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1.  Association Between Retinal Thickness Measured by Spectral-Domain OCT and Rod-Mediated Dark Adaptation in Non-exudative Age-Related Maculopathy 
The British journal of ophthalmology  2011;95(10):10.1136/bjo.2010.190355.
Purpose
To examine associations between retinal thickness and rod-mediated dark adaptation in older adults with non-exudative age-related maculopathy (ARM) or normal macular health.
Methods
A cross-sectional study was conducted with 74 adults ≥ 50 years old from the comprehensive ophthalmology and retina services of an academic eye center. ARM presence and disease severity in the enrollment eye was defined by the masked grading of stereofundus photos using the Clinical Age-Related Maculopathy (CARMS) grading system. High-definition, spectral-domain optical coherence tomography was used to estimate retinal thickness in a grid of regions in the macula. Rod-mediated dark adaptation, recovery of light sensitivity after a photo-bleach, was measured over a 20-minute period for a 500 nm target presented at 5° on the inferior vertical meridian. Main outcomes of interest were retinal thickness in the macula (μm) and parameters of rod-mediated dark adaptation (second slope, third slope, average sensitivity, final sensitivity).
Results
In non-exudative disease retinal thickness was decreased in greater disease severity; thinner retina was associated with reductions in average and final rod-mediated sensitivity even after adjustment for age and visual acuity.
Conclusions
Impairment in rod-mediated dark adaptation in non-exudative ARM is associated with macular thinning.
doi:10.1136/bjo.2010.190355
PMCID: PMC3882115  PMID: 21289019
age-related maculopathy; dark adaptation; rod photoreceptors; optical coherence tomography
2.  Detection of retinal Nerve Fiber Layer Progression: Comparison of the Fast and Extended Modes of GDx Guided Progression Analysis 
The British journal of ophthalmology  2011;95(12):10.1136/bjophthalmol-2011-300354.
Purpose
To compare detection of retinal nerve fiber layer (RNFL) changes using GDx Guided Progression Analysis (GPA) fast mode (which assumes fixed variability of a reference population) and extended mode (which measures individual variability) and to determine how they compare to photography and visual field based conventional methods for identifying glaucoma progression.
Methods
172 eyes from 117 participants in the Diagnostic Innovations in Glaucoma Study (DIGS) (12 healthy, 108 glaucoma suspect and 52 glaucoma eyes) with ≥4 GDx VCC visits and ≥3 good quality GDx VCC scans at each visit were included. Results: Agreement between the GDx GPA fast mode and GDx GPA extended mode was limited. The GDx fast mode and extended mode detected 15 and 18 eyes, respectively as “likely progression” but only 7 of them agreed. The conventional reference standard (stereophotograph based optic disc and/or visual field progression) identified 9 eyes as progressing of which 2 eyes were also identified by the GDx fast and 3 eyes by the extended mode. In the GDx fast mode, we found that the progression detection varies depending on which 2 scans are included in the baseline and follow-up images. Conclusion: There was limited agreement between the GDx fast mode and the GDx extended mode for progression detection, and between different scans included in the GDx fast mode progression analysis. Longer follow-up is needed to determine the proportion of eyes classified as “likely progression” by the GDx analysis that are early change and the proportion that are false positive results.
doi:10.1136/bjophthalmol-2011-300354
PMCID: PMC3855018  PMID: 21979898
glaucoma; imaging; diagnostic tests/investigation
6.  Lipid metabolites in the pathogenesis and treatment of neovascular eye disease 
The British journal of ophthalmology  2011;95(11):1496-1501.
Lipids and lipid metabolites have long been known to play biological roles that go beyond energy storage and membrane structure. In age-related macular degeneration and diabetes, for example, dysregulation of lipid metabolism is closely associated with disease onset and progression. At the same time, some lipids and their metabolites can exert beneficial effects in the same disorders. This review summarises our current knowledge of the contributions of lipids to both the pathogenesis and treatment of neovascular eye disease. The clinical entities covered are exudative age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity, with a special emphasis on the potential therapeutic effects of ω3-(also known as n-3) polyunsaturated fatty acids.
doi:10.1136/bjo.2010.194241
PMCID: PMC3711020  PMID: 21421650
7.  The oil spill in ageing Bruch membrane 
The British journal of ophthalmology  2011;95(12):1638-1645.
Ageing is the largest risk factor for age-related macular degeneration (AMD), and soft drusen and basal linear deposits are lipid-rich extracellular lesions specific to AMD. Oil red O binding neutral lipid represents a major age-related deposition in the Bruch membrane (BrM) and the first identified druse component. Decades after these seminal observations, a natural history of neutral lipid deposition has been articulated and a biochemical model proposed. Results obtained with multiple biochemical, histochemical, and ultrastructural methods, and supported indirectly by epidemiology, suggest that the RPE secretes apolipoprotein B (apoB)-lipoprotein particles of unusual composition into BrM, where they accumulate with age eventually forming a lipid wall, a precursor of basal linear deposit. The authors propose that constituents of these lesions interact with reactive oxygen species to form pro-inflammatory peroxidised lipids that elicit neovascularisation. Here, the authors summarise key evidence supporting both accumulation of BrM lipoproteins leading to lesion formation and lipoprotein production by the RPE. The authors update their model with genetic associations between AMD and genes historically associated with plasma HDL metabolism, and suggest future directions for research and therapeutic strategies based on an oil-spill analogy.
doi:10.1136/bjophthalmol-2011-300344
PMCID: PMC3633599  PMID: 21890786
8.  Variation in optical coherence tomography signal quality as an indicator of retinal nerve fibre layer segmentation error 
Purpose
Commercial optical coherence tomography (OCT) systems use global signal quality indices to quantify scan quality. Signal quality can vary throughout a scan, contributing to local retinal nerve fibre layer segmentation errors (SegE). The purpose of this study was to develop an automated method, using local scan quality, to predict SegE.
Methods
Good-quality (global signal strength (SS)≥6; manufacturer specification) peripapillary circular OCT scans (fast retinal nerve fibre layer scan protocol; Stratus OCT; Carl Zeiss Meditec, Dublin, California, USA) were obtained from 6 healthy, 19 glaucoma-suspect and 43 glaucoma subjects. Scans were grouped based on SegE. Quality index (QI) values were computed for each A-scan using software of our own design. Logistic mixed-effects regression modelling was applied to evaluate SS, global mean and SD of QI, and the probability of SegE.
Results
The difference between local mean QI in SegE regions and No-SegE regions was −5.06 (95% CI −6.38 to 3.734) (p<0.001). Using global mean QI, QI SD and their interaction term resulted in the model of best fit (Akaike information criterion=191.8) for predicting SegE. Global mean QI≥20 or SS≥8 shows little chance for SegE. Once mean QI<20 or SS<8, the probability of SegE increases as QI SD increases.
Conclusions
When combined with a signal quality parameter, the variation of signal quality between A-scans provides significant information about the quality of an OCT scan and can be used as a predictor of segmentation error.
doi:10.1136/bjophthalmol-2011-300044
PMCID: PMC3375178  PMID: 21900227
9.  Mutations in RLBP1 associated with fundus albipunctatus in consanguineous Pakistani families 
The British journal of ophthalmology  2011;95(7):1019-1024.
Objective
To identify disease-causing mutations in two consanguineous Pakistani families with fundus albipunctatus.
Methods
Affected individuals in both families underwent a thorough clinical examination including funduscopy and electroretinography. Blood samples were collected from all participating members and genomic DNA was extracted. Exclusion analysis was completed with microsatellite short tandem repeat markers that span all reported loci for fundus albipunctatus. Two-point logarithm of odds (LOD) scores were calculated, and coding exons and exon–intron boundaries of RLBP1 were sequenced bi-directionally.
Results
The ophthalmic examination of affected patients in both families was consistent with fundus albipunctatus. The alleles of markers on chromosome 15q flanking RLBP1 segregated with the disease phenotype in both families and linkage was further confirmed by two-point LOD scores. Bi-directional sequencing of RLBP1 identified a nonsense mutation (R156X) and a missense mutation (G116R) that segregated with the disease phenotype in their respective families.
Conclusions
These results strongly suggest that mutations in RLBP1 are responsible for fundus albipunctatus in the affected individuals of these consanguineous Pakistani families.
doi:10.1136/bjo.2010.189076
PMCID: PMC3459316  PMID: 21447491
10.  Geographic Variations in Microbial Keratitis: An analysis of the Peer-Reviewed Literature 
summary
The epidemiology of microbial keratitis has been investigated in several studies by analysis of organisms cultured from corneal scrapes. However, a comparison of the frequency of different organisms causing keratitis in different parts of the world is lacking. We present a review incorporating an analysis of data from studies worldwide. The data provide a comparison of the frequency of culture-positive organisms found in different parts of the world.
The highest proportion of bacterial corneal ulcers was reported in studies from North America, Australia, the Netherlands and Singapore. The highest proportion of staphylococcal ulcers was found in a study from Paraguay whilst the highest proportion of pseudomonas ulcers was reported in a study from Bangkok. The highest proportions of fungal infections were found in studies from India and Nepal. Possible explanations for these observed geographic variations are discussed.
doi:10.1136/bjo.2009.169607
PMCID: PMC3403809  PMID: 21478201
cornea; keratitis; eye; infection; epidemiology
11.  In vivo identification of alteration of inner neurosensory layers in branch retinal artery occlusion 
Background/aims
To characterise the extension and progression of alteration of neurosensory layers following acute and chronic branch retinal artery occlusion (BRAO) in vivo using spectral-domain optical coherence tomography.
Methods
In this observational case series, eight eyes with acute BRAO and nine eyes with chronic BRAO were analysed using a Spectralis Heidelberg Retina Angiograph (HRA)+optical coherence tomography system including eye tracking. Patients with acute BRAO were examined within 36±5 h after primary event and at weekly/monthly intervals thereafter. Segmentation measurements of all individual neurosensory layers were performed on single A-scans at six locations in affected and corresponding non-affected areas. The thickness values of the retinal nerve fibre layer together with the ganglion cell layer (NFL/GCL), inner plexiform layer (IPL), inner nuclear layer together with outer plexiform layer (INL/OPL), outer nuclear layer (ONL), and photoreceptor layers together with the retinal pigment epithelium (PR/RPE) were measured and analysed.
Results
Segmentation evaluation revealed a distinct increase in thickness of inner neurosensory layers including the NFL/GCL (35%), IPL (80%), INL/OPL (48%) and mildly the ONL by 21% in acute ischaemia compared with corresponding layers in non-ischaemic areas. Regression of intraretinal oedema was followed by persistent retinal atrophy with loss of differentiation between IPL and INL/OPL at month 2. In contrast, the ONL and subjacent PR/RPE retained their physiological thickness in patients with chronic BRAO.
Conclusion
In vivo assessment of retinal layer morphology allows a precise identification of the pathophysiology in retinal ischaemia.
doi:10.1136/bjo.2010.198937
PMCID: PMC3261730  PMID: 21515559
Branch retinal artery occlusion; optical coherence tomography; retina; imaging
12.  Long-term surgical outcomes of porous polyethylene orbital implants: a review of 314 cases 
Purpose
This study reports on the long-term surgical outcomes after the insertion of porous Medpor orbital implants into anophthalmic sockets.
Methods
A retrospective chart review of 314 eyes from 314 patients who underwent evisceration, enucleation and secondary procedures using Medpor orbital implants was completed focusing on implant-associated complications and their corrective methods as surgical outcomes.
Results
The mean follow-up was 50 months (range 6–107 months). The most common complication was blepharoptosis (n=33, 10.5%). Other postoperative complications were exposure (n=14, 4.5%) and implant infection (n=3, 1%). The complications were successfully managed by surgical repair and/or conservative care.
Conclusion
Using Medpor resulted in similar surgical outcomes, in terms of the types and frequencies of complications, as other kinds of porous orbital implants.
doi:10.1136/bjophthalmol-2011-300132
PMCID: PMC3308469  PMID: 22096144
Anophthalmia; eye lids; implant complications; inflammation; lacrimal drainage; lacrimal gland; orbit; porous polyethylene (Medpor) orbital implant
13.  Diffuse Large B-Cell Lymphoma of the Eyelid in a Patient with Acquired Immunodeficiency Syndrome 
A 49-year-old man was evaluated for rapidly enlarging left lower eyelid and left neck masses. Biopsies of the masses showed diffuse large B-cell lymphoma (DLBCL). He tested positive for Human Immunodeficiency Virus (HIV). The patient was treated with chemotherapy and antiretroviral therapy, and the masses reduced in size.
doi:10.1136/bjo.2009.163121
PMCID: PMC3032002  PMID: 20675727
Acquired Immunodeficiency Syndrome; Diffuse Large B-Cell Lymphoma; Rituximab; c-Myc Gene; Eyelids; Orbit
14.  Retinal nerve fibre layer and visual function loss in glaucoma: the tipping point 
Aims
To determine the retinal nerve fibre layer (RNFL) thickness at which visual field (VF) damage becomes detectable and associated with structural loss.
Methods
In a prospective cross-sectional study, 72 healthy and 40 glaucoma subjects (one eye per subject) recruited from an academic institution had VF examinations and spectral domain optical coherence tomography (SD-OCT) optic disc cube scans (Humphrey field analyser and Cirrus HD-OCT, respectively). Comparison of global mean and sectoral RNFL thicknesses with VF threshold values showed a plateau of threshold values at high RNFL thicknesses and a sharp decrease at lower RNFL thicknesses. A ‘broken stick’ statistical model was fitted to global and sectoral data to estimate the RNFL thickness ‘tipping point’ where the VF threshold values become associated with the structural measurements. The slope for the association between structure and function was computed for data above and below the tipping point.
Results
The mean RNFL thickness threshold for VF loss was 75.3 μm (95% CI: 68.9 to 81.8), reflecting a 17.3% RNFL thickness loss from age-matched normative value. Above the tipping point, the slope for RNFL thickness and threshold value was 0.03 dB/μm (CI: −0.02 to 0.08) and below the tipping point, it was 0.28 dB/μm (CI: 0.18 to 0.38); the difference between the slopes was statistically significant (p<0.001). A similar pattern was observed for quadrant and clock-hour analysis.
Conclusions
Substantial structural loss (~17%) appears to be necessary for functional loss to be detectable using the current testing methods.
doi:10.1136/bjo.2010.196907
PMCID: PMC3193885  PMID: 21478200
15.  2245G/A polymorphism of the receptor for advanced glycation end-products (RAGE) gene is associated with diabetic retinopathy in the Malaysian population 
Background/aims
The receptor for advanced glycation end-products (RAGE) has been implicated in the pathogenesis of diabetic microvascular complications. The aim of this study was to investigate the association between 2245G/A gene polymorphism of the RAGE gene and retinopathy in Malaysian type 2 diabetic patients.
Methods
342 unrelated type 2 diabetic patients (171 with retinopathy (DR), 171 without retinopathy (DNR)) and 235 unrelated healthy subjects from all over Malaysia were recruited for this study. Genomic DNA was isolated from 3 ml samples of whole blood using a modified conventional DNA extraction method. The genotype and allele frequencies of 2245G/A were studied using the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method.
Results
A statistically significant difference in 2245A minor allele frequency was found between control (5.5%) and DR groups (15.2%) (p<0.001, OR=3.06, 95% CI 1.87 to 5.02) as well as between DNR (8.2%) and DR (15.2%) groups (p<0.01, OR=2.01, 95% CI 1.24 to 3.27). However, when the frequency was compared between control and DNR groups, there was no significant difference (p>0.05).
Conclusions
This is the first study that shows an association between the 2245A allele of the RAGE gene and development of diabetic retinopathy in the Malaysian population.
doi:10.1136/bjophthalmol-2011-300658
PMCID: PMC3261748  PMID: 22116960
Diabetic retinopathy; Malaysian; polymorphism; rage gene; genetics
16.  The relationship between corneal hysteresis and the magnitude of intraocular pressure reduction with topical prostaglandin therapy 
Aims
To evaluate corneal hysteresis (CH) and intraocular pressure (IOP) before and after IOP lowering with prostaglandin analogue (PGA) therapy in medication-naïve eyes.
Methods
In this retrospective study, we included records from 57 consecutive patients with open angle glaucoma who were initiated on PGA. Patients underwent ocular response analyser measurement with IOP assessment at baseline (untreated) and at follow-up (treated).
Results
Median follow-up time between IOP measurements was 1.4 (range 0.4–13.5) months. IOP was reduced by 3.2 mm Hg (18.8%) from 17.0 to 13.8 mm Hg (p<0.001). CH increased by 0.5 mm Hg (5.2%) from 9.7 to 10.2 mm Hg (p=0.02). Baseline CH (but not baseline central corneal thickness) was a significant predictor of the magnitude of IOP reduction, with patients in the lowest quartile of CH (mean 7.0 mm Hg) experiencing a 29.0% reduction in IOP while those in the highest CH quartile (mean 11.9 mm Hg) experienced a 7.6% reduction in IOP (p=0.006). A multivariate analysis controlling for baseline IOP demonstrated that baseline CH independently predicted the magnitude of IOP reduction with PGA therapy in both per cent (ß=3.5, p=0.01) and absolute (ß=0.6, p=0.02) terms.
Conclusion
Although CH is influenced by IOP, baseline CH is independently associated with the magnitude of IOP reduction with PGA therapy.
doi:10.1136/bjo.2010.196899
PMCID: PMC3261726  PMID: 21436180
Corneal hysteresis; ocular response analyser; corneal thickness; glaucoma; prostaglandin analogue; intraocular pressure; diagnostic tests/investigation; treatment medical
17.  Toxicological evaluation of preservative-containing and preservative-free topical prostaglandin analogues on a three-dimensional-reconstituted corneal epithelium system 
Aims
Using an established three-dimensional (3D) toxicological model based on reconstituted human corneal epithelium (HCE), this study investigated the tolerability of four topical intraocular-pressure-lowering agents: the commercial solutions of benzalkonium chloride (BAC)-containing 0.005% latanoprost, 0.004% travoprost, 0.03% bimatoprost containing 0.02%, 0.015% and 0.005% BAC, respectively, and the preservative-free (PF) tafluprost. Solutions of 0.01% and 0.02% BAC alone were also evaluated for comparison.
Methods
The 3D-HCEs were treated with solutions for 24 h followed or not by a 24 h recovery period. We used a modified MTT (3(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) procedure to assess cell viability in the HCE. Frozen sections of HCE were analysed using fluorescence microscopy for the evaluation of apoptosis (terminal deoxynucleotidyl transferase mediated dUTP nick end labelling), inflammation (ICAM-1) and proliferation (Ki67). Corneal epithelial tight junctions (occludin and tight junction protein 1 (zona occludens 1)) were also assessed by en face confocal microscopy in response to the different eye-drops.
Results
The MTT test revealed that the cytotoxicity of antiglaucoma eye-drops was primarily related to the concentration of their common BAC preservative (0.02% BAC-latanoprost>0.015% BAC-travoprost>0.005% BAC-bimatoprost). PF-tafluprost did not induce any obvious cytotoxicity, showed the least expression of inflammatory or apoptotic markers and revealed preservation of membrane immunostaining of tight junction proteins in comparison with BAC-containing solutions.
Conclusion
The toxicological model of the 3D reconstructed corneal epithelia model confirmed the ocular surface cytotoxicity of BAC-containing antiglaucomatous solutions. Compared with the formulations containing the toxic preservative BAC, PF-tafluprost was well tolerated without inducing significant corneal epithelium deterioration.
doi:10.1136/bjo.2010.189449
PMCID: PMC3099447  PMID: 21429894
Cornea; immunology; inflammation; drugs; ocular surface
18.  Re-operation of idiopathic full-thickness macular holes after initial surgery with internal limiting membrane peel 
The British Journal of Ophthalmology  2011;95(11):1564-1567.
Background/aims
A retrospective consecutive case series to evaluate the efficacy of re-operation in patients with persistent or recurrent idiopathic full-thickness macular hole after initial surgery with internal limiting membrane peel (ILM).
Methods
491 patients underwent surgery for full-thickness macular hole from January 2004 to November 2007. Fifty-five patients either did not close or reopened during the follow-up period. Thirty patients with initial ILM peel underwent repeat surgery involving vitrectomy, enlargement of ILM rhexis and gas tamponade.
Results
Anatomical closure rate was 88.8% for primary surgery and 46.7% (14/30) for re-operation. There was a statistically significant improvement in overall best corrected visual acuity (BCVA) from re-operation baseline BCVA (p=0.02) within 1 year. For holes that did not close after the second surgery, visual acuity did not worsen.
Conclusion
Re-operation has a reduced success rate of anatomical closure. However, BCVA is statistically significantly improved from re-operation baseline, so even though we cannot return vision to pre-pathological baseline, re-operation can improve on this new baseline.
doi:10.1136/bjo.2010.195826
PMCID: PMC3199446  PMID: 21355018
Macular hole; re-operation; internal limiting membrane peeling; indocyanine green; vitrectomy; vitreous; macula; vision; treatment surgery; vitreous; macula; vision; treatment surgery
19.  A systematic review and meta-analysis of clinical outcomes of vitrectomy with or without intravitreal bevacizumab pretreatment for severe diabetic retinopathy 
The British Journal of Ophthalmology  2011;95(9):1216-1222.
Aims
To examine possible benefits of intravitreal bevacizumab (IVB) pretreatment in vitrectomy for severe diabetic retinopathy.
Methods
A comprehensive literature search was performed using the Cochrane Collaboration methodology to identify randomised controlled trials and comparative studies of vitrectomy with or without IVB pretreatment for severe or complicated diabetic retinopathy. Meta-analyses were performed for intraoperative (including intraoperative bleeding, endodiathermy, iatrogenic retinal tears and mean surgical time) and postoperative outcome parameters (including best-corrected visual acuity, recurrent vitreous haemorrhage, reabsorption time of blood and other complications).
Results
Six randomised controlled trials and one comparative study were identified and used for comparing vitrectomy alone (142 eyes, control group) with vitrectomy with IVB pretreatment (139 eyes). The intraoperative findings showed that the incidence of intraoperative bleeding and frequency of endodiathermy were statistically significantly less in the IVB pretreatment group (p<0.01) than in the vitrectomy alone group. The IVB pretreatment group took significantly less surgical time than the control group (p=0.003). Postoperative results indicated that reabsorption time of blood was significantly shorter (p=0.04), incidence of recurrent VH was almost significantly less (p=0.05), and final best-corrected visual acuity was significantly better (p=0.003) in the IVB group than in the control group. Other complications, including final retinal detachment, and reoperation, were statistically insignificant.
Conclusion
IVB pretreatment in vitrectomy can achieve excellent clinical outcomes for severe diabetic retinopathy. It potentially facilitates surgeons' manoeuvres and reduces intra- and postoperative complications.
doi:10.1136/bjo.2010.189514
PMCID: PMC3161500  PMID: 21278146
Diabetic retinopathy; vitrectomy; bevacizumab; vitreous; retina; neovascularisation; treatment surgery

Results 1-19 (19)