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Abstract

Anti-vascular endothelial growth factor drugs (anti-VEGF) are used in the treatment of retinal conditions including neovascular age-related macular degeneration (nAMD), and macular oedema associated with diabetic retinopathy or vein occlusions. Despite the fact that treatment often extends over many years, requiring repeated injections, little is known about the long-term effects on the healthy retina also exposed to the treatment. The aim of this research was to investigate the relationship between cumulative dose of anti-VEGF received and parameters of extramacular function and retinal layer thicknesses in people undergoing treatment for nAMD. Chapter 2 presents a systematic review of the literature conducted to evaluate current evidence regarding the effect of anti-VEGF drugs on peripheral retinal function and structure of animals and humans. The review found that the majority of evidence was not supportive of a detrimental effect of treatment on retinal function or structure. Crucially, however, there were significant limitations in the evidence base available to date. Of particular note was the dearth of studies which evaluated the effect of multiple injections over a prolonged period of time in animals or humans (for example, only 22.5% of the assessed studies followed up the subjects/participants for longer than 9 months after the first anti-VEGF treatment). A few studies with longer follow up times did report a small effect of treatment on retinal function in humans, but sample sizes were small. It was concluded that there is a need for research evaluating the cumulative effect of multiple retreatments of anti-VEGF drugs on retinal structure and function in humans. Chapters 3 and 4 report on aspects of electroretinogram (ERG) protocol development. In Chapter 3 the basic protocol for the PhD research was piloted, and the repeatability assessed. The final protocol consisted of a Transient Cone ERG (ISCEV standard; white 3 cd.s.m-2 stimulus, 4 ms duration, 2 Hz, over a white background of 30 cd.m-2), a flicker ERG (41 Hz, red stimulus peak wavelength 635 nm, 12 ms duration, 41 Hz, mean luminance 30 cd.m-2), and a photopic negative response (PhNR) recorded to a series of stimulus intensities (0.11-3.35 cd.s.m-2 red stimulus, peak wavelength 635 nm, 4 ms duration, 2 Hz, blue LED background, peak wavelength 465 nm, 158.8 scotopic cd.m-2). In Chapter 4, the repeatability of a desktop ERG recording system (Espion™, Diagnosys) was compared to that of a handheld system which uses skin electrodes instead of conjunctival electrodes (RETeval®, LKC). Reliability was found to be similar between the two. Amplitudes, but not times to peak, were substantially different in the hand held device. An electrode placement study aimed to determine the impact of the position of the skin sensor strip when recording ERGs using the handheld RETeval® device. Placement was important with respect to amplitudes – skin surface electrodes recorded lower amplitude values when placed further away from the manufacturer recommended position (2mm below the lower lid margin). However, time to peak was relatively unaffected by electrode position. Chapter 5 presents a cross-sectional study which aimed to investigate the relationship between number of anti-VEGF injections received by people with nAMD and parameters of the full-field ERG and optical coherence tomography (OCT) layer thicknesses (adjacent to the macula). Thirty-two participants were recruited from St Thomas’ Hospital. There was a tendency across all stimulus intensities for PhNR amplitude to reduce with increasing number of injections, a relationship that was statistically significant prior to Bonferroni correction at three intensities. Increasing number of injections was also associated with a reduced thickness of the nasal outer segment layer. Increasing time since first injection was significantly associated with reduced PhNR 0.11 cd.s.m-2 amplitude, and increased Transient Cone ERG b-wave time to peak, as well as reduced nasal nerve fibre layer thickness, photoreceptor outer segment layer thickness and total retinal thickness, and reduced temporal ganglion cell complex thickness, and outer segment thickness. A second study was conducted at a different test site using the RETeval® hand held device, with the aim of determining whether these ERG findings were consistent in a second set of participants (n = 19). There was a trend across all data towards reducing amplitudes and increasing implicit times with increasing number of injections. However, this was only statistically significant for the time to peak of the a-wave in the PhNR ERG protocol. The signal to noise ratio was small, however, and the lower than desired sample size means that this study was not powered to detect weak correlations. To conclude, the cross-sectional analysis of participants undergoing anti-VEGF therapy for nAMD highlighted a possible relationship between number of injections and certain parameters of the full-field ERG and retinal layer thicknesses measured adjacent to the macula. Of particular note was the relationship between PhNR amplitude and number of injections, and the apparent thinning of the photoreceptor outer segments with increasing number of injections and increasing time since first injection. However, the effect size was small. A number of potential confounding variables have been identified, including the effect of the disease process itself on the outcome measures assessed. Furthermore, interpretation of these findings should be made with caution given the low sample size, which limited the ability to detect small and medium effect sizes. The results of this study suggest that it is unlikely that long term anti-VEGF treatment causes a large negative effect on retinal structure or function which may be reassuring to practitioners and patients.

Publication Type:	Thesis (Doctoral)
Subjects:	R Medicine > RE Ophthalmology
Departments:	School of Health & Psychological Sciences > School of Health & Psychological Sciences Doctoral Theses School of Health & Psychological Sciences > Optometry & Visual Sciences

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