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

Ayman G Elnahry, Ahmed A Abdel-Kader, Karim A Raafat, Khaled Elrakhawy, Ayman G Elnahry, Ahmed A Abdel-Kader, Karim A Raafat, Khaled Elrakhawy

Abstract

Objective: To evaluate macular perfusion changes following intravitreal bevacizumab injections for diabetic macular edema (DME) using spectral domain optical coherence tomography angiography (SD-OCTA).

Methods: This study was a prospective noncomparative interventional case series. Treatment naïve patients with DME underwent full ophthalmological examination and SD-OCTA scanning at baseline and after 3 intravitreal bevacizumab injections. Both the 6 × 6 and 3 × 3 mm macular scan protocols were used. Pretreatment and posttreatment OCTA images were automatically aligned using a commercially available retina alignment software (i2k Align Retina software); then the fractal dimension (FD), vascular density (VD), and skeleton VD changes were obtained at the full retinal thickness (Full) and superficial (SCP) and deep (DCP) capillary plexuses after processing images using a semiautomated program. The foveal avascular zone (FAZ) was manually measured and FD was calculated using the FracLac plugin of ImageJ.

Results: Forty eyes of 26 patients were included. Following injections, there were an 8.1% increase in FAZ, 1.3% decrease in FD-Full and FD-SCP, 1.9% decrease in FD-DCP, 8% decrease in VD-Full, 9.1% decrease in VD-SCP, 10.6% decrease in VD-DCP, 13.3% decrease in skeleton VD-Full, 12.5% decrease in skeleton VD-SCP, and 16.3% decrease in skeleton VD-DCP in the 6 × 6 mm macular area and a 2.6% decrease in FD-Full, 3.4% decrease in FD-SCP, 11.5% decrease in VD-Full, 14.3% decrease in VD-SCP, and 25.1% decrease in skeleton VD-SCP in the 3 × 3 mm macular area which were all statistically significant (p < 0.05). Using univariate and multivariate analysis, the pretreatment FD, VD, and skeleton VD at each capillary layer significantly negatively correlated with the change in FD, VD, and skeleton VD at the corresponding capillary layer, respectively (p < 0.05).

Conclusion: OCTA is a useful noninvasive tool for quantitative evaluation of macular perfusion changes following DME treatment. This trial is registered with NCT03246152.

Conflict of interest statement

The authors declare that they have no conflicts of interest.

Copyright © 2020 Ayman G. Elnahry et al.

Figures

Figure 1
Figure 1
Automated image alignment. Original 6 × 6 mm pre- and posttreatment images (a and b) were automatically registered and aligned (c and d) using a commercially available retina alignment software to allow comparison of only areas common to both images.
Figure 2
Figure 2
FAZ area measurement. The FAZ area was measured manually using ImageJ for the pre- and posttreatment 3 × 3 mm (a and b) and 6 × 6 mm (d and e) macular scan images. FAZ area change between pre- and posttreatment images was then calculated (c and f).
Figure 3
Figure 3
Image processing technique. En-face OCTA images (a, d, and g) were converted into a binary image (b, e, and h) by using a combined method consisting of a global threshold, hessian filter, and adaptive threshold in MATLAB. Skeletonized images were created by deleting the pixels in the outer boundary of the binarized, white-pixelated vessels until only 1 pixel remained along the width of the vessels (c, f, and i).
Figure 4
Figure 4
Boxplots of pre- and posttreatment values from both the 6 × 6 and 3 × 3 mm scan protocols at different segmentation levels. In the 6 × 6 mm scan group, there was a statistically significant decrease in the FD, VD, and skeleton VD of Full, SCP, and DCP (a, b, and c). In the 3 × 3 mm scan group, there was a statistically significant decrease in the FD and VD-Full and SCP and the skeleton VD-SCP. There was a decrease in skeleton VD-Full and FD, VD, and skeleton VD-DCP but these were not statistically significant (d, e, and f).
Figure 5
Figure 5
Examples of scatter plots for factors significantly associated with posttreatment changes using univariate analysis. There was a significant negative correlation between (a) pretreatment FD-Full and the change in FD-Full (r = −0.541, p < 0.001), (b) the change in CMT and the change in FD-SCP (r = −0.324, p=0.042), (c) pretreatment VD-Full and the change in VD-Full (r = −0.560, p < 0.001), (d) the change in CMT and the change in VD-SCP (r = −0.389, p=0.013), and (e) pretreatment skeleton VD-Full and the change in skeleton VD-Full (r = −0.694, p < 0.001).

References

    1. Korobelnik J.-F., Do D. V., Schmidt-Erfurth U., et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014;121(11):2247–2254. doi: 10.1016/j.ophtha.2014.05.006.
    1. Zhang X., Saaddine J. B., Chou C.-F., et al. Prevalence of diabetic retinopathy in the United States, 2005–2008. JAMA. 2010;304(6):649–656. doi: 10.1001/jama.2010.1111.
    1. Klein B. E. K. Overview of epidemiologic studies of diabetic retinopathy. Ophthalmic Epidemiology. 2007;14(4):179–183. doi: 10.1080/09286580701396720.
    1. Herman W. H., Aubert R. E., Engelgau M. M., et al. Diabetes mellitus in Egypt: glycaemic control and microvascular and neuropathic complications. Diabetic Medicine. 1998;15(12):1045–1051. doi: 10.1002/(sici)1096-9136(1998120)15:12<1045::aid-dia696>;2-l.
    1. Malarcher J. W. Y., 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. Yokoi M., Yamagishi S. I., Takeuchi M., et al. Elevations of AGE and vascular endothelial growth factor with decreased total antioxidant status in the vitreous fluid of diabetic patients with retinopathy. British Journal of Ophthalmology. 2005;89(6):673–675. doi: 10.1136/bjo.2004.055053.
    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. 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 doi: 10.1016/j.ajoc.2019.100508.100508
    1. Elnahry A. G., Khafagy M. M., Esmat S. M., Mortada H. A. Prevalence and associations of posterior segment manifestations in a cohort of Egyptian patients with pathological myopia. Current Eye Research. 2019;44(9):955–962. doi: 10.1080/02713683.2019.1606252.
    1. Grenga P. L., Fragiotta S., Meduri A., Lupo S., Marenco M., Vingolo E. M. Fixation stability measurements in patients with neovascular age-related macular degeneration treated with ranibizumab. Canadian Journal of Ophthalmology. 2013;48(5):394–399. doi: 10.1016/j.jcjo.2013.04.006.
    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. 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;2019:4. doi: 10.1155/2019/3936168.3936168
    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) Retina. 2010;30(5):781–786. doi: 10.1097/iae.0b013e3181d2f145.
    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. Spaide R. F., Klancnik J. M., 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. Ramsey D. J., Sunness J. S., Malviya P., Applegate C., Hager G. D., Handa J. T. Automated image alignment and segmentation to follow progression of geographic atrophy in age-related macular degeneration. Retina. 2014;34(7):1296–1307. doi: 10.1097/iae.0000000000000069.
    1. Reif R., Qin J., An L., Zhi Z., Dziennis S., Wang R. Quantifying optical microangiography images obtained from a spectral domain optical coherence tomography system. International Journal of Biomedical Imaging. 2012;2012:11. doi: 10.1155/2012/509783.509783
    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. 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. Archives of Ophthalmology. 2001;119(6):861–866. doi: 10.1001/archopht.119.6.861.
    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. 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):35–44. doi: 10.1016/j.ajo.2015.04.021.
    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.e0205773
    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. Yannuzzi L. A., Rohrer K. T., Tindel L. J., et al. Fluorescein angiography complication survey. Ophthalmology. 1986;93(5):611–617. doi: 10.1016/s0161-6420(86)33697-2.
    1. Reddy R. K., Pieramici D. J., Gune S., et al. Efficacy of ranibizumab in eyes with diabetic macular edema and macular nonperfusion in RIDE and RISE. Ophthalmology. 2018;125(10):1568–1574. doi: 10.1016/j.ophtha.2018.04.002.
    1. Mastropasqua L., Toto L., Borrelli E., Carpineto P., Di Antonio L., Mastropasqua R. Optical coherence tomography angiography assessment of vascular effects occurring after aflibercept intravitreal injections in treatment-naive patients with wet age-related macular degeneration. Retina. 2017;37(2):247–256. doi: 10.1097/iae.0000000000001145.
    1. Kamba T., McDonald D. M. Mechanisms of adverse effects of anti-VEGF therapy for cancer. British Journal of Cancer. 2007;96(12):1788–1795. doi: 10.1038/sj.bjc.6603813.
    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. 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. 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. Grenga P. L., Fragiotta S., Cutini A., Meduri A., Vingolo E. M. Enhanced depth imaging optical coherence tomography in adult-onset foveomacular vitelliform dystrophy. European Journal of Ophthalmology. 2016;26(2):145–151. doi: 10.5301/ejo.5000687.
    1. Yiu G., Manjunath V., Chiu S. J., Farsiu S., Mahmoud T. H. Effect of anti-vascular endothelial growth factor therapy on choroidal thickness in diabetic macular edema. American Journal of Ophthalmology. 2014;158(4):745–751. doi: 10.1016/j.ajo.2014.06.006.
    1. Lim H. B., Kim Y. W., Kim J. M., Jo Y. J., Kim J. Y. The importance of signal strength in quantitative assessment of retinal vessel density using optical coherence tomography angiography. Scientific Reports. 2018;8(1) doi: 10.1038/s41598-018-31321-9.
    1. Barash A., Chui T. Y. P., Garcia P., Rosen R. B. Acute macular and peripapillary angiographic changes with intravitreal injections. Retina. 2018;40(4):648–656. doi: 10.1097/iae.0000000000002433.
    1. Feucht N., Schönbach E. M., Lanzl I., Lohmann C. P., Kotliar K., 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. Bonnin P., Pournaras J.-A. C., 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. 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. 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. 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 (Cambridge, England) 1998;125(125):1591–1598.
    1. Lindhal P., Johansson B. E., Leveen 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. 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. 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.

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