Tissue ischemia due to pathologic retinal non-perfusion (RNP) is a fundamental component of diabetic retinopathy (DR), retinal venous occlusive disease, and possibly even age-related macular degeneration if underlying choroidal ischemia is included. Specifically within the context of DR, RNP may be a very early marker of disease progression [1] and increased RNP area has been correlated with increased DR severity [2, 3].
From prospective clinical trials, we have known since the Early Treatment Diabetic Retinopathy Study (ETDRS) that the presence of fluorescein-angiographically-identified RNP is an important prognostic indicator [4]. More recent prospective trials have also identified RNP as a predictor of higher risk of disease progression, both with [5] and without concurrent anti-vascular endothelial growth factor (anti-VEGF) therapy [6, 7]. The retinal ischemic index, measured by the ratio of RNP area over total fundus area, has also been used as a marker for RNP burden, with a strong association between ischemic index and DR severity [8, 9].
Given its importance in assessing retinal vascular disease progression, tremendous effort has been invested towards identifying possible therapeutics that could impact RNP. These efforts include slowing RNP progression, which anti-VEGF therapy may be able to achieve with consistent, frequent dosing in some populations [10,11,12], or ideally lead to reperfusion, a phenomenon not commonly observed with anti-VEGF therapy [13]. Additionally, multiple molecular entities pursuing new mechanisms of action, including manipulating the Sema-3A-Nrp1 pathway, are actively being explored in prospective clinical trials [14, 15].
Despite these advancements, RNP is not a registration trial endpoint that can be utilized for regulatory approval. Work towards defining the correlation between perfusion status and visual function – in combination with adequately powered clinical trials with robust methodology assessing RNP as the primary outcome—are needed in order to validate RNP as a potential surrogate outcome that could be acceptable for regulatory approval. One relevant ongoing study is the Safety and Efficacy of Faricimab in Patients with NPDR (MAGIC [NCT05681884]), which aims to measure RNP area change in eyes with NPDR [16].
RNP location also appears to be relevant. For example, the far and mid-peripheral retinal zones may be more sensitive to the impact of diabetes mellitus [17, 18]. Confusingly however, RNP localization has been inconsistently defined in the literature, ranging from broad categorizations (peripheral, mid-peripheral, central, and generalized) [19], to more specific categories (posterior (<10 mm from the disc), mid-peripheral (10 mm to 15 mm), and peripheral (>15 mm)) [20]. Within this sphere, Romano et al. describe current nomenclature challenges associated with topographical localization of images captured with optical coherence tomography angiography (OCTA) images [21].
To build on their proposals, there are other dimension to consider—for example, depth and location. Retinal vasculature is complex, with up to four layers of vasculature, including the radial peripapillary capillary network, the superficial vascular plexus, and the deep capillary complex. These various networks are region specific [22] and may be differentially impacted by retinal vascular diseases. For example, lower capillary density has been reported in the deep vascular plexus compared to the superficial vascular plexus among diabetic patients, both with [23] and without clinically detectible DR [24, 25].
In order to facilitate robust prospective analyses of RNP, and its longitudinal change with current and future therapeutics, it is critical to have a standardized approach to nomenclature and quantification. Ideally, such nomenclature would reflect relevant physiology, including known topographic differences in the retinal vascular tree, and not simply be determined by distances.
Change history
28 March 2024
A Correction to this paper has been published: https://doi.org/10.1038/s41433-024-03048-7
References
de Carlo TE, Chin AT, Bonini Filho MA, Adhi M, Branchini L, Salz DA, et al. Detection of microvascular changes in eyes of patients with diabetes but not clinical diabetic retinopathy using optical coherence tomography angiography. Retina. 2015;35:2364.
Wykoff CC, Yu HJ, Avery RL, Ehlers JP, Tadayoni R, Sadda SR. Retinal non-perfusion in diabetic retinopathy. Eye. 2022;36:249.
Huang Z, Qiu K, Yi J, Lin H, Zheng D, Huang D, et al. Diabetic retinopathy with extensively large area of capillary non-perfusion: characteristics and treatment outcomes. BMC Ophthalmol. 2022;22:293.
Fluorescein Angiographic Risk Factors for Progression of Diabetic Retinopathy: ETDRS Report Number 13. Ophthalmology. 1991;98:834–40.
Ip 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.
Silva PS, Marcus DM, Liu D, Aiello LP, Antoszyk A, Elman M, et al. Association of ultra-widefield fluorescein angiography–identified retinal nonperfusion and the risk of diabetic retinopathy worsening over time. JAMA Ophthalmol. 2022;140:936–45.
Wykoff CC, Do DV, Goldberg RA, Dhoot DS, Lim JI, Du W, et al. Ocular and systemic risk factors for disease worsening among patients with NPDR: post hoc analysis of the PANORAMA Trial. Ophthalmol Retina [Internet]. 2023 [cited 2024 Jan 23];0. Available from: https://www.ophthalmologyretina.org/article/S2468-6530 (23)00567-5/fulltext.
Patel RD, Messner LV, Teitelbaum B, Michel KA, Hariprasad SM. Characterization of ischemic index using ultra-widefield fluorescein angiography in patients with focal and diffuse recalcitrant diabetic macular edema. Am J Ophthalmol. 2013;155:1038–44.e2.
Ehlers 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.
Nanji K, Sarohia GS, Xie J, Patil NS, Phillips M, Zeraatkar D, et al. Anti-vascular endothelial growth factor therapy and retinal non-perfusion in diabetic retinopathy: a meta-analysis of randomised trials. Acta Ophthalmol (Copenh). 2024;102:e31–41.
Campochiaro 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.
Wykoff 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 Retin. 2019;3:1076–86.
Sorour OA, Mehta N, Baumal CR, Ishibazawa A, Liu K, Konstantinou EK, et al. Morphological changes in intraretinal microvascular abnormalities after anti-VEGF therapy visualized on optical coherence tomography angiography. Eye Vis. 2020;7:29.
Joyal JS, Sitaras N, Binet F, Rivera JC, Stahl A, Zaniolo K, et al. Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A. Blood. 2011;117:6024–35.
Zippel N, Kenny CH, Wu H, Garneau M, Kroe-Barrett R, Gupta P, et al. Sema3A antibody BI-X prevents cell permeability and cytoskeletal collapse in HRMECs and increases tip cell density in mouse oxygen-induced retinopathy. Transl Vis Sci Technol. 2022;11:17.
Greater Houston Retina Research. Faricimab for Retinal Non-Perfusion Associated With Non-Proliferative Diabetic Retinopathy: The MAGIC Phase 2, Multi-Center, Open-Label, Randomized Controlled Trial [Internet]. clinicaltrials.gov; 2023 [cited 2023 Dec 31]. Report No.: NCT05681884. Available from: https://clinicaltrials.gov/study/NCT05681884.
Silva PS, Cavallerano JD, Sun JK, Soliman AZ, Aiello LM, Aiello LP. Peripheral lesions identified by mydriatic ultrawide field imaging: distribution and potential impact on diabetic retinopathy severity. Ophthalmology. 2013;120:2587–95.
Antaki F, Coussa RG, Mikhail M, Archambault C, Lederer DE. The prognostic value of peripheral retinal nonperfusion in diabetic retinopathy using ultra-widefield fluorescein angiography. Graefes Arch Clin Exp Ophthalmol. 2020;258:2681–90.
Niki T, Muraoka K, Shimizu K. Distribution of capillary nonperfusion in early-stage diabetic retinopathy. Ophthalmology. 1984;91:1431–9.
Baxter SL, Ashir A, Nguyen BJ, Nudleman E. Quantification of retinal nonperfusion associated with posterior segment neovascularization in diabetic retinopathy using ultra-widefield fluorescein angiography. Ophthalmic Surg Lasers Imaging Retin. 2019;50:86–92.
Romano F, Ding X, Miller JB. Expanded field: filling the gap between macula and widefield. Eye (2024). https://doi.org/10.1038/s41433-024-02978-6.
Campbell JP, Zhang M, Hwang TS, Bailey ST, Wilson DJ, Jia Y, et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Sci Rep. 2017;7:42201.
Dupas B, Minvielle W, Bonnin S, Couturier A, Erginay A, Massin P, et al. Association between vessel density and visual acuity in patients with diabetic retinopathy and poorly controlled type 1 diabetes. JAMA Ophthalmol. 2018;136:721–8.
Meshi A, Chen KC, You QS, Dans K, Lin T, Bartsch DU, et al. Anatomical and functional testing in diabetic patients without retinopathy: results of optical coherence tomography angiography and visual acuity under varying contrast and luminance conditions. Retina. 2019;39:2022.
Singer M, Ashimatey BS, Zhou X, Chu Z, Wang R, Kashani AH. Impaired layer specific retinal vascular reactivity among diabetic subjects. PLoS ONE. 2020;15:e0233871.
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The original online version of this article was revised: reference 21 was corrected from “Romano F, Ding X, Miller JB. Expanded field: filling the gap between macula and widefield. Eye. (2024) [IN PRESS]” to “Romano F, Ding X, Miller JB. Expanded field: filling the gap between macula and widefield. Eye (2024). https://doi.org/10.1038/s41433-024-02978-6”.
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Cao, J.A., Al-khersan, H., Chaudhary, V. et al. Retinal non-perfusion: recognizing and defining what is important. Eye (2024). https://doi.org/10.1038/s41433-024-02981-x
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DOI: https://doi.org/10.1038/s41433-024-02981-x