Multimodal characterization of proliferative diabetic retinopathy reveals alterations in outer retinal function and structure.

PURPOSE: To identify changes in retinal function and structure in persons with proliferative diabetic retinopathy (PDR), including the effects of panretinal photocoagulation (PRP). DESIGN: Cross-sectional study. PARTICIPANTS: Thirty adults who underwent PRP for PDR, 15 adults with untreated PDR, and 15 age-matched controls. METHODS: Contrast sensitivity, frequency doubling perimetry (FDP), Humphrey visual fields, photostress recovery, and dark adaptation were assessed. Fundus photography and macular spectral-domain optical coherence tomography (SD OCT) were performed. To quantify retinal layer thicknesses, SD OCT scans were segmented semiautomatically. MAIN OUTCOME MEASURES: Visual function measures were compared among patients with PDR and PRP, untreated patients with PDR, and controls. Mean retinal layer thicknesses were compared between groups. Correlation analyses were performed to evaluate associations between visual function measures and retinal layer thicknesses. RESULTS: A significant reduction of FDP mean deviation (MD) was exhibited in PRP-treated patients with PDR (MD ± standard deviation, -8.20±5.76 dB; P < 0.0001) and untreated patients (-5.48±4.48 dB; P < 0.0001) relative to controls (1.07±2.50 dB). Reduced log contrast sensitivity compared with controls (1.80±0.14) also was observed in both PRP-treated patients (1.42±0.17; P < 0.0001) and untreated patients (1.56±0.20; P = 0.001) with PDR. Compared with controls, patients treated with PRP demonstrated increased photostress recovery time (151.02±104.43 vs. 70.64±47.14 seconds; P = 0.001) and dark adaptation speed (12.80±5.15 vs. 9.74±2.56 minutes; P = 0.022). Patients who underwent PRP had diffusely thickened nerve fiber layers (P = 0.024) and diffusely thinned retinal pigment epithelium (RPE) layers (P = 0.009) versus controls. Untreated patients with PDR also had diffusely thinned RPE layers (P = 0.031) compared with controls. CONCLUSIONS: Patients with untreated PDR exhibited inner retinal dysfunction, as evidenced by reduced contrast sensitivity and FDP performance, accompanied by alterations in inner and outer retinal structure. Patients who underwent PRP had more profound changes in outer retinal structure and function. Distinguishing the effects of PDR and PRP may guide the development of restorative vision therapies for patients with advanced diabetic retinopathy.

Treated PDR Reveals Age-Appropriate Vision Deterioration But Distorted Retinal Organization.

Purpose: We determined the progression of visual function, macular structure, and quality of life in patients with regressed proliferative diabetic retinopathy (PDR) after panretinal photocoagulation (PRP). Methods: In this prospective study, 22 patients who underwent PRP for PDR and 11 age-matched control participants underwent examinations at baseline and after 5 years. Visual acuity, contrast sensitivity, reading acuity, frequency doubling perimetry, Humphrey field analyzer, and dark adaptation were measured. The Low Luminance Questionnaire and National Eye Institute Vision Function Questionnaire-25 were administered. Macular spectral-domain optical coherence tomography was taken. Results: After 5 years, patients who had previously undergone PRP for PDR (18.4 ± 7.9 years previously) showed significant deterioration in contrast sensitivity, reading acuity, frequency doubling perimetry 24-2 pattern standard deviation, and Humphrey field analyzer 10-2 foveal sensitivity, which were equivalent to age-related decreases in control participants. They revealed no further impairment in vision-related activities on questionnaires. In contrast with controls, their maculas showed pathologic disorganization of the retinal layers, especially the nerve fiber layer, which were thicker and constituted a greater proportion of the overall retinal thickness than the norm and associated with impaired vision. Conclusions: Patients with treated PDR had age-related decreases in vision, but stable quality of life. Prior injuries from the diabetes and, possibly, laser treatment led to substantial disruption in the retinal structure, which may explain the loss of vision. Translational Relevance: Despite PRP treatment, patients with regressed PDR had pathologic progression of the nerve fiber layer; further investigation may identify a new therapeutic target to reverse the visual deficits.

Computational modeling of retinal hypoxia and photoreceptor degeneration in patients with age-related macular degeneration.

Although drusen have long been acknowledged as a primary hallmark of dry age-related macular degeneration (AMD) their role in the disease remains unclear. We hypothesize that drusen accumulation increases the barrier to metabolite transport ultimately resulting in photoreceptor cell death. To investigate this hypothesis, a computational model was developed to evaluate steady-state oxygen distribution in the retina. Optical coherence tomography images from fifteen AMD patients and six control subjects were segmented and translated into 3D in silico representations of retinal morphology. A finite element model was then used to determine the steady-state oxygen distribution throughout the retina for both generic and patient-specific retinal morphology. Oxygen levels were compared to the change in retinal thickness at a later time point to observe possible correlations. The generic finite element model of oxygen concentration in the retina agreed closely with both experimental measurements from literature and clinical observations, including the minimal pathological drusen size identified by AREDS (64 µm). Modeling oxygen distribution in the outer retina of AMD patients showed a substantially stronger correlation between hypoxia and future retinal thinning (Pearson correlation coefficient, r = 0.2162) than between drusen height and retinal thinning (r = 0.0303) indicating the potential value of this physiology-based approach. This study presents proof-of-concept for the potential utility of finite element modeling in evaluating retinal health and also suggests a potential link between transport and AMD pathogenesis. This strategy may prove useful as a prognostic tool for predicting the clinical risk of AMD progression.

The Effects of Diabetic Retinopathy and Pan-Retinal Photocoagulation on Photoreceptor Cell Function as Assessed by Dark Adaptometry.

PURPOSE: The pathophysiology of vision loss in persons with diabetic retinopathy (DR) is complex and incompletely defined. We hypothesized that retinal pigment epithelium (RPE) and rod and cone photoreceptor dysfunction, as measured by dark adaptometry, would increase with severity of DR, and that pan-retinal photocoagulation (PRP) would exacerbate this dysfunction. METHODS: Dark adaptation (DA) was measured in subjects with diabetes mellitus and healthy controls. Dark adaptation was measured at 5° superior to the fovea following a flash bleach, and the data were analyzed to yield cone and rod sensitivity curves. Retinal layer thicknesses were quantified using spectral-domain optical coherence tomography (OCT). RESULTS: The sample consisted of 23 controls and 73 diabetic subjects. Subjects with moderate nonproliferative diabetic retinopathy (NPDR) exhibited significant impairment of rod recovery rate compared with control subjects (P = 0.04). Cone sensitivity was impaired in subjects with proliferative diabetic retinopathy (PDR) (type 1 diabetes mellitus [T1DM]: P = 0.0047; type 2 diabetes mellitus [T2DM]: P < 0.001). Subjects with untreated PDR compared with subjects treated with PRP exhibited similar rod recovery rates and cone sensitivities. Thinner RPE as assessed by OCT was associated with slower rod recovery and lower cone sensitivity, and thinner photoreceptor inner segment/outer segment layer was associated with lower cone sensitivity. CONCLUSIONS: The results suggest that RPE and photoreceptor cell dysfunction, as assessed by cone sensitivity level and rod- and RPE-mediated dark adaptation, progresses with worsening DR, and rod recovery dysfunction occurs earlier than cone dysfunction. Function was preserved following PRP. The findings suggest multiple defects in retinoid function and provide potential points to improve visual function in persons with PDR.