. Investig Ophthalmol Vis Sci 2016;57:5200-6.
45Gulshan V, Peng L, Coram M, Stumpe MC, Wu D, Narayanaswamy A, et al. Development and validation of a deep learning algorithm for detection of diabetic retinopathy in retinal fundus photographs. JAMA 2016;316:2402-10.
46Ghasemi Falavarjani K, Wang K, Khadamy J, Sadda SR. Ultra-wide-field imaging in diabetic retinopathy; an overview. J Curr Ophthalmol 2016;28:57-60.
47Zheng Y, Kwong MT, Maccormick IJ, Beare NA, Harding SP. A comprehensive texture segmentation framework for segmentation of capillary non-perfusion regions in fundus fluorescein angiograms. PloS One 2014;9:e93624.
48Buchanan CR, Trucco E. Contextual detection of diabetic pathology in wide-field retinal angiograms. Annu Int Conf IEEE Eng Med Biol Soc. 2008;2008:5437-40.
49Trucco E, Buchanan CR, Aslam T, Dhillon B. Contextual detection of ischemic regions in ultra-wide-field-of-view retinal fluorescein angiograms. Annu Int Conf IEEE Eng Med Biol Soc 2007;2007:6740-43.
50Zhao Y, MacCormick IJ, Parry DG, Leach S, Beare NA, Harding SP, et al. Automated detection of leakage in fluorescein angiography images with application to malarial retinopathy. Sci Rep 2015;5:10425.
51Jiang A, Srivastava S, Figueiredo N, Babiuch A, Hu M, Reese J, et al. Repeatability of automated leakage quantification and microaneurysm identification utilising an analysis platform for ultra-widefield fluorescein angiography. Br J Ophthalmol 2020;104:500-3.
52Ehlers JP, Wang K, Vasanji A, Hu M, Srivastava SK. Automated quantitative characterisation of retinal vascular leakage and microaneurysms in ultra-widefield fluorescein angiography. Br J Ophthalmol 2017;101:696-9.
53Ehlers JP, Jiang AC, Boss JD, Hu M, Figueiredo N, Babiuch A, et al. Quantitative ultra-widefield angiography and diabetic retinopathy severity: An assessment of panretinal leakage index, ischemic index and microaneurysm count. Ophthalmology 2019;126:1527-32.
54Sim DA, Keane PA, Rajendram R, Karampelas M, Selvam S, Powner MB, et al. Patterns of peripheral retinal and central macula ischemia in diabetic retinopathy as evaluated by ultra-widefield fluorescein angiography. Am J Ophthalmol 2014;158:144-53 e1.
55Wessel MM, Nair N, Aaker GD, Ehrlich JR, D'Amico DJ, Kiss S. Peripheral retinal ischaemia, as evaluated by ultra-widefield fluorescein angiography, is associated with diabetic macular oedema. Br J Ophthalmol 2012;96:694-8.
56Nicholson L, Ramu J, Chan EW, Bainbridge JW, Hykin PG, Talks SJ, et al. Retinal nonperfusion characteristics on ultra-widefield angiography in eyes with severe nonproliferative diabetic retinopathy and proliferative diabetic retinopathy. JAMA Ophthalmol 2019;137:626-31.
57Wykoff CC, Nittala MG, Zhou B, Fan W, Velaga SB, Lampen SIR, et al. Intravitreal aflibercept for retinal nonperfusion in proliferative diabetic retinopathy: Outcomes from the randomized RECOVERY trial. Ophthalmol Retina 2019;3:1076-86.
58Rabiolo A, Parravano M, Querques L, Cicinelli MV, Carnevali A, Sacconi R, et al. Ultra-wide-field fluorescein angiography in diabetic retinopathy: A narrative review. Clin Ophthalmol 2017;11:803-7.
59Silva PS, Dela Cruz AJ, Ledesma MG, van Hemert J, Radwan A, Cavallerano JD, et al. Diabetic retinopathy severity and peripheral lesions are associated with nonperfusion on ultrawide field angiography. Ophthalmology 2015;122:2465-72.
60Figueiredo N, Srivastava SK, Singh RP, Babiuch A, Sharma S, Rachitskaya A, et al. Longitudinal panretinal leakage and ischemic indices in retinal vascular disease after aflibercept therapy: The PERMEATE study. Ophthalmol Retina 2020;4:154-63.
61Bonnin S, Dupas B, Lavia C, Erginay A, Dhundass M, Couturier A, et al. Anti-vascular endothelial growth factor therapy can improve diabetic retinopathy score without change in retinal perfusion. Retina 2019;39:426-34.
62Diabetic Retinopathy Clinical Research Network, Elman MJ, Qin H, Aiello LP, Beck RW, Bressler NM, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: Three-year randomized trial results. Ophthalmology 2012;119:2312-8.
63Liu Y, Shen J, Fortmann SD, Wang J, Vestweber D, Campochiaro PA. Reversible retinal vessel closure from VEGF-induced leukocyte plugging. JCI Insight 2017;2:e95530.
64Wykoff CC, Eichenbaum DA, Roth DB, Hill L, Fung AE, Haskova Z. Ranibizumab induces regression of diabetic retinopathy in most patients at high risk of progression to proliferative diabetic retinopathy. Ophthalmol Retina 2018;2:997-1009.
65Bressler SB, Liu D, Glassman AR, Blodi BA, Castellarin AA, Jampol LM, et al. Change in diabetic retinopathy through 2 years: Secondary analysis of a randomized clinical trial comparing aflibercept, bevacizumab, and ranibizumab. JAMA Ophthalmol 2017;135:558-68.
66Diabetic Retinopathy Clinical Research Network, Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117:1064-77.e35.
67Rajendram R, Fraser-Bell S, Kaines A, Michaelides M, Hamilton RD, Esposti SD, et al. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema: 24-month data: Report 3. Arch Ophthalmol 2012;130:972-9.
68Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: The 36-month results from two phase III trials: RISE and RIDE. Ophthalmology 2013;120:2013-22.
69Brown DM, Schmidt-Erfurth U, Do DV, Holz FG, Boyer DS, Midena E, et al. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID studies. Ophthalmology 2015;122:2044-52.
70Elman MJ, Bressler NM, Qin H, Beck RW, Ferris FL 3rd, Friedman SM, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2011;118:609-14.
71Bressler SB, Qin H, Melia M, Bressler NM, Beck RW, Chan CK, et al. Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. JAMA Ophthalmol 2013;131:1033-40.
72Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol 2012;130:1145-52.
73Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, et al. The RESTORE study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011;118:615-25.
74Heier JS, Korobelnik JF, Brown DM, Schmidt-Erfurth U, Do DV, Midena E, et al. Intravitreal aflibercept for diabetic macular edema: 148-week results from the VISTA and VIVID studies. Ophthalmology 2016;123:2376-85.
75Writing Committee for the Diabetic Retinopathy Clinical Research Network, Gross JG, Glassman AR, Jampol LM, Inusah S, Aiello LP, et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: A randomized clinical trial. Jama 2015;314:2137-46.
76Bressler SB, Beaulieu WT, Glassman AR, Gross JG, Jampol LM, Melia M, et al. Factors associated with worsening proliferative diabetic retinopathy in eyes treated with panretinal photocoagulation or ranibizumab. Ophthalmology 2017;124:431-9.
77Diabetic Retinopathy Clinical Research Network. Randomized clinical trial evaluating intravitreal ranibizumab or saline for vitreous hemorrhage from proliferative diabetic retinopathy. JAMA Ophthalmol 2013;131:283-93.
78Sivaprasad S, Prevost AT, Vasconcelos JC, Riddell A, Murphy C, Kelly J, et al. Clinical efficacy of intravitreal aflibercept versus panretinal photocoagulation for best corrected visual acuity in patients with proliferative diabetic retinopathy at 52 weeks (CLARITY): A multicentre, single-blinded, randomised, controlled, phase 2b, non-inferiority trial. Lancet 2017;389:2193-203.
79Multicenter 12 months clinical study to evaluate efficacy and safety of ranibizumab alone or in combination with laser photocoagulation vs. laser photocoagulation alone in proliferative diabetic retinopathy (PRIDE) – Full Text View – ClinicalTrials. gov. Available from: [Last accessed on 2022 May 07].
80Maturi RK, Glassman AR, Josic K, Antoszyk AN, Blodi BA, Jampol LM, et al. Effect of intravitreous anti–vascular endothelial growth factor vs sham treatment for prevention of vision-threatening complications of diabetic retinopathy: The protocol W randomized clinical trial. JAMA Ophthalmol 2021;139:701-12.
81Available from: [Last accessed on 2022 May 07].
82Lim JI. Intravitreal aflibercept injection for nonproliferative diabetic retinopathy: Year 2 results from the PANORAMA study. Investig Ophthalmol Vis Sci. 2020;61:1381.
83Kernt M, Hadi I, Pinter F, Seidensticker F, Hirneiss C, Haritoglou C, et al. Assessment of diabetic retinopathy using nonmydriatic ultra-widefield scanning laser ophthalmoscopy (Optomap) compared with ETDRS 7-field stereo photography. Diabetes Care 2012;35:2459-63.
84Dhoot DS, Baker K, Saroj N, Vitti R, Berliner AJ, Metzig C, et al. Baseline factors affecting changes in diabetic retinopathy severity scale score after intravitreal aflibercept or laser for diabetic macular edema: Post hoc analyses from VISTA and VIVID. Ophthalmology 2018;125:51-6.
85Tadayoni R. Time to call into question the fundus-based evaluation of diabetic retinopathy after intravitreal injections. J Ophthalmic Vis Res 2020;15:4-6.
86Goldberg R, Hill L, Abolian A, Stoilov I. PA041 What Happens to Diabetic Retinopathy Severity Scores With Less Aggressive Treatment? A Post Hoc Analysis of the RISE/RIDE Open-Label Extension Study. San Francisco, CA: AAO; 2019.
87Marcus DM, Taylor C, Starnes D. Ultra wide-field fluorescein angiographic-guided aflibercept (WFFAGA) monotherapy for proliferative diabetic retinopathy (PDR). J Clin Ophthalmol 2019;3:166-73.
88Talks SJ MV, Steel DHW, Peto T, Taylor R. New vessels detected on wide-field imaging compared to two-field and seven-field imaging: Implications for diabetic retinopathy screening image analysis. Br J Ophthalmol 2015;12:1606-9.
89Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006;26:275-8.