Characterization and validation of a chronic retinal neovascularization rabbit model by evaluating the efficacy of anti-angiogenic and anti-inflammatory drugs

AIM: To establish a rabbit model with chronic condition of retinal neovascularization (RNV) induced by intravitreal (IVT) injection of DL-2-aminoadipic acid (DL-AAA), a retinal glial (Müller) cell toxin, extensive characterization of DL-AAA induced angiographic features and the suitability of the model to evaluate anti-angiogenic and anti-inflammatory therapies for ocular vascular diseases. METHODS: DL-AAA (80 mmol/L) was administered IVT into both eyes of Dutch Belted rabbit. Post DL-AAA delivery, clinical ophthalmic examinations were performed weekly following modified McDonald-Shadduck Scoring System. Color fundus photography, fluorescein angiography (FA), and optical coherence tomography (OCT) procedures were performed every 2 or 4wk until stable retinal vascular leakage was observed. Once stable retinal leakage (12wk post DL-AAA administration) was established, anti-vascular endothelial growth factor (VEGF) (bevacizumab, ranibizumab and aflibercept) and anti-inflammatory (triamcinolone, TAA) drugs were tested for their efficacy after IVT administration. Fluorescein angiograms were scored before and after treatment following a novel grading system, developed for the DL-AAA rabbit model. RESULTS: Post DL-AAA administration, eyes were presented with moderate to severe retinal/choroidal inflammation which was accompanied by intense vitreous flare and presence of inflammatory cells in the vitreous humor. Retinal hemorrhage was restricted to the tips of neo-retinal vessels. FA revealed maximum retinal vascular leakage at 2wk after DL-AAA injection and then persisted as evidenced by stable mean FA scores in weeks 8 and 12. Retinal vascular angiographic and tomographic features were stable and consistent up to 36mo among two different staggers induced for RNV at two different occasions. Day 7, mean FA scores showed that 1 µg/eye of bevacizumab, ranibizumab, aflibercept and 2 µg/eye of TAA suppress 65%, 90%, 100% and 50% retinal vascular leakage, respectively. Day 30, bevacizumab and TAA continued to show 66% and 44% suppression while ranibizumab effect was becoming less effective (68%). In contrast, aflibercept was still able to fully (100%) suppress vascular leakage on day 30. On day 60, bevacizumab, ranibizumab and TAA showed suppression of 7%, 12%, and 9% retinal vascular leakage, respectively, however, aflibercept continued to be more effective showing 50% suppression of vascular leakage. CONCLUSION: The DL-AAA rabbit model mimics RNV angiographic features like RNV and chronic retinal leakage. Based on these features the DL-AAA rabbit model provides an invaluable tool that could be used to test the therapeutic efficacy and duration of action of novel anti-angiogenic formulations, alone or in combination with anti-inflammatory compounds.

Role of Optical Coherence Tomography Angiography to differentiate Intraretinal microvascular abnormalities and retinal neovascularization in Diabetic Retinopathy

Objective: To assess proliferative diabetic retinopathy (PDR) and to describe the difference in angiographic representation of new vessels (NVs) and Intra retinal microvascular abnormalities (IRMA) on optical coherence tomography angiography (OCTA). Methods: A cross-sectional observational study was performed at ISRA Postgraduate Institute of Ophthalmology, Karachi, from March 2018 to September 2018. Forty-two eyes of 21 patients with history of diabetes mellitus (DM) were examined. Twenty-eight eyes with a clinical diagnosis of severe non proliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR) according to early treatment diabetic retinopathy study (ETDRS) were included and evaluated using Swept source optical coherence tomography angiography (SS-OCTA). Then face wide field SS-OCTA images and co registered structural optical coherence tomography (OCT) with flow overlay were used to distinguish the features of IRMA and retinal NVs. Results: Forty-two eyes (21 patients) were examined clinically. Fourteen eyes had moderate NPDR, 15 had severe NPDR and 13 eyes had changes consistent with PDR. After clinical diagnosis, we included 28 eyes in our study based on inclusion criteria. These 28 eyes went through SS-OCTA evaluation and we observed 15 cases with PDR and 13 with severe NPDR changes. The OCTA and clinical diagnosis were similar except in 2 eyes, which is critical but not statically significant showing the importance of this noninvasive technology. Conclusions: Widefield OCTA can work as an alternative to fundus fluorescein angiography (FFA) in the diagnosis of diabetic retinopathy (DR). As it is a non-invasive and depth encoded technique so can be used frequently to monitor the retinal changes and their progression. doi: https://doi.org/10.12669/pjms.38.1.3891 How to cite this:Memon AS, Memon NA, Mahar PS. Role of Optical Coherence Tomography Angiography to differentiate Intraretinal microvascular abnormalities and retinal neovascularization in Diabetic Retinopathy. Pak J Med Sci. 2022;38(1):---------. doi: https://doi.org/10.12669/pjms.38.1.3891 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.