Oxygen sensing mechanisms in retinal vascular development and disease.

Oxygen sensing is a fundamental biological process which is critical for appropriate development of the eye and implicated in neovascular eye disease including age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. This thesis describes a programme of work designed to investigate the role of hypoxia-inducible transcription factors (Hif’s), its downstream effector proteins, and its upstream regulator, the von Hippel Lindau protein (Vhl), in the development of the eye and neovascular eye disease. The first part of this work investigates the consequences of Hif activation in the developing retinal pigment epithelium (RPE) using a tissue specific knockout technology in mice. It demonstrates that appropriate regulation of Hif’s by Vhl is essential for normal RPE and iris development, ocular growth and vascular development and indicates that ocular hypoxia may be a previously unrecognised mechanism in the development of microphthalmia. The second part of this work studies the role of Hif1a in myeloid cells in the development of pathological neovascularisation using tissue-specific knockout technology and murine models for retinal and choroidal neovascularisation. It demonstrates that Hif1a signalling in myeloid cells contributes substantially to the development of retinal and choroidal neovascularisation and provides a rationale for developing antiangiogenic treatments that target Hif1a signalling in myeloid cells in neovascular eye disease. The third part of this work investigates the oxygen distribution in the vitreous and its relation to HIF1a and its downstream molecules in proliferative diabetic retinopathy (PDR) in man. It identifies significant intraocular oxygen gradients in PDR with areas of hyperoxia and hypoxia and demonstrates increased levels of HIF1a in the vitreous in PDR which correlate with increased levels of inflammatory and angiogenic cytokines in PDR. These findings suggest that HIF1a activation by inflammation and/or hypoxia is a central feature in the progression of PDR and that its inhibition may potentially serve as a target for therapeutic intervention

Positioning In Macular hole Surgery (PIMS): statistical analysis plan for a randomised controlled trial

UK National Institute for Health Research (NIHR) through its Research for Patient Benefit scheme (grant number PB-PG-0213-30085)

Central serous chorioretinopathy: An evidence-based treatment guideline.

Central serous chorioretinopathy (CSC) is a relatively common disease that causes vision loss due to macular subretinal fluid leakage and it is often associated with reduced vision-related quality of life. In CSC, the leakage of subretinal fluid through defects in the retinal pigment epithelial layer's outer blood-retina barrier appears to occur secondary to choroidal abnormalities and dysfunction. The treatment of CSC is currently the subject of controversy, although recent data obtained from several large randomized controlled trials provide a wealth of new information that can be used to establish a treatment algorithm. Here, we provide a comprehensive overview of our current understanding regarding the pathogenesis of CSC, current therapeutic strategies, and an evidence-based treatment guideline for CSC. In acute CSC, treatment can often be deferred for up to 3-4 months after diagnosis; however, early treatment with either half-dose or half-fluence photodynamic therapy (PDT) with the photosensitive dye verteporfin may be beneficial in selected cases. In chronic CSC, half-dose or half-fluence PDT, which targets the abnormal choroid, should be considered the preferred treatment. If PDT is unavailable, chronic CSC with focal, non-central leakage on angiography may be treated using conventional laser photocoagulation. CSC with concurrent macular neovascularization should be treated with half-dose/half-fluence PDT and/or intravitreal injections of an anti-vascular endothelial growth factor compound. Given the current shortage of verteporfin and the paucity of evidence supporting the efficacy of other treatment options, future studies-ideally, well-designed randomized controlled trials-are needed in order to evaluate new treatment options for CSC

Pilot randomised controlled trial of face-down posturing following phacovitrectomy for macular hole

BACKGROUND: To gather information on the effect of postoperative face-down posturing following combined phacoemulsification and vitrectomy for macular hole surgery in order to assist in the design of a larger definitive study. METHODS: Thirty phakic patients with stage II–IV full-thickness macular hole had combined phacoemulsification and pars plana vitrectomy with internal limiting membrane peel and 14% perfluoropropane (C(3)F(8)) gas. At the conclusion of surgery, patients were randomised either to face-down posture or to no posture, for 10 days. The primary outcome was macular hole closure. RESULTS: The macular hole was successfully closed in 93.8% of the face-down posture group and in all of the no-posture group. Mean visual improvement was 0.63 (SD=0.21) logMAR units in the face-down group and 0.53 (SD=0.22) in the no posture patients. CONCLUSION: Following combined phacoemulsification and vitrectomy, postoperative face-down posturing appears to make little difference to the final anatomical or visual outcome. If we assume a success rate of 95% in the posturing arm, and that there is no difference between posturing and non-posturing, then 798 patients would be required to be 90% sure that the 95% confidence interval will exclude a difference of more than 5%