Impact of senescence and disease on the structural and functional performance of the visual pathway

The diagnosis and monitoring of ocular disease presents considerable clinical difficulties for two main reasons i) the substantial physiological variation of anatomical structure of the visual pathway and ii) constraints due to technical limitations of diagnostic hardware. These are further confounded by difficulties in detecting early loss or change in visual function due to the masking of disease effects, for example, due to a high degree of redundancy in terms of nerve fibre number along the visual pathway. This thesis addresses these issues across three areas of study: 1. Factors influencing retinal thickness measures and their clinical interpretation As the retina is the principal anatomical site for damage associated with visual loss, objective measures of retinal thickness and retinal nerve fibre layer thickness are key to the detection of pathology. In this thesis the ability of optical coherence tomography (OCT) to provide repeatable and reproducible measures of retinal structure at the macula and optic nerve head is investigated. In addition, the normal physiological variations in retinal thickness and retinal nerve fibre layer thickness are explored. Principal findings were: • Macular retinal thickness and optic nerve head measurements are repeatable and reproducible for normal subjects and diseased eyes • Macular and retinal nerve fibre layer thickness around the optic nerve correlate negatively with axial length, suggesting that larger eyes have thinner retinae, potentially making them more susceptible to damage or disease • Foveola retinal thickness increases with age while retinal nerve fibre layer thickness around the optic nerve head decreases with age. Such findings should be considered during examination of the eye with suspect pathology or in long-term disease monitoring 2. Impact of glucose control on retinal anatomy and function in diabetes Diabetes is a major health concern in the UK and worldwide and diabetic retinopathy is a major cause of blindness in the working population. Objective, quantitative measurements of retinal thickness. particularly at the macula provide essential information regarding disease progression and the efficacy of treatment. Functional vision loss in diabetic patients is commonly observed in clinical and experimental studies and is thought to be affected by blood glucose levels. In the first study of its kind, the short term impact of fluctuations in blood glucose levels on retinal structure and function over a 12 hour period in patients with diabetes are investigated. Principal findings were: • Acute fluctuations in blood glucose levels are greater in diabetic patients than normal subjects • The fluctuations in blood glucose levels impact contrast sensitivity scores. SWAP visual fields, intraocular pressure and diastolic pressure. This effect is similar for type 1 and type 2 diabetic patients despite the differences in their physiological status. • Long-term metabolic control in the diabetic patient is a useful predictor in the fluctuation of contrast sensitivity scores. • Large fluctuations in blood glucose levels and/or visual function and structure may be indicative of an increased risk of development or progression of retinopathy 3. Structural and functional damage of the visual pathway in glaucomatous optic neuropathy The glaucomatous eye undergoes a number of well documented pathological changes including retinal nerve fibre loss and optic nerve head damage which is correlated with loss of functional vision. In experimental glaucoma there is evidence that glaucomatous damage extends from retinal ganglion cells in the eye, along the visual pathway, to vision centres in the brain. This thesis explores the effects of glaucoma on retinal nerve fibre layer thickness, ocular anterior anatomy and cortical structure, and its correlates with visual function in humans. Principal findings were: • In the retina, glaucomatous retinal nerve fibre layer loss is less marked with increasing distance from the optic nerve head, suggesting that RNFL examination at a greater distance than traditionally employed may provide invaluable early indicators of glaucomatous damage • Neuroretinal rim area and retrobulbar optic nerve diameter are strong indicators of visual field loss • Grey matter density decreases at a rate of 3.85% per decade. There was no clear evidence of a disease effect • Cortical activation as measured by fMRI was a strong indicator of functional damage in patients with significant neuroretinal rim loss despite relatively modest visual field defects These investigations have shown that the effects of senescence are evident in both the anterior and posterior visual pathway. A variety of anatomical and functional diagnostic protocols for the investigation of damage to the visual pathway in ocular disease are required to maximise understanding of the disease processes and thereby optimising patient care.

Cataract, macular characteristics and assessing lens opacities

Age-related macular degeneration and cataract are very common causes of visual impairment in the elderly. Macular pigment optical density is known to be a factor affecting the risk of developing age-related macular degeneration but its behaviour due to light exposure to the retina and the effect of macular physiology on this measurement are not fully understood. Cataract is difficult to grade in a way which reflects accurately the visual status of the patient. A new technology, optical coherence tomography, which allows a cross sectional slice of the crystalline lens to be imaged has the potential to be able to provide objective measurements of cataract which could be used for grading purposes. This thesis set out to investigate the effect of cataract removal on macular pigment optical density, the relationship between macular pigment optical density and macular thickness and the relationship between cortical cataract density as measured by optical coherence tomography and other measures of cataract severity. These investigations found: 1) Macular pigment optical density in a pseudophakic eye is reduced when compared to a fellow eye with age related cataract, probably due to differences in light exposure between the eyes. 2) Lower macular pigment optical density is correlated with thinning of the entire macular area, but not with thinning of the fovea or central macula. 3) Central macular thickness decreases with age. 4) Spectral domain optical coherence tomography can be used to successfully acquire images of the anterior lens cortex which relate well to slit lamp lens sections. 5) Grading of cortical cataract with spectral domain optical coherence tomography instruments using a wavelength of 840nm is not well correlated with other established metrics of cataract severity and is therefore not useful as presented as a grading method for this type of cataract.

Ocular biometric correlates of ciliary muscle thickness in human myopia

Purpose - Anterior segment optical coherent tomography (AS-OCT) is used to further examine previous reports that ciliary muscle thickness (CMT) is increased in myopic eyes. With reference to temporal and nasal CMT, interrelationships between biometric and morphological characteristics of anterior and posterior segments are analysed for British-White and British-South-Asian adults with and without myopia. Methods - Data are presented for the right eyes of 62 subjects (British-White n = 39, British-South-Asian n = 23, aged 18–40 years) with a range of refractive error (mean spherical error (MSE (D)) -1.74 ± 3.26; range -10.06 to +4.38) and separated into myopes (MSE (D) <-0.50, range -10.06 to -0.56; n = 30) and non-myopes (MSE (D) =-0.50, -0.50 to +4.38; n = 32). Temporal and nasal ciliary muscle cross-sections were imaged using a Visante AS-OCT. Using Visante software, manual measures of nasal and temporal CMT (NCMT and TCMT respectively) were taken in successive posterior 1 mm steps from the scleral spur over a 3 mm distance (designated NCMT1, TCMT1 et seq). Measures of axial length and anterior chamber depth were taken with an IOLMaster biometer. MSE and corneal curvature (CC) measurements were taken with a Shin-Nippon auto-refractor. Magnetic resonance imaging was used to determine total ocular volume (OV) for 31 of the original subject group. Statistical comparisons and analyses were made using mixed repeated measures anovas, Pearson's correlation coefficient and stepwise forward multiple linear regression. Results - MSE was significantly associated with CMT, with thicker CMT2 and CMT3 being found in the myopic eyes (p = 0.002). In non-myopic eyes TCMT1, TCMT2, NCMT1 and NCMT2 correlated significantly with MSE, AL and OV (p < 0.05). In contrast, myopic eyes failed generally to exhibit a significant correlation between CMT, MSE and axial length but notably retained a significant correlation between OV, TCMT2, TCMT3, NCMT2 and NCMT3 (p < 0.05). OV was found to be a significantly better predictor of TCMT2 and TCMT3 than AL by approximately a factor of two (p < 0.001). Anterior chamber depth was significantly associated with both temporal and nasal CMT2 and CMT3; TCMT1 correlated positively with CC. Ethnicity had no significant effect on differences in CMT. Conclusions - Increased CMT is associated with myopia. We speculate that the lack of correlation in myopic subjects between CMT and axial length, but not between CMT and OV, is evidence that disrupted feedback between the fovea and ciliary apparatus occurs in myopia development.

Ophthalmic engineering:the development of novel instrumentation to further research in the field

The principle theme of this thesis is the advancement and expansion of ophthalmic research via the collaboration between professional Engineers and professional Optometrists. The aim has been to develop new and novel approaches and solutions to contemporary problems in the field. The work is sub divided into three areas of investigation; 1) High technology systems, 2) Modification of current systems to increase functionality, and 3) Development of smaller more portable and cost effective systems. High Technology Systems: A novel high speed Optical Coherence Tomography (OCT) system with integrated simultaneous high speed photography was developed achieving better operational speed than is currently available commercially. The mechanical design of the system featured a novel 8 axis alignment system. A full set of capture, analysis, and post processing software was developed providing custom analysis systems for ophthalmic OCT imaging, expanding the current capabilities of the technology. A large clinical trial was undertaken to test the dynamics of contact lens edge interaction with the cornea in-vivo. The interaction between lens edge design, lens base curvature, post insertion times and edge positions was investigated. A novel method for correction of optical distortion when assessing lens indentation was also demonstrated. Modification of Current Systems: A commercial autorefractor, the WAM-5500, was modified with the addition of extra hardware and a custom software and firmware solution to produce a system that was capable of measuring dynamic accommodative response to various stimuli in real time. A novel software package to control the data capture process was developed allowing real time monitoring of data by the practitioner, adding considerable functionality of the instrument further to the standard system. The device was used to assess the accommodative response differences between subjects who had worn UV blocking contact lens for 5 years, verses a control group that had not worn UV blocking lenses. While the standard static measurement of accommodation showed no differences between the two groups, it was determined that the UV blocking group did show better accommodative rise and fall times (faster), thus demonstrating the benefits of the modification of this commercially available instrumentation. Portable and Cost effective Systems: A new instrument was developed to expand the capability of the now defunct Keeler Tearscope. A device was developed that provided a similar capability in allowing observation of the reflected mires from the tear film surface, but with the added advantage of being able to record the observations. The device was tested comparatively with the tearscope and other tear film break-up techniques, demonstrating its potential. In Conclusion: This work has successfully demonstrated the advantages of interdisciplinary research between engineering and ophthalmic research has provided new and novel instrumented solutions as well as having added to the sum of scientific understanding in the ophthalmic field.

Factors affecting corneoscleral topography

PURPOSE: To evaluate factors affecting corneoscleral profile (CSP) using Anterior Segment Optical Coherence Tomography (AS-OCT) in combination with conventional videokeratoscopy. METHODS: OCT data were collected from 204 subjects of mean age 34.9 years (SD: ±15.2 yrs, range 18 to 65) using the Zeiss Visante AS-OCT and Medmont M300 corneal topographer. Measurements of corneal diameter (CD), corneal sagittal height (CS), iris diameter (ID), corneoscleral junction angle (CSJ) and scleral radius (SR) were extracted from multiple OCT images. Horizontal visible iris diameter (HVID) and vertical palpebral aperture (PA) were measured using a slit lamp graticule. Subject body height was also measured. Associations were then sought between CSP variables and age, height, ethnicity, sex and refractive error data collected. Results: Significant correlations were found between age and ocular topography variables of HVID, PA, CSJ, SR and ID (P<0.0001), while height correlated with HVID, CD and ID, and power vector terms only with vertical plane keratometry, CD and CS. Significant differences were noted between ethnicities with respect to CD (P=0.0046), horizontal and vertical CS (P=0.0068 and P=0.0095), and also horizontal ID (P=0.0010), while the same variables, with the exception of vertical CS, also varied with sex; horizontal CD (P=0.0018), horizontal CS (P=0.0018) and ID (P=0.0012). Age accounted for up to 36% of the variance in CSP variables. Conclusion: Age is the main factor influencing corneoscleral topography; consequently, this should be taken into consideration in contact lens design, in the optimization of surgical procedures involving the cornea and sclera and in IOL selection.

Impact of soft contact lens edge design and mid-peripheral lens shape on the epithelium and its indentation with lens mobility

Purpose. To evaluate the influence of soft contact lens midperipheral shape profile and edge design on the apparent epithelial thickness and indentation of the ocular surface with lens movement. Methods. Four soft contact lens designs comprising of two different plano midperipheral shape profiles and two edge designs (chiseled and knife edge) of silicone-hydrogel material were examined in 26 subjects aged 24.7 ± 4.6 years, each worn bilaterally in randomized order. Lens movement was imaged enface on insertion, at 2 and 4 hours with a high-speed, high-resolution camera simultaneous to the cross-section of the edge of the contact lens interaction with the ocular surface captured using optical coherence tomography (OCT) nasally, temporally, and inferiorly. Optical imaging distortions were individually corrected for by imaging the apparent distortion of a glass slide surface by the removed lens. Results. Apparent epithelial thickness varied with edge position (P < 0.001). When distortion was corrected for, epithelial indentation decreased with time after insertion (P = 0.010), changed after a blink (P < 0.001), and varied with position on the lens edge (P < 0.001), with the latter being affected by midperipheral lens shape profile and edge design. Horizontal and vertical lens movement did not change with time postinsertion. Vertical motion was affected by midperipheral lens shape profile (P < 0.001) and edge design (P < 0.001). Lens movement was associated with physiologic epithelium thickness for lens midperipheral shape profile and edge designs. Conclusions. Dynamic OCT coupled with high-resolution video demonstrated that soft contact lens movement and image-corrected ocular surface indentation were influenced by both lens edge design and midperipheral lens shape profiles. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

Anterior ophthalmic imaging

Improvements in imaging chips and computer processing power have brought major advances in imaging of the anterior eye. Digitally captured images can be visualised immediately and can be stored and retrieved easily. Anterior ocular imaging techniques using slitlamp biomicroscopy, corneal topography, confocal microscopy, optical coherence tomography (OCT), ultrasonic biomicroscopy, computerised tomography (CT) and magnetic resonance imaging (MRI) are reviewed. Conventional photographic imaging can be used to quantify corneal topography, corneal thickness and transparency, anterior chamber depth and lateral angle and crystalline lens position, curvature, thickness and transparency. Additionally, the effects of tumours, foreign bodies and trauma can be localised, the corneal layers can be examined and the tear film thickness assessed. © 2006 The Authors.

Parametric study of femtosecond inscription of microstructures for OCT artefact fabrication

As optical coherence tomography (OCT) becomes widespread, validation and characterization of systems becomes important. Reference standards are required to qualitatively and quantitatively measure the performance between difference systems. This would allow the performance degradation of the system over time to be monitored. In this report, the properties of the femtosecond inscribed structures from three different systems for making suitable OCT characterization artefacts (phantoms) are analyzed. The parameter test samples are directly inscribed inside transparent materials. The structures are characterized using an optical microscope and a swept-source OCT. The high reproducibility of the inscribed structures shows high potential for producing multi-modality OCT calibration and characterization phantoms. Such that a single artefact can be used to characterize multiple performance parameters such the resolution, linearity, distortion, and imaging depths. © 2012 SPIE.

Use of imaging technology to better understand soft contact lens fit dynamics

The principal theme of this thesis is the identification of additional factors affecting, and consequently to better allow, the prediction of soft contact lens fit. Various models have been put forward in an attempt to predict the parameters that influence soft contact lens fit dynamics; however, the factors that influence variation in soft lens fit are still not fully understood. The investigations in this body of work involved the use of a variety of different imaging techniques to both quantify the anterior ocular topography and assess lens fit. The use of Anterior-Segment Optical Coherence Tomography (AS-OCT) allowed for a more complete characterisation of the cornea and corneoscleral profile (CSP) than either conventional keratometry or videokeratoscopy alone, and for the collection of normative data relating to the CSP for a substantial sample size. The scleral face was identified as being rotationally asymmetric, the mean corneoscleral junction (CSJ) angle being sharpest nasally and becoming progressively flatter at the temporal, inferior and superior limbal junctions. Additionally, 77% of all CSJ angles were within ±50 of 1800, demonstrating an almost tangential extension of the cornea to form the paralimbal sclera. Use of AS-OCT allowed for a more robust determination of corneal diameter than that of white-to-white (WTW) measurement, which is highly variable and dependent on changes in peripheral corneal transparency. Significant differences in ocular topography were found between different ethnicities and sexes, most notably for corneal diameter and corneal sagittal height variables. Lens tightness was found to be significantly correlated with the difference between horizontal CSJ angles (r =+0.40, P =0.0086). Modelling of the CSP data gained allowed for prediction of up to 24% of the variance in contact lens fit; however, it was likely that stronger associations and an increase in the modelled prediction of variance in fit may have occurred had an objective method of lens fit assessment have been made. A subsequent investigation to determine the validity and repeatability of objective contact lens fit assessment using digital video capture showed no significant benefit over subjective evaluation. The technique, however, was employed in the ensuing investigation to show significant changes in lens fit between 8 hours (the longest duration of wear previously examined) and 16 hours, demonstrating that wearing time is an additional factor driving lens fit dynamics. The modelling of data from enhanced videokeratoscopy composite maps alone allowed for up to 77% of the variance in soft contact lens fit, and up to almost 90% to be predicted when used in conjunction with OCT. The investigations provided further insight into the ocular topography and factors affecting soft contact lens fit.

25th RCOphth Congress, President's Session paper:25 years of progress in medical retina

The quarter century since the foundation of the Royal College of Ophthalmologists has coincided with immense change in the subspecialty of medical retina, which has moved from being the province of a few dedicated enthusiasts to being an integral, core part of ophthalmology in every eye department. In age-related macular degeneration, there has been a move away from targeted, destructive laser therapy, dependent on fluorescein angiography to intravitreal injection therapy of anti-growth factor agents, largely guided by optical coherence tomography. As a result of these changes, ophthalmologists have witnessed a marked improvement in visual outcomes for their patients with wet age-related macular degeneration (AMD), while at the same time developing and enacting entirely novel ways of delivering care. In the field of diabetic retinopathy, this period also saw advances in laser technology and a move away from highly destructive laser photocoagulation treatment to gentler retinal laser treatments. The introduction of intravitreal therapies, both steroids and anti-growth factor agents, has further advanced the treatment of diabetic macular oedema. This era has also seen in the United Kingdom the introduction of a coordinated national diabetic retinopathy screening programme, which offers an increasing hope that the burden of blindness from diabetic eye disease can be lessened. Exciting future advances in retinal imaging, genetics, and pharmacology will allow us to further improve outcomes for our patients and for ophthalmologists specialising in medical retina, the future looks very exciting but increasingly busy.

Spectrum of morphological and visual changes due to vitreomacular interface disorders encountered in a large consecutive cohort of patients

Aim: Identify the incidence of vitreomacular traction (VMT) and frequency of reduced vision in the absence of other coexisting macular pathology using a pragmatic classification system for VMT in a population of patients referred to the hospital eye service. Methods: A detailed survey of consecutive optical coherence tomography (OCT) scans was done in a high-throughput ocular imaging service to ascertain cases of vitreomacular adhesion (VMA) and VMT using a departmental classification system. Analysis was done on the stages of traction, visual acuity, and association with other macular conditions. Results: In total, 4384 OCT scan episodes of 2223 patients were performed. Two hundred and fourteen eyes had VMA/VMT, with 112 eyes having coexisting macular pathology. Of 102 patients without coexisting pathology, 57 patients had VMT grade between 2 and 8, with a negative correlation between VMT grade and number of Snellen lines (r= -0.61717). There was a distinct cutoff in visual function when VMT grade was higher than 4 with the presence of cysts and sub retinal separation and breaks in the retinal layers. Conclusions: VMT is a common encounter often associated with other coexisting macular pathology. We estimated an incidence rate of 0.01% of VMT cases with reduced vision and without coexisting macular pathology that may potentially benefit from intervention. Grading of VMT to select eyes with cyst formation as well as hole formation may be useful for targeting patients who are at higher risk of visual loss from VMT.

Transversal and longitudinal images from the retina of the living eye using low coherence interferometry

An optical coherence tomography (OCT) system to produce both longitudinal and transversal images of the in vivo human eye is presented. For the first time, OCT transversal images collected from the living eye at 50-µm depth steps show details unobtainable with the state-of-the-art scanning laser ophthalmoscope. Images of up to 3×3?mm are produced from the retina in less than a second. For images larger than 1.6×1.6?mm, a path modulation is introduced by the galvanometric scanning mirror and is used as an effective phase modulation method.

Effect of initial retinal thickness on outcome of intravitreal bevacizumab therapy for diabetic macular edema

Purpose: To investigate whether eyes with diabetic macular edema (DME) and central retinal thickness (CRT) >400 μm had better visual and anatomical outcomes compared to eyes with a CRT <400 μm when treated with intravitreal bevacizumab in a real-world setting. Patients and methods: Patients undergoing intravitreal bevacizumab therapy for DME were identified from the departmental database of a tertiary referral unit. Following the initial injection, a retreatment was performed for any persistent macular edema, unless there had been no previous response to repeated doses. Recorded parameters included visual acuity, CRT on optical coherence tomography (spectral domain optical coherence tomography [SD-OCT]), and SD-OCT characteristics. Comparisons were made between data at baseline and 12 months after the first injection, and differences were tested for statistical significance using the Student's t-test. Results: In all, 175 eyes of 142 patients were analyzed. Patients in group 2 (CRT >400 μm) had significantly more injections than group 1 (CRT <400 μm) (4.0 versus 3.3; P=0.003). Both groups had similar numbers of eyes with preexisting epiretinal membrane and/or vitreomacular traction at baseline. The reduction in CRT was significantly greater in group 2 when compared to group 1 (P<0.0001). In terms of visual gain between baseline and month 12, each gained significantly by a mean of 0.12 logarithm of the minimum angle of resolution units (P=0.0001), but there was no difference between groups 1 and 2 (P=0.99). Conclusion: These results do not support a 400 μm baseline CRT cut-off for treating DME with bevacizumab, in contrast to published data on ranibizumab. Our results also indicate that patients with a thicker CRT require more bevacizumab injections, making treatment less cost-effective for these patients. Our results could be used by practitioners to support the use of bevacizumab in DME without applying a CRT cut-off. © 2014 Mushtaq et al.

Improving the cost-effectiveness of photographic screening for diabetic macular oedema:a prospective, multi-centre, UK study

Background/aims: Retinal screening programmes in England and Scotland have similar photographic grading schemes for background (non-proliferative) and proliferative diabetic retinopathy, but diverge over maculopathy. We looked for the most cost-effective method of identifying diabetic macular oedema from retinal photographs including the role of automated grading and optical coherence tomography, a technology that directly visualises oedema. Methods: Patients from seven UK centres were recruited. The following features in at least one eye were required for enrolment: microaneurysms/dot haemorrhages or blot haemorrhages within one disc diameter, or exudates within one or two disc diameters of the centre of the macula. Subjects had optical coherence tomography and digital photography. Manual and automated grading schemes were evaluated. Costs and QALYs were modelled using microsimulation techniques. Results: 3540 patients were recruited, 3170 were analysed. For diabetic macular oedema, England's scheme had a sensitivity of 72.6% and specificity of 66.8%; Scotland 's had a sensitivity of 59.5% and specificity of 79.0%. When applying a ceiling ratio of £30 000 per quality adjusted life years (QALY) gained, Scotland's scheme was preferred. Assuming automated grading could be implemented without increasing grading costs, automation produced a greater number of QALYS for a lower cost than England's scheme, but was not cost effective, at the study's operating point, compared with Scotland's. The addition of optical coherence tomography, to each scheme, resulted in cost savings without reducing health benefits. Conclusions: Retinal screening programmes in the UK should reconsider the screening pathway to make best use of existing and new technologies.

Myopic foveoschisis:a clinical review

To review the literature on epidemiology, clinical features, diagnostic imaging, natural history, management, therapeutic approaches, and prognosis of myopic foveoschisis. A systematic Pubmed search was conducted using search terms: myopia, myopic, staphyloma, foveoschisis, and myopic foveoschisis. The evidence base for each section was organised and reviewed. Where possible an authors' interpretation or conclusion is provided for each section. The term myopic foveoschisis was first coined in 1999. It is associated with posterior staphyloma in high myopia, and is often asymptomatic initially but progresses slowly, leading to loss of central vision from foveal detachment or macular hole formation. Optical coherence tomography is used to diagnose the splitting of the neural retina into a thicker inner layer and a thinner outer layer, but compound variants of the splits have been identified. Vitrectomy with an internal limiting membrane peel and gas tamponade is the preferred approach for eyes with vision decline. There has been a surge of new information on myopic foveoschisis. Advances in optical coherence tomography will continually improve our understanding of the pathogenesis of retinal splitting, and the mechanisms that lead to macular damage and visual loss. Currently, there is a good level of consensus that surgical intervention should be considered when there is progressive visual decline from myopic foveoschisis.