Laskaratos, G; (2014) What are the major susceptibility factors for glaucoma progression? Doctoral thesis (PhD), UCL (University College London).

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Abstract

Elevated intraocular pressure (IOP) is a major risk factor for open angle glaucoma (OAG) and medical IOP reduction is the standard treatment, yet no randomised placebo-controlled study of medical IOP reduction has been undertaken previously. In the present thesis, the methodology, baseline characteristics and results from the United Kingdom Glaucoma Treatment Study (UKGTS), the first randomised, double-masked, placebo-controlled, multicentre treatment trial for OAG, are presented. Survival analysis shows a statistically significant difference in the time from baseline to the event of confirmed visual field progression in the medical treatment (latanoprost) group, as compared to placebo, over 24 months. The role of average IOP during follow-up, as a risk factor for progression, is evaluated. Median IOP, as measured by Goldmann Applanation Tonometry (GAT), Dynamic Contour Tonometry and the Ocular Response Analyzer, is significantly, but weakly, correlated with visual field progression. Corneal compensated IOP (IOPcc) is the best predictor of progression across all the UKGTS sites. While the addition of central corneal thickness (CCT) slightly improves the GAT IOP prediction model, CCT on its own is not a significant predictor of progression in the UKGTS. The role of mitochondrial dysfunction and oxidative stress as risk factors for glaucoma progression is investigated within an exploratory study. Experiments conducted on the lymphocytes of healthy subjects and patients, contrast individuals at the extremes of IOP susceptibility: rapidly progressing patients with Normal Tension Glaucoma (NTG) and non-progressing patients with Ocular Hypertension (OHT). The experimental data presented show, for the first time, that OHT patients may have more efficient mitochondria at a systemic level, when compared to age-similar NTG subjects and nonglaucomatous controls. Overall, OHT lymphocytes produce higher levels of ATP (Complex I and Complexes II/III), have higher mitochondrial membrane potential, enhanced capacity to deal with exogenous oxidative stress insults, higher serum levels of urate, a potent antioxidant, and are more capable of taking up and buffering cytosolic calcium, as compared to NTG and control lymphocytes. Lymphocytes from NTG patients, when compared to the OHT and control groups, show lower ATP synthesis from Complex IV, lower aconitase activity, lower serum levels of vitamin C, and enhanced antioxidant defence (SOD2). In conclusion, this study implicates the role of a) systemic oxidative damage and complex IV-linked mitochondrial defects in the pathogenesis of NTG and b) efficient systemic mitochondria in resistance to glaucomatous optic neuropathy development and progression, particularly in the context of OHT.

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