Acute infective conjunctivitis (AlC) is a common self-limiting condition presenting to general practice. However, evidence is limited on GPs current management of AlC, patients' understanding of conjunctivitis or the most appropriate management strategy for AlC in general practice. The aims of this thesis where to: 1) To determine GPs' current management strategies for AlC 2) To gain an understanding of patients concerns and beliefs about AlC and develop a patient information leaflet (PIL). 3) To assess the effect of common management strategies for AlC on symptom resolution and patients belief in antibiotics. Three complementary studies were used: 1) A postal survey of 300 GPs regarding their diagnosis and management of AlC. 2) A qualitative study involving interviews with 25 patients to explore conjunctivitis from the patients' perspective. 3) An open randomised controlled tria~ with 307 recruits, to assess the effect of different management strategies (immediate, delayed or no offer of antibiotics; a patient information leaflet and an eye swab) for AlC in general practice. The results were: 1) Survey: 95% of responding GPs usually prescribe topical antibiotics for AlC despite 58% stating that they thought at least half of the cases they see are viral in origin. Only 36% of GPs believed they could discriminate between viral and bacterial infection 2) Qualitative study: patients regarded conjunctivitis as a minor illness although some considered it might become more serious if not treated. They stated a preference not to take medication but believed that conjunctivitis would not clear without treatment. However, they were open to alternative management approaches (e.g. delayed prescription approach) because they trusted their GPs judgement. Once aware of the selflimiting nature of conjunctivitis, patients felt they would prefer to wait a few days to see if it improved before seeking medical advice even if this resulted in a few more days of symptoms. 3) Randomised trial: different prescribing strategies did not affect symptom severity in the ftrst 3 days, but duration of moderately bad symptoms was less with antibiotics (control 4.83 days, immediate 3.26 days (p=O.OOl), delayed 3.86 days (p=O.002)). Compared with no initial offer of antibiotics, antibiotic use was higher in the immediate group (control 30%, immediate 99% (p=0.001), delayed 53% (p=O.004)) as was belief in the effectiveness of antibiotics (control 47%, immediate 67% (p=0.03); delayed 55% (p=0.35)) and intention to re-consult (control 40%, immediate 68% (p=0.001), delayed 41 % (p=0.98)). A patient information leaflet or an eye swab had no affect on the main outcomes, but an eye swab seemed to increase patient worry about AlC and a PIL seemed to increase satisfaction with the consultation and the amount of information received. Re-attendance in the next two weeks was less in the delayed group (delayed OR 0.33 (0.11;0.98); immediate OR 0.65 (0.26; 1.63)). In conclusion: Most general practitioners prescribe topical antibiotics for most cases of acute infective conjunctivitis -a self-limiting condition. Most patients are unaware of the self-limiting nature of AlC. A delayed prescribing approach is probably the most appropriate strategy to use for the management of acute conjunctivitis in primary care - it reduces antibiotic use by nearly 50%, shows no evidence of 'medicalisation', provides similar symptom duration and severity to immediate prescribing and reduces re-attendance in the short term compared with no offer of antibiotics.

Nystagmus is a disorder of eye movement characterised by irregular, uncontrolled and repetitive eye movements. It can occur in a broad spectrum of clinical situations and diseases or it may occur in isolation and an inherited disorder. Surprisingly little is known about the underlying mechanisms of ocular-motor control. Similarly, the pathophysiological mechanisms underpinning nystagmus is also poorly understood. By studying pedigrees in whom nystagmus seems to be inherited as an isolated trait (Congenital Idiopathic Nystagmus), it may be possible to identify some of the genetic causes of this disorder and subsequently understand the pathophysiology. This thesis describes a molecular genetic study of congenital nystagmus. A clinical phenotyping study is followed by linkage analysis and positional cloning. A novel nystagmus gene is investigated in a large cohort of Congenital Idiopathic Nystagmus (CIN) patients and X-inactivation studies are performed. Subsequently, cell culture and RT-PCR work is performed to study expression of this gene. Additionally a pedigree with an atypical congenital nystagmus disorder is investigated and a new mutation within a known cerebellar disease gene is identified. This work contributed to the identification of the first gene for Congenital Idiopathic Nystagmus (CIN). The first detailed temporal expression study of the FRMD7 nystagmus gene was also performed in this study which has directed further studies into the pathogenesis of CIN. Identification of a new mutation in the CACNA1A gene in a pedigree with nystagmus and subtle cerebellar signs has lead to the consideration of this gene in patients who present to hospital with isolated atypical nystagmus.

Chronic Open Angle Glaucoma (COAG) refers to a chronic progressive condition that is characterised by damage to the optic nerve, resulting in peripheral visual loss that can progress to involve the fovea and central vision; subsequently causing blindness. COAG is reported to have a poor level of adherence to treatment due to its asymptomatic nature. In this study, a Glaucoma Expert Patient Programme (GEPP) demonstrated new ways of improving patients' experience and adherence to COAG treatment. The research has employed an Information-Motivation-8ehavioural Skills Model to understand the association between knowledge, motivation and behavioural skills in an attempt to improve adherence amongst recently diagnosed patients. Patient participation was at the heart of every component of the study. In this research, four Expert Patients were trained and supported to deliver an educational programme (termed the GEPP) to 25 recently diagnosed patients with COAG (Intervention Group) and then a comparison was made to 25 participants (Control Group) that were also recently diagnosed with COAG but did not receive the educational programme. Three pre and post educational programme validated questionnaires were used to measure patients' knowledge, satisfaction and adherence at baseline and then discern changes at 1 month and 6 months follow up to the GEPP intervention. Staff (N = 10), Expert Patient (N = 4), Intervention Group (N=10) and Control Group (N=10) semi-structured interviews were also conducted to obtain deeper insight into their experiences of engaging in the programme. Data analysis indicated IMPROVING AWARENESS was the main theme that emerged supported by three subthemes: knowledge, satisfaction and adherence. This research has taken the Patient-Patient relationship to a higher level. It is viewed that the Expert Patients' experience is crucial and valuable to improving the experience, knowledge and adherence of newly diagnosed patients with COAG. The GEPP delineated in this study provided insight regarding individuals' life experiences of living with and managing chronic complex glaucoma. Implications for practice relate to the development of tailored educational programmes. This research contributed new knowledge to improving the adherence practices of glaucoma patients. It also demonstrated the value of Expert Patients' experience and their contribution to assisting newly diagnosed patients in self-managing their COAG.

Age-Related Macular Degeneration (ARMD) is the most common cause of legal blindness in the elderly in the western world. One of the earliest signs of aging is the accumulation of lipid rich debris within and underneath the Retinal Pigmented Epithelium (RPE) cells, known as “drusen”. The disease is poorly understood - mainly because it occurs late in life as well as the lack of appropriate cell and animal models. RPE lipo-toxicity (the increased content of lipids within the RPE cell) is suggested to be a major factor affecting both the molecular mechanisms and the metabolic responses of the RPE cells leading to changes associated with drusen formation and ARMD pathology. To investigate this phenomenon, aged ARPE-19 cultures were induced to long term lipid loading with a free fatty acids (FFAs) mixture to ensures the increase of the intra-cellular lipid level within the cells. The accumulation of lipids was found to correlate with a destruction of the ARPE-19 monolayer integrity, an increase in VEGF-A secretion in media and most importantly the production of sub-RPE deposits positive for apolipoprotein E, vitronectin and Amyloid beta 1-42, all of which are prominent constituents of drusen, supporting the hypothesis of lipo-toxicity. To further investigate the effect of inflammation in ARMD, we introduced the aged ARPE-19 cell cultures to long term complement activation in the presence and absence of lipid loading. Complement activation showed protective response suggesting that the complement system plays a secondary modulating response role to a primary destructive initiator “lipid loading”. These findings suggest the use of aged ARPE-19 cell culture as a promising model for ocular aged related diseases study including drusen deposition mechanisms, while the use of ARPE-19 lipo-toxicity model will facilitate the analysis of molecular and cellular characteristics of ARMD pathogenesis, augmenting the therapeutic strategies for dry ARMD.

The core function of optometrists is the prescribing of spectacles in order to alleviate symptoms and improve visual function. Most commonly, the spectacles are used to correct refractive errors and, less frequently, they are also used to correct a decompensated heterophoria. Whilst identifying and diagnosing a marked refractive error or decompensated heterophoria is relatively straightforward, the management of marginal or borderline cases is much more difficult, for there is no clear cut-off point between normality and abnormality. The literature search in this thesis reveals a lack of evidence-based research on the criteria for determining when a refractive or prismatic correction is required. The aim of the present research was to investigate at what point optometrists currently decide to prescribe spectacles in borderline cases, and to see if current prescribing habits relate to the advice given in the literature. Further aims were to investigate whether the correction of borderline refractive errors and decompensated heterophoria improves reading performance, and to investigate any association between an improvement in reading performance and symptoms. A practitioner survey was given to practitioners attending CET events during 2001 and to the UK Optometry E-mail discussion list. A wide variety of prescribing criteria were reported from the 37 respondents, and the presence of symptoms greatly influenced the decision to prescribe. Practitioners reported that their likelihood of prescribing when symptoms are present exceeded 50% for: horizontal aligning prism of ≥ 1.5Δ, vertical aligning prism ≥ 1.0Δ, hypermetropia of ≥ +0.75, reading additions of ≥ +0.75DS and astigmatism of ≥ -0.75DC. For asymptomatic patients, practitioners’ likelihood of prescribing exceeded 50% for: reading additions of ≥+1.50DS and astigmatic corrections of ≥-1.50DC. In the absence of symptoms, optometrists would not regularly correct any degree of hypermetropia or aligning prism up to the limits of the survey. In a prospective clinical trial, 58 subjects with decompensated heterophoria and 208 subjects with borderline refractive errors had their reading performance assessed with the Wilkins Rate of Reading Test both with the refractive or prismatic lens in place and with a placebo control lens using a double-masked randomised design. Analysis of the data indicated that prescribing prism for decompensated exophoria of 2Δ, a reading addition of +1.00DS and correcting oblique cylindrical errors is likely to result in an improvement in reading performance. Correlations between symptoms and the change in reading performance with small refractive or prismatic corrections were very weak. It is concluded that the correction of borderline decompensated heterophoria and refractive errors can improve rate of reading. Guidelines are suggested for the correction of these anomalies that are based on the present data on visual performance, as well as the literature on the effect of these anomalies on symptoms.

Background / Aims: Maternal drug misuse in pregnancy is a significant clinical and public health problem. Consequences for the newborn infant include prematurity, intrauterine growth restriction (IUGR) and neonatal abstinence syndrome (NAS). There is increasing evidence that maternal drug misuse in pregnancy may have longer term adverse effects on infant visual and neurodevelopmental outcome. Most of the evidence regarding visual outcomes in particular derives from small uncontrolled studies with a lack of adequately powered, controlled studies to date. The visual evoked potential (VEP) can be used to assess the integrity and maturity of the infant visual pathway and both visual and neurodevelopmental abnormalities can be predicted by abnormal VEPs in infancy. Drug misuse is also associated with alteration of the VEP in adults and in animal models. Many drugs used in pregnancy can cross the placenta and enter the fetal circulation, including illicit drugs and prescribed methadone, which is the currently recommended treatment for pregnant opiate-dependent women. Hitherto few studies have investigated the effects of maternal drug misuse upon the newborn infant VEP. This study investigates in detail the effects of prescribed methadone and additional illicit drug use in pregnancy upon the infant VEP recorded at birth and at six months of age, and explores any association with NAS. The range and incidence of visual and neurodevelopmental abnormalities at six months of age is described, and how these relate to a history of NAS and the pattern of in utero drug exposure is explored. Pilot work: Pilot work demonstrated the feasibility of recording neonatal flash VEPs in a small group of infants exposed to methadone in utero, and showed that drug exposed infants had abnormal VEPs compared to unmatched controls. A further pilot study described longer term visual outcomes, which included nystagmus, reduced visual acuity and strabismus, in a selected group of infants and children exposed to methadone in utero, thus informing clinical and electrophysiological assessment at six months of age. The pilot studies were followed by a major prospective cohort study. Prospective Study: One hundred and two term infants of mothers prescribed substitute methadone during pregnancy and 50 comparison infants matched for birth weight, gestation and socio-economic group were recruited in the neonatal period. Flash and flicker VEPs were recorded from the occipital scalp of infants within three days of birth. Drug exposure was determined by maternal history, maternal and infant urine and meconium toxicology. Excess alcohol exposure in utero was determined by elevated fatty acid ethyl esters in meconium. Neonatal flash VEPs were classified as mature, typical, or immature according to waveform morphology, and amplitude and latencies measured. Flicker VEPs were analysed using a fast-Fourier transformation and responses at each flicker frequency determined. The same cohort of drug-exposed and comparison infants was invited for clinical visual evaluation at six months of age in conjunction with pattern-onset VEPs and Griffiths developmental assessment. Results: Neonatal testing: Neonatal VEPs were successfully recorded from 100 drug-exposed infants and 50 matched comparison infants at a median age of 24 hours (IQR 13-44). Gestational age, birth weight and socio-economic group did not differ between groups. Flash VEPs from methadone-exposed infants had fewer P1 components (p=0.001), and were more likely to be of immature waveform (p<0.001) compared to comparisons. VEPs from methadone-exposed infants were also smaller in overall amplitude (median 27µV vs 39.5µV, p<0.001). The relative risk of an abnormal VEP in the methadone-exposed cohort was 5.6 with an attributable risk percent of 82%. The majority of infants were exposed to illicit drugs in addition to prescribed methadone, most commonly opiates (74%) and benzodiazepines (66%). VEPs did not differ between infants exposed to opiates only, those additionally exposed to benzodiazepines and those exposed to stimulants. Regression analysis confirmed that the difference in VEP parameters between drug-exposed and comparison infants was associated with methadone exposure and not other drugs of misuse. 48% of the methadone-exposed cohort developed NAS requiring pharmacological treatment; there was no association between neonatal VEPs and subsequent onset or severity of NAS. Flicker VEP analysis demonstrated an optimal flicker frequency of 4.6 Hz in both groups, but there were few differences in the proportion of responses between groups. Six month follow-up: Retention rate to six month follow-up was 79% for the methadone-exposed cohort and 52% for comparison infants. Age at assessment (median 27 weeks, range 26-30 wk), weight and OFC did not differ between groups. The demographic characteristics of comparison infants who were followed up were compared to those of comparison infants who were not followed up. There were no significant differences in birth weight (2 sample t-test p=0.445), OFC (2 sample t-test p=0.712), gestation (Mann-Whitney test p=0.984), 5-minute Apgar score (Mann-Whitney test p=0.263) or DEPCAT score (Mann-Whitney test p=0.258) between groups. Methadone-exposed infants were more likely to have visual abnormalities than comparison infants, even after correcting for excess in utero alcohol exposure (40% vs 8%; adjusted p=0.007). Abnormalities in the methadone-exposed cohort included nystagmus (11%), strabismus (25%) and reduced visual acuity (22%). The relative risk of an abnormal visual outcome in the methadone-exposed cohort was 5.1 with an attributable risk percent of 80%. Electrophysiological abnormalities persisted at six months of age: methadone- exposed infants had smaller amplitude pattern VEPs (25 μV vs 34 μV; p=0.005) with delayed peak latencies (115ms vs 99ms; p=0.019) and fewer responses at the small check size (p=0.003), compared to controls. Methadone-exposed infants had significantly lower neurodevelopmental scores compared to comparison infants (GQ 97 for cases vs 105 for controls; p<0.001), even after correcting for maternal smoking, antidepressant treatment and excess alcohol consumption during pregnancy. Infants exposed to poly-drug misuse and treated for NAS in the newborn period performed particularly poorly on their neurodevelopmental scores. Visual impairment was an independent predictor of poor neurodevelopmental outcome and most infants scoring <85 on neurodevelopmental assessment had co-existing visual problems. Conclusions: In utero exposure to prescribed methadone and other substances of misuse is associated with an alteration in visual electrophysiology in the newborn period suggestive of immature visual maturation. These changes are independent of additional benzodiazepine or stimulant exposure, and appear to be associated with prescribed substitute methadone. At six months of age, there is a high incidence of clinical visual abnormalities in infants exposed to methadone and other drugs of misuse in utero. Persistence of electrophysiological abnormalities beyond the neonatal period suggests that opiates may have a longer term effect on the developing visual system. Drug-exposed infants also have poorer neurodevelopmental scores than matched comparison infants after correcting for maternal smoking and excess alcohol intake. The bias of loss to follow-up was minimised by the high retention rate of drug-exposed infants. Although there was a higher loss of comparison infants, there were no differences in demographic characteristics between comparison infants followed up and those not followed up, suggesting the groups were similar. In addition, published data suggest the incidence of visual abnormalities described in the comparison population to be representative of the larger population.

With the help of modern technology, blindness caused by retinal diseases such as age-related macular degeneration or retinitis pigmentosa is now considered reversible. Scientists from various fields such as Neuroscience, Electrical Engineering, Computer Science, and Bioscience have been collaborating to design and develop retinal prostheses, with the aim of replacing malfunctioning parts of the retina and restoring vision in the blind. Human trials conducted to test retinal prostheses have yielded encouraging results, showing the potential of this approach in vision recovery. However, a retinal prosthesis has several limitations with regard to its hardware and biological functions, and several attempts have been made to overcome these limitations. This thesis focuses on the biological aspects of retinal prostheses: the biological processes occurring inside the retina and the limitations of retinal prostheses corresponding to those processes have been analysed. Based on these analyses, three major findings regarding information processing inside the retina have been presented and these findings have been used to conceptualise retinal prostheses that have the characteristics of asymmetrical and separate pathway stimulations. In the future, when nanotechnology gains more popularity and is completely integrated inside the prosthesis, this concept can be utilized to restore useful visual information such as colour, depth, and contrast to achieve high-quality vision in the blind.

Idiopathic intracranial hypertension (IIH) is common in obese women and can lead to significant visual impairment. The cause of IIH is unknown and management controversial, due to the lack of prospective trials. This thesis provides a comprehensive review of the aetiology and management of IIH. The hypothesis that IIH is associated with a pro-inflammatory cytokine profile, suggested by its established association with female gender and obesity, was tested. Laboratory studies demonstrated the novel finding of elevated leptin in the cerebrospinal fluid from women with IIH, suggesting a role in the pathogenesis of IIH. The first randomised controlled trial in IIH is then reported. Treatment with acetazolamide was examined prospectively in 50 patients, providing seminal information to guide the design of future large-scale trials and data on the natural history of the condition. The observation that management of IIH is guided by a variety of clinical parameters was translated into a simple composite scoring system which was prospectively tested. Visual fields and optic disc appearance are shown to have the greatest influence on clinical outcome. Finally, a systematic study of the evaluation of papilloedema in IIH highlights the major limitations of the widely adopted Frisen staging scheme in the condition.

Idiopathic intracranial hypertension (IIH) is a blinding condition amongst the young obese female population characterised by elevated intracranial pressure (ICP). The aetiology of IIH is not known and, as highlighted in the 2005 Cochrane review, an evidence base for treatment has not been established, although weight loss is frequently advocated. Obesity is associated with dysregulation of cortisol metabolism by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Additionally, 11β-HSD1 has a role in the regulation of intraocular pressure. This thesis hypothesised that 11β-HSD1 is involved in the aetiology of IIH and examined the roles of obesity, 11β-HSD1 and metabolic changes in the pathogenesis and treatment of IIH. We demonstrated that ICP regulating structures (choroid plexus and arachnoid granulation tissue), are potential glucocorticoid target tissues expressing 11β-HSD1. Metabolomic analysis identified a unique biofluid metabolite biomarker profile, with potential implications for IIH pathogenesis. We established the therapeutic efficacy of weight loss in IIH (improving headaches, papilloedema and ICP) and provided evidence that the beneficial effects may relate to alterations in the glucocorticoid profile driving 11β-HSD1 and potentially, 5α reductase. These studies have started to address the important issues of causation and treatment in IIH and provide avenues for future research into this complex condition.

Vigabatrin, a GABA (γ-aminobutyric acid) agonist is a drug widely prescribed in Europe and Asia between 1989 and 1997 for drug resistant, partial epilepsy and has been associated with visual field defects. Uncertainity in the effect of Vigabatrin on vision resulted in decreased prescriptions. However, there has been poor reproducibility in previous studies due to many factors, especially poor sensitivity and specificity of tests for Vigabatrin associated visual dysfunction. The wide field multifocal electroretinogram (WF-mfERG) can objectively measure discrete areas of retinal function up to 90 degrees. The results of 204 patients with epilepsy divided into four groups are presented. A subgroup of 89 patients had repeat investigations. The patients were divided into four groups. Group 1.The Vigabatrin group comprised patients who had been taking Vigabatrin for at least 1 year (56 patients). Group 2. Forty nine patients who had previously taken Vigabatrin for at least 1 year but had stopped taking this treatment for at least 2 years comprised the ex-Vigabatrin group. Group 3.The GABA group had 46 patients who used other anti-epileptic drugs (AED) with GABA action other than Vigabatrin. Group 4. Fifty three patients who had never used an AED with GABA action including Vigabatrin made up the non-GABA group. Surprisingly, the percentage of patients with visual field defects were high in all groups investigated (Vigabatrin group 59%, ex-Vigabatrin group 46%, GABA group 30.2% and non-GABA group 21.2%). However, abnormal bilateral WF-mfERG responses were only found in the Vigabatrin group (48%) and the ex-Vigabatrin group (22%). The study suggests that there are probably different causes of visual field abnormalities in patients with epilepsy not related to Vigabatrin. We propose that the most sensitive and specific tests that can be used to detect visual dysfunction associated with Vigabatrin is the WF-mfERG