Evaluation of retinal nerve fibre layer thickness as a possible measure of diabetic retinal neurodegeneration in the EPIC-Norfolk Eye Study

Background/aimsMarkers to clinically evaluate structural changes from diabetic retinal neurodegeneration (DRN) have not yet been established. To study the potential role of peripapillary retinal nerve fibre layer (pRNFL) thickness as a marker for DRN, we evaluated the relationship between diabetes, as well as glycaemic control irrespective of diabetes status and pRNFL thickness.MethodsLeveraging data from a population-based cohort, we used general linear mixed models (GLMMs) with a random intercept for patient and eye to assess the association between pRNFL thickness (measured using GDx) and demographic, systemic and ocular parameters after adjusting for typical scan score. GLMMs were also used to determine: (1) the relationship between: (A) glycated haemoglobin (HbA1c) irrespective of diabetes diagnosis and pRNFL thickness, (B) diabetes and pRNFL thickness and (2) which quadrants of pRNFL may be affected in participants with diabetes and in relation to HbA1c.Results7076 participants were included. After controlling for covariates, inferior pRNFL thickness was 0.94 µm lower (95% CI −1.28 µm to −0.60 µm), superior pRNFL thickness was 0.83 µm lower (95% CI −1.17 µm to −0.49 µm) and temporal pRNFL thickness was 1.33 µm higher (95% CI 0.99 µm to 1.67 µm) per unit increase in HbA1c. Nasal pRNFL thickness was not significantly associated with HbA1c (p=0.23). Similar trends were noted when diabetes was used as the predictor.ConclusionSuperior and inferior pRNFL was significantly thinner among those with higher HbA1c levels and/or diabetes, representing areas of the pRNFL that may be most affected by diabetes.

Retinal Neurodegeneration in Diabetes: an Emerging Concept in Diabetic Retinopathy

Purpose of Review Diabetic retinopathy (DR), the leading cause of blindness in working-aged adults, remains clinically defined and staged by its vascular manifestations. However, early retinal neurodegeneration may precede vascular pathology, suggesting that this neuronal damage may contribute to disease pathogenesis and represent an independent target for intervention. This review will discuss the evidence and implications for diabetic retinal neurodegeneration. Recent Findings A growing body of literature has identified progressive retinal thinning and visual dysfunction in patients with diabetes even prior to the onset of DR, though advances in retinal vascular imaging suggest that vascular remodeling and choroidal changes occur during these early stages as well. Animal models of diabetes and in vitro studies have also suggested that diabetes may directly affect the retinal neural and glial tissue, providing support to the concept that diabetic retinal neurodegeneration occurs early in the disease and suggesting potentially relevant molecular pathways. Summary Diabetic retinal neurodegeneration may represent a “preclinical” manifestation of diabetic retinal disease and remains an active area of investigation. As the natural history and molecular mechanisms become increasingly understood, it may lead to upcoming developments in not only the treatment options but also the clinical definition of DR.

Off-Label Use of 0.19 mg Fluocinolone Acetonide Intravitreal Implant: A Systematic Review

Corticosteroids are used in a variety of ophthalmological diseases. One challenge faced by ophthalmologists is to deliver corticosteroids to the posterior segment of the eye with efficacy and safety. Sustained-release corticosteroid implants may be the answer to this problem. The 0.19 mg fluocinolone acetonide (FAc) implant (Iluvien®) releases FAc for 36 months, and it is approved for the treatment of diabetic macular edema (DME) and noninfectious uveitis. We decided to do a systematic review to acknowledge in which other diseases FAc implant is being used off-label. A literature search was performed in the following three electronic databases: PubMed, Scopus, and Web of Science (from January 1st, 2000, to September 20th, 2020), using the following query: (“Fluocinolone Acetonide” OR Iluvien®) AND (“eye” OR “ocular” OR “intravitreal).” A total of 11 papers were included, and the use of FAc implant was analyzed in the following diseases: radiation-induced maculopathy (RM); paraneoplastic visual syndromes (melanoma-associated retinopathy (MAR) and cancer-associated retinopathy (CAR)); Sjogren’s syndrome-related keratopathy; retinal vein occlusion (RVO); cystoid macular edema (CME); diabetic retinal neurodegeneration (DRN); and retinitis pigmentosa (RP). FAc implant may be a potential treatment for these diseases; however, the level of scientific evidence of the included studies in this review is limited. Further studies with larger cohorts and longer follow-ups are needed to validate this data.

Recent Developments in Diabetic Retinal Neurodegeneration: A Literature Review

Neurodegeneration plays a significant role in the complex pathology of diabetic retinopathy. Evidence suggests the onset of neurodegeneration occurs early on in the disease, and so a greater understanding of the process is essential for prompt detection and targeted therapies. Neurodegeneration is a common pathway of assorted processes, including activation of inflammatory pathways, reduction of neuroprotective factors, DNA damage, and apoptosis. Oxidative stress and formation of advanced glycation end products amplify these processes and are elevated in the setting of hyperglycemia, hyperlipidemia, and glucose variability. These key pathophysiologic mechanisms are discussed, as well as diagnostic modalities and novel therapeutic avenues, with an emphasis on recent discoveries. The aim of this article is to highlight the crucial role of neurodegeneration in diabetic retinopathy and to review the molecular basis for this neuronal dysfunction, its diagnostic features, and the progress currently made in relevant therapeutic interventions.

En face slab optical coherence tomography imaging successfully monitors progressive degenerative changes in the innermost layer of the diabetic retina

ObjectiveTo evaluate the usefulness of en face slab optical coherence tomography (OCT) imaging for monitoring diabetic retinal neurodegeneration with supporting animal experimental data.Research design and methodsWe retrospectively examined 72 diabetic eyes over 3 years using Cirrus-HD OCT. Two-dimensional en face slab OCT images of the innermost retina were reconstructed and graded according to the ratio of dark area to total area, and relative red, green, and blue color area ratios were calculated and used as indexes for each en face slab OCT image. Values from en face OCT images were used for statistical analyses. To obtain insight into the pathogenesis of diabetic retinal neurodegeneration, we used the InsPr-Cre;Pdk1flox/flox diabetic mouse model.ResultsBoth OCT grade and relative red color area ratio significantly increased with the advancing stage of diabetic retinopathy (p=0.018 and 0.006, respectively). After a mean follow-up period of 4.6 years, the trend was unchanged in the analyses of 42 untreated eyes (p<0.001 and 0.001, respectively). Visual acuity showed a weak but significant negative correlation with the red color ratio on en face slab OCT images, but central retinal thickness did not exhibit a clinically meaningful correlation with values obtained from en face slab OCT images. Immunohistochemical analyses of InsPr-Cre;Pdk1flox/flox diabetic mice demonstrated the loss of ganglion axon bundles and thinning of laminin without apparent retinal vascular change at the age of 20 weeks.ConclusionsEn face slab OCT imaging would be a novel useful modality for the assessment of diabetic retinal neurodegeneration as it could detect subtle optical changes occurring in the innermost retina in diabetic eyes. Our animal experimental data suggest that dark areas observed on en face slab OCT images might be the impairment of the extracellular matrix as well as neurons.