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The multifocal electroretinogram (mfERG) provides spatial and temporal information on the retina’s function in an objective manner, making it a valuable tool for monitoring a wide range of retinal abnormalities. Analysis of this clinical test can however be both difficult and subjective, particularly if recordings are contaminated with noise, for example muscle movement or blinking. This can sometimes result in inconsistencies in the interpretation process. An automated and objective method for analysing the mfERG would be beneficial, for example in multi-centre clinical trials when large volumes of data require quick and consistent interpretation. The aim of this thesis was therefore to develop a system capable of standardising mfERG analysis. A series of methods aimed at achieving this are presented. These include a technique for grading the quality of a recording, both during and after a test, and several approaches for stating if a waveform contains a physiological response or no significant retinal function. Different techniques are also utilised to report if a response is within normal latency and amplitude values. The integrity of a recording was assessed by viewing the raw, uncorrelated data in the frequency domain; clear differences between acceptable and unacceptable recordings were revealed. A scale ranging from excellent to unreportable was defined for the recording quality, first in terms of noise resulting from blinking and loss of fixation, and secondly, for muscle noise. 50 mfERG tests of varying recording quality were graded using this method with particular emphasis on the distinction between a test which should or should not be reported. Three experts also assessed the mfERG recordings independently; the grading provided by the experts was compared with that of the system. Three approaches were investigated to classify a mfERG waveform as ‘response’ or ‘no response’ (i.e. whether or not it contained a physiological response): artificial neural networks (ANN); analysis of the frequency domain profile; and the signal to noise ratio. These techniques were then combined using an ANN to provide a final classification for ‘response’ or ‘no response’. Two methods were studied to differentiate responses which were delayed from those within normal timing limits: ANN; and spline fitting. Again the output of each was combined to provide a latency classification for the mfERG waveform. Finally spline fitting was utilised to classify responses as ‘decreased in amplitude’ or ‘not decreased’. 1000 mfERG waveforms were subsequently analysed by an expert; these represented a wide variety of retinal function and quality. Classifications stated by the system were compared with those of the expert to assess its performance. An agreement of 94% was achieved between the experts and the system when making the distinction between tests which should or should not be reported. The final system classified 95% of the 1000 mfERG waveforms correctly as ‘response’ or ‘no response’. Of those said to represent an area of functioning retina it concurred with the expert for 93% of the responses when categorising them as normal or abnormal in terms of their P1 amplitude and latency. The majority of misclassifications were made when analysing waveforms with a P1 amplitude or latency close to the boundary between normal and abnormal. It was evident that the multilayered system has the potential to provide an objective and automated assessment of the mfERG test; this would not replace the expert but can provide an initial analysis for the expert to review.

The ability to examine the appearance of the retina is of paramount importance for the diagnosis and monitoring of ophthalmic disease and for the evaluation of treatment outcomes. Direct cross-sectional imaging of retinal structure could be useful for early diagnosis and more sensitive monitoring of a variety of retinal conditions such as macular oedema and glaucoma. The view of the fundus given by ophthalmoscopy provides very limited depth information and clinicians will often have to resort to additional techniques such as flourescein angiography or visual field testing for information on structural abnormalities within the retina. Other currently available imaging techniques do not provide sufficient depth resolution to produce useful cross-sectional images of retinal structure. Optical coherence tomography (OCT) is a new imaging technique which is capable of producing cross-sectional images of the retina with a resolution that surpasses that of conventional imaging techniques. This new technique has axial resolution of around 1 O.tm and can resolve individual retinal layers, thus providing information on retinal structure. In principle, OCT is very similar to ultrasound however it makes use of a light source rather than an acoustic one. The technique is non-contact and non-invasive and is generally well tolerated by patients. This thesis describes the evaluation of this new imaging technique with regards to its potential within routine clinical practice. A number of investigations were performed to fuffil this evaluation. Tests were carried out to experimentally measure the system's resolution and the accuracy and precision of measurements made from the OCT scans. A number of factors that could affect the quality of the scans were identified and their effects were minimised wherever possible. The software provided with the system was rigorously tested and potential sources of error were identified. Various studies were undertaken to quantify the repeatability and reproducibility of measurements made from scans and normative values were established. These results were used to assess the ability of the technique to detect and quantify several retinal disorders. The potential of the technique for corneal imaging was investigated - a scanning protocol was established and customised software for processing cornea! scans was developed. The relationship between OCT bands and retinal morphology was investigated by correlating scans from canine retina with corresponding light microscopy images and by observing the position of retinal abnormalities on scans from patients with a variety of conditions that affected different parts of the retina. Finally the clinical potential of OCT was investigated by carrying out various studies on a number of retinal conditions. Further clinical studies which combine anatomical information from OCT with functional information from electrophysiology are currently underway. Current developments are aimed at improving the imaging processing features and user interface so as to provide a more robust, user-friendly system for routine clinical use.

Proliferative vitreoretinopathy, a potentially blinding condition, involves excessive proliferation of retinal pigment epithelium (RPE) cells and is the main complication following retinal detachment (RD). Complicated cases of RD are treated with silicone oil (SiO) tamponades which can potentially be used as drug reservoirs. The aim of this study was to investigate different methodologies to develop a sustained and controlled drug release of anti-proliferative and anti inflammatory drugs from SiO tamponades using all-trans retinoic acid (atRA) and ibuprofen (Ibu). In detailed studies of atRA and Ibu, including atRA degradation behaviour, the drugs were found to be non-toxic to an adult RPE cell line (ARPE 19) below 10-5 M. The solubility of both drugs in SiO was assessed using radioisotope techniques. Prodrugs of atRA and Ibu were synthesised via conjugation to polyethylene oxide (PEO), and cleavage of the resulting ester bond, toxicity towards RPE cells, solubility in SiO and release into media were assessed. Prodrug cleavage was successful in vitro for Ibu but not achieved in the case of atRA due to its highly conjugated nature. Cytotoxicity assays showed PEO attachment had no effect on cytotoxicity and PEO prodrug solubility in SiO followed the expected trend of decreasing solubility with increased PEO chain length. Overall the saturation concentration of drug in SiO achieved through the use of PEO-prodrugs was too low for an effective therapy. Lipophilic prodrugs with a poly(dimethylsiloxane) (PDMS) pro-moiety were synthesised and investigated. Their cleavage was problematic due to PDMS being highly hydrophobic and cleavage could only be achieved in vitro when a small hydrophilic spacer was added between PDMS and the drug. The effects of PDMS prodrugs as additives in SiO were investigated and the presence of PDMS-atRA in SiO was shown to have a positive effect on both atRA solubility and longevity of release. The clinically-relevant release period (6-8 weeks) was independent of atRA starting concentration but dependant on the PDMS-atRA concentration within the blend. This has potential for further development into tamponade drug reservoirs for future patient benefits. A series of linear and branched amphiphilic copolymer architectures were also evaluated as additives for SiO. Monomer selection included oligoethylene oxide methacrylate (OEGMA), 2-hydroxyethyl methacrylate, PDMS-methacrylate (PDMSMA) and the brancher PDMS-dimethacrylate (PDMSDMA). SiO solubility of p(OEGMA-co-PDMSDMA) was investigated and copolymers which contained the smallest hydrophilic and largest lipophilic components only achieved small solubility (0.1 % v/v). To overcome these solubility issues, hydrophobic PDMSMA monomer was utilised. Both linear p(PDMSMA-co-OEGMA) and branched p(PDMSMA-co-OEGMA-co-PDMSDMA) were successfully synthesised and displayed high solubility within SiO, up to 40-50 % v/v. The potential for SiO tamponades as long-acting drug reservoirs has been demonstrated after inclusion of a novel end-modified PDMS additive leading to long term release of atRA. The formation of novel polymer architectures that show considerable miscibility with SiO also shows the scope of the opportunity for further additive development to tailor release profiles.

D.Phil. / That the eye is essentially a first-order optical instrument is evidenced by the success Gaussian optics has met with in optometry and ophthalmology. An unfortunate consequence of this approach is that a brief review of the literature on the topic of intraocular lens power calculation gives one the impression that the character of such a lens is described fully by its dioptric power. This is not so. Indeed, the idea that a thin refracting interface can somehow embody the optical character of the thick intraocular lens can, and in many ways has, limited the scope of intraocular lens power formula. The purpose of this dissertation is to apply the methods of linear algebra to the investigation of the first-order optical character of the stigmatic and astigmatic pseudophakic eye. This work attempts to lay a solid foundation for the study of the pseudophakic eye in the context of first-order astigmatic optics. While the majority of concepts and results of this dissertation are directly applicable to the study of the pseudophakic eye, an attempt has been made to ensure that the methods outlined in this work may be applied to the study of optical systems in the broader context of first-order optics. Central to this work are the members of the non-abelian symplectic group Sp(2n) under the operation of conventional matrix multiplication. The elements are evendimensional, non-singular symplectic matrices with unit determinant which are referred to here as ray transferences. These matrices act on the members of even-dimensional vector spaces so as to preserve a particular skew-symmetric, non-degenerate bilinear pairing referred to as the symplectic form. The laws that govern the operation of these matrices, the three symplectic relations, flow naturally from the structure of the symplectic group. From the ray transference four 2„e 2 fundamental properties of an optical system may be defined, the dilation A , the disjugacy B , the divergence C and the divarication D. A number of additional optical properties can be derived from the fundamental properties. Examples of derived properties include the dioptric power F , the negative of the divergence C and refractive state 0 F . The ray transference is used here in the derivation of a set of new intraocular lens formulae for the pseudophakic eye. These formulae are entirely general, working equally well in both stigmatic and astigmatic pseudophakic eyes in which additional (possibly astigmatic) intraocular devices may already be present. Formulae for both distant and near objects are provided. The constraints under which the divergence of a thick (possibly bitoric) intraocular lens is conserved despite changes in the lens are investigated. Furthermore, the constraints under which the refractive state of the pseudophakic is conserved in spite of changes in the thick intraocular lens are investigated. We find that there exist an infinite number of thick intraocular lenses that will produce a given refractive outcome, say emmetropia, in the pseudophakic eye. The basic theory of matrix differentiation with respect to a scalar variable is utilized in the study of the changes in the optical character of the pseudophakic eye following axial translation of a variety of intraocular lens systems. A novel method of representing the changes in the stigmatic and antistigmatic properties of refraction on account of axial translation and rotation of a toric intraocular lens in the astigmatic eye is presented and numerical examples are provided. The analysis permits the calculation of the ideal axial lens position and orientation in the astigmatic pseudophakic eye. Such methods will prove increasingly important in refractive data analysis, particularly in light of the development of continuously adjustable intraocular devices. / Prof. W.F. Harris

PURPOSE: To investigate the plausibility of clinically significant oxygen toxicity in patients with retinal disorders being treated with hyperoxia therapy. Supplemental oxygen therapy is a promising form of treatment that may help reduce ischemia and the subsequent symptoms in patients suffering from diabetic retinopathy (DR), retinal vein occlusions (RVOs), and age-related macular degeneration (AMD). Currently, few studies perform ongoing assessments of current hyperoxia trials in patient populations. By investigating a current cohort of patients using supplemental oxygen to mitigate symptoms in their ocular conditions, we hope to demonstrate the extremely low likelihood of oxygen toxicity in patients utilizing hyperoxia therapy. Through these results, we hope to demonstrate that supplemental oxygen therapy is a viable, safe method of treatment for patients with ocular disorders. METHODS: A cohort of 16 patients was analyzed for changes in their C Reactive Protein (CRP), white blood cell count (WBC), hematocrit (Hct), and hemoglobin (Hb) levels after continuous use of hyperoxia therapy as part of treatment for varying retinal disorders. All study patients were diagnosed and under treatment at Beth Israel Deaconess Medical Center in Boston, MA. Patients diagnosed with diabetic retinopathy, retinal vein occlusions, or age-related macular degeneration were included in the study. Each of these patients must have also been prescribed 5 L/min of nocturnal hyperoxia therapy. Patients with insufficient data either before or after beginning the hyperoxia therapy were excluded. Primary outcome variables were arranged as pre- and post- hyperoxia therapy data points for CRP, WBC, Hb, and Hct. P-values below 0.05 would indicate statistically significant risk of oxygen toxicity in these variables under the current hyperoxia treatment. RESULTS: The mean age of the sample population was 64, with 6 of the 16 patients diagnosed with diabetes (37.5%). Patient groups were divided into diabetic vs. non-diabetic to assess whether or not one group was affected differently by the hyperoxia therapy. Results showed p-values well over 0.05 for both groups, indicating that oxygen toxicity is not a major risk factor when using supplemental oxygen under the study’s conditions. CONCLUSION: A large number of patients with diabetes suffer from retinal problems, especially with the onset of old age. These problems eventually require treatment via eye injections, laser, and even surgery in order to preserve vision and mitigate edema and ischemia. Given the high cost and invasive nature of these procedures, hyperoxia therapy provides a safe and potentially beneficial alternative to mitigate the symptoms of these disorders. This study hoped to demonstrate the plausibility of widespread clinical application for supplemental oxygen therapy in retina patients, while concluding that oxygen toxicity is not a significant risk factor in this type of treatment. The outcomes of this study support this hypothesis, and lay the groundwork for future studies that may assess the risks of oxygen toxicity on a larger scale. More research is required to gauge the true risks of oxygen toxicity in patients using supplemental oxygen. A case-controlled longitudinal study would also prove useful in providing data on changes in visual acuity and other experimental factors of interest, while accounting for several limitations present in this study. / 2021-06-17T00:00:00Z

The effect of unilateral optic nerve section (UONS) on the susceptibility rat rod photoreceptors to damage by visible light was studied. The optic nerve was cut intracranially by a ventral approach so as not to interfere with structures in the orbit of the eye, the brain or the blood supply to the eye. It was found that retinas with optic nerves cut (ONS) suffered substantially less damage from light than did those with intact optic nerves (ONI) in the same animals or in sham operated animals. The effect occurred in pigmented and albino rats and with varying light damage conditions. / One possible explanation for these results is that fewer photons are being absorbed by the ONS retina because fewer are reaching it or because of changes in retinal photochemistry. Monitoring the behavior of UONS rats during bright light exposure indicated that, if anything, rats tend to allow more light into their ONS eye. By measuring steady state bleach, whole retina dark adapted rhodopsin, and regeneration rate it was found that the same amount of light is absorbed by both retinas of a UONS rat. Parameters which control rhodopsin content were measured in the superior half of the vertical meridian of the retina. These include rod outer segment length, photoreceptor cell density, and rhodopsin packing density. There were no significant differences between the ONS and ONI eyes. So, even in the region of the retina used to assay light damage susceptibility, visual pigment content cannot explain the protective effect of ONS. / Correlations of light damage protection with other changes occurring in the retina after ONS are discussed and a possible neurochemical explanation is presented. / Source: Dissertation Abstracts International, Volume: 49-08, Section: B, page: 2964. / Major Professor: Theodore P. Williams. / Thesis (Ph.D.)--The Florida State University, 1988.

A retrospective case study of 3 patients that developed epithelial ingrowth after laser in situ keratomileusis (LASIK). This study was conducted at Boston Eye Group in Brookline, Massachusetts. The Oculus Pentacam was used to study corneal densitometry for each patient. Corneal densitometry readings were obtained for each patient pre-operatively and post-operatively after ingrowth was discovered. Densitometry was recorded at the central nest of opacity and at the leading edges of the ingrowth. For all patients, the most severe stages of epithelial ingrowth observed on slit lamp photographs correlated to the highest densitometry readings, with peak densitometry ranging from 73.3 - 95.1. These values were much higher than pre-operative densitometry readings, which ranged from 21.8 - 27.2. In two cases, the Pentacam densitometry map revealed progression of ingrowth towards the visual axis that was only faintly detectable or not detectable at all on corresponding slit lamp photographs. Corneal densitometry can be used as an objective measure of the severity and progression of epithelial ingrowth.

The eye is a glucocorticoid target tissue which orchestrates expression of target genes through the glucocorticoid receptor (GR). The classical function of GR involves its interaction with glucocorticoid to influence transcription of genes involved in numerous physiological processes which include inflammation. The first line of defence in the ocular tissues includes the mucosal barrier and expression of receptors that recognise pathogen. These mechanisms activate the innate immune response during inflammation, however, in the ‘normal’ eye, immunomodulatory components exist to promote immune privilege. 11beta hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates cortisol locally in tissues and has already been localised to to some ocular surface and intraocular tissues. The aim of this thesis is to evaluate the functional role of 11β-HSD1 in the eye and the orbit and whether the 11β-HSD1 can be targeted to modify various disease processes in the eye. An animal model was used to characterise the pre-receptor regulation of glucocorticoids and this was further characterised in human ocular and orbital tissues and cells. The results showed that 11β-HSD1 is functional in certain ocular (corneal epithelial, fibroblast and conjunctival fibroblast) and orbital (orbital preadipocyte) cells. The data therefore emphasises the putative role of 11β-HSDs in the ocular and orbital microenvronment.