Posterior retinal contour in adult human anisomyopia

PURPOSE. It is well documented that myopia is associated with an increase in axial length or, more specifically, in vitreous chamber depth. Whether the transverse dimensions of the eye also increase in myopia is relevant to further understanding of its development. METHODS. The posterior retinal surface was localized in two-dimensional space in both eyes of young adult white and Taiwanese-Chinese iso- and anisomyopes (N = 56), from measured keratometry, A-scan ultrasonography, and central and peripheral refraction (±35°) data, with the aid of a computer modeling program designed for this purpose. Anisomyopes had 2 D or more interocular difference in their refractive errors, with mean values in their more myopic eyes of -5.57 D and in their less myopic eyes of -3.25 D, similar to the means of the two isomyopic groups. The derived retinal contours for the more and less myopic eyes were compared by way of investigating ocular shape changes that accompany myopia, in the posterior region of the vitreous chamber. The presence and size of optic disc crescents were also investigated as an index of retinal stretching in myopia. RESULTS. Relative to the less myopic eyes of anisometropic subjects, the more myopic eyes were more elongated and also distorted into a more prolate shape in both the white and Chinese groups. However, the Chinese eyes showed a greater and more uniform relative expansion of the posterior retinal surface in their more myopic eyes, and this was associated with larger optic disc crescents. The changes in the eyes of whites displayed a nasal-temporal axial asymmetry, reflecting greater enlargement of the nasal retinal sector. CONCLUSIONS. Myopia is associated with increased axial length and a prolate shape. This prolate shape is consistent with the proposed idea that axial and transverse dimensions of the eye are regulated differently. The observations that ocular shape changes are larger but more symmetrical in Chinese eyes than in eyes of whites warrant further investigation.

Topography of visual evoked magnetic responses to pattern shift, pattern onset and flash stimuli

Different visual stimuli may activate separate channels in the visual system and produce magnetic responses from the human bran which originate from distinct regions of the visual cortex. To test this hypothesis, we have investigated the distribution of visual evoked magnetic responses to three distinct visual stimuli over the occipital region of the scalp with a DC-SQUID second-order gradiometer in an ubshielded environment. Patterned stimuli were presented full field and to the right half field, while a flash stimulus was presented full field only, in five normal subjects. Magnetic responses were recorded from 20 to 42 positions over the occipital scalp. Topographic maps were prepared of the major positive component within the first 150ms to the three stimuli, i.e., the P100m (pattern shift), C11m (pattern onset) and P2m (flash). For the pattern shift stimulus the data suggested the source of the P100m was close to the midline with the current directed towards the medial surface. The data for the pattern onset C11m suggested a source at a similar depth but with the current directed away from the midline towards the lateral surface. The flash P2m appeared to originate closer to the surface of the occipital pole than both the patterned stimuli. Hence the pattern shift (which may represent movement), and the pattern onset C11m (representing contrast and contour) appear to originate in similar areas of brain but to represent different asepcts of cortical processing. By contrast, the flash P2m (representing luminance change) appears to originate in a distinct area of visual cortex closer to the occipital pole.

Topography of the visual evoked magnetic response and hemispherical specialization

The visual evoked magnetic response CIIm component to a pattern onset stimulus presented half field produced a consistent scalp topography in 15 normal subjects. The major response was seen over the contralateral hemisphere, suggesting a dipole with current flowing away from the medial surface of the brain. Full field responses were more unpredictable. The reponses of five subjects were studied to the onset of a full, left half and right half checkerboard stimuli of 38 x 27 min arc checks appearing for 200 ms. In two subjects the full field CIIm topography was consistent with that of the mathematical summation of their relevant half field distribution. The remaining subjects had unpredictable full field topographies, showing little or no relationship to their half or summated half fields. In each of these subjects, a distribution matching that of the summated half field CIIm distribution appears at an earlier latency than that of the predominant full field waveform peak. By examining the topography of the full and half field responses at 5 ms intervals along the waveform for one such subject, the CIIm topography of the right hemisphere develops 10 ms before that of the left hemisphere, and is replaced by the following CIIIm component 20 ms earlier. Hence, the large peak seen in full field results from a combination of the CIIm component of the left hemisphere plus that of the CIIIm from the right. The earlier peak results from the CIIm generated in both hemispheres, at a latency where both show similar amplitudes. As the relative amplitudes of these two peaks alter with check and field size, topographic studies would be required for accurate CIIm identification. In addition. the CIIm-CIIIm complex lasts for 80 ms in the right hemisphere and 135 ms in the left, suggesting hemispherical apecialization in the visual processing of the pattern onset response.

Ocular biometric correlates of early-and late-onset myopia

Myopia is a refractive condition and develops because either the optical power of the eye is abnormally great or the eye is abnormally long, the optical consequences being that the focal length of the eye is too short for the physical length of the eye. The increase in axial length has been shown to match closely the dioptric error of the eye, in that a lmm increase in axial length usually generates 2 to 3D of myopia. The most common form of myopia is early-onset myopia (EO M) which occurs between 6 to 14 years of age. The second most common form of myopia is late-onset myopia (LOM) which emerges in late teens or early twenties, at a time when the eye should have ceased growing. The prevalence of LOM is increasing and research has indicated a link with excessive and sustained nearwork. The aim of this thesis was to examine the ocular biometric correlates associated with LOM and EOM development and progression. Biometric data was recorded on SO subjects, aged 16 to 26 years. The group was divided into 26 emmetropic subjects and 24 myopic subjects. Keratometry, corneal topography, ultrasonography, lens shape, central and peripheral refractive error, ocular blood flow and assessment of accommodation were measured on three occasions during an ISmonth to 2-year longitudinal study. Retinal contours were derived using a specially derived computer program. The thesis shows that myopia progression is related to an increase in vitreous chamber depth, a finding which supports previous work. The myopes exhibited hyperopic relative peripheral refractive error (PRE) and the emmetropes exhibited myopic relative PRE. Myopes demonstrated a prolate retinal shape and the retina became more prolate with myopia progression. The results show that a longitudinal, rather than equatorial, increase in the posterior segment is the principal structural correlate of myopia. Retinal shape, relative PRE and the ratio of axial length to corneal curvature have been indicated, in this thesis, as predictive factors for myopia onset and development. Data from this thesis demonstrates that myopia progression in the LOM group is the result of an increase in anterior segment power, owing to an increase in lens thickness, in conjunction with posterior segment elongation. Myopia progression in the EOM group is the product of a long posterior segment, which over-compensates for a weak anterior segment power. The weak anterior segment power in the EOM group is related to a combination of crystalline lens thinning and surface flattening. The results presented in this thesis confirm that posterior segment elongation is the main structural correlate in both EOM and LOM progression. The techniques and computer programs employed in the thesis are reproducible and robust providing a valuable framework for further myopia research and assessment of predictive factors.

Ocular biometric investigation of anisometropia

The thesis aims to define further the biometric correlates in anisometropic eyes in order to provide a structural foundation for propositions concerning the development of ametropia.Biometric data are presented for 40 anisometropes and 40 isometropic controls drawn from Caucasian and Chinese populations.The principal finding was that the main structural correlate of myopia is an increase in axial rather than equatorial dimensions of the posterior globe. This finding has not been previously reported for in vivo work on humans. The computational method described in the thesis is a more accessible method for determination of eye shape than current imaging techniques such as magnetic resonance imaging or laser Doppler interferometry (LDI). Retinal contours derived from LDI and computation were shown to be closely matched. Corneal topography revealed no differences in corneal characteristics in anisometropic eyes, which supports the finding that anisometropia arises from differences in vitreous chamber depth.The corollary to axial expansion in myopia, that is retinal stretch in central regions of the posterior pole, was investigated by measurement of disc-to-fovea distances (DFD) using a scanning laser ophthalmoscope. DFD was found to increase with increased myopia, which demonstrates the primary contribution made by posterior central regions of the globe to axial expansion.The ocular pulse volume and choroidal blood flow, measured with the Ocular Blood Flow Tonograph, were found to be reduced in myopia; the reductions were found to be significantly correlated with vitreous chamber depth. The thesis includes preliminary data on whether the relationship arises from the influx of a blood bolus into eyes of different posterior volumes or represents actual differences in choroidal blood flow.The results presented in this thesis show the utility of computed retinal contour and demonstrate that the structural correlate of myopia is axial rather than equatorial expansion of the vitreous chamber. The technique is suitable for large population studies and its relative simplicity makes it feasible for longitudinal studies on the development of ametropia in, for example, children.

Topographic, haemodynamic and psychophysical investigation of glaucomatous optic neuropathy

Loss of optic nerve head (ONH) axons in primary open angle glaucoma (POAG) has been attributed to both mechanical and vascular factors. Confocal scanning laser ophthalmoscopy (cSLO) provides a promising tool for the topographic follow-up of the ONH in glaucoma, while scanning laser Doppler flowmetry (SLDF) facilitates the rapid non-invasive assessment of retinal capillary blood flow. The purposes of these investigations were to optimise the techniques and explore their potential to classify and monitor disease. Preliminary investigations explored the reproducibility and validity of cSLO and SLDF and showed that: For cSLO: In a model eye, measurements are accurate over a range of axial lengths. For best reproducibility, seven images per visit are required, with a contour line located on Elschnig's scleral ring and transferred automatically between images. For SLDF: Three perfusion images are required for optimum reproducibility. Physiological changes induced by gas perturbation can be measured. Cross-sectional comparison of groups of normal subjects and early POAG patients showed that: cSLO parameters differentiate the early POAG group. Blood volume measured by SLDF showed group differences in superior nasal retina only. Longitudinal investigation of ONH topography, haemodynamic and visual field indices in normal subjects and POAG patients showed that: cSLO detects topographical change over time more frequently in the POAG group. Important parameters include: C:D area ratio, cup and rim area, mean depth in contour, volumes above and below reference and surface. Factor analysis identified "cup" and "rim" factors that can be used to detect change over time in individual patients. Blood flow changes were most apparent in the inferior nasal peripapillary retina of the POAG group. Perimetry is of clinical value for the identification of glaucoma but is less sensitive than cSLO for monitoring glaucomatous change.

Physiological and pathological human ocular perfusion characteristics

There were three principle aims to this thesis. Firstly, the acquisition protocols of clinical blood flow apparatus were investigated in order to optimise them for both cross-sectional and longitudinal application. Secondly, the effects of physiological factors including age and systematic circulation on ocular blood flow were investigated. Finally, the ocular perfusion characteristics of patients diagnosed with ocular diseases considered to be of a vascular origin were investigated. The principle findings of this work are:- 1) Optimisation of clinical investigationsPhotodiode sensitivity of the scanning laser Doppler flowmeter should be kept within a range of 70-150 DC when acquiring images of the retina and optic nerve head in order to optimise the reproducibility of capillary blood flow measures. Account of the physiological spatial variation in retinal blood flow measures can be made using standard analysis protocols of the scanning laser Doppler flowmeter combined with a local search strategy. Measurements of pulsatile ocular blood flow using the ocular blood flow analyser are reproducible, however this reproducibility can be improved when consecutive intraocular pressure pulses are used to calculate pulsatile ocular blood flow. Spectral analysis of the intraocular pressure pulse-wave is viable and identifies the first four harmonic components of the waveform. 2) Physiological variation in ocular perfusionAge results in a significant reduction in perfusion of the retinal microcirculation, which is not evident in larger vessel beds such as the choroid. Despite known asymmetry in the systemic vasculature, no evidence of interocular asymmetry in ocular perfusion is apparent. 3) Pathological variation in ocular perfusionIn primary open angle glaucoma, perfusion is reduced in the retinal microcirculation of patients classified as having early to moderate visual field defects. However, ocular pulsatility defects are masked when patients and subjects are matched for systemic variables (pulse rate and mean arterial pressure); differentiation is facilitated by the application of waveform analysis to the continuos intraocular pressure curve even in the early stages of disease. Diabetic patients with adequate glycaemic control, exhibit maintenance of macular blood flow, macular topography and visual function following phacoemulsification.

Optimising the clinical analysis of retinal image quality in the human eye

Visual perception is dependent on both light transmission through the eye and neuronal conduction through the visual pathway. Advances in clinical diagnostics and treatment modalities over recent years have increased the opportunities to improve the optical path and retinal image quality. Higher order aberrations and retinal straylight are two major factors that influence light transmission through the eye and ultimately, visual outcome. Recent technological advancements have brought these important factors into the clinical domain, however the potential applications of these tools and considerations regarding interpretation of data are much underestimated. The purpose of this thesis was to validate and optimise wavefront analysers and a new clinical tool for the objective evaluation of intraocular scatter. The application of these methods in a clinical setting involving a range of conditions was also explored. The work was divided into two principal sections: 1. Wavefront Aberrometry: optimisation, validation and clinical application The main findings of this work were: • Observer manipulation of the aberrometer increases variability by a factor of 3. • Ocular misalignment can profoundly affect reliability, notably for off-axis aberrations. • Aberrations measured with wavefront analysers using different principles are not interchangeable, with poor relationships and significant differences between values. • Instrument myopia of around 0.30D is induced when performing wavefront analysis in non-cyclopleged eyes; values can be as high as 3D, being higher as the baseline level of myopia decreases. Associated accommodation changes may result in relevant changes to the aberration profile, particularly with respect to spherical aberration. • Young adult healthy Caucasian eyes have significantly more spherical aberration than Asian eyes when matched for age, gender, axial length and refractive error. Axial length is significantly correlated with most components of the aberration profile. 2. Intraocular light scatter: Evaluation of subjective measures and validation and application of a new objective method utilising clinically derived wavefront patterns. The main findings of this work were: • Subjective measures of clinical straylight are highly repeatable. Three measurements are suggested as the optimum number for increased reliability. • Significant differences in straylight values were found for contact lenses designed for contrast enhancement compared to clear lenses of the same design and material specifications. Specifically, grey/green tints induced significantly higher values of retinal straylight. • Wavefront patterns from a commercial Hartmann-Shack device can be used to obtain objective measures of scatter and are well correlated with subjective straylight values. • Perceived retinal stray light was similar in groups of patients implanted with monofocal and multi focal intraocular lenses. Correlation between objective and subjective measurements of scatter is poor, possibly due to different illumination conditions between the testing procedures, or a neural component which may alter with age. Careful acquisition results in highly reproducible in vivo measures of higher order aberrations; however, data from different devices are not interchangeable which brings the accuracy of measurement into question. Objective measures of intraocular straylight can be derived from clinical aberrometry and may be of great diagnostic and management importance in the future.

Regional differences in oxygen saturation in retinal arterioles and venules

BACKGROUND: Retinal vessel oxygenation saturation measurements have been the focus of much attention in recent years as a potential diagnostic parameter in a number of ocular and systemic pathologies. This interest has been heightened by the ability to measure oxygen saturation in vivo using a photographic technique. METHODS: Retinal vessel oxygenation in venules and arterioles of 279 retinal vessels of 12 healthy Caucasian participants (mean age: 30 SD (+/- 6) years) were measured consecutively three times to evaluate short-term variation in oxygen saturation and regional variability of retinal vessel oxygen saturation using dual-wavelength technology (Oxymetry Modul, Imedos, Germany). All subjects underwent standard optometric assessment including non-contact intra-ocular pressure assessment as well as having their systemic blood pressure measured. RESULTS: Vessels were grouped as either near-macula or peripheral, depending on their location. Peripheral arterioles and venules exhibited significantly lower oxygen saturation compared to their near-macula counterparts (arterioles: 94.7% (SD 3.9) vs. 99.7% (SD 3.2); venules: 65.1% (SD 7.2) vs. 90.3% (SD 6.7)). Both arterioles and venules, main branches, and those feeding and draining the retina near the macula and periphery showed low short-term variability of oxygen saturation (arterioles: COV 1.2-1.8%; venules: COV 2.9-4.9%). CONCLUSIONS: Retinal arterioles and venules exhibit low short-term variation of oxygen saturation in healthy subjects. Regional differences in oxygen saturation could be a potential useful marker for risk stratification and diagnostic purposes of area-specific retinal pathology such as age-related macula degeneration and diabetic maculopathy.

Abnormal retinal vascular function and lipid levels in a sample of healthy UK South Asians

Background/aims To investigate ethnic differences in retinal vascular function and their relationship to traditional risk indicators for cardiovascular disease (CVD). Methods A total of 90 normoglycaemic subjects (45 South Asian (SA) and 45 age- and gender-matched white Europeans (WEs)) were recruited for the present study. Retinal vessel reactivity to flickering light was assessed by means of the dynamic retinal vessel analyser according to a modified protocol. Fasting plasma glucose, triglycerides (TG), total, LDL and HDL cholesterol were also measured in all individuals. Results SA individuals showed higher fasting triglyceride (p=0.001) and lower HDL levels (p=0.007), leading to a higher TG:HDL-C ratio (p=0.001) than age-matched WE subjects. Additionally, in SAs, the retinal arterial reaction time in response to flicker stimulation was significantly longer in the last flicker cycle than in the WEs (p=0.039), and this change correlated positively with measured plasma TG levels (r=0.60; p=0.01). No such relationship was observed in the WEs (p>0.05). Conclusion Even in the absence of overt vascular disease, in otherwise healthy SAs there are potential signs of retinal vascular function impairment that correlates with established plasma markers for CVD risk.

Continuous retinal vessel diameter m easurements: the future in retinal vessel assessment?

PURPOSE. To establish an alternative method, sequential and diameter response analysis (SDRA), to determine dynamic retinal vessel responses and their time course in serial stimulation compared with the established method of averaged diameter responses and standard static assessment. METHODS. SDRA focuses on individual time and diameter responses, taking into account the fluctuation in baseline diameter, providing improved insight into reaction patterns when compared with established methods as delivered by retinal vessel analyzer (RVA) software. SDRA patterns were developed with measurements from 78 healthy nonsmokers and subsequently validated in a group of 21 otherwise healthy smokers. Fundus photography and retinal vessel responses were assessed by RVA, intraocular pressure by contact tonometry, and blood pressure by sphygmomanometry. RESULTS. Compared with the RVA software method, SDRA demonstrated a marked difference in retinal vessel responses to flickering light (P 0.05). As a validation of that finding, SDRA showed a strong relation between baseline retinal vessel diameter and subsequent dilatory response in both healthy subjects and smokers (P 0.001). The RVA software was unable to detect this difference or to find a difference in retinal vessel arteriovenous ratio between smokers and nonsmokers (P 0.243). However, SDRA revealed that smokers’ vessels showed both an increased level of arterial baseline diameter fluctuation before flicker stimulation (P 0.005) and an increased stiffness of retinal arterioles (P 0.035) compared with those in nonsmokers. These differences were unrelated to intraocular pressure or systemic blood pressure. CONCLUSIONS. SDRA shows promise as a tool for the assessment of vessel physiology. Further studies are needed to explore its application in patients with vascular diseases.

Retinal and systemic vascular function in health and disease: the effect of smoking and coronary artery disease

The purpose of the following studies was to explore the effect of systemic vascular and endothelial dysfunction upon the ocular circulation and functionality of the retina. There are 6 principal sections to the present work. Retinal vessel activity in smokers and non-smokers: the principal findings of this work were: chronic smoking affects retinal vessel motion at baseline and during stimulation with flickering light; chronic smoking leads to a vaso-constrictory shift in retinal arteriolar reactivity to flicker; retinal arteriolar elasticity is decreased in chronic smokers. The effect of acute smoking on retinal vessel dynamics in smokers and non-smokers: the principal finding of this work was that retinal reactivity in chronic smokers is blunted when exposed to clicker light provocation immediately after smoking one cigarette. Ocular blood flow in coronary artery disease: The principal findings of this work were: retrobulbar and retinal blood flow is preserved in CAD patients, despite a change pulse wave transmission; arterial retinal response to flickering light provocation is significantly delayed in CAD patients; retinal venular diameters are significantly dilated in CAD patients. Autonomic nervous system function and peripheral circulation in CAD: The principal findings in this work were: CAD patients demonstrate a sympathetic overdrive during a 24 period; a delay in peripheral vascular reactivity (nail-fold capillaries) as observed in patients suffering from CAD could be caused by either arteriosclerotic changes of the vascular walls or due to systemic haemodynamic changes. Visual function in CAD: The principal findings in this work were: overall visual function in CAD patients is preserved, despite a decrease in contrast sensitivity; applying a filtering technique selecting those with greater coefficient of variance which in turn represents a decrease in reliability, some patients appear to have an impaired visual function as assessed using FDT visual field evaluation. Multiple functional, structural and biochemical vascular endothelial dysfunctions in patients suffering from CAD: relationships and possible implications: The principal findings of this work were: BMI significantly correlated with vWF (a marker of endothelial function) in CAD patients. Retinal vascular reactivity showed a significant correlation with peripheral reactivity parameters in controls which lacked in the CAD group and could reflect a loss in vascular endothelial integrity; visual field parameters as assessed by frequency doubling technology were strongly related with systemic vascular elasticity (ambulatory arterial stiffness index) in controls but not CAD patients.

Abnormal retinal vascular reactivity in individuals with impaired glucose tolerance:a preliminary study

To investigate the relationship between vascular function parameters measured at the retinal and systemic level and known markers for cardiovascular risk in patients with impaired glucose tolerance (IGT). Sixty age- and gender- matched White-European adults (30 IGT and 30 normal glucose tolerance -NGT) were recruited for the study. Fasting plasma glucose, lipids and 24-hour blood pressure (BP) was measured in all subjects. Systemic vascular and endothelial function was assessed using carotid-artery intimal media thickness (cIMT) and flow mediated dilation (FMD). Retinal vascular reactivity was assessed by the Dynamic Retinal Vessel Analyser (DVA). Additionally, blood glutathione (GSH, GSSG and tGSH) and plasma von-Willebrand (vWF) factor levels were also measured. Individuals with IGT demonstrated higher BP values (p<0.001), fasting TG and TG:HDL ratios (p<0.001) than NGT subjects. Furthermore, Total:HDL-C ratios and Framingham scores were raised (p=0.010 and p<0.001 respectively). Blood glutathione levels (GSH, GSSG and tGSH) were lower (p<0.001, p=0.039 and p<0.001 respectively) while plasma vWF was increased (p=0.014) in IGT subjects compared to controls. IGT individuals also demonstrated higher IMT in right and left carotid arteries (p=0.017 and p=0.005, respectively) alongside larger brachial artery diameter (p=0.015), lower FMD% (p=0.026) and GTN induced dilation (GID) (p=0.012) than healthy controls. At the retinal arterial level, the IGT subjects showed higher baseline fluctuations (BDF) (p=0.026), longer reaction time (RT) (p=0.032) and reduced baseline-corrected flicker response (bFR) (p=0.045). In IGT subjects retinal BDF correlated with and Total:HDL (p= 0.003) and HDL-C (p= 0.004). Arterial RT also correlated with FMD (p=0.017) in IGT but not NGT subjects. In IGT individuals there is a relationship between macro- and microvascular function, as well as a direct correlation between the observed retinal microcirculatory changes and established plasma markers for CVD. Multifactorial preventive interventions to decrease vascular risk in these individuals should be considered.