Objective methods for anterior ocular grading

This thesis set out to develop an objective analysis programme that correlates with subjective grades but has improved sensitivity and reliability in its measures so that the possibility of early detection and reliable monitoring of changes in anterior ocular surfaces (bulbar hyperaemia, palpebral redness, palpebral roughness and corneal straining) could be increased. The sensitivity of the program was 20x greater than subjective grading by optometrists. The reliability was found to be optimal (r=1.0) with subjective grading up to 144x more variable (r=0.08). Objective measures were used to create formulae for an overall ‘objective-grade’ (per surface) equivalent to those displayed by the CCLRU or Efron scales. The correlation between the formulated objective verses subjective grades was high, with adjusted r2 up to 0.96. Determination of baseline levels of objective grade were investigated over four age groups (5-85years n= 120) so that in practice a comparison against the ‘normal limits’ could be made. Differences for bulbar hyperaemia were found between the age groups (p<0.001), and also for palpebral redness and roughness (p<0.001). The objective formulae were then applied to the investigation of diurnal variation in order to account for any change that may affect the baseline. Increases in bulbar hyperaemia and palpebral redness were found between examinations in the morning and evening. Correlation factors were recommended. The program was then applied to clinical situations in the form of a contact lens trial and an investigation into iritis and keratoconus where it successfully recognised various surface changes. This programme could become a valuable tool, greatly improving the chances of early detection of anterior ocular abnormalities, and facilitating reliable monitoring of disease progression in clinical as well as research environments.

An optical study of human ocular dimensions

Many workers have studied the ocular components which occur in eyes exhibiting differing amounts of central refractive error but few have ever considered the additional information that could be derived from a study of peripheral refraction. Before now, peripheral refraction has either been measured in real eyes or has otherwise been modelled in schematic eyes of varying levels of sophistication. Several differences occur between measured and modelled results which, if accounted for, could give rise to more information regarding the nature of the optical and retinal surfaces and their asymmetries. Measurements of ocular components and peripheral refraction, however, have never been made in the same sample of eyes. In this study, ocular component and peripheral refractive measurements were made in a sample of young near-emmetropic, myopic and hyperopic eyes. The data for each refractive group was averaged. A computer program was written to construct spherical surfaced schematic eyes from this data. More sophisticated eye models were developed making use of linear algebraic ray tracing program. This method allowed rays to be traced through toroidal aspheric surfaces which were translated or rotated with respect to each other. For simplicity, the gradient index optical nature of the crystalline lens was neglected. Various alterations were made in these eye models to reproduce the measured peripheral refractive patterns. Excellent agreement was found between the modelled and measured peripheral refractive values over the central 70o of the visual field. This implied that the additional biometric features incorporated in each eye model were representative of those which were present in the measured eyes. As some of these features are not otherwise obtainable using in vivo techniques, it is proposed that the variation of refraction in the periphery offers a very useful optical method for studying human ocular component dimensions.

Measurement of ocular component contributions to residual astigmatism in adult human eyes

The aim of this study was to determine whether an ophthalmophakometric technique could offer a feasible means of investigating ocular component contributions to residual astigmatism in human eyes. Current opinion was gathered on the prevalence, magnitude and source of residual astigmatism. It emerged that a comprehensive evaluation of the astigmatic contributions of the eye's internal ocular surfaces and their respective axial separations (effectivity) had not been carried out to date. An ophthalmophakometric technique was developed to measure astigmatism arising from the internal ocular components. Procedures included the measurement of refractive error (infra-red autorefractometry), anterior corneal surface power (computerised video keratography), axial distances (A-scan ultrasonography) and the powers of the posterior corneal surface in addition to both surfaces of the crystalline lens (multi-meridional still flash ophthalmophakometry). Computing schemes were developed to yield the required biometric data. These included (1) calculation of crystalline lens surface powers in the absence of Purkinje images arising from its anterior surface, (2) application of meridional analysis to derive spherocylindrical surface powers from notional powers calculated along four pre-selected meridians, (3) application of astigmatic decomposition and vergence analysis to calculate contributions to residual astigmatism of ocular components with obliquely related cylinder axes, (4) calculation of the effect of random experimental errors on the calculated ocular component data. A complete set of biometric measurements were taken from both eyes of 66 undergraduate students. Effectivity due to corneal thickness made the smallest cylinder power contribution (up to 0.25DC) to residual astigmatism followed by contributions of the anterior chamber depth (up to 0.50DC) and crystalline lens thickness (up to 1.00DC). In each case astigmatic contributions were predominantly direct. More astigmatism arose from the posterior corneal surface (up to 1.00DC) and both crystalline lens surfaces (up to 2.50DC). The astigmatic contributions of the posterior corneal and lens surfaces were found to be predominantly inverse whilst direct astigmatism arose from the anterior lens surface. Very similar results were found for right versus left eyes and males versus females. Repeatability was assessed on 20 individuals. The ophthalmophakometric method was found to be prone to considerable accumulated experimental errors. However, these errors are random in nature so that group averaged data were found to be reasonably repeatable. A further confirmatory study was carried out on 10 individuals which demonstrated that biometric measurements made with and without cycloplegia did not differ significantly.

Modelling ocular monochromatic aberrations using schematic eyes with homogeneous optical media

Previous research has indicated that schematic eyes incorporating aspheric surfaces but lacking gradient index are unable to model ocular spherical aberration and peripheral astigmatism simultaneously. This limits their use as wide-angle schematic eyes. This thesis challenges this assumption by investigating the flexibility of schematic eyes comprising aspheric optical surfaces and homogeneous optical media. The full variation of ocular component dimensions found in human eyes was established from the literature. Schematic eye parameter variants were limited to these dimensions. The levels of spherical aberration and peripheral astigmatism modelled by these schematic eyes were compared to the range of measured levels. These were also established from the literature. To simplify comparison of modelled and measured data, single value parameters were introduced; the spherical aberration function (SAF), and peripheral astigmatism function (PAF). Some ocular components variations produced a wide range of aberrations without exceeding the limits of human ocular components. The effect of ocular component variations on coma was also investigated, but no comparison could be made as no empirical data exists. It was demonstrated that by combined manipulation of a number of parameters in the schematic eyes it was possible to model all levels of ocular spherical aberration and peripheral astigmatism. However, the unique parameters of a human eye could not be obtained in this way, as a number of models could be used to produce the same spherical aberration and peripheral astigmatism, while giving very different coma levels. It was concluded that these schematic eyes are flexible enough to model the monochromatic aberrations tested, the absence of gradient index being compensated for by altering the asphericity of one or more surfaces.

The detection of automated perimetric stimuli in ocular disease

Automated perimetry has made viable a rapid threshold examination of the visual field and has reinforced the role of perimetry in the diagnostic procedure. The aim of this study was twofold: to isolate the influence of certain extraneous factors on the sensitivity gradient, since these might limit the early detection and accurate monitoring of visual field loss and to investigate the efficacy of certain novel combinations of stimulus parameters in the detection of early visual field loss. The work was carried out with particular reference to glaucoma and to ocular hypertension. The effects of media opacities on the visual field were assessed by forward intraocular light scatter (n= 15) and were found to mask diffuse glaucomatous visual field loss and underestimate focal loss. Correction of the visual field indices for the effects of forward intraocular light scatter (n= 26) showed the focal losses to be, in reality, unaffected. Measurements of back scatter underestimated forward intraocular light scatter (n= 60) and the resultant depression of the visual field. Perimetric sensitivity improved with patient learning (n= 25) and exhibited eccentricity- and depth-dependency effects whereby improvements in sensitivity were greatest for peripheral areas of the field and for those areas which initially demonstrated the lowest sensitivity. The effects of practice were retained over several months (n= 16). Perimetric sensitivity decreased during prolonged examination due to fatigue effects (n&61 19); these demonstrated a similar eccentricity-dependency, being greatest for eccentricities beyond 30o. Mean sensitivities over the range of adaptation levels employed obeyed the Weber-Fechner law (n= 10) and, as would be expected, were independent of pupil size. No relationship was found between short-term fluctuation and adaptation level. Detection of diffuse glaucomatous visual field loss was facilitated using a size III stimulus of duration 200msec at an adaptation level of 31.5asb, compared with a size III stimulus of duration 100msec at an adaptation level of 4asb (n= 20). In a pilot study (n= 10), temporal summation was found to be higher in glaucomatous patients compared with age-matched controls, although the difference was not statistically significant.

Biometric and physiological factors in human ocular perfusion

By addressing the vascular features that characterise myopia, this thesis aims to provide an understanding of the early structural changes associated with human myopia and the progression to co-morbidity with age. This thesis addresses three main areas of study: 1. Ocular perfusion features and autoregulatory mechanisms in human myopia; 2. Choroidal thickness at the macular area of myopic eyes; 3. Effect of chronic smoking on the ocular haemodynamics and autoregulation. This thesis demonstrated a reduced resting ocular pulse amplitude and retrobulbar blood flow in human myopia, associated with an apparent oversensitivity to the vasodilatory effects of hypercapnia, which may be due to anatomical differences in the volume of the vessel beds. In young smokers, normal resting state vascular characteristics were present; however there also appeared to be increased reactivity to hypercapnia, possibly due to relative chronic hypoxia. The systemic circulation in myopes and smokers over-reacted similarly to hypercapnia suggesting that physiologic differences are not confined to the eye. Age also showed a negative effect on autoregulatory capacity in otherwise normal eyes. Collectively, these findings suggest that myopes and smokers require greater autoregulatory capacity to maintain appropriate oxygenation of retinal tissue, and since the capacity for such regulation reduces with age, these groups are at greater risk of insufficient autoregulation and relative hypoxia with age.

Ocular changes and other factors relating to two forms of contact lenses:a comparative study

The work utilising a new material for contact lenses has fallen into three parts: Physioloeical considerations: Since the cornea is devoid of blood vessels, its oxygen is derived from the atmosphere. Early hydrophilic gel contact lenses interrupted the flow of oxygen and corneal insult resulted. Three techniques of fenestration were tried to overcome this problem. High speed drilling with 0.1 mm diameter twist drills. was found to be mechanically successful, but under clinical conditions mucous blockage of the fenestrations occurred. An investigation was made into the amount of oxygen arriving at the corneal interface; related to gel lens thickness. The results indicated an improvement in corneal oxygen as lens thickness was reduced. The mechanism is thought to be a form of mechanical pump. A series of clinical studies con:firmed the experimental work; the use of thin lenses removing the symptoms of corneal hypoxia. Design: The parameters of lens back curvature. lens thickness and lens diameter have been isolated and related to three criteria of vision (a) Visual acuity. (b) Visual stability and (c) Induced astigmatism. From the results achieved a revised and basically successful design of lens has been developed. Comparative study: The developed form of lens was compared with traditional lenses in a controlled survey. Twelve factors were assessed over a twenty week period of wear using a total of eighty four patients. The results of this study indicate that whilst the expected changes were noted with the traditional lens wearers, gel lens wearers showed no discernible change in any of the factors measured. ldth the exception of' one parameter. In addition to a description of' the completed l'iork. further investigations are ·sug~ested l'lhich. it is hoped. l'iould further improve the optical performance of gel lenses.

Role of contact lenses in relieving ocular allergy

Purpose: To examine the potential barrier and lubricating effects of modern daily disposable contact lenses (DD) against airborne antigens. Methods: Ten patients with skin prick and ocular conjunctival provocation confirmed allergic sensitivity to grass pollen were recruited (average age 27.4±7.7 years). Each had their ocular symptoms (on a 0 none to 5 extreme scale) and appearance of bulbar and limbal conjunctival redness, palpebral conjunctival redness and roughness, and corneal and conjunctival fluorescein staining (CCLRU scale) graded before and five minutes after exposure to 400 grains grass pollen/m3 for 2 minutes in a purpose-designed exposure chamber to simulate the conditions of a ‘very high’ pollen-count day. This was repeated on three occasions separated by >72 hours wearing etafilcon A (sDD), nelfilcon A with enhanced lubricating agents (ELDD) and no contact lenses in random order out of the pollen season. Each sign and symptom was compared to baseline for each condition. The duration of the symptoms was also recorded. www.clinicaltrials.gov NCT01125540 Results: Only symptoms of burning and stinging were significantly reduced in severity by ELDD (Chi-Sq=7.6, p=0.02), but overall symptoms were significantly reduced in duration (F=3.60, p=0.05). Bulbar hyperaemia, corneal and conjunctival staining, and palpebral conjunctival roughness were significantly reduced by DD wear (p<0.01), with limbal and palpebral conjunctival redness further reduced in ELDD (p<0.05). Conclusion: Daily disposable contact lenses offer a barrier to airborne antigen which is enhanced by modern lenses with enhanced lubricating agents.

Accuracy of Goldmann, ocular response analyser, Pascal and TonoPen XL tonometry in keratoconic and normal eyes

Aim: The aim of this study was to evaluate the practicality and accuracy of tonometers used in routine clinical practice for established keratoconus (KC). Methods: This was a prospective study of 118 normal and 76 keratoconic eyes where intraocular pressure (IOP) was measured in random order using the Goldman applanation tonometer (GAT), Pascal dynamic contour tonometer (DCT), Reichert ocular response analyser (ORA) and TonoPen XL tonometer. Corneal hysteresis (CH) and corneal resistance factor (CRF), as calculated by the ORA, were recorded. Central corneal thickness (CCT) was measured using an ultrasound pachymeter. Results: The difference in IOP values between instruments was highly significant in both study groups (p<0.001). All other IOP measures were significantly higher than those for GAT, except for the Goldmann-correlated IOP (average of the two applanation pressure points) (IOPg) as measured by ORA in the control group and the CH-corrected IOP (corneal-compensated IOP value) (IOPcc) measures in the KC group. CCT, CH and CRF were significantly less in the KC group (p<0.001). Apart from the DCT, all techniques tended to measure IOP higher in eyes with thicker corneas. Conclusion: The DCT and the ORA are currently the most appropriate tonometers to use in KC for the measurement of IOPcc. Corneal factors such as CH and CRT may be of more importance than CCT in causing inaccuracies in applanation tonometry techniques.

Ocular and systemic vascular dysfunction in neurodegenerative disease

The important role played by vascular factors in the pathogenesis of neurodegenerative disease has been increasingly realised over recent years. The nature and impact of ocular and systemic vascular dysfunction in the pathogenesis of comparable neurodegenerative diseases such as glaucoma and Alzheimer’s disease (AD) has however never been fully explored. The aim of this thesis was therefore to investigate the presence of macro- and micro-vascular alterations in both glaucoma and AD and to explore the relationships between these two chronic, slowly progressive neurodegenerative diseases. The principle sections and findings of this work were: 1. Is the eye a window to the brain? Retinal vascular dysfunction in Alzheimer’s disease · Mild newly diagnosed AD patients demonstrated ocular vascular dysfunction, in the form of an altered retinal vascular response to flicker light, which correlated with their degree of cognitive impairment. 2. Ocular and systemic vascular abnormalities in newly diagnosed normal tension glaucoma (NTG) patients · NTG patients demonstrated an altered retinal arterial constriction response to flicker light along with an increased systemic arterial stiffness and carotid artery intima-media thickness (IMT). These findings were not replicated by healthy age matched controls. 3. Ocular vascular dysregulation in AD compares to both POAG and NTG · AD patients demonstrated altered retinal arterial reactivity to flicker light which was comparable to that of POAG patients and altered baseline venous reactivity which was comparable to that of NTG patients. Neither alteration was replicated by healthy controls. 4. POAG and NTG: two separate diseases or one continuous entity? The vascular perspective · POAG and NTG patients demonstrated comparable alterations in nocturnal systolic blood pressure (SBP) variability, ocular perfusion pressure, retinal vascular reactivity, systemic arterial stiffness and carotid IMT. · Nocturnal SBP variability was found to correlate with both retinal artery baseline diameter fluctuation and carotid IMT across the glaucoma groups.

Tear analysis and lens-tear interactions:part II. Ocular lipids-nature and fate of meibomian gland phospholipids

Purpose: Published data indicate that the polar lipid content of human meibomian gland secretions (MGS) could be anything between 0.5% and 13% of the total lipid. The tear film phospholipid composition has not been studied in great detail and it has been understood that the relative proportions of lipids in MGS would be maintained in the tear film. The purpose of this work was to determine the concentration of phospholipids in the human tear film. Methods: Liquid chromatography mass spectrometry (LCMS) and thin layer chromatography (TLC) were used to determine the concentration of phospholipid in the tear film. Additionally, an Amplex Red phosphatidylcholine-specific phospholipase C (PLC) assay kit was used for determination of the activity of PLC in the tear film. Results: Phospholipids were not detected in any of the tested human tear samples with the low limit of detection being 1.3 µg/mL for TLC and 4 µg/mL for liquid chromatography mass spectrometry. TLC indicated that diacylglycerol (DAG) may be present in the tear film. PLC was in the tear film with an activity determined at approximately 15 mU/mL, equivalent to the removal of head groups from phosphatidylcholine at a rate of approximately 15 µM/min. Conclusions: This work shows that phospholipid was not detected in any of the tested human tear samples (above the lower limits of detection as described) and suggests the presence of DAG in the tear film. DAG is known to be at low concentrations in MGS. These observations indicate that PLC may play a role in modulating the tear film phospholipid concentration.

Ocular and systemic endothelial function in the off spring of diabetics:a pilot study

Purpose To investigate ocular and systemic correlates of endothelial function in the normoglycaemic offspring of Type 2 Diabetics (T2DM). Methods Healthy participants aged between 25-65 with (n=30) and without (n=39) a family history were recruited. Retinal vessel reactivity was assessed by using the Retinal Vessel Analyser (RVA, Imedos GmBH). In addition, systemic endothelial function was assessed by using the flow mediated dilation (FMD) technique. Results Parametric testing showed no significant differences in anthropometric, blood assay or ocular and systemic function between both groups (p>0.05). The average maximum dilation in the measured retinal artery correlated significantly with the maximum dilation of the measured brachial artery (p=0.002 R=0.55) in healthy controls; however, this was not true for subjects with family history of T2DM. Conclusion Subjects with family history of T2DM show possibly early signs of endothelial dysfunction that, in certain conditions, could contribute to the higher risk of this group of developing similar pathology to their parents.

Multispectral imaging of the ocular fundus using light emitting diode illumination

We present an imaging system based on light emitting diode (LED) illumination that produces multispectral optical images of the human ocular fundus. It uses a conventional fundus camera equipped with a high power LED light source and a highly sensitive electron-multiplying charge coupled device camera. It is able to take pictures at a series of wavelengths in rapid succession at short exposure times, thereby eliminating the image shift introduced by natural eye movements (saccades). In contrast with snapshot systems the images retain full spatial resolution. The system is not suitable for applications where the full spectral resolution is required as it uses discrete wavebands for illumination. This is not a problem in retinal imaging where the use of selected wavelengths is common. The modular nature of the light source allows new wavelengths to be introduced easily and at low cost. The use of wavelength-specific LEDs as a source is preferable to white light illumination and subsequent filtering of the remitted light as it minimizes the total light exposure of the subject. The system is controlled via a graphical user interface that enables flexible control of intensity, duration, and sequencing of sources in synchrony with the camera. Our initial experiments indicate that the system can acquire multispectral image sequences of the human retina at exposure times of 0.05 s in the range of 500-620 nm with mean signal to noise ratio of 17 dB (min 11, std 4.5), making it suitable for quantitative analysis with application to the diagnosis and screening of eye diseases such as diabetic retinopathy and age-related macular degeneration.

Cross-orientation masking is speed invariant between ocular pathways but speed dependent within them

In human (D. H. Baker, T. S. Meese, & R. J. Summers, 2007b) and in cat (B. Li, M. R. Peterson, J. K. Thompson, T. Duong, & R. D. Freeman, 2005; F. Sengpiel & V. Vorobyov, 2005) there are at least two routes to cross-orientation suppression (XOS): a broadband, non-adaptable, monocular (within-eye) pathway and a more narrowband, adaptable interocular (between the eyes) pathway. We further characterized these two routes psychophysically by measuring the weight of suppression across spatio-temporal frequency for cross-oriented pairs of superimposed flickering Gabor patches. Masking functions were normalized to unmasked detection thresholds and fitted by a two-stage model of contrast gain control (T. S. Meese, M. A. Georgeson, & D. H. Baker, 2006) that was developed to accommodate XOS. The weight of monocular suppression was a power function of the scalar quantity ‘speed’ (temporal-frequency/spatial-frequency). This weight can be expressed as the ratio of non-oriented magno- and parvo-like mechanisms, permitting a fast-acting, early locus, as befits the urgency for action associated with high retinal speeds. In contrast, dichoptic-masking functions superimposed. Overall, this (i) provides further evidence for dissociation between the two forms of XOS in humans, and (ii) indicates that the monocular and interocular varieties of XOS are space/time scale-dependent and scale-invariant, respectively. This suggests an image-processing role for interocular XOS that is tailored to natural image statistics—very different from that of the scale-dependent (speed-dependent) monocular variety.