The financial burden of AMD depends on the stage of AMD present, with considerable costs associated with the late stages of the disease (Schmier and Levine 2013). In 2010, hospital spending on Lucentis was the third highest of all drugs costing the NHS £129 million. When considering early AMD there are no direct non medical costs or indirect costs and changes to visual function have not yet taken place. Treating at the earlier stage of the disease is therefore appealing, but faces a number of challenges. These include the
requirement for clinical measurements for trial outcomes, a greater understanding of the earlier stages of the condition to develop treatments, methods of diagnosing the
condition before clinical signs and symptoms are present.
The principal objective of the research presented in this thesis was to determine the role of retinal hypoxia in visual dysfunction in early AMD. This will help to clarify the role of hypoxia in AMD onset and will determine whether aspects of visual function may be assessed in early AMD as biomarkers for hypoxia in the disease process. This could ultimately lead to the development of clinical tests which are sensitive to desease progression and would hasten the development of new treatments targeted at the early stages of the disease. The specific aims were:
1) To investigate if the dark adapted healthy retina is hypoxic by comparing scotopic thresholds under hyperoxic and normoxic gas conditions.
Hypothesis: the dark adapted retina is on a hypoxic knife edge, however it is hypothesised that in the normal population the oxygen supply meets its needs and therefore there will be no decrease in scotopic thresholds when breathing 60% oxygen, but that there will be an increase in scotopic thresholds when breathing 14% oxygen.
2) To investigate if there is a topographical retinal effect of hyperoxia or hypoxia on scotopic thresholds.
between 9-15 degrees (Feigl et al. 2011; Connolly and Hosking 2008b). Therefore it is hypothesised that hypoxia will affect the retina preferentially at 12 degrees. 3) To investigate the effect of hyperoxia on scotopic threshold of participants with
early AMD.
Hypothesis: As hypoxia has the ability to raise scotopic thresholds in healthy young participants, it could be that hypoxia also causes the rise in scotopic thresholds seen in patients with early AMD. If this is the case then temporarily reducing hypoxia in participants with early AMD, by the inhalation of 60% oxygen, should result in a decrease in scotopic thresholds.
4) To investigate the effect of hypoxia on the scotopic thresholds of participants with early AMD
Hypothesis: A hypoxic episode will cause an increase in scotopic thresholds in both participants with early AMD and age-matched controls, but the effect will be greater in participants with early AMD.
5) To investigate the effect of hypoxia on the amplitude and implicit time of the scotopic full field ERG a-wave and b-wave, and the amplitude and implicit time of the first harmonic of the flicker ERG.
Hypothesis: A hypoxic episode will result in a reduction in amplitude of the
scotopic full field ERG a-wave and a reduction in amplitude and increase in implicit time of the b-wave in participants with early AMD and in the control group. These changes are expected to be greater in the group with early AMD. It is also
hypothesised that there will be a delay in the onset and a reduction in the amplitude of the first harmonic of the flicker ERG.
In order to develop a detailed understanding of the effect of hypoxia and visual function, and its potential influence on the pathogenesis of AMD, two systematic literature reviews were conducted:
1) A systematic literaure review into the effect of hypoxia on visual function.
2) A systematic literature review into the role of hypoxia in early age-related macular degeneration.
2 A review of literature regarding the
effect of hypoxia on visual function and
the role of hypoxia in the pathogenesis
of Age-related macular degeneration.
This chapter summarises the findings from two literature reviews which were conducted on the effect of hypoxia on visual function and the role of hypoxia in the pathogenesis of AMD.
The first section of this chapter will present the findings of a literature review investigating the effect of hypoxia on visual function. This question has been of
longstanding interest since the advent of aviation due to the reduction in atmospheric pressure with increases in altitude, resulting in a decrease in the oxygen concentration of inspired air. As early as 1939, hypoxia was shown to have an effect on many aspects of visual function (McFarland and Evans 1939). As this PhD aims to investigate the effect of hypoxia and hyperoxia on visual function in AMD, it is valuable to review current
understanding of the impact of blood oxygenation in people without the condition.
The second section of this chapter will present the findings of a review conducted to investigate the relationship between hypoxia and AMD. The hypothesis that hypoxia has a role in the pathogenesis of AMD is based on the knowledge that the normal retina is on a
hypoxic knife-edge in the dark (Wangsa-Wirawan et al. 2003; Feigl et al. 2008). The theory suggests that, in early AMD, extra strain is placed upon an already critically limited outer retinal blood supply due to histological changes in the retina and associated structures, including the choriocapillaris and Bruch’s membrane. The resultant hypoxia then causes changes at a cellular level, can upregulate growth factors and also cause apoptosis leading to the signs seen in nAMD and GA respectively (Ambati et al. 2003; Gerona et al. 2010; Guma et al. 2009). Current evidence suggests that there are three potential aetiologies for AMD (i.e. hypoxia, inflammation and oxidation; see section 1.4.4).
However, there are possible overlaps between these putative mechanisms. For example, it has been proposed that inflammation may lead to hypoxia by increasing the metabolic demand of the retina, or that there may be changes in blood vessels secondary to inflammation (Arjamaa et al. 2009). There are also associations between hypoxia and genetics (Feigl 2009), and between the oxidative stress and hypoxia theories, with ROIs being created in hypoxic conditions (Kaur et al. 2008; Arjamaa et al. 2009).
The findings of both studies will be summarised at the end of the Chapter.