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2.  Cancer-associated retinopathy caused by benign thymoma 
doi:10.1136/bjo.2008.151563
PMCID: PMC3487380  PMID: 20424218
3.  Cataract and Cognitive Impairment: A Review of the Literature 
Acquired cataract and cognitive impairment are both common age related problems, and ophthalmologists are increasingly likely to encounter patients who have both. Dementia types which display early visuo-perceptual impairment may present first to ophthalmology services. When these patients have coexisting cataract it may be difficult to distinguish visual complaints due to cataract from those due to dementia.
The interaction between visual impairment due to cataract, and neurodegenerative disorders affecting the central visual pathways, is not fully understood. Visual impairment due to cataract may stress impaired attentional mechanisms, and cataract extraction may improve cognitive performance in some patients with early cognitive impairment; however the benefits of cataract surgery in established dementia are less clear. Here we review the literature on this subject and consider the implications for practice.
doi:10.1136/bjo.2009.165902
PMCID: PMC4119932  PMID: 20807709
Cataract; Dementia; Cognitive impairment; Visuo-perceptual impairment
4.  EFFECT OF ISOMETRIC EXERCISE ON CHOROIDAL BLOOD FLOW IN PATIENTS WITH AGE-RELATED MACULAR DEGENERATION (AMD) 
The British journal of ophthalmology  2010;94(12):1629-1631.
Aim
To investigate the choroidal vascular regulation in age related macular degeneration (AMD) we compared the regulatory responses induced by isometric exercise in control subjects and patients with AMD.
Methods
Seventeen eyes of 17 patients with dry AMD in the study eye and 19 eyes of 19 controls were included in this study. Both groups were well matched in regards to age, race and gender. Brachial artery blood pressure determinations and laser Doppler flowmetry (Oculix) measurements of relative foveolar choroidal blood velocity, volume, and flow were obtained in the study eye of each subject during 30 seconds of baseline, and then, during 3 minutes of isometric exercise consisting of squeezing a hand grip in each hand. Similar measurements were then also obtained during the two minutes following the cessation of exercise. Using non-paired, two-tailed t-test, changes in circulatory parameters during exercise and following the end of exercise were compared between AMD patients and control subjects. The slope for the relationship between circulatory changes and perfusion pressure changes was calculated and compared between AMD patients and controls using linear regression analysis. Analysis of data was performed in a masked fashion. Circulatory measurements are shown in arbitrary units (AU).
Results
There were no statistically significant differences between the changes in ChBVel, ChBVol and ChBFlow observed in control subjects and AMD patients during the isometric exercise phase and after exercise.
Conclusions
Our results suggest that the response of the choroidal circulation to this type of isometric exercise resulting in a moderate increase in blood pressure does not seem to be affected by AMD.
doi:10.1136/bjo.2009.176859
PMCID: PMC4077432  PMID: 20837789
Isometric exercises; choroidal blood flow; Age-Related Macular Degeneration (AMD)
5.  Family history, near work, outdoor activity, and myopia in Singapore Chinese preschool children 
The British journal of ophthalmology  2010;94(8):1012-1016.
Aims
To investigate the risk factors for myopia, including near work and outdoor activity, in Singapore Chinese preschool children.
Methods
A cross-sectional study, with disproportionate random sampling by 6-month age groups, of 3009 Singapore Chinese children aged 6–72 months was performed. Information on family history, near work and outdoor activity was obtained. Spherical equivalent refraction (SEA) was assessed.
Results
Children with two myopic parents were more likely to be myopic (adjusted OR=1.91; 95% CI 1.38 to 2.63) and to have a more myopic SER (regression coefficient=−0.35; 95% CI −0.47 to −0.22) than children without myopic parents. For each 1 cm taller height, the SER was more myopic by 0.01 dioptres. Neither near work nor outdoor activity was associated with preschool myopia.
Conclusions
A family history of myopia was the strongest factor associated with preschool myopia. In contrast, neither near work nor outdoor activity was found to be associated with early myopia. These data suggest that genetic factors may play a more substantial role in the development of early-onset myopia than key environmental factors.
doi:10.1136/bjo.2009.173187
PMCID: PMC4041336  PMID: 20472747
6.  Eye movement recordings to investigate a supranuclear component in chronic progressive external ophthalmoplegia: a cross-sectional study 
The British journal of ophthalmology  2010;94(9):1165-1168.
Background
It has been postulated that eye movement disorders in chronic progressive external ophthalmoplegia (CPEO) have a neurological as well as a myopathic component to them.
Aim
To investigate whether there is a supranuclear component to eye movement disorders in CPEO using eye movement recordings.
Methods
Saccade and smooth pursuit (SP) characteristics together with vestibulo-ocular reflex (VOR) gain and VOR suppression (VORS) gain in 18 patients with CPEO and 34 normal patients were measured using Eyelink II video-oculography.
Results
The asymptotic values of the peak velocity main sequence curves were reduced in the CPEO group compared to those of normal patients, with a mean of 161°/s (95% CI 126°/s to 197°/s) compared with 453°/s (95% CI 430 to 475°/s), respectively. Saccadic latency was longer in CPEO (263 ms; 95% CI 250 to 278), compared to controls (185 ms; 95% CI 181 to 189). Smooth pursuit and VOR gains were impaired in CPEO, although this could be explained by non-supranuclear causes. VORS gain was identical in the two groups.
Conclusions
This study does not support a supranuclear component to the ophthalmoplegia of CPEO, although the increased latencies observed may warrant further investigation.
doi:10.1136/bjo.2009.165639
PMCID: PMC4038492  PMID: 20576783
7.  Change in function and spectacle-use 2 months after providing presbyopic spectacles in rural Tanzania 
The British journal of ophthalmology  2010;94(6):10.1136/bjo.2008.145607.
Aims
To examine near vision spectacle retention and use, and changes in self-reported and performance-based near vision, 2 months after the provision of near vision spectacles.
Methods
We conducted a 2-month follow-up of a population-based cohort of persons in rural Tanzania with near vision impairment who had received spectacles. Previously, residents age ≥40 years were examined for distance and near vision acuity. Those with presbyopia and hyperopia (‘functional presbyopia’) were given near vision spectacles. At baseline, subjects were asked to thread a needle; they were also asked questions on the perception of their near vision, ability to be independent and general health. At 2 months, subjects were again queried. Questions on the perceived affordability of replacement spectacles were also asked.
Results
Of the 866 people provided with spectacles, 89% were seen at 2 months. Ninety-two per cent were still using the spectacles. Users were more likely to have any education (51.8%) than non-users (28.3%) (p<0.001). Only 31% had successfully threaded a needle at baseline, increasing to 91% at follow-up (p<0.001). Spectacle-users showed a significant improvement in satisfaction with near vision and ability to be independent, but no change in perception of general health, from baseline to follow-up. Men were more likely than women to be able to afford spectacles and to know where to get them.
Conclusions
Our cohort maintained their spectacles and reported tangible improvements associated with their use. The value of simple reading spectacles for those with near vision impairment suggests that a greater emphasis on near vision is needed in the Vision 2020 agenda.
doi:10.1136/bjo.2008.145607
PMCID: PMC3820013  PMID: 20508042
8.  Comparison of two probe designs for determining intraocular oxygen distribution 
Introduction
Alterations in intraocular oxygen levels are important contributors to, or indications of ocular disease. Polarographic electrodes and fiberoptic sensors (optodes) have been used to measure oxygen and to map the distribution of oxygen in animal models and in human eyes. A recent study reported the use of a commercial electrode to compare oxygen distribution in the vitreous of patients undergoing vitrectomy related to central retinal vein occlusion, macular hole or preretinal membrane. The results of this study were at variance with previous measures of oxygen distribution in the human vitreous using polarographic or optical sensors. To resolve this discrepancy, the present study compared measurements made in vitro or in animal eyes, using the electrode employed in the previous study or a fiberoptic sensor of different design.
Study design
Comparative in vitro and in vivo measurements.
Results
In vitro, the two devices reported similar levels of oxygen, although the electrode consistently detected levels above the calculated values. In rabbit eyes, the electrode had a slow response time and was unable to detect oxygen gradients that were readily measured by the smaller optode. When the electrode was inserted into an eye of similar size to the human eye, the reference thermistor measured the temperature outside the eye, not in the vitreous.
Conclusions
The design of the electrode used in the previous study makes it unsuitable for measurements of oxygen distribution in the eye.
doi:10.1136/bjo.2010.186064
PMCID: PMC3736552  PMID: 20870641
9.  Spectral-domain OCT peripapillary retinal nerve fibre layer thickness measurements in patients with stargardt disease 
Aims
To evaluate the presence of peripapillary retinal nerve fibre layer (RNFL) defects in patients with Stargardt disease by using spectral-domain optical coherence tomography (SD-OCT).
Methods
Fifty-two eyes of 27 patients with Stargardt disease underwent peripapillary RNFL thickness measurements using SD-OCT.
Results
Twenty-seven patients with Stargardt disease were enrolled. Their mean (±SD) age was 38.3 (14.7) years. Fourteen patients (51.9%) showed a thinning of the peripapillary RNFL in one or more quadrants in at least one eye, and four patients (14.8%) in both eyes. Five patients (18.5%) showed a thickening of the peripapillary RNFL in at least one eye, and four patients (14.8%) in both eyes.
Conclusion
This study demonstrated the presence of defects in the peripapillary RNFL thickness in patients with Stargardt disease by using SD-OCT. It would be clinically prudent that Stargardt patients considered for various treatment options be considered for RNFL thickness measurements.
doi:10.1136/bjo.2010.189720
PMCID: PMC3697128  PMID: 20935302
10.  Quality Assurance in Trichiasis Surgery: a methodology 
SUMMARY
Trachoma remains a significant cause of blindness in many parts of the world. The major route to blindness involves upper lid entropion leading to trachomatous trichiasis (TT) which promotes progressive corneal opacification. The provision of surgery to correct TT in the populations most severely affected is a major challenge for the global effort to eliminate Trachoma blindness by the year 2020.
Most attention has been paid to increasing the quantity of TT surgery performed, and large numbers of non-doctor operators have been trained to this end. Surgical audit by those performing TT surgery is not a routine part of any national trachoma control programme, and no effective mechanism exists for identifying surgeons experiencing poor outcomes.
We propose a methodology for surgical audit at the level of the individual surgeon based on Lot Quality Assurance. A set number of patients operated on previously for upper eyelid TT are examined to detect the recurrence of TT. The number of recurrent cases found will lead to categorisation of the TT surgeon to either “high recurrence” or “low recurrence” with reasonable confidence. The threshold of unacceptability can be set by individual programmes according to previous local studies of recurrence rates or those from similar settings. Identification of surgeons delivering unacceptably high levels of recurrent TT will guide managers on the need for remedial intervention such as re-training.
doi:10.1136/bjo.2010.186197
PMCID: PMC3670403  PMID: 20881027
Trachoma; Trichiasis; Audit; Trichiasis Surgery
11.  The effect of genetic variants in SERPING1 on the risk of neovascular age-related macular degeneration 
Purpose
Genetic factors influence an individual’s risk for developing age-related macular degeneration (AMD), a leading cause of irreversible vision loss. Previous studies investigating the potential association between all AMD subtypes and the SERPING1 gene, which encodes a key regulator of the classical complement pathway, have yielded conflicting results. The purpose of this study was to determine whether variations in SERPING1 are associated with the neovascular form of AMD.
Methods
A total of 556 patients with neovascular AMD and 256 ethnically-matched controls were genotyped for polymorphisms in SERPING1. A tagging single nucleotide polymorphism (tSNP) approach was used to cover the SERPING1 gene plus 2 kilobases (kb) on each side, spanning the promoter and the 3′ untranslated regions. Ten SNPs with a minimum allele frequency of 0.10 were covered by three tSNPs (rs1005510, rs11603020, rs2511989).
Results
SERPING1 SNPs rs1005510 and rs2511989 were significantly associated with neovascular AMD in our cohort, with rs1005510 conferring an adverse risk effect (OR 1.49, 95% CI 1.18–1.88) and rs2511989 conferring a protective effect (OR 0.73, 95% CI 0.59–0.90). For both tSNPs, logistic regression of individual genotypes demonstrated statistically-significant stepwise changes in the risk of developing AMD. Combined analysis of rs1005510 with variants in CFH and HTRA1 confirmed an independent risk effect. The rs11603020 variant had no effect on AMD susceptibility in this study (OR 0.98, 95% CI 0.78–1.24).
Conclusions
This study comprehensively investigates the SERPING1 gene (using three tSNPs) and evaluates these genetic variants in the largest neovascular AMD cohort to date. Our results support the hypothesis that SERPING1 has a modest effect on the risk of neovascular AMD.
doi:10.1136/bjo.2009.172007
PMCID: PMC3655725  PMID: 20606025
SERPING1; Complement cascade; Age-Related Macular Degeneration; Choroidal Neovascularization
12.  Imaging of the retinal nerve fibre layer with spectral domain optical coherence tomography for glaucoma diagnosis 
Optical coherence tomography (OCT) techniques have been applied to develop a new generation of the technology, called spectral domain (SD) or Fourier domain (FD) OCT. The commercially available SD-OCT technology offers benefits over the conventional time domain (TD) OCT such as a scanning speed up to 200 times faster and higher axial resolution (3 to 6 μm). Overall, SD-OCT offers improved performance in terms of reproducibility. SD-OCT has a level of discriminating capability, between healthy and perimetric glaucoma eyes similar to that obtained with TD-OCT. Furthermore, the capabilities and features of SD-OCT are rapidly evolving, mainly due to three-dimensional imaging and image rendering. More sophisticated approaches for macular and optic disc assessment are expected to be employed in clinical practice. Analysis software should be further refined for interpretation of SD-OCT images in order to enhance the sensitivity and specificity of glaucoma diagnostics. Most importantly for SD-OCT is determination of its ability to diagnostic structural glaucomatous progression. Considering the recent launch time of the commercially available SD-OCT and slow progressing characteristic of glaucoma, we must wait for longitudinal SD-OCT data, with a long enough follow-up, to become available.
doi:10.1136/bjo.2010.186924
PMCID: PMC3421150  PMID: 21030413
13.  Nonsense mutation in MERTK causes autosomal recessive retinitis pigmentosa in a consanguineous Pakistani family 
The British Journal of Ophthalmology  2010;94(8):1094-1099.
Background
Retinitis pigmentosa (RP) is one of the most common ophthalmic disorders affecting one in approximately 5000 people worldwide. A nuclear family was recruited from the Punjab province of Pakistan to study the genetic basis of autosomal recessive RP.
Methods
All affected individuals underwent a thorough ophthalmic examination and the disease was characterised based upon results for fundus photographs and electroretinogram recordings. Genomic DNA was extracted from peripheral leucocytes. Exclusion studies were performed with short tandem repeat (STR) markers flanking reported autosomal recessive RP loci. Haplotypes were constructed and results were statistically evaluated.
Results
The results of exclusion analyses suggested that family PKRP173 was linked to chromosome 2q harbouring mer tyrosine kinase protooncogene (MERTK), a gene previously associated with autosomal recessive RP. Additional STR markers refined the critical interval and placed it in a 13.4 cM (17 Mb) region flanked by D2S293 proximally and D2S347 distally. Significant logarithm of odds (LOD) scores of 3.2, 3.25 and 3.18 at θ=0 were obtained with markers D2S1896, D2S2269 and D2S160. Sequencing of the coding exons of MERTK identified a mutation, c.718G→T in exon 4, which results in a premature termination of p.E240X that segregates with the disease phenotype in the family.
Conclusion
Our results strongly suggest that the nonsense mutation in MERTK, leading to premature termination of the protein, is responsible for RP phenotype in the affected individuals of the Pakistani family.
doi:10.1136/bjo.2009.171892
PMCID: PMC3393880  PMID: 20538656
14.  Blind subjects implanted with the Argus II retinal prosthesis are able to improve performance in a spatial-motor task 
Background/aims
To determine to what extent subjects implanted with the Argus II retinal prosthesis can improve performance compared with residual native vision in a spatial-motor task.
Methods
High-contrast square stimuli (5.85 cm sides) were displayed in random locations on a 19″ (48.3 cm) touch screen monitor located 12″ (30.5 cm) in front of the subject. Subjects were instructed to locate and touch the square centre with the system on and then off (40 trials each). The coordinates of the square centre and location touched were recorded.
Results
Ninety-six percent (26/27) of subjects showed a significant improvement in accuracy and 93% (25/27) show a significant improvement in repeatability with the system on compared with off (p<0.05, Student t test). A group of five subjects that had both accuracy and repeatability values <250 pixels (7.4 cm) with the system off (ie, using only their residual vision) was significantly more accurate and repeatable than the remainder of the cohort (p<0.01). Of this group, four subjects showed a significant improvement in both accuracy and repeatability with the system on.
Conclusion
In a study on the largest cohort of visual prosthesis recipients to date, we found that artificial vision augments information from existing vision in a spatial-motor task.
Clinical trials registry no
NCT00407602.
doi:10.1136/bjo.2010.179622
PMCID: PMC3345188  PMID: 20881025
15.  Health-related quality of life measures (HRQoL) in patients with amblyopia and strabismus: a systematic review 
Background/aims
Health-related quality of life (HRQoL) measures are used in healthcare to help inform clinical decision-making and policy-making decisions. A number of disease-specific or condition-specific measures have been developed and applied in ophthalmology; however, their use in the specific fields of amblyopia and strabismus are not as established. The purpose of this study is to identify and discuss specific HRQoL instruments that may be used in the investigation and management of patients with amblyopia and/or strabismus.
Methods
A systematic literature review was undertaken in November 2009. The electronic databases of AMED (Allied and Complementary Medicine: 1985 to November 2009), the British Nursing Index and Archive (1985 to October 2009), Ovid Medline In-Process and Other Non-Indexed Citations and Ovid Medline (1950 to present) and PsycINFO (1806 to November Week 1 2009) were searched. No language restrictions were applied to the search.
Results
Four instruments were identified: the Amblyopia and Strabismus Questionnaire (A&SQ), the Amblyopia Treatment Index (ATI), the Adult Strabismus Questionnaire (AS-20) and the Intermittent Exotropia Questionnaire (IXTQ).
Conclusion
The use of HRQoL measures in patients with amblyopia and/or strabismus is a developing area. Further research is necessary to determine the impact of issues such as diplopia and poor cosmesis upon patient groups, and to determine the influence of ethnicity and parental reporting in these patients.
doi:10.1136/bjo.2009.178889
PMCID: PMC3062043  PMID: 20693563
16.  Adverse effects of smoking on patients with ocular inflammation 
Background
To evaluate how smoking affects the time to disease quiescence and time to disease recurrence in patients with ocular inflammation.
Methods
A retrospective cohort study of patients with ocular inflammation who were followed longitudinally and had smoking information available in the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study database.
Results
Among 2676 patients with active ocular inflammation, smokers were more likely to have bilateral ocular disease and poorer visual acuity on presentation compared with non-smokers and previous smokers. In a multivariate analysis, there was no statistically significant difference in the time to disease quiescence between groups. However, the median time to recurrence of ocular inflammation was statistically significantly longer for non-smokers (9.4 months) and for previous smokers (10.7 months) than for current smokers (7.8 months) (p=0.02). The RR of ocular inflammation recurrence was higher for smokers than for non-smokers (adjusted HR=1.19, 95% CI 1.03 to 1.37) and tended towards significance in previous smokers (adjusted HR=1.11, 95% CI 0.93 to 1.35).
Conclusions
Smoking was associated with an increased likelihood of bilateral ocular inflammation and reduced vision upon presentation, and an increased risk of recurrence compared with not smoking. These results suggest that patients with ocular inflammation should be counselled to stop smoking as part of routine management.
doi:10.1136/bjo.2009.174466
PMCID: PMC3227535  PMID: 20606023
17.  Scleritis and multiple systemic autoimmune manifestations in chronic natural killer cell lymphocytosis associated with elevated TCR alpha/beta+ CD3+CD4−CD8− double-negative T cells 
Background/Aims
Chronic natural killer lymphocytosis (CNKL) has been associated with systemic autoimmunity, but its association with scleritis or ocular autoimmunity has not been characterized. We evaluated the natural kill cell (NK) function and immunophenotype of a patient with CNKL who developed bilateral scleritis and multiple systemic autoimmune findings.
Methods
The ophthalmic records of a patient with CNKL and scleritis were reviewed over a 6-year period. Flow cytometry was performed to evaluate T-cell, NK, and B-cell populations. NK cellular functions (i.e. NK cytotoxicity and cytokine/chemokine production following IL-2 stimulation) were evaluated.
Results
A 56-year-old female with vitiligo, psoriatic arthritis, thyroiditis, erythema nodosum, bilateral anterior scleritis and Sjogren syndrome was managed with multiple immunosuppressive medications including prednisone, mycophenolate mofetil and methotrexate. Flow cytometry showed a persistent elevation of CD56+CD3− NK cells greater than 40%, which was consistent with CNKL. NK cell cytotoxicity assay identified a deficiency of K562 cell lysis in the patient (1.46 mean-fold greater in control vs. patient). NK cytokine/chemokine production following IL-2 stimulation was also deficient (2.5–32.5 fold greater in control). Cytokines/chemokines assessed included pro-inflammatory (IFN-γ, TNF-α, IL-1, MCP-1) and immunoregulatory cytokines (IL-4, IL-5 and IL-10). An abnormal elevation of TCRα/β+ CD3+CD4−CD8− T-cells suggestive of autoimmune lymphoproliferative syndrome was observed but apoptosis dysfunction was not found.
Conclusion
The association of increased but dysfunctional NK cells in the context of multiple systemic and ocular manifestations suggests a role of NK cells in the pathogenesis of our patient’s disease. Further studies regarding NK cell dysfunction and ocular autoimmunity are needed.
doi:10.1136/bjo.2009.171264
PMCID: PMC3172679  PMID: 20508050
Scleritis; thyroiditis; vitiligo; natural killer cell lymphocytosis; episcleritis; keratoconjunctivitis sicca; double-negative T-cells; autoimmune lymphoproliferative syndrome
18.  The Quality of Pharmacoeconomic Evaluations of Age-Related Macular Degeneration Therapeutics: A Systematic Review and Quantitative Appraisal of the Evidence 
The British journal of ophthalmology  2010;94(9):1118-1126.
Aim
To appraise the quality of published pharmacoeconomic studies of therapeutic interventions for age-related macular degeneration (AMD).
Methods
Systematic review of the literature and evaluation of study quality using the Quality of Health Economic Studies (QHES) instrument. A systematic search of the English-language literature for economic studies of therapeutic interventions for AMD from 1990 – March 2008 was performed.
Results
A total of 3637 articles were initially identified. Only 24 met eligibility criteria and were rated using the QHES. The mean quality overall rating was 61.6, with quality scores ranging from 18 to 92. There was a higher mean quality score in the studies designed as clinical trials vs. observational type designed studies (mean = 74.7(11.4), 52.6(16.5) respectively, p=0.002) and studies in which the statistical analyses were clearly presented vs. studies in which the statistical analyses was not so clear (mean = 74.3(12.3), 53.1(16.1) respectively, p=0.004). Interestingly, government funded studies exhibited a similar mean quality score to studies that were funded by industry (mean=71.0(15.1), 61.7(18.5) respectively, p=0.25). A general linear model was fitted using those independent variables which were significantly associated with quality score. The variables “study design” and “statistics presented clearly” were found to be jointly significant and explained nearly 70% of the variation in the dependent variable (R2=0.68).
Conclusions
Our analysis reveals that the methodological quality of the health economic analysis of AMD therapeutic interventions in the literature is sub-optimal. There is considerable variation in methodological rigor between the articles, and we have identified several attributes that are predictive of study quality.
doi:10.1136/bjo.2009.170282
PMCID: PMC3108024  PMID: 20813751
Quality; Health Economic Study; Age-Related Macular Degeneration; QHES
19.  Gene therapy for ocular diseases 
The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.
doi:10.1136/bjo.2009.174912
PMCID: PMC3154727  PMID: 20733027
20.  Evidence of outer retinal changes in glaucoma patients as revealed by ultrahigh-resolution in vivo retinal imaging 
Aims
It is well established that glaucoma results in a thinning of the inner retina. To investigate whether the outer retina is also involved, ultrahigh-resolution retinal imaging techniques were utilised.
Methods
Eyes from 10 glaucoma patients (25–78 years old), were imaged using three research-grade instruments: (1) ultrahigh-resolution Fourier-domain optical coherence tomography (UHR-FD-OCT), (2) adaptive optics (AO) UHR-FD-OCT and (3) AO-flood illuminated fundus camera (AO-FC). UHR-FD-OCT and AO-UHR-FD-OCT B-scans were examined for any abnormalities in the retinal layers. On some patients, cone density measurements were made from the AO-FC en face images. Correlations between retinal structure and visual sensitivity were measured by Humphrey visual-field (VF) testing made at the corresponding retinal locations.
Results
All three in vivo imaging modalities revealed evidence of outer retinal changes along with the expected thinning of the inner retina in glaucomatous eyes with VF loss. AO-UHR-FD-OCT images identified the exact location of structural changes within the cone photoreceptor layer with the AO-FC en face images showing dark areas in the cone mosaic at the same retinal locations with reduced visual sensitivity.
Conclusion
Losses in cone density along with expected inner retinal changes were demonstrated in well-characterised glaucoma patients with VF loss.
doi:10.1136/bjo.2010.183756
PMCID: PMC3020908  PMID: 20956277
21.  Serum VEGF Levels Correlate with Number and Location of Micrometastases in a Murine Model of Uveal Melanoma 
Background
A preliminary animal study was performed to determine if hepatic micrometastases from uveal melanoma secrete vascular endothelial growth factor (VEGF) that is measurable in serum.
Methods
We analyzed the serum of a C57Bl/6 mouse model of uveal melanoma at days 4, 7, 14 and 21 post-inoculation for VEGF levels. We compared the serum VEGF levels with the number and location of hepatic micrometastases and their respective expression of VEGF mRNA.
Results
Serum VEGF levels rose after inoculation of C57Bl/6 mice eyes with B16LS9 cutaneous melanoma cells. Beginning on day 14 there was a statistically significant (p < 0.05) increase in VEGF levels, rising to an average peak level of 37.985 pg/mL at day 21. Peak serum VEGF levels correlated with the total number of hepatic micrometastases (R=0.444) and there was moderate correlation of peak VEGF serum levels with micrometastases in more hypoxic locations (R=0.572). VEGF mRNA expression by micrometastases was highest in the most hypoxic regions of the hepatic lobule.
Conclusions
Hepatic micrometastastic melanoma arising in a mouse model of ocular melanoma secretes VEGF. The number and location of the micrometastases correlate with serum VEGF levels.
doi:10.1136/bjo.2010.182402
PMCID: PMC3000446  PMID: 20819828
22.  Dynamic soft drusen remodelling in age-related macular degeneration 
The British journal of ophthalmology  2010;94(12):1618-1623.
Aims
To demonstrate and quantify the dynamic remodelling process of soft drusen resorption and new drusen formation in age-related macular degeneration (AMD) with novel interactive methods.
Methods
Twenty patients with large soft drusen bilaterally and without advanced AMD were imaged at baseline and again at a mean interval of 2 years (40 eyes, 80 images). Each of the 40 serial pairs of images was precisely registered by an automated technique. The drusen were segmented by a user-interactive method based on a background levelling algorithm and classified into three groups: new drusen (only in the final image), resorbed drusen (present initially but not in the final image) and stable drusen (present in both images). We measured each of these classes as well as the absolute change in drusen |D1 – D0| and the dynamic drusen activity (creation and resorption) Dnew+Dresorbed.
Results
Mean dynamic activity for the right eye (OD) was 7.33±65.50%, significantly greater than mean absolute change (2.71±2.89%, p=0.0002, t test), with similar results for the left eye (OS). However, dynamic activity OD compared with OS (mean 7.33±5.50 vs 7.91±4.16%, NS) and absolute net change OD versus OS (2.71±2.89 vs 3.46±3.97%, NS) tended to be symmetrical between fellow eyes.
Conclusions
Dynamic remodelling processes of drusen resorption and new drusen formation are distinct disease activities that can occur simultaneously and are not captured by change in total drusen load. Dynamic changes occur at rates more than twice that of net changes, and may be a useful marker of disease activity.
doi:10.1136/bjo.2009.166843
PMCID: PMC2948612  PMID: 20530179
23.  Photorefractive Keratectomy for the Treatment of Purely Refractive Accommodative Esotropia: Six Year Experience 
Background/aims
To report the long term outcomes of photorefractive keratectomy (PRK) for the treatment of hyperopia associated with purely refractive accommodative esotropia.
Methods
Retrospective chart review of 40 patients age 17–39 who underwent PRK to eliminate their dependence on glasses. Pre and post-operative best spectacle corrected visual acuity (BSCVA), uncorrected visual acuity (UCVA), refractive spherical equivalent (SEQ), ocular alignment, and stereoacuity were reviewed.
Results
Forty patients (80 eyes) with mean age 27.9 years were treated for a mean pre-operative SEQ of +3.06D hyperopia. The mean final post-operative SEQ was +0.06. Pre-operative BSCVA was 0.04 logMAR, and did not change post-operatively. Mean UCVA significantly improved from 0.30 logMAR preoperatively to 0.08 logMAR post-operatively. Mean pre-operative esotropia at distance and near was 18.6 PD. All patients were orthophoric without correction at the one month, one year, and final post-operative evaluations. Visual acuity, refractive error and alignment remained stable after the one year post-operative examination. Stereoacuity was unchanged in 80% of patients postoperatively. There were no complications.
Conclusion
PRK can be used to treat low to moderate hyperopia associated with purely refractive accommodative esotropia in young adults.
doi:10.1136/bjo.2009.160218
PMCID: PMC2992963  PMID: 20139292
hyperopia; accommodative esotropia; refractive surgery; photorefractive keratectomy
24.  Validation of a fornix depth measurer: a putative tool for the assessment of progressive cicatrising conjunctivitis 
Background/aims
Documentation of conjunctival forniceal foreshortening in cases of progressive cicatrising conjunctivitis (PCC) is important in ascertaining disease stage and progression. Lower fornix shortening is often documented subjectively or semi-objectively, whereas upper forniceal obliteration is seldom quantified. Although tools such as fornix depth measurers (FDMs) have been described, their designs limit upper fornix measurement. The purpose of this study was to custom-design a FDM to evaluate the upper fornix and to assess variability in gauging fornix depth.
Methods
A polymethylmethacrylate FDM was constructed using industry-standard jewellery computer software and machinery. Two observers undertook a prospective independent evaluation of central lower fornix depth in a heterogeneous cohort of patients with clinically normal and abnormal conjunctival fornices both subjectively and by using the FDM (in mm). Upper central fornix depth was also measured. Agreement was assessed using Bland–Altman plots.
Results
Fifty-one eyes were evaluated. There was 100% intraobserver agreement to within 1 mm for each observer for lower fornix measurement. The mean difference in fornix depth loss using the FDM between observer 1 and 2 was 1.19%, with 95% confidence of agreement (±2SD) of −15% to +20%. In total, 86% (44/51) of measurements taken by the two observers agreed to within 10% of total lower fornix depth (ie, ±1 mm) versus only 63% (32/51) of the subjective measurements. Mean upper fornix difference was 0.57 mm, with 95% confidence of agreement of between −2 and +3 mm.
Conclusions
This custom-designed FDM is well tolerated by patients and shows low intraobserver and interobserver variability. This enables repeatable and reproducible measurement of upper and lower fornix depths, facilitating improved rates of detection and better monitoring of progression of conjunctival scarring.
doi:10.1136/bjo.2010.188011
PMCID: PMC3099360  PMID: 20956276
Conjunctiva; inflammation; diagnostic tests/investigations; treatment medical
25.  Serum vascular endothelial growth factor (VEGF) levels correlate with number and location of micrometastases in a murine model of uveal melanoma 
Background
A preliminary animal study was performed to determine if hepatic micrometastases from uveal melanoma secrete vascular endothelial growth factor (VEGF) that is measurable in serum.
Methods
We analysed the serum of a C57Bl/6 mouse model of uveal melanoma (n=10) at days 4, 7, 14 and 21 post-inoculation for VEGF levels. We compared the serum VEGF levels with the number and location of hepatic micrometastases and their respective expression of VEGF mRNA.
Results
Serum VEGF levels rose after inoculation of C57Bl/6 mice eyes with B16LS9 cutaneous melanoma cells. Beginning on day 14 there was a statistically significant (p<0.05) increase in VEGF levels, rising to an average peak level of 37.985 pg/ml at day 21. Peak serum VEGF levels correlated with the total number of hepatic micrometastases (R=0.444) and there was moderate correlation of peak VEGF serum levels with micrometastases in more hypoxic locations (R=0.572). VEGF mRNA expression by micrometastases was highest in the most hypoxic regions of the hepatic lobule.
Conclusions
Hepatic micrometastastic melanoma arising in a mouse model of ocular melanoma secretes VEGF. The number and location of the micrometastases correlate with serum VEGF levels.
doi:10.1136/bjo.2010.182402
PMCID: PMC3000446  PMID: 20819828
Pathology; neoplasia

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