Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Pathology

Supervisor

Dr. Cindy Hutnik

2nd Supervisor

Dr. Subrata Chakrabarti

Joint Supervisor

Abstract

Diabetic retinopathy (DR) is the result of microvascular changes in the retina due to hyperglycemia which alter the blood-retinal barrier (BRB). The increased permeability of BRB results in the accumulation of extracellular fluid, the development of diabetic macular edema (DME) and capillary occlusion. Capillary occlusion results in retinal ischemia which increases vascular endothelial growth factor (VEGF) levels, increases vascular permeability and results in neovascularization in proliferative diabetic retinopathy (PDR) patients. The treatments clinically used for DR are panretinal photocoagulation (PRP) for PDR and injectable vascular endothelial growth factor inhibitors (anti-VEGFs) for DME.

The safety of PRP and anti-VEGF therapy on the retina and optic nerve was evaluated in treatment-naïve DR patients by undergoing structural (OCT, HRT) and functional (visual field, visual acuity) diagnostic tests over a two year time period. Streptozotocin (STZ)-induced diabetic rats received different doses of intravitreal anti-VEGF injections to analyze the safety of VEGF inhibition on neuronal cells. Retinal cell cultures were exposed to different doses of anti-VEGF to assess metabolic activity, function and toxicity by colorimetric assays.

This study found that patients treated with PRP, despite showing an improvement in peripheral perfusion, had a significant and progressive decline in peripheral vision. There was a discrepancy between the grading of the optic nerves post-PRP by ophthalmologists despite the absence of significant morphological changes. Anti-VEGF treatment was found to be potentially detrimental to the optic nerve by decreasing retinal nerve fiber layer thickness, increasing cup/disk ratio and cup volume over time. STZ-induced diabetic rats receiving intravitreal anti-VEGF injections had a dose-dependent increase in retinal ganglion cell death. Results from retinal cell cultures suggest that anti-VEGF treatment may be detrimental to the retina by decreasing cellular metabolic activity, and increasing cytotoxicity of retinal cells. Overall, PRP was relatively safe and improved peripheral perfusion but resulted in misdiagnosis of glaucoma based on non-morphological colouration changes of the optic nerve post-PRP. Anti-VEGF treatment appeared to be detrimental to the optic nerve by causing damage to retinal cells. In contrast to current recommendations, it is suggested to monitor both the retina and optic nerve status in patients undergoing frequent injections.