The angiofibrotic switch in neovascular AMD

Content of this project: The content of this research project is to identify the angiofibrotic switch, the transition from angiogenesis to fibrosis, in neovascular age-related macular degeneration (nAMD) longitudinally. AMD is the most important cause of vision loss of the elderly in industrialized countries. Despite optimal treatment about 50% of eyes with nAMD develop fibrosis within 2 years, causing irreversible damage to the retina and functional loss. Objective measurement of fibrosis, however, is challenging, since clinical staging is subjective and current imaging modalities such as color fundus photography (CFP), fluorescein angiography (FA) and optical coherence tomography (OCT) often do not allow clear delineation. Novel imaging modalities such as polarization-sensitive OCT (PS-OCT), OCT angiography (OCTA) and adaptive-optics OCT (AO-OCT) offer identification of fibrous components and microvasculature of fibrotic lesions non-invasively with highest precision and shall thus be used in this study. Hypotheses: We hypothesize to detect and quantify subclinical (i.e. not detectable on dilated fundus examination) areas of fibrosis using PS-OCT and determine the rate and exact location within the neovascular lesion. Furthermore, we expect neuroretinal and microvascular changes, which we will assess by AO-OCT and OCTA. Methods: Eighty eyes of 80 patients with chronic nAMD will be included and examined cross- sectionally to evaluate the accuracy of PS-OCT to detect and quantify fibrosis in comparison to gold standard imaging modalities. In addition, OCTA and AO-OCT will be performed to analyze the relationship between fibrous, neovascular and neuroretinal structures. Furthermore, forty eyes of 40 participants with treatment-nave nAMD will be included and followed over 12 months with predefined follow-up intervals. Using PS-OCT, we will determine the angiofibrotic switch and observe the impact of anti-VEGF treatment longitudinally. Current gold standard imaging modalities will be performed for validation. What is new: In the present project we will apply novel non-invasive imaging to objectively determine the exact time and extent of the angiofibrotic switch in nAMD during state-of-the- art therapy. This approach has not been done before and is clinically relevant for multiple reasons: Firstly, only little is known about the development of fibrosis in AMD during therapy. Secondly, the clinical diagnosis of subretinal fibrosis is subjective and does not allow reliable quantification. Thirdly, current gold standard imaging modalities (i.e. CFP and FA) for detection of fibrosis involve invasive, time-consuming and potentially harmful procedures and do not allow three-dimensional analysis. Finally, our study may identify objective endpoints for future interventional trials.

The content of this research project was to identify the angiofibrotic switch, the transition from angiogenesis to fibrosis, in neovascular age-related macular degeneration (nAMD) longitudinally. AMD is the most important cause of vision loss of the elderly in industrialized countries. Despite optimal treatment about 50% of eyes with nAMD develop fibrosis within 2 years, causing irreversible damage to the retina and functional loss. Objective measurement of fibrosis, however, is challenging, since clinical staging is subjective and current imaging modalities such as color fundus photography (CFP), fluorescein angiography (FA) and optical coherence tomography (OCT) often do not allow clear delineation. Novel imaging modalities such as polarization-sensitive OCT (PS-OCT) or OCT angiography (OCTA) offer identification of fibrous components and microvasculature of fibrotic lesions non-invasively with highest precision and was hence used in this study. The results of this research project offer new perspectives on the evolution of subretinal fibrosis and led to the publication of numerous papers in internationally renowned journals and presentations at international congress meetings. Our study has investigated different aspects of the development of subretinal fibrosis, the most important ones of which will be briefly discussed below: In one important aspect of our study, we identified the rate of subretinal fibrosis in nAMD using a novel PS-OCT device with a new automated algorithm. The results of fibrosis detection were compared to the clinical diagnosis based on CFP, and the precision of fibrotic area measurement was assessed. The PS-OCT based method was able to reliably detect and quantify lesions larger than 0.7 mm2. The algorithm should therefore be useful for diagnostics and follow-up studies in larger patient cohorts. Another part of our project focused on morphologic and microvascular differences between macular neovascularization with and without subretinal fibrosis. This multimodal imaging approach demonstrated in vivo microvascular and morphological differences in eyes with and without subretinal fibrosis. Eyes with subretinal fibrosis tend to have larger MNV lesions with thicker vessels and are often associated with the presence of outer retinal tubulations. In another published report of our research project we focused on the identification of baseline predictors for subretinal fibrosis in nAMD. There were no quantitative baseline microvascular predictors for subretinal fibrosis in our study. Low baseline best-corrected visual acuity, the presence of intraretinal fluid and subretinal hyperreflective material in OCT imaging, however, are easily identifiable baseline parameters indicating increased risk. In another analysis, our study group demonstrated that multimodal imaging significantly improves the chance of accurate detection of subretinal fibrosis compared to the use of just one imaging modality. In conclusion, the results of our project highlight the need for new and reliable methods for subretinal fibrosis identification and quantification and illustrate novel approaches to improve current diagnostic modalities.