Epidemiology; Eye Lids; Conjunctiva
We examined whether retinitis pigmentosa (RP) subjects' worse-than-usual vision measures were related to episodic changes in psychosocial factors and/or general health.
In a prospective, cohort study, 37 RP subjects self-administered personal computer (PC)-based visual acuity (VA), contrast sensitivity (CS) and visual field (VF) tests at home twice a week, for 16 sessions in 2–3 months. Subjects rated their general health prior to each vision test session, and completed the Perceived Stress Scale, Positive and Negative Affect Schedules, and Epworth and Stanford Sleepiness Scales immediately after each session.
Nine subjects with reduced mean VA >0.5 log minimal angle of resolution (logMAR) on average had statistically significant 26% more sessions with measured deviations ≥0.1 logMAR from their mean (95% CI 20% to 32%; p<0.001), which were not significantly related to changes in psychosocial factors or general health. Measured deviations ≥0.1 logCS from mean CS were not statistically significantly related to any measured factors. We found a statistically significant increased frequency of sessions with ≥20% VF reduction from the mean (p<0.001) as mean log VF area was reduced. Subjects reporting reduced general health during a session had a statistically significant over twofold greater odds of having a VF reduction from the mean beyond 1 SD (95% CI 1.26 to 5.00; p=0.009).
Measured episodic VF reductions were more common in advanced RP and related to decreased general health at a session, which should be considered during clinical examinations and trials when determining true changes in vision. We did not find evidence that fluctuations in psychosocial factors were significantly correlated with vision reductions across subjects.
This paper will compare the visual outcomes of two different penetrating keratoplasty (PKP) techniques in patients with keratoconus. It is a retrospective comparative surgical case series of 116 keratoconus patients (137 eyes) who had PKP at the Cornea Eye Institute, Beverly Hills, California, USA.
56 keratoconus patients (66 eyes) underwent femtosecond laser-enabled keratoplasty (FLEK) with a zig-zag incision configuration. Their visual parameters were compared with those of 60 patients (71 eyes) who had traditional blade mechanical trephination PKP. The range of follow-up was between 3 and 6 months. The main outcome measures included uncorrected visual acuity and best spectacle-corrected visual acuity (BSCVA), manifest refractive spherical equivalent and topographically determined astigmatism.
BSCVA was significantly better as early as 3 months postoperatively (p=0.001) in the FLEK group. Visual recovery to 20/40 after 3 months was significantly better in the FLEK group (p<0.001). Topographic astigmatism was lower in the FLEK group, but the difference between the two groups reached significance only at 3 months of follow-up (p=0.001). Postoperative complications noted were not different between the two groups.
Faster visual recovery and better long-term outcomes were observed in keratoconus patients who had FLEK compared with those who had the mechanical PKP procedure with 6 months of postoperative follow-up.
To evaluate the glaucoma discriminating ability of macular retinal layers as measured by spectral-domain optical coherence tomography (SD-OCT).
Healthy, glaucoma suspect and glaucomatous subjects had a comprehensive ocular examination, visual field testing and SD-OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec, Dublin, CA) in the macular and optic nerve head regions. OCT macular scans were segmented into macular nerve fiber layer (mNFL), ganglion cell layer with inner plexiform layer (GCIP), ganglion cell complex (GCC) (composed of mNFL and GCIP), outer retinal complex (ORC) and total retina (TR). Glaucoma discriminating ability was assessed using the area under the receiver operator characteristic curve (AUC) for all macular parameters and mean circumpapillary (cp) RNFL. Glaucoma suspects and glaucoma subjects were grouped together for the calculation of AUCs.
Analysis was performed on 51 healthy, 49 glaucoma suspect and 63 glaucomatous eyes. The median visual field MD was −2.21dB (interquartile range (IQR): −6.92 to −0.35) for the glaucoma group, −0.32dB (IQR: −1.22 to 0.73) for the suspect group and −0.18dB (IQR: −0.92 to 0.71) for the healthy group. Highest age adjusted AUCs for discriminating between healthy and glaucomatous eyes were found for average GCC and GCIP (AUC=0.901 and 0.900, respectively), and their sectoral measurements: infero-temporal (0.922 and 0.913), inferior (0.904 and 0.912) and supero-temporal (0.910 and 0.897). These values were similar to the discriminating ability of the mean cpRNFL (AUC=0.913). Comparison of these AUCs did not yield any statistically significant difference (all p>0.05). Similar discrimination performance but with slight reduction in AUCs was achieved for comparison between healthy and the combination of glaucoma and glaucoma suspect eyes.
SD-OCT GCIP and GCC measurements showed similar glaucoma diagnostic ability and was comparable with that of cpRNFL.
Ocular imaging devices provide quantitative structural information that might improve glaucoma progression detection. This study examined scanning laser polarimetry (SLP) population-derived versus individual-derived cut-off criteria for detecting progression.
Forty-eight healthy, glaucoma suspect and glaucoma subjects, providing 76 eyes were used. All subjects had reliable visual field (VF) and SLP scans acquired at the same visits from ≥ 4 visits. VF progression was defined by guided progression analysis (GPA) and by the VF index (VFI). SLP measurements were analyzed by fast mode (FM) GPA, compared to the population rate of progression, and extended mode (EM) GPA, compared to the individual variability. The agreement between progression detection methods was measured.
Poor agreement was observed between progression defined by VF and FM and EM. The difference in TSNIT average rate of change between VF defined progressors and non-progressors for both FM (p=0.010) and EM (p=0.015) was statistically significant.
There is poor agreement between VF and SLP progression regardless of the use of population derived or individual variability criteria. The best SLP progression detection method could not be ascertained, therefore, acquiring three SLP scans per visit is recommended.
Scanning laser polarimetry; glaucoma progression
Optical coherence tomography (OCT) is an interferometry-based imaging modality that generates high-resolution cross-sectional images of the retina. Circumpapillary retinal nerve fiber layer (cpRNFL) and optic nerve head assessments are the mainstay of glaucomatous structural measurements in OCT. However, because these measurements are not always available or precise, it would be useful to have another reliable indicator. The macula has been suggested as an alternative scanning location for glaucoma diagnosis. Using time-domain (TD-) OCT, macular measurements have shown to provide good glaucoma diagnostic capabilities. With the adoption of spectral-domain OCT, which allows a higher image resolution than TD-OCT, segmentation of inner macular layers becomes possible. These layers are specifically prone to glaucomatous damage and thickness measurements show a comparable performance to that of glaucomatous cpRNFL measurements. The role of macular measurements for detection of glaucoma progression is still under investigation. More sophisticated measurement and analysis tools that can amplify the advantages of macular measurements are expected. For example, improvement of image quality would allow better visualization, development of various scanning modes would optimize macular measurements, and further refining of the analytical algorithm would provide more accurate segmentation. With these achievements, macular measurement can be an important surrogate for glaucomatous structural assessment.
To evaluate the utility of gold nanorods (AuNRs) as a contrast agent for ocular optical coherence tomography (OCT).
Mice were intravitreally injected with sterile AuNRs coated with either poly(strenesulfate) (PSS-AuNRs) or anti-CD90.2 antibodies (Ab-AuNRs), and imaged using OCT. After 24 hours, eyes were processed for transmission electron microscopy or rendered into single cell suspensions for flow cytometric analysis to determine absolute numbers of CD45+ leukocytes and subsets (T cells, myeloid cells, macrophages, neutrophils). Generalized estimation equations were used to compare cell counts between groups.
PSS-AuNRs and Ab-AuNRs were visualized in the vitreous 30min and 24h post- injection with OCT. At 24h, a statistically significant increase in leukocytes, comprised primarily of neutrophils, was observed in eyes that received either AuNR in comparison to eyes that received saline. The accumulation of leukocytes was equal in eyes given PSS-AuNR or Ab- AuNR. Endotoxin-resistant C3H/HeJ mice also showed ocular inflammation after injection with AuNRs, indicating that the inflammatory response was not due to lipopolysaccharide contamination of AuNRs.
Although AuNRs can be visualized in the eye using OCT they can induce ocular inflammation, which limits their use as a contrast agent.
gold nanoparticles; optical coherence tomography; contrast enhancement; immune response
Blindness; visual impairment; maps; cartogram; number of ophthalmologists
To evaluate the effects of inferior oblique muscle recession (IOR) in cases of laterally incomitant hypertropia <10 prism dioptres (PD) in central gaze thact 2t are clinically consistent with superior oblique palsy (SOP).
We retrospectively reviewed patients with SOP and hypertropias <10 PD in central gaze who underwent graded IOR. Primary outcomes were reduction of lateral incomitance and number of overcorrections in central gaze.
Twenty-five patients were included. Mean follow-up was 13.8 months (range 1.4–66). Mean central gaze hypertropia decreased from 5.6±2.1 to 0.2±1.6 PD (p<0.001). Contralateral gaze hypertropia decreased from 15.9±7.6 to 2.3±3.3 PD (p<0.001). Lateral incomitance (central vs contralateral gaze) was 10.3±6.9 PD preoperatively and 2.0±3.0 PD postoperatively (p<0.001). There were two patients overcorrected in central gaze, and one patient overcorrected in downgaze. One patient necessitated further surgery for overcorrection.
Although small hypertropias can be treated with prisms or small, adjustable inferior rectus recessions, IOR collapses incomitance without causing much overcorrection. IOR is a reasonable treatment for small, laterally incomitant hypertropia due to SOP.
Three types of open-angle glaucoma (OAG) – primary, pigmentary, and pseudoexfoliative – are frequently encountered. The aim of this study was to compare demographic, ocular, and systemic medical information collected on people with these three OAG types at diagnosis, and determine if the OAG type affected prognosis.
Information on 607 participants of the Collaborative Initial Glaucoma Treatment Study was accessed. Descriptive statistics characterized their demographic, ocular, and medical status at diagnosis. Comparisons were made using analysis of variance (ANOVA), and chi-square or Fisher exact tests. Multinomial, mixed, and logistic regression analyses were also performed.
Relative to people with primary OAG, those with pigmentary OAG were younger, more likely to be white, less likely to have a family history of glaucoma, and were more myopic. Those with pseudoexfoliative OAG were older, more likely to be white, more likely to be female, less likely to have bilateral disease, and presented with higher IOP and better VA. The type of glaucoma was not associated with intraocular pressure or visual field progression during follow-up.
Characteristics of newly-diagnosed enrollees differed by the type of OAG. While some of these differences relate to the pathogenesis of OAG type, other differences are noteworthy for further evaluation within population-based samples of subjects with newly-diagnosed OAG.
Macula; retina; choroid; angiogenesis; drugs
Gelatinous drop-like corneal dystrophy (GDLD), also known as familial subepithelial corneal amyloidosis, is an autosomal recessive disorder that causes progressive corneal opacity due to accumulation of amyloid fibrils in the corneal stroma. Genetic analyses have revealed that a mutation in membrane component chromosome 1 surface marker 1 gene is responsible for GDLD. However, the mechanism of amyloid formation in the corneal stroma remains unclear. The present study attempted to reveal the role of advanced glycation end products (AGE) and d-amino acids in amyloid formation in GDLD.
Informed consent was obtained from five patients with GDLD, three patients with bullous keratopathy and three patients with interstitial keratitis and all the specimens were analysed. Localisation of amyloid fibrils was analysed using Congo-red and thioflavin T staining. In addition, the localisation of AGE (Nɛ-carboxy(methyl)-l-lysine, pyrraline and pentosidine) and d-β-aspartic acid-containing proteins, a major form of d-amino acid-containing proteins, was analysed immunohistochemically.
In all GDLD specimens, strong immunoreactivity to AGE and d-β-aspartic acid-containing proteins was detected in the subepithelial amyloid-rich region. In contrast, amyloid fibrils, AGE, or d-amino acid-containing proteins were slightly detected in the corneal stroma of patients with bullous keratopathy and interstitial keratitis.
Abnormally accumulated proteins rich in AGE and d-β-aspartic acid co-localise in the amyloid lesions in GDLD. These results indicate that non-enzymatic post-translational modifications of proteins, including AGE formation and isomerisation of aspartyl residues, will be the cause as well as the result of amyloid fibril formations in GDLD.
Advanced glycation end products; biochemistry; cornead-amino acids; d-β-aspartic acid; familial subepithelial corneal amyloidosis; GDLD; gelatinous drop-like corneal dystrophy; M1S1; Nɛ-(carboxy)methyl-l-lysin; optics and refraction; pathology; pentosidine; physiology; pyrraline; treatment surgery; tumour-associated calcium signal transducer 2 (TACSTD2)
Retinal endothelial cells are crucially involved in the genesis of diabetic retinopathy which is treated with vascular endothelial growth factor (VEGF) inhibitors. Of these, ranibizumab can completely restore VEGF-induced effects on immortalised bovine retinal endothelial cells (iBREC). In most experiments supporting diabetic retinopathy therapy with bevacizumab, only non-retinal EC or retinal pigment epithelial cells have been used. Also, bevacizumab but not ranibizumab can accumulate in retinal pigment epithelial cells.
To investigate the effects of bevacizumab on VEGF-induced changes of iBREC properties and potential uptake and accumulation of both inhibitors.
Uptake of VEGF inhibitors by iBREC with or without pretreatment with VEGF165 was visualised by immunofluorescence staining and western blot analyses. Measured transendothelial resistance (TER) of iBREC (±VEGF165) showed effects on permeability, indicated also by the western blot-determined tight junction protein claudin-1. The influence of bevacizumab on proliferation and migration of iBREC was studied in the presence and absence of VEGF165.
Bevacizumab strongly inhibited VEGF-stimulated and basal migration, but was less efficient than ranibizumab in inhibiting VEGF-induced proliferation or restoring the VEGF-induced decrease of TER and claudin-1. This ability was completely lost after storage of bevacizumab for 4 weeks at 4°C. Ranibizumab and bevacizumab were detectable in whole cell extracts after treatment for at least 1 h; bevacizumab accumulated during prolonged treatment. Ranibizumab was found in the membrane/organelle fraction, whereas bevacizumab was associated with the cytoskeleton.
Both inhibitors had similar effects on retinal endothelial cells; however, some differences were recognised. Although barrier properties were not affected by internalised bevacizumab in vitro, potential adverse effects due to accumulation after repetitive intravitreal injections remain to be investigated.
Retinal endothelial cells; VEGF inhibition; diabetic macular oedema; diabetic retinopathy; biochemistry; diagnostic tests/investigation; macula; neovascularisation; retina
Cornea; lens and zonules
To investigate age-related lesions in the far-anterior retina that migrate from the ciliary body (CB) and how they affect the neural retina and retinal pigmented epithelium (RPE).
One eye from three healthy subjects aged 87, 92 and 93 years were used. Retinae were photographed, embedded in resin and then sectioned at 2 μm.
Multiple elliptically shaped lesions were present in the CB. Larger lesions extended into the peripheral retina. Lesions resulted from deposits that had lenticular qualities. These develop centrally along Bruch's membrane sweeping away the RPE, such that piles of RPE cells were present around the deposits that resulted in retinal atrophy. The internal composition of the deposits revealed large numbers of spherical bodies, unlike those seen in drusen. RPE cells adjacent to these deposits and their underlying lesions became highly irregular, with melanin granules spacing themselves out within the cell and adopting similar orientations. This is a highly distinctive feature.
These far-anterior deposits were different in nature from drusen in terms of morphology, composition and origin. They swept away the RPE, exposing the Bruch's membrane and isolating the retina, leading to atrophy. They appeared to originate from the CB and progressed centrally. The deposits may have developed from the ciliary muscle, which would account for their elongated orientation. Their impact on melanin distribution in RPE cells was unexpected and unusual, implying that they release a signal that influences melanin organisation.
Lesions/deposits; far-peripheral retina; RPE; retina; ciliary body; degeneration; pathology
To determine the relationship between retinal ischaemia and the presence of macular oedema (DMO) in patients with diabetic retinopathy (DR) using ultra-widefield fluorescein angiography (UWFA) imaging.
A retrospective review of 122 eyes of 70 treatment-naïve diabetic patients who underwent diagnostic UWFA using the Optos 200Tx imaging system. Two independent, masked graders quantified the area of retinal ischaemia. Based on clinical examination and optical coherence tomography (OCT), each patient was given a binary classification as either having DMO or no DMO. McNemar's test (with Yates' correction as indicated) and a two-sample test of proportions were used to determine the relationship between DMO and ischaemia for binary and proportional data, respectively. Linear and logistic models were constructed using generalised estimating equations to test relationships between independent variables, covariates and outcomes while controlling for inter-eye correlation, age, gender, haemoglobin A1c, mean arterial pressure and dependence on insulin.
Seventy-six eyes (62%) exhibited areas of retinal ischaemia. There was a significant direct correlation between DMO and peripheral retinal ischaemia as seen on UWFA (p<0.001). In addition, patients with retinal ischaemia had 3.75 times increased odds of having DMO compared with those without retinal ischaemia (CI 1.26 to 11.13, p<0.02).
Retinal ischaemia is significantly correlated with DMO in treatment-naïve patients with DR. UWFA is a useful tool for detecting peripheral retinal ischaemia, which may have direct implications in the diagnosis, follow-up and treatment such as targeted peripheral photocoagulation.
Ultra-wide field imaging; fluorescein angiography; diabetes; diabetic retinopathy; diabetic macular oedema; retina; epidemiology; retina
To evaluate the cost-effectiveness of ranibizumab as either monotherapy or combined with laser therapy, compared with laser monotherapy, in the treatment of diabetic macular oedema (DME) causing visual impairment from a UK healthcare payer perspective.
A Markov model simulated long-term outcomes and costs of treating DME in one eye (BCVA ≤75 letters) based on data from the RESTORE Phase III trial. Outcomes measured in quality-adjusted life-years (QALYs) were simulated for a 15-year time horizon based on 12-month follow-up from RESTORE and published long-term data. Costs included treatment, disease monitoring, visual impairment and blindness (at 2010 price levels).
Ranibizumab monotherapy resulted in a 0.17 QALY gain at an incremental cost of £4191 relative to laser monotherapy, yielding an incremental cost-effectiveness ratio (ICER) of £24 028. Probabilistic sensitivity analysis showed a 64% probability of being cost-effective at a threshold of £30 000 per QALY. Combined ranibizumab and laser therapy resulted in a 0.13 QALY gain at an incremental cost of £4695 relative to laser monotherapy (ICER £36 106; 42% probability of ICER <£30 000).
Based on RESTORE 1-year follow-up data, ranibizumab monotherapy appears to be cost-effective relative to laser monotherapy, the current standard of care. Cost-effectiveness of combination therapy is less certain. Ongoing studies will further inform on disease progression and the need for additional ranibizumab treatment.
Ranibizumab; diabetic macular oedema; visual impairment; cost-effectiveness; macula; treatment medical; clinical trial; epidemiology; public health; vision; retina
UK estimates of age related macular degeneration (AMD) occurrence vary.
To estimate prevalence, number and incidence of AMD by type in the UK population aged ≥50 years.
Age-specific prevalence rates of AMD obtained from a Bayesian meta-analysis of AMD prevalence were applied to UK 2007–2009 population data. Incidence was estimated from modelled age-specific prevalence.
Overall prevalence of late AMD was 2.4% (95% credible interval (CrI) 1.7% to 3.3%), equivalent to 513 000 cases (95% CrI 363 000 to 699 000); estimated to increase to 679 000 cases by 2020. Prevalences were 4.8% aged ≥65 years, 12.2% aged ≥80 years. Geographical atrophy (GA) prevalence rates were 1.3% (95% CrI 0.9% to 1.9%), 2.6% (95% CrI 1.8% to 3.7%) and 6.7% (95% CrI 4.6% to 9.6%); neovascular AMD (NVAMD) 1.2% (95% CrI 0.9% to 1.7%), 2.5% (95% CrI 1.8% to 3.4%) and 6.3% (95% CrI 4.5% to 8.6%), respectively. The estimated number of prevalent cases of late AMD were 60% higher in women versus men (314 000 cases in women, 192 000 men). Annual incidence of late AMD, GA and NVAMD per 1000 women was 4.1 (95% CrI 2.4% to 6.8%), 2.4 (95% CrI 1.5% to 3.9%) and 2.3 (95% CrI 1.4% to 4.0%); in men 2.6 (95% CrI 1.5% to 4.4%), 1.7 (95% CrI 1.0% to 2.8%) and 1.4 (95% CrI 0.8% to 2.4%), respectively. 71 000 new cases of late AMD were estimated per year.
These estimates will guide health and social service provision for those with late AMD and enable estimation of the cost of introducing new treatments.
Prevalence; incidence; AMD; UK; epidemiology; clinical trial
Currently, the border of idiopathic epiretinal membranes (iERM) is outlined intraoperatively using vital dyes. Therefore, the authors set out to investigate the role of the preoperative retinal thickness map (RTM) of the optical coherence tomography (OCT) in identifying the shape and the size of the iERMs.
15 eyes of 15 patients with iERM who underwent vitrectomy with indocyanine green-assisted membrane peeling were included in this study. The authors analysed the intraoperative fundus images and preoperative Cirrus HD-OCT to detect the shape and the size of the iERM as well as the shape and the size of each thickness-indicating colour (white, red, orange and yellow) on the RTM, respectively. The correlation of areas and morphologic characteristics between both groups was explored.
Analysis of iERM morphologic characteristics (shape) showed a similarity between the iERM contour and the corresponding RTM in 13 cases (86.6%). Furthermore, retinal folds were found in six iERMs and in their corresponding RTMs. Analysis of iERM size (area) revealed a positive correlation between the iERM area and each studied coloured area in RTM. The most significant correlation was between iERM and the red area (440–480 μm; r=0.87, p<0.0001).
The iERM-related retinal folds are clearly distinguishable on the HD-OCT. The red area in RTM representing the 440–480 μm retinal thickness can be a reliable predictor of the extent and the shape of the iERM.
Optical coherence tomography; epiretinal membrane; indocyanine green; retinal thickness map; retina; vitreous; treatment surgery; imaging; neovascularisation; treatment lasers
In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) may cause blindness by neovascularisation followed by fibrosis of the retina. It has previously been shown that a shift in the balance between levels of CTGF and VEGF in the eye is associated with this angiofibrotic switch. This study investigated whether anti-VEGF agents induce accelerated fibrosis in patients with PDR, as predicted by this model.
CTGF and VEGF levels were measured by ELISA in 52 vitreous samples of PDR patients, of which 24 patients had received intravitreal bevacizumab 1 week to 3 months before vitrectomy, and were correlated with the degree of vitreoretinal fibrosis as determined clinically and intra-operatively.
CTGF correlated positively, and VEGF correlated negatively with the degree of fibrosis. The CTGF/VEGF ratio was the strongest predictor of fibrosis. Clinically, increased fibrosis was observed after intravitreal bevacizumab.
These results confirm that the CTGF/VEGF ratio is a strong predictor of vitreoretinal fibrosis in PDR, and show that intravitreal anti-VEGF treatment causes increased fibrosis in PDR patients. These findings provide strong support for the model that the balance of CTGF and VEGF determines the angiofibrotic switch, and identify CTGF as a possible therapeutic target in the clinical management of PDR.
Angiogenesis; choroid; CTGF; diabetic retinopathy; drugs; fibrosis; imaging; macula; retina; VEGF; vitreous
To elucidate the morphological features of optic neuropathy in an ischaemic model of glaucoma in macaque monkeys.
The regional degenerative process was investigated by experimentally occluding the paraoptic branches of the lateral short posterior ciliary artery, that is, the circle of Haller and Zinn, in 11 eyes. Morphological changes in nerve fibres in the lamina cribrosa were evaluated by histopathology, immunocytochemistry and angiography, and the findings were compared with those observed in an aged macaque with spontaneous glaucomatous optic neuropathy.
Retinal ganglion cell axons were grouped in bundles and traversed through pores in columns of the lamina cribrosa. The processes of astrocytes extended to the bundles, and capillaries branched in surrounding connective tissue from the circular arterioles. Experimental ischaemia induced time-dependent anoxic deterioration of phosphorylated fibres in the temporal arcuate zone, accompanied by glial proliferation. A monkey with spontaneous visual impairment had nerve fibre loss and gliosis with collagenous proliferation in the temporal hemisphere, suggesting glaucomatous neuropathy.
Circulatory interference in the circle of Haller and Zinn caused time-dependent deterioration in the area where anoxic segmental degeneration is associated with pathogenesis of open-angle glaucoma.
Experimental glaucoma; circle of Haller and Zinn; ischaemic optic neuropathy; macaque glaucoma; glaucoma