Optical Coherence Tomography Angiography of Macular Perfusion Changes after Anti-VEGF Therapy for Diabetic Macular Edema: A Systematic Review

Ayman G Elnahry, Gehad A Elnahry, Ayman G Elnahry, Gehad A Elnahry

Abstract

Background: Diabetic macular edema (DME) is a major cause of vision loss in diabetics that is currently mainly treated by antivascular endothelial growth factor (VEGF) agents. The effect of these agents on macular perfusion (MP) is a current concern. Optical coherence tomography angiography (OCTA) is an imaging modality that allows noninvasive high-resolution retinal microvasculature imaging. Several recent studies evaluated the effect of anti-VEGF agents on the MP of DME patients using OCTA. Our aim is to provide a systematic review of these studies.

Methods: Multiple databases were searched including PubMed, Ovid Medline, EMBASE, and Google Scholar for relevant studies published between January 2016 and November 2020 which were included in this review. Studies were compared regarding their design, the number of included patients, the machine and scanning protocol used, the inclusion and exclusion criteria, the number of injections given, the type of anti-VEGF agent used, the outcome measures assessed, and the effect of injections on different MP parameters.

Results: A total of 16 studies were included. The studies assessed various OCTA parameters that define MP including the foveal avascular zone area and superficial and deep vascular density and yielded conflicting results. Seven studies showed stable or improved MP following treatment, while 7 studies showed worsening MP following treatment, and 2 studies showed inconclusive results. This could have been due to differences in study design, inclusion criteria, type of anti-VEGF agents used, treatment duration, and methods of image analysis and vascular density quantification. All identified studies were noncomparative case series, and 14 of them (87.5%) used the RTVue XR Avanti OCTA machine. Only one study compared OCTA to fluorescein angiography findings.

Conclusion: Analysis of MP changes following VEGF inhibition for DME could benefit from a unified scanning protocol and analysis approach that uses similar study designs to eliminate potential sources of bias. This may provide more definitive conclusions regarding the effect of treatment on MP.

Conflict of interest statement

Ayman G. Elnahry declares that he has no conflict of interest. Gehad A. Elnahry declares that he has no conflict of interest.

Copyright © 2021 Ayman G. Elnahry and Gehad A. Elnahry.

Figures

Figure 1
Figure 1
Optical coherence tomography (OCT) of the macula of a diabetic patient showing improvement of DME before (a) and after (b) anti-VEGF injections. There is marked improvement in the central foveal thickness as measured by OCT.
Figure 2
Figure 2
Compared to fluorescein angiography (a), optical coherence tomography angiography (Optovue, Inc., Fremont, CA, USA) of the macula (b) allows imaging of the retinal capillaries and foveal avascular zone in high resolution without obscuration by dye leakage or macular xanthophyll pigment shadowing.
Figure 3
Figure 3
Flow diagram showing search results and reasons for exclusion of studies.

References

    1. Yau J. W., Rogers S. L., Kawasaki R., et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556–564. doi: 10.2337/dc11-1909.
    1. Bahrami B., Zhu M., Hong T., Chang A. Diabetic macular oedema: pathophysiology, management challenges and treatment resistance. Diabetologia. 2016;59(8):1594–1608. doi: 10.1007/s00125-016-3974-8.
    1. Elnahry A. G., Hassan F. K., Abdel-Kader A. A. Bevacizumab for the treatment of intraretinal cystic spaces in a patient with gyrate atrophy of the choroid and retina. Ophthalmic Genetics. 2018;39(6):759–762. doi: 10.1080/13816810.2018.1536220.
    1. Dugel P. U., Jaffe G. J., Sallstig P., et al. Brolucizumab versus aflibercept in participants with neovascular age-related macular degeneration: a randomized trial. Ophthalmology. 2017;124(9):1296–1304. doi: 10.1016/j.ophtha.2017.03.057.
    1. Elnahry A. G., Sallam E. M., Guirguis K. J., Talbet J. H., Abdel-Kader A. A. Vitrectomy for a secondary epiretinal membrane following treatment of adult- onset Coats' disease. American Journal of Ophthalmology Case Reports. 2019;15:p. 100508. doi: 10.1016/j.ajoc.2019.100508.
    1. Elnahry A. G., Aboulfotouh M. R., Nassar G. A. Treatment of intraretinal cystic spaces associated with gyrate atrophy of the choroid and retina with intravitreal bevacizumab. Journal of Pediatric Ophthalmology & Strabismus. 2020;57(6):400–406. doi: 10.3928/01913913-20200813-01.
    1. Xu X., Zhu Q., Xia X., Zhang S., Gu Q., Luo D. Blood-retinal barrier breakdown induced by activation of protein kinase C via vascular endothelial growth factor in streptozotocin-induced diabetic rats. Current Eye Research. 2004;28(4):251–256. doi: 10.1076/ceyr.28.4.251.27834.
    1. Ferrara N., Kerbel R. S. Angiogenesis as a therapeutic target. Nature. 2005;438(7070):967–974. doi: 10.1038/nature04483.
    1. Alon T., Hemo I., Itin A., Pe'er J., Stone J., Keshet E. Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nature Medicine. 1995;1(10):1024–1028. doi: 10.1038/nm1095-1024.
    1. Kurihara T., Westenskow P. D., Bravo S., Aguilar E., Friedlander M. Targeted deletion of Vegfa in adult mice induces vision loss. Journal of Clinical Investigation. 2012;122(11):4213–4217. doi: 10.1172/JCI65157.
    1. Sun F. Y., Guo X. Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factor. Journal of Neuroscience Research. 2005;79(1-2):180–184. doi: 10.1002/jnr.20321.
    1. Elnahry A. G., Abdel-Kader A. A., Raafat K. A., Elrakhawy K. Evaluation of the effect of repeated intravitreal bevacizumab injections on the macular microvasculature of a diabetic patient using optical coherence tomography angiography. Case Reports in Ophthalmological Medicine. 2019;2019 doi: 10.1155/2019/3936168.3936168
    1. Manousaridis K., Talks J. Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease? British Journal of Ophthalmology. 2012;96(2):179–184. doi: 10.1136/bjophthalmol-2011-301087.
    1. Dorrell M. I., Aguilar E., Scheppke L., Barnett F. H., Friedlander M. Combination angiostatic therapy completely inhibits ocular and tumor angiogenesis. Proceedings of the National Academy of Sciences. 2007;104(3):967–972. doi: 10.1073/pnas.0607542104.
    1. Baffert F., Le T., Sennino B., et al. Cellular changes in normal blood capillaries undergoing regression after inhibition of VEGF signaling. American Journal of Physiology-Heart and Circulatory Physiology. 2006;290(2):H547–H559. doi: 10.1152/ajpheart.00616.2005.
    1. Rajendram R., Fraser-Bell S., Kaines A., 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. Archives of Ophthalmology. 2012;130(8):972–979. doi: 10.1001/archophthalmol.2012.393.
    1. Michaelides M., Kaines A., Hamilton R. D., et al. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (BOLT study) 12-month data: report 2. Ophthalmology. 2010;117(6):1078–1086.e2. doi: 10.1016/j.ophtha.2010.03.045.
    1. Michaelides M., Fraser-Bell S., Hamilton R., et al. Macular perfusion determined by fundus fluorescein angiography at the 4-month time point in a prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular edema (Bolt Study): Report 1. Retina. 2010;30(5):781–786. doi: 10.1097/iae.0b013e3181d2f145.
    1. Feucht N., Schönbach E. M., Lanzl I., Kotliar K., Lohmann C. P., Maier M. Changes in the foveal microstructure after intravitreal bevacizumab application in patients with retinal vascular disease. Clinical Ophthalmology. 2013;7:173–178. doi: 10.2147/OPTH.S37544.
    1. Erol N., Gursoy H., Kimyon S., Topbas S., Colak E. Vision, retinal thickness, and foveal avascular zone size after intravitreal bevacizumab for diabetic macular edema. Advances in Therapy. 2012;29(4):359–369. doi: 10.1007/s12325-012-0009-9.
    1. Campochiaro P. A., Wykoff C. C., Shapiro H., Rubio R. G., Ehrlich J. S. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology. 2014;121(9):1783–1789. doi: 10.1016/j.ophtha.2014.03.021.
    1. Wykoff C. C., Shah C., Dhoot D., et al. Longitudinal retinal perfusion status in eyes with diabetic macular edema receiving intravitreal aflibercept or laser in VISTA study. Ophthalmology. 2019;126(8):1171–1180. doi: 10.1016/j.ophtha.2019.03.040.
    1. Hwang T. S., Gao S. S., Liu L., et al. Automated quantification of capillary nonperfusion using optical coherence tomography angiography in diabetic retinopathy. JAMA Ophthalmology. 2016;134(4):367–373. doi: 10.1001/jamaophthalmol.2015.5658.
    1. Ishibazawa A., Nagaoka T., Takahashi A., et al. Optical coherence tomography angiography in diabetic retinopathy: a prospective pilot study. American Journal of Ophthalmology. 2015;160(1) doi: 10.1016/j.ajo.2015.04.021.
    1. Garcia J. M., Lima T. T., Louzada R. N., Rassi A. T., Isaac D. L., Avila M. Diabetic macular ischemia diagnosis: comparison between optical coherence tomography angiography and fluorescein angiography. Journal of Ophthalmology. 2016;2016 doi: 10.1155/2016/3989310.
    1. Elnahry A. G., Ramsey D. J. Automated image alignment for comparing microvascular changes detected by fluorescein angiography and optical coherence tomography angiography in diabetic retinopathy. Seminars in Ophthalmology. 2021 doi: 10.1080/08820538.2021.1901122.
    1. Rabiolo A., Gelormini F., Sacconi R., et al. Comparison of methods to quantify macular and peripapillary vessel density in optical coherence tomography angiography. PLoS One. 2018;13(10)) doi: 10.1371/journal.pone.0205773.
    1. Lei J., Durbin M. K., Shi Y., et al. Repeatability and reproducibility of superficial macular retinal vessel density measurements using optical coherence tomography angiography en face images. JAMA Ophthalmology. 2017;135(10):1092–1098. doi: 10.1001/jamaophthalmol.2017.3431.
    1. Al-Sheikh M., Tepelus T. C., Nazikyan T., Sadda S. R. Repeatability of automated vessel density measurements using optical coherence tomography angiography. British Journal of Ophthalmology. 2017;101(4):449–452. doi: 10.1136/bjophthalmol-2016-308764.
    1. Eladawi N., Elmogy M., Helmy O., et al. Automatic blood vessels segmentation based on different retinal maps from OCTA scans. Computers in Biology and Medicine. 2017;89:150–161. doi: 10.1016/j.compbiomed.2017.08.008.
    1. Kim A. Y., Chu Z., Shahidzadeh A., Wang R. K., Puliafito C. A., Kashani A. H. Quantifying microvascular density and morphology in diabetic retinopathy using spectral-domain optical coherence tomography angiography. Investigative Opthalmology & Visual Science. 2016;57(9) doi: 10.1167/iovs.15-18904.
    1. Ghasemi Falavarjani K., Iafe N. A., Hubschman J. P., Tsui I., Sadda S. R., Sarraf D. Optical coherence tomography angiography analysis of the foveal avascular zone and macular vessel density after anti-VEGF therapy in eyes with diabetic macular edema and retinal vein occlusion. Investigative Opthalmology & Visual Science. 2017;58(1):30–34. doi: 10.1167/iovs.16-20579.
    1. Sorour O. A., Sabrosa A. S., Yasin Alibhai A., et al. Optical coherence tomography angiography analysis of macular vessel density before and after anti-VEGF therapy in eyes with diabetic retinopathy. International Ophthalmology. 2019;39(10):2361–2371. doi: 10.1007/s10792-019-01076-x.
    1. Hsieh Y. T., Alam M. N., Le D., et al. OCT angiography biomarkers for predicting visual outcomes after ranibizumab treatment for diabetic macular edema. Ophthalmology Retina. 2019;3(10):826–834. doi: 10.1016/j.oret.2019.04.027.
    1. Conti F. F., Song W., Rodrigues E. B., Singh R. P. Changes in retinal and choriocapillaris density in diabetic patients receiving anti-vascular endothelial growth factor treatment using optical coherence tomography angiography. International Journal of Retina and Vitreous. 2019;5(1) doi: 10.1186/s40942-019-0192-9.
    1. Michalska-Małecka K., Heinke K. A. Optical coherence tomography angiography in patients with diabetic retinopathy treated with anti-VEGF intravitreal injections: case report. Medicine (Baltimore) 2017;96(45) doi: 10.1097/MD.0000000000008379.
    1. Zhu Z., Liang Y., Yan B., et al. Clinical effect of conbercept on improving diabetic macular ischemia by OCT angiography. BMC Ophthalmology. 2020;20(1) doi: 10.1186/s12886-020-01648-x.
    1. Mirshahi R., Falavarjani K. G., Molaei S., et al. Macular microvascular changes after intravitreal bevacizumab injection in diabetic macular edema. Canadian Journal of Ophthalmology. 2020;56(1):57–65. doi: 10.1016/j.jcjo.2020.07.004.
    1. Couturier A., Rey P. A., Erginay A., 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(12):1685–1694. doi: 10.1016/j.ophtha.2019.06.022.
    1. Elnahry A. G., Abdel-Kader A. A., Raafat K. A., Elrakhawy K. Evaluation of changes in macular perfusion detected by optical coherence tomography angiography following 3 intravitreal monthly bevacizumab injections for diabetic macular edema in the IMPACT study. Journal of Ophthalmology. 2020;2020 doi: 10.1155/2020/5814165.5814165
    1. Pereira F., Godoy B. R., Maia M., Regatieri C. V. Microperimetry and OCT angiography evaluation of patients with ischemic diabetic macular edema treated with monthly intravitreal bevacizumab: a pilot study. International Journal of Retina and Vitreous. 2019;5(1) doi: 10.1186/s40942-019-0176-9.
    1. Barash A., Chui T. Y. P., Garcia P., Rosen R. B. Acute macular and peripapillary angiographic changes with intravitreal injections. Retina. 2020;40(4):648–656. doi: 10.1097/IAE.0000000000002433.
    1. Statler B., Conti T. F., Conti F. F., et al. Twenty-four-month OCTA assessment in diabetic patients undergoing fixed-interval intravitreal aflibercept therapy. Ophthalmic Surgery, Lasers and Imaging Retina. 2020;51(8):448–455. doi: 10.3928/23258160-20200804-05.
    1. Golshani C., Conti T. F., Conti F. F., et al. Diabetic macular edema treated with intravitreal aflibercept injection after treatment with other anti-VEGF agents (SWAP-TWO study)—12-month analysis. Journal of VitreoRetinal Diseases. 2020;4(5):364–371. doi: 10.1177/2474126420916074.
    1. Busch C., Wakabayashi T., Sato T., et al. Retinal microvasculature and visual acuity after intravitreal aflibercept in diabetic macular edema: an optical coherence tomography angiography study. Scientific Reports. 2019;9(1) doi: 10.1038/s41598-018-38248-1.
    1. Dastiridou A., Karathanou K., Riga P., et al. OCT angiography study of the macula in patients with diabetic macular edema treated with intravitreal aflibercept. Ocular Immunology and Inflammation. 2020:1–6. doi: 10.1080/09273948.2019.1704028.
    1. Wykoff C. C., Nittala M. G., Zhou B., et al. Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy Study Group. Intravitreal aflibercept for retinal nonperfusion in proliferative diabetic retinopathy: outcomes from the randomized recovery trial. Ophthalmology Retina. 2019;3(12):1076–1086. doi: 10.1016/j.oret.2019.07.011.
    1. Bonnin S., Dupas B., Lavia C., et al. Anti-vascular endothelial growth factor therapy can improve diabetic retinopathy score without change in retinal perfusion. Retina. 2019;39(3):426–434. doi: 10.1097/IAE.0000000000002422.
    1. Figueiredo N., Srivastava S. K., Singh R. P., et al. Longitudinal panretinal leakage and ischemic indices in retinal vascular disease after aflibercept therapy: the PERMEATE study. Ophthalmology Retina. 2020;4(2):154–163. doi: 10.1016/j.oret.2019.09.001.
    1. Elnahry A. G., Abdel-Kader A. A., Habib A. E., Elnahry G. A., Raafat K. A., Elrakhawy K. Review on recent trials evaluating the effect of intravitreal injections of anti-VEGF agents on the macular perfusion of diabetic patients with diabetic macular edema. Reviews on Recent Clinical Trials. 2020;15(3):188–198. doi: 10.2174/1574887115666200519073704.
    1. Gill A., Cole E. D., Novais E. A., et al. Visualization of changes in the foveal avascular zone in both observed and treated diabetic macular edema using optical coherence tomography angiography. International Journal of Retina and Vitreous. 2017;3 doi: 10.1186/s40942-017-0074-y.
    1. Spaide R. F., Fujimoto J. G., Waheed N. K., Sadda S. R., Staurenghi G. Optical coherence tomography angiography. Progress in Retinal and Eye Research. 2018;64:1–55. doi: 10.1016/j.preteyeres.2017.11.003.
    1. Spaide R. F., Fujimoto J. G., Waheed N. K. Image artifacts in optical coherence tomography angiography. Retina. 2015;35(11):2163–2180. doi: 10.1097/IAE.0000000000000765.
    1. Spaide R. F., Klancnik J. M., Jr., Cooney M. J. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmology. 2015;133(1):45–50. doi: 10.1001/jamaophthalmol.2014.3616.
    1. Elnahry A. G., Ramsey D. J. Optical coherence tomography angiography imaging of the retinal microvasculature is unimpeded by macular xanthophyll pigment. Clinical & Experimental Ophthalmology. 2020;48(7):1012–1014. doi: 10.1111/ceo.13824.
    1. Mansour A. M., Elnahry A. G., Tripathy K., et al. Analysis of optical coherence angiography in cystoid macular oedema associated with gyrate atrophy. Eye. 2020 doi: 10.1038/s41433-020-01166-6.
    1. Couturier A., Mané V., Bonnin S., et al. Capillary plexus anomalies in diabetic retinopathy on optical coherence tomography angiography. Retina. 2015;35(11):2384–2391. doi: 10.1097/IAE.0000000000000859.
    1. Viswanathan M., Berkman N. D. Development of the RTI Item Bank on Risk of Bias and Precision of Observational Studies Methods research report. Rockville, MD: Agency for Healthcare Research and Quality: Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2007-0056-I AHRQ Publication No. 11-EHC028-EF; 2011. .
    1. Rosen R., Romo J. S., Toral M. V., et al. Reference-based OCT angiography perfusion density mapping for identifyingacute and chronic changes in eyes with retinopathy over time. Invest Ophthalmol Vis Sci. 2019;60(11)
    1. Tolentino M. J., Miller J. W., Gragoudas E. S., et al. Intravitreous injections of vascular endothelial growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology. 1996;103(11):1820–1828. doi: 10.1016/s0161-6420(96)30420-x.
    1. Hofman P., van Blijswijk B. C., Gaillard P. J., Vrensen G. F., Schlingemann R. O. Endothelial cell hypertrophy induced by vascular endothelial growth factor in the retina: new insights into the pathogenesis of capillary nonperfusion. Archives of Ophthalmology. 2001;119(6):861–866. doi: 10.1001/archopht.119.6.861.
    1. Kurt M. M., Çekiç O., Akpolat Ç., Elçioglu M. Effects of intravitreal ranibizumab and bevacizumab on the retinal vessel size in diabetic macular edema. Retina. 2018;38(6):1120–1126. doi: 10.1097/IAE.0000000000001682.
    1. Zhu X., Wu S., Dahut W. L., Parikh C. R. Risks of proteinuria andhypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. American Journal of Kidney Diseases. 2007;49(2):186–193. doi: 10.1053/j.ajkd.2006.11.039.
    1. Bonnin P., Pournaras J. A., Lazrak Z., et al. Ultrasound assessment of short-term ocular vascular effects of intravitreal injection of bevacizumab (Avastin(®) ) in neovascular age-related macular degeneration. Acta Ophthalmologica. 2010;88(6):641–645. doi: 10.1111/j.1755-3768.2009.01526.x.
    1. Benjamin L. E., Hemo I., Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development. 1998;125(9):1591–1598.
    1. Lindahl P., Johansson B. R., Levéen P., Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997;277(5323):242–245. doi: 10.1126/science.277.5323.242.
    1. Stitt A. W., Gardiner T. A., Archer D. B. Histological and ultrastructural investigation of retinal microaneurysm development in diabetic patients. British Journal of Ophthalmology. 1995;79(4):362–367. doi: 10.1136/bjo.79.4.362.
    1. Mané V., Dupas B., Gaudric A., et al. Correlation between cystoid spaces in chronic diabetic macular edema and capillary nonperfusion detected by optical coherence tomography angiography. Retina. 2016;36(Supplement 1):S102–S110. doi: 10.1097/IAE.0000000000001289.
    1. Parravano M., Costanzo E., Borrelli E., et al. Appearance of cysts and capillary non perfusion areas in diabetic macular edema using two different OCTA devices. Scientific Reports. 2020;10(1):p. 800. doi: 10.1038/s41598-020-57680-w.
    1. de Carlo T. E., Chin A. T., Joseph T., et al. Distinguishing diabetic macular edema from capillary nonperfusion using optical coherence tomography angiography. Ophthalmic Surgery, Lasers and Imaging Retina. 2016;47(2):108–114. doi: 10.3928/23258160-20160126-02.
    1. Alagorie A. R., Nittala M. G., Velaga S., et al. Association of intravitreal aflibercept with optical coherence tomography angiography vessel density in patients with proliferative diabetic retinopathy: a secondary analysis of a randomized clinical trial. JAMA Ophthalmology. 2020;138(8):851–857. doi: 10.1001/jamaophthalmol.2020.2130.
    1. Chung E. J., Roh M. I., Kwon O. W., Koh H. J. Effects of macular ischemia on the outcome of intravitreal bevacizumab therapy for diabetic macular edema. Retina. 2008;28(7):957–963. doi: 10.1097/IAE.0b013e3181754209.

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