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