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.

The effect of intraocular scattered light on the contrast sensitivity function

Intraocular light scatter is high in certain subject groups eg the elderly, due to increased optical media turbidity, which scatters and attenuates light travelling towards the retina. This causes reduced retinal contrast especially in the presence of glare light. Such subjects have depressed Contrast Sensitivity Functions (CSF). Currently available clinical tests do not effectively reflect this visual disability. Intraocular light scatter may be quantified by measuring the CSF with and without glare light and calculating Light Scatter Factors (LSF). To record the CSF on clinically available equipment (Nicolet CS2000), several psychophysical measurement techniques were investigated, and the 60 sec Method of Increasing Contrast was selected as the most appropriate. It was hypothesised that intraocular light scatter due to particles of different dimensions could be identified by glare sources at wide (30°) and narrow (3.5°) angles. CSFs andLSFs were determined for: (i) Subjects in young, intermediate and old age groups. (ii) Subjects during recovery from large amounts of induced corneal oedema. (iii) A clinical sample of contact lens (CL) wearers with a group of matched controls. The CSF was attenuated at all measured spatial frequencies with the intermediate and old group compared to the young group. High LSF values were found only in the old group (over 60 years). It was concluded that CSF attenuation in the intermediate group was due to reduced pupil size, media absorption and/or neural factors. In the old group, the additional factor was high intraocular light scatter levels of lenticular origin. The rate of reduction of the LSF for the 3.5° glare angle was steeper than that for the 30° angle, following induced corneal oedema. This supported the hypothesis, as it was anticipated that epithelial oedema would recover more rapidly than stromal oedema. CSFs and LSFs were markedly abnormal in the CL wearers. The analytical details and the value of these investigative techniques in contact lens research are discussed.

Ionic and neutral hydrogels for dermal and ophthalmic applications

This thesis is concerned with the use of ionic and neutral hydrogels in dermal and ocular applications with particular reference to controlled release applications. The work consists of three interconnected themes.The first area of study is the use of skin adhesive bioelectrode hydrogels as ground plate electrodes for ophthalmic iontophoresis applications. The work provides a basis of understanding the relative contributions made by ionic monomers (such as sodium s-(acrylamide)-2-methyl propane sulphonate and acrylic acid-bis-(3-sulfopropyl-ester, potassium salt) and neutral monomers (such as acryloymorpholine, N,N-dimethylacrylamide and N-vinyl pyrrolidone) to adhesion, rheology and impedance of bioelectrode gels. The general advantage of neutral monomers, which have been used to successfully replace ionic monomers, is that they enable more effective control of independent anion and cation species (for example potassium chloride and sodium chloride) unlike ionic monomers where polymerisation produces an immobile polyanion thus limiting cation mobility. Secondly, release from a completely neutral hydrogel under the influence of mechanical shaking was studied for the case of crosslinked polyvinyl alcohol (PVA) containing low concentration of linear soluble PVA in a contact lens application. The soluble PVA was observed to be eluting by reptation from the lens matrix due to the mechanical action of the eyelid. This process was studied in an in vitro model, which in this research was used as a basis for developing a lens made with enhanced release polymer. The third area of work is related to the factors that control drug release (in particular non-steroidal anti-inflammatory drugs) from a hydrogel matrix. This links both electrotherapy applications, such as transcutaneous electrical nerve stimulation, in which the passive diffusion from the gel could be used in conjunction with enhanced transmission across the dermal surface with passive diffusion from a contact lens matrix and the development of therapeutic contact lenses.

New strategy to overcome the intrinsic difficulty of phospholipids solubilisation and delivery to the eye

Purpose: Lipids play a vital role at interfaces such as the tear film in the protection of the anterior eye. Their role is to act as lubricants and reduce surface and interfacial tension. Although there is a lack of appropriate methods to solubilize and dilute phospholipids to the tear film. Here, we report that styrene-maleic acid copolymers (PSMA), can form polymer–lipid complexes in the form of monodisperse nanometric particles, which can easily solubilise these phospholipid molecules by avoiding for example, the use of any kind of surfactant. Method: The interactions of PSMA with phospholipids have been studied by its adsorption from aqueous solutions into monolayers of dimyristoyl-phosphorylcholine (DMPC). The Langmuir trough (LT) technique is used to study this pH-dependant complex formation. The formed nanoparticles have been also analysed by 31P NMR, particle size distribution by light scattering (DLS) and morphology by electron microscopy (SEM). Results: The LT has been found to be a useful technique for in vitro simulation of in vivo lipid layer behaviour: The limiting surface pressure of unstable tear films ranges between 20 and 30 mN/m. More stable tear films show an increase in surface pressure, within the range of 35–45 mN/m. The DMPC monolayers have a limiting surface pressure of 38 mN/m (water), and 45 mN/m (pH 4 buffer), and the PSMA-DMPC complexes formed at pH 4 have a value of 42 mN/m, which resembles that of the stable tear film. The average particle size distribution is 53 ± 10 nm with a low polydispersity index (PDI) of 0.24 ± 0.03. Conclusions: New biocompatible and cheap lipid solubilising agents such as PSMA can be used for the study of the tear film composition and properties. These polymer–lipid complexes in the form of nanoparticles can be used to solubilise and release in a controlled way other hydrophobic molecules such as some drugs or proteins.

Fibre optics sensors in tear electrolyte analysis:towards a novel point of care potassium sensor

The diagnosis of ocular disease is increasingly important in optometric practice and there is a need for cost effective point of care assays to assist in that. Although tears are a potentially valuable source of diagnostic information difficulties associated with sample collection and limited sample size together with sample storage and transport have proved major limitations. Progressive developments in electronics and fibre optics together with innovation in sensing technology mean that the construction of inexpensive point of care fibre optic sensing devices is now possible. Tear electrolytes are an obvious family of target analytes, not least to complement the availability of devices that make the routine measurement of tear osmolarity possible in the clinic. In this paper we describe the design, fabrication and calibration of a fibre-optic based electrolyte sensor for the quantification of potassium in tears using the ex vivo contact lens as the sample source. The technology is generic and the same principles can be used in the development of calcium and magnesium sensors. An important objective of this sensor technology development is to provide information at the point of routine optometric examination, which would provide supportive evidence of tear abnormality.

Clinical evaluation of the Oculus Keratograph

AIM: To determine the validity and reliability of the measurement of corneal curvature and non-invasive tear break-up time (NITBUT) measures using the Oculus Keratograph. METHOD: One hundred eyes of 100 patients had their corneal curvature assessed with the Keratograph and the Nidek ARKT TonorefII. NITBUT was then measured objectively with the Keratograph with Tear Film Scan software and subjectively with the Keeler Tearscope. The Keratograph measurements of corneal curvature and NITBUT were repeated to test reliability. The ocular sensitivity disease index questionnaire was completed to quantify ocular comfort. RESULTS: The Keratograph consistently measured significantly flatter corneal curvatures than the ARKT (MSE difference: +1.83±0.44D), but was repeatable (p>0.05). Keratograph NITBUT measurements were significantly lower than observation using the Tearscope (by 12.35±7.45s; pp < 0.001) and decreased on subsequent measurement (by -1.64 ± 6.03s; p < 0.01). The Keratograph measures the first time the tears break up anywhere on the cornea with 63% of subjects having NI-TBUT's <5s and a further 22% having readings between 5 and 10s. The Tearscope results were found to correlate better with the patients symptoms (r = -0.32) compared to the Keratograph (r = -0.19). Conclusions: The Keratograph requires a calibration off-set to be comparable to other keratometry devices. Its current software detects very early tear film changes, recording significantly lower NITBUT values than conventional subjective assessment. Adjustments to instrumentation software have the potential to enhance the value of Keratograph objective measures in clinical practice.

Keratoconus:a review

Keratoconus is the most common primary ectasia. It usually occurs in the second decade of life and affects both genders and all ethnicities. The estimated prevalence in the general population is 54 per 100,000. Ocular signs and symptoms vary depending on disease severity. Early forms normally go unnoticed unless corneal topography is performed. Disease progression is manifested with a loss of visual acuity which cannot be compensated for with spectacles. Corneal thinning frequently precedes ectasia. In moderate and advance cases, a hemosiderin arc or circle line, known as Fleischer's ring, is frequently seen around the cone base. Vogt's striaes, which are fine vertical lines produced by Descemet's membrane compression, is another characteristic sign. Most patients eventually develop corneal scarring. Munson's sign, a V-shape deformation of the lower eyelid in downward position; Rizzuti's sign, a bright reflection from the nasal area of the limbus when light is directed to the limbus temporal area; and breakages in Descemet's membrane causing acute stromal oedema, known as hydrops, are observed in advanced stages. Classifications based on morphology, disease evolution, ocular signs and index-based systems of keratoconus have been proposed. Theories into the genetic, biomechanical and biochemical causes of keratoconus have been suggested. Management varies depending on disease severity. Incipient cases are managed with spectacles, mild to moderate cases with contact lenses and severe cases can be treated with keratoplasty. This article provides a review on the definition, epidemiology, clinical features, classification, histopathology, aetiology and pathogenesis, and management and treatment strategies for keratoconus.

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.

A decade of silicone hydrogel development:surface properties, mechanical properties, and ocular compatibility

Since the initial launch of silicone hydrogel lenses, there has been a considerable broadening in the range of available commercial material properties. The very mobile silicon–oxygen bonds convey distinctive surface and mechanical properties on silicone hydrogels, in which advantages of enhanced oxygen permeability, reduced protein deposition, and modest frictional interaction are balanced by increased lipid and elastic response. There are now some 15 silicone hydrogel material variants available to practitioners; arguably, the changes that have taken place have been strongly influenced by feedback based on clinical experience. Water content is one of the most influential properties, and the decade has seen a progressive rise from lotrafilcon-A (24%) to efrofilcon-A (74%). Moduli have decreased over the same period from 1.4 to 0.3 MPa, but not solely as a result of changes in water content. Surface properties do not correlate directly with water content, and ingenious approaches have been used to achieve desirable improvements (e.g., greater lubricity and lower contact angle hysteresis). This is demonstrated by comparing the hysteresis value of the earliest (lotrafilcon-A, >40°) and most recent (delefilcon-A, <10°) coated silicone hydrogels. Although wettability is important, it is not of itself a good predictor of ocular response because this involves a much wider range of physicochemical and biochemical factors. The interference of the lens with ocular dynamics is complex leading separately to tissue–material interactions involving anterior and posterior lens surfaces. The biochemical consequences of these interactions may hold the key to a greater understanding of ocular incompatibility and end of day discomfort.

The relationship between measurement method and corneal structure on apparent intraocular pressure in glaucoma and ocular hypertension

Purpose: To analyse the relationship between measured intraocular pressure (IOP) and central corneal thickness (CCT), corneal hysteresis (CH) and corneal resistance factor (CRF) in ocular hypertension (OHT), primary open-angle (POAG) and normal tension glaucoma (NTG) eyes using multiple tonometry devices. Methods: Right eyes of patients diagnosed with OHT (n=47), normal tension glaucoma (n=17) and POAG (n=50) were assessed, IOP was measured in random order with four devices: Goldmann applanation tonometry (GAT); Pascal(R) dynamic contour tonometer (DCT); Reichert(R) ocular response analyser (ORA); and Tono-Pen(R) XL. CCT was then measured using a hand-held ultrasonic pachymeter. CH and CRF were derived from the air pressure to corneal reflectance relationship of the ORA data. Results: Compared to the GAT, the Tonopen and ORA Goldmann equivalent (IOPg) and corneal compensated (IOPcc) measured higher IOP readings (F=19.351, p<0.001), particularly in NTG (F=12.604, p<0.001). DCT was closest to Goldmann IOP and had the lowest variance. CCT was significantly different (F=8.305, p<0.001) between the 3 conditions as was CH (F=6.854, p=0.002) and CRF (F=19.653, p<0.001). IOPcc measures were not affected by CCT. The DCT was generally not affected by corneal biomechanical factors. Conclusion: This study suggests that as the true pressure of the eye cannot be determined non-invasively, measurements from any tonometer should be interpreted with care, particularly when alterations in the corneal tissue are suspected.

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.

Albumin in tears

Albumin is not endogenous to the tear film and is present as a product of plasma leakage. It is used as a diagnostic marker of ocular insult and inflammation. Tear albumin is, however, poorly understood, with large variations in reported concentrations between studies. There is also no authoritative information on whether its presence in tears is responsive or part of an adaptive reaction.The presented research aimed to resolve the disparities in published tear albumin concentrations and investigate the role of albumin in the tear film. Collation and evaluation of the available literature identified collection method, stimulus, assay technique, and disease state as factors able to influence quoted tear albumin to different extents. Difference in sampling technique exhibited the largest variations in mean tear albumin concentrations. Review of the literature also highlighted that little systematic investigations of the daily cycle of tear albumin levels, and subject-to-subject-variation, had been carried out. In order to remedy this shortcoming, variations in tear albumin concentration were investigated in 13 subjects throughout the waking day. Results identified a time period where albumin levels are relatively stable (2-6 hours post-waking). This was designated a suitable baseline for the determinations of tear albumin concentrations and subject-to-subject comparisons. Significantly, a previously unrecognised progressive increase in albumin concentration during the latter part of the day was also identified in the population. This increase suggests that albumin may play a more active and dynamic role in the ocular environment than is commonly perceived. To facilitate the collection of additional tear albumin data, tear sampling and point-of-care analysis in contact lens clinics were investigated. Two instruments were evaluated and were found to be suitable for the analysis of tear albumin in commercial institutions. Collectively, the described research has provided new insight into tear albumin and a strong foundation for further studies.

A preliminary investigation into the effects of ocular lubricants on higher order aberrations in normal and dry eye subjects

Purpose: To study the effects of ocular lubricants on higher order aberrations in normal and self-diagnosed dry eyes. Methods: Unpreserved hypromellose drops, Tears Again™ liposome spray and a combination of both were administered to the right eye of 24 normal and 24 dry eye subjects following classification according to a 5 point questionnaire. Total ocular higher order aberrations, coma, spherical aberration and Strehl ratios for higher order aberrations were measured using the Nidek OPD-Scan III (Nidek Technologies, Gamagori, Japan) at baseline, immediately after application and after 60. min. The aberration data were analyzed over a 5. mm natural pupil using Zernike polynomials. Each intervention was assessed on a separate day and comfort levels were recorded before and after application. Corneal staining was assessed and product preference recorded after the final measurement for each intervention. Results: Hypromellose drops caused an increase in total higher order aberrations (p= <0.01 in normal and dry eyes) and a reduction in Strehl ratio (normal eyes: p= <0.01, dry eyes p= 0.01) immediately after instillation. There were no significant differences between normal and self-diagnosed dry eyes for response to intervention and no improvement in visual quality or reduction in higher order aberrations after 60. min. Differences in comfort levels failed to reach statistical significance. Conclusion: Combining treatments does not offer any benefit over individual treatments in self-diagnosed dry eyes and no individual intervention reached statistical significance. Symptomatic subjects with dry eye and no corneal staining reported an improvement in comfort after using lubricants. © 2013 British Contact Lens Association.

Editorial

Readers may have noted that a short but very important announcement was made in the last issue of CLAE, at the top of the contents page. CLAE has been accepted by Thomson Reuters for abstracting and indexing in its SciSearch, Journal Citation Reports, and Current Contents services. This will ensure a greater visibility to the international research community. In addition, in June 2012 CLAE will receive its very first official Impact Factor – a measure of journal influence of importance to authors and readers alike. The impact factor value has not yet been decided but internal estimates by Elsevier estimate it will be around 1, and it will be applied to all CLAE issue back to January 2009 (volume 32). I would guess readers at this stage would have one of two responses – either ‘that's good news’ or perhaps ‘what's an impact factor?’ If you are in the latter camp then allow me to try and explain. Basically the impact factor or citation index of a journal is based on how many times in the previous year papers published in that journal in the previous two years were cited by authors publishing in other journals. So the 2012 impact factor for CLAE is calculated on how many times in 2011 papers that were published in CLAE in 2010 and 2009 were cited in other journals in 2011, divided by the number of papers published in CLAE 2010 and 2009. Essentially authors will try and get their work published in journals with a higher impact factor as it is thought that the paper will be cited more by other authors or the paper will have higher visibility in the arena. For universities having its published output in higher journals is one of the markers used to judge esteem. For individual authors publishing in journals with a higher impact factor or the number of times one of their papers is published is something that they are likely to add to their CVs or demonstrate the importance of their work. Journals with higher impact factors tend to be more review journals or journals with a wider spectrum so for a relatively small journal with a specialised field like CLAE it is great to be listed with a citation index. The awarding of a citation index crowns many changes that CLAE has undergone since the current Editor took the reins in 2005. CLAE has increased from four issues (in 2004) to six issues per year with at least one review article per issue and one article with continuing education per issue. The rejection rate has gone up significantly meaning that only best papers are published (currently it stands at 37%). CLAE has been Medline/Pubmed indexed for a few years now which is also a very important factor in improving visibility of the journal. The submission and reviewing process for CLAE in now entirely online and finally the editorial board has changed from being merely a list of keynote people to being an active group of keynote people who are enthusiastically involved with the journal. From the editorial board one person is appointed as a Reviews Editor plus we have two additional editors who work as Regional Editors. As ever, on behalf of CLAE I would like to thank the BCLA Council for their continued support (especially Vivien Freeman) and Elsevier for their continuing guidance (in particular Andrew Miller and Rosie Davey) and the excellent Editorial Board (Christopher Snyder, Pauline Cho, Eric Papas, Jan Bergmanson, Roger Buckley, Patrick Caroline, Dwight Cavanagh, Robin Chalmers, Michael Doughty, Nathan Efron, Michel Guillon, Nizar Hirji, Meng Lin, Florence Malet, Philip Morgan, Deborah Sweeney, Brian Tighe, Eef van Der Worp, Barry Weissman, Mark Willcox, James Wolffsohn and Craig Woods). And finally, a big thanks to the authors and reviewers who work tirelessly putting manuscripts together for publication in CLAE. Copyright © 2012 Published by Elsevier Ltd.

EUROMCONTACT

Editorial