Browsing by Author "Sivaprasad, Sobha"

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    Current and new concepts in the diagnosis and management of diabetic macular oedema
    (Cranfield University, 2013) Jyothi, Sreedhar; Bailey, Tracey A.; Sivaprasad, Sobha
    Diabetic macular oedema, which can cause rapid visual deterioration, may not have early warning signs at times. Assessment of diabetic retinal complications is made chiefly by clinical examination combined with optical coherence tomography (OCT) and fundus fluoroscein angiography (FFA). However, assessment usually does not occur until the late stages of diabetic retinopathy (DR), and, as retinal neurologic changes precede clinical changes, as tested in this thesis, by the time clinical assessment is performed, much of the functional visual loss has already occurred. More robust diagnostic modalities are required to detect progression of retinopathy in the early stages, before irreversible damage has already happened, and advances in the treatment of diabetic macular oedema is imperative as the current standard treatment in the form of laser photocoagulation is ineffective in improving the vision as authenticated in the following chapters. In this thesis, both treatment and diagnostic strategies of diabetic macular oedema (DMO) are investigated. Although laser photocoagulation is effective in short term in treating diabetic macular oedema, its mechanism of action is unknown; is associated with considerable collateral damage; and long term visual prognosis is meagre at a mean change in visual acuity at 5 years of -5.23. The 3-year outcome was also inferior to the clinical trial results with more people gaining vision (≥ 15 letter gain) in the diabetic retinopathy clinical research network (DRCRN) group compared to this cohort (26% versus 9%). Furthermore, three times more patients lost vision (> 15 letter loss) in the real-life setting of this cohort compared to the clinical trial results of the DRCRN group (27% versus 8%, respectively). Therefore, improved preventative and treatment modalities are essential to prevent progression in the early stages and to improve functional vision in late stages. In an attempt to look for new treatment strategies, we hypothesized that retinal oxygenation by inhibition of dark adaptation in the rod photoreceptor, could possibly inhibit progression of diabetic maculopathy. Illuminated-mask treatment of individuals with early diabetic maculopathy revealed encouraging results that point to an inexpensive and non-invasive therapy. Whilst 19 out of 34 study eyes with cysts at the beginning of the trial improved, 11 out of 30 fellow eyes with no demonstrable cysts at the onset developed cystic macular changes towards the end of 6 month trial. In the final chapters the correlation of visual functions with anatomic appearance were examined. The results of functional assessments, including visual acuity, colour contrast sensitivity, and microperimetry, had variable relation to structural changes at the macula with OCT. Therefore, an urgent need remains for the development of reliable diagnostic and preventative tools for the early assessment and treatment of visual function defects related to diabetic macular oedema.
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    Investigations of a possible link between age-related macular degeneration and atherosclerosis
    (Cranfield University, 2005-08) Sivaprasad, Sobha; Bailey, Tracey A.; Chong, Victor N. H.; Woodman, Anthony C.
    Increasing epidemiological evidence suggests a link between atherosclerosis and age-related macular degeneration (AMD). There are two main hypotheses that explain the link. One hypothesis is that AMD and atherosclerosis are tissue responses to injury. The ‘Response to Injury’ hypothesis defined as ‘abnormal reparative response to chronic, recurrent injurious stimuli’ speculates that AMD and atherosclerosis may be cellular effects of chronic or repetitive risk factors. The second hypothesis suggests that AMD is secondary to vascular insufficiency caused by atherosclerosis. The research in this thesis is an attempt to test these hypotheses to better understand the correlation of AMD and atherosclerosis. Both basic and clinical science approaches are employed. Part one focuses on the role of extracellular matrix (ECM) proteins in the pathogenesis of AMD. Both serum elastin derived peptides (S-EDP) and matrix metalloproteinases (MMP-2 and MMP-9) are raised in subjects with atherosclerosis. The circulating levels of these matrix components were tested in patients with varying degree of severity of AMD and compared to age-matched controls. Both S-EDP and MMP-9 were found to be significantly raised in patients with AMD, while MMP-2 did not correlate with it. S-EDP is elevated in abdominal aortic aneurysm (AAA), a manifestation of atherosclerosis. Since S-EDP correlates with size of both AAA and severity of AMD, this research looked at a possible association between the two diseases but found no significant correlation. The second part of this thesis investigates whether chronic inflammation may explain the co-existence of the two diseases. With the recent finding that Complement Factor H (CFH) is related to AMD, this study focused on the role of complement activation in AMD, speculating that the final common pathway of both diseases may be chronic inflammation. Increased systemic complement activation was found in neovascular AMD, as assessed by the measurement of C3a des Arg. Part three of this thesis tested the second hypothesis that AMD is secondary to the vascular insufficiency caused by atherosclerosis. Both the choroidal blood flow and retinal vessel calibre in patients with asymmetric AMD were studied and no significant changes in ocular haemodynamics were noted. In conclusion, this research favours the concept that atherosclerosis and AMD are parallel responses to chronic, recurrent injurious stimuli, with extracellular matrix remodelling and probably inflammatory response being the common cellular responses. This research did not find any significant ocular haemodynamic changes in subjects with asymmetric AMD.
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    Investigations of the inflammatory pathogenesis of age related macular degeneration and a therapeutic role for Minocycline
    (Cranfield University, 2015-03) DaCosta, Joanna; Cellek, Selim; Sivaprasad, Sobha
    Age related macular degeneration (AMD) is the leading cause of blindness in people over the age of 50 in the western world. The wet form of AMD is associated with choroidal neovascularisation. The pathogenesis of choroidal neovascularisation is complex involving neovascular growth, vascular leakage, hypoxia and inflammation. Evidence suggests that immunological events play a key role in the pathogenesis of AMD. In AMD a chronic low grade inflammatory process may instigate the pathophysiological process culminating in eventual visual loss. Minocycline is a tetracycline derivative with anti-inflammatory in addition to antibiotic effects. This study investigated the effects of minocycline on retinal pigment epithelial cells in culture. Cell viability and apoptosis was studied with flow cytometry. Cells were exposed to glycated albumin and hypoxia as these processes occur during ageing. The effects of minocycline on IL-8 and MCP-1 production from ARPE-19 cells in culture were investigated with enzyme linked immunosorbent assay. The results showed a potential narrow therapeutic window for minocycline to act on retinal pigment epithelial cells. Cell viability decreased rapidly at minocycline doses above 5μM. Minocycline suppressed the production of inflammatory cytokines IL-8 and MCP-1 in cell culture. A clinical trial was conducted to investigate whether combination therapy aimed at targeting different pathways in the AMD disease process would be effective. This trial was powered to determine adverse events when a quadruple therapy ii of reduced fluence photodynamic therapy (PDT), intravitreal ranibizumab, dexamethasone and oral minocycline were used as treatments. The clinical trial demonstrated that anti-VEGF treatment administered in combination with other agents was not as effective as monthly anti-VEGF monotherapy at sustaining visual improvement. However, the trial did demonstrate that combination therapy could be delivered safely. The results demonstrate that minocycline has a potential therapeutic role for the inflammatory changes in neovascular age related macular degeneration.