Diabetic macular oedema: the role of steroids and VEGF.
Doctoral thesis, UCL (University College London).
Despite advances in controlling diabetes, diabetic macular oedema remains the leading cause of blind registration in the working population in England and Wales. The only proven effective treatment for diabetic macular oedema is laser photocoagulation. However this treatment has limited benefits since it reduces the chance of moderate visual loss by approximately 50% and is unlikely to improve visual acuity. Intravitreal steroids have been used in the treatment for diabetic macular oedema. Initial pilot studies suggest it can decrease retinal thickening and increase visual acuity in the long-term. Vascular endothelial growth factor is thought to play a critical role during the pathogenesis of diabetic macular oedema. The mechanism of action of both steroids and vascular endothelial growth factor on permeability has still to be fully elucidated. The aims of this thesis were to establish a reliable model of retinal microvascular endothelial cells and to characterise cellular changes following exposure to corticosteroids or vascular endothelial growth factor. Separate clinical work was aimed at evaluating the benefits of steroid treatment alone or combined with pars plana vitrectomy as a treatment of diabetic macular oedema. We also aimed to identify any prognostic indicators for treatment by both examining the morphological features of diabetic macular oedema observed on optical coherence tomography and by assaying the vascular endothelial growth factor concentration in the ocular fluids of eyes with diabetic macular oedema. Our results show that our retinal and brain microvascular endothelial cells were morphologically very similar; in particular with respect to the spatial localization of junctional proteins. Vascular endothelial growth factor led to an increase in the permeability and a decrease in the staining of the junctional proteins. By using signal transduction inhibitors, we showed that vascular endothelial growth factor-induced permeability and vascular endothelial growth factor-induced zonula occludens-1 loss occurred via different pathways suggesting that zonula occludens-1 loss was unlikely to be the downstream effector of vascular endothelial growth factor-induced permeability. Hydrocortisone leads to a decrease in permeability and an increase in the junctional expression of a number of tight junctional proteins. Both hydrocortisone and triamcinolone were able to inhibit vascular endothelial growth factor but not lysophosphatidic acid induced permeability suggesting that steroids are able to counteract the effects of certain but all vasoactive compounds. Overall our results suggested that steroids and VEGF lead to opposing effects on microvascular endothelial cells. Our randomized controlled trial showed that intravitreal triamcinolone was no more beneficial than laser photocoagulation for persistent diabetic macular oedema. A retrospective analysis of the morphological characteristics observed on Optical coherence tomography did not provide any characteristic that was prognostic of the outcome of intervention. Additionally, an exploratory case series of pars plana vitrectomy with 4 mg intravitreal triamcinolone was unable to show that combined treatment was of benefit in the long-term. Lastly the intraocular concentration of vascular endothelial growth factor was not predictive of the outcome of treatment.
|Title:||Diabetic macular oedema: the role of steroids and VEGF|
|Open access status:||An open access version is available from UCL Discovery|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology|
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