Longitudinal Analysis of Structural and Functional Changes in Presence of Reticular Pseudodrusen Associated With Age-Related Macular Degeneration

Abstract

To examine longitudinal changes of retinal thickness and retinal sensitivity in patients with intermediate age-related macular degeneration (iAMD) and predominantly reticular pseudodrusen (RPD). METHODS. At baseline 30 eyes of 25 iAMD patients underwent optical coherence tomography imaging, mesopic and scotopic fundus-controlled perimetry (FCP) with follow-up examinations at month 12 (20 eyes), 24 (12 eyes), and 36 (11 eyes). Thicknesses of different retinal layers and results of FCP testing (n = 56 stimuli) were spatially and longitudinally analyzed using linear mixed-effects models. RESULTS. At baseline, the thickness of the partial outer retinal layer (pORL, 70.21 vs. 77.47 μm) and both mesopic (16.60 vs. 18.72 dB) and scotopic (12.14 vs. 18.67 dB) retinal sensitivity were decreased in areas with RPD compared with unremarkable areas (P < 0.001). Over three years, mean change of pORL was −0.66 normative standard deviation (SD; i.e., z-score, P < 0.001) for regions with existing RPD, −0.40 SD (P < 0.001) for regions with new occurring RPD, and −0.17 SD (P = 0.041) in unremarkable regions. Decrease of scotopic and mesopic sensitivity over three years was more pronounced in areas with existing (−3.51 and −7.76 dB) and new occurring RPD (−2.06 and −5.97 dB). Structure-function analysis revealed that 1 SD decrease of pORL thickness was associated with a sensitivity reduction of 3.47 dB in scotopic and 0.79 dB in mesopic testing. CONCLUSIONS. This study demonstrates progressive outer retinal degeneration and impairment of photoreceptor function in eyes with iAMD and RPD over three years. Preservation of outer retinal thickness and reduction of RPD formation may constitute meaningful surrogate endpoints in interventional trials on eyes with AMD and RPD aiming to slow outer retinal degeneration.

Clinical Perspectives and Trends: Microperimetry as a Trial Endpoint in Retinal Disease

“…Although researchers in macular disease were amongst the first to recognise the benefits of MP, initially due to its compensation for poor fixation in GA [138], more recently its potential as an endpoint has moved centre stage [6, 12, 13]. Interest in mesopic and scotopic MP modalities has increased as their ability to capture subtle functional deficits in early and intermediate AMD [51, 59, 139-142] and quantify progression over time [143, 144] has been demonstrated. Of note, significant reductions in mesopic sensitivity over a period as short as 12 months have been shown [73, 145], implying MP endpoints may allow for shorter trial durations.…”

“…With respect to future alternative endpoints, reporting change in PWS is also likely to be important. PWS offers a more robust way of identifying local alterations and, in combination with multimodal imaging, has enhanced our understanding of specific functional deficits present with precise structural changes in AMD [55, 143, 144]. In fact, PWS over reticular pseudodrusen has been shown to exhibit faster progression than that detected in unremarkable retinal regions in the same eye.…”

Shared Features in Retinal Disorders With Involvement of Retinal Pigment Epithelium

“…RPD lesions visible in fundus images of AMD patients confer increased risk of advanced disease. 24 , 51 – 53 …”

Longitudinal choriocapillaris changes in the presence of reticular pseudodrusen

“…With the availability of OCT angiography (OCTA), several groups demonstrated decreased flow signals at the CC level and increased areas of flow deficits in eyes with RPD 9 , 10 . Using OCT, mesopic and scotopic fundus-controlled perimetry, Sassmannshausen et al demonstrated progressive outer retinal degeneration and corresponding impairment of photoreceptor function in eyes with RPD over 3 years 11 . Zhang et al used adaptive optics scanning laser ophthalmoscopy over a 3.5-year period to describe the evolution of progression and regression of individual RPD lesions presumably reflecting the process of outer retinal atrophy 12 , 13 .…”