Prevalence of age-related macular degeneration in an elderly UK Caucasian population-The Bridlington Eye Assessment Project: a cross-sectional study.

ImportanceThere is paucity of data on prevalence and disease asymmetry of age-related macular degeneration (AMD), particularly the earlier stages, in the UK population.Objective and PurposeTo determine the prevalence of age-related macular degeneration in an elderly Caucasian UK population.DesignCross-sectional population study, 2002-2006.ParticipantsResidents in the study area of Bridlington aged 65 years and older.MethodsFull-ophthalmic examination was undertaken in 3549 participants, of eligible 6319 Caucasian population (response rate of 56%). Non-stereoscopic Colour fundus photographs (30°) were graded masked using a modified Rotterdam Classification for 3475 (98%) participants with gradable images. Prevalence for different AMD grades were calculated. Demographic details were analysed then integrated with the AMD gradings for full analysis. Prevalence rates for the different AMD Grades were calculated, as well as the age-specific prevalences.ResultsAMD prevalence in the worst eye were 38.5% grade 0, 41.4% grade 1, 12.8% grade 2, 2.8% grade 3, and 4.6% grade 4. Geographic atrophy (grade 4a) occurred in 2.5%, and neovascular AMD (grade 4b) in 1.8%. Prevalence increased with age such that grade 4 (advanced) AMD was 2.2% in the 65-69 years group, 15.8% for the 85-90, and 21.2% for over 90 years. There was significant asymmetry between the two eyes of individuals with advanced AMD (P<0.001), such that vision loss was unilateral. Persons with more advanced AMD grades were more likely to be dissatisfied with their vision.ConclusionsAdvanced AMD occurs more commonly in the UK Caucasian population than previously reported. Significant asymmetry between the two eyes occurs in individuals with unilateral advanced AMD so that visual impairment statistics do not represent true prevalence of advanced AMD. Persons with more advanced AMD were more likely to be dissatisfied with their vision.

Dexamethasone reverses the effects of high glucose on human retinal endothelial cell permeability and proliferation in vitro.

Diabetic macular oedema (DMO), a leading cause of preventable visual loss in the working population, is caused by an increase in microvascular endothelial cell permeability, and its prevalence is on the increase in parallel with the rising worldwide prevalence of diabetes. It is known that retinal vascular leakage in DMO is contributed to by VEGF upregulation as well as non-VEGF dependent inflammatory pathways, and the potential use of anti-inflammatory agents such as the glucocorticoids, including dexamethasone are being extensively studied. However, the mechanisms of action of dexamethasone in DMO reduction are not fully understood. Using human primary retinal endothelial cells (REC) the in vitro effect of dexamethasone in modulating the proliferation, permeability and gene expression of key tight and adheren junction components, and the expression of angiopoietins (Ang) 1 and 2 in high (25 mM) glucose conditions were investigated. High glucose decreased REC proliferation, an effect that was reversed by dexamethasone. High glucose conditions significantly increased REC permeability and decreased claudin-5, occludin and JAM-A gene expression; dexamethasone was effective in partially reversing these changes, restoring EC permeability to the normal or near normal state. High glucose levels resulted in reduction of Ang1 secretion, although Ang2 levels were consistently high. DEX increased Ang1 and decreased Ang2, indicating that the balance of Ang1/Ang2 may be important in determining functional changes in REC under high glucose conditions.

Prevalence of reticular pseudodrusen in newly presenting adult onset foveomacular vitelliform dystrophy.

PurposeTo report the association and prevalence of reticular pseudodrusen (RPD) in eyes with newly presenting adult onset foveomacular vitelliform dystrophy (AFVD). To compare the strength of association with other pathologies resulting from dysfunction of the choroid-Bruch's membrane-retinal pigment epithelium (RPE) complex, including eyes with geographic atrophy (GA) and angioid streaks.MethodsRetrospective single-centre review of all consecutive newly presenting AFVD. Multimodal imaging with spectral domain optical coherence tomography, fundus photographs, red-free/blue light images, and fundus fluorescein angiograms were graded for the presence of RPD. For comparison, all consecutive newly presenting cases of GA and eyes with angioid streaks were studied.ResultsFifteen (15) patients were identified with AFVD (mean age of 77.3 years; 73.3% female). Mean age of patients with AFVD and RPD was 80.5 years (SD 3.7), whereas that of patients with AFVD without RPD was 75.1 years (SD 7.0). This age difference did not reach statistical significance, P=0.1. Six (40%) had identifiable RPD; being a bilateral finding in 100% of patients. No males with AFVD and RPD were identified. A total of 92 eyes presented with GA. Twenty-three (23) of these (25.0%) had RPD. Twelve (12) patients presented with identifiable angioid streaks, with 4 (36.4%) having RPD.ConclusionRPD are a frequent finding in eyes with newly presenting AFVD; not being restricted to AMD, but a finding common among diseases where pathophysiological mechanisms involve damage to Bruch's membrane and the RPE, whether genetic or degenerative. Our study supports the concept that they occur with high but variable frequencies in eyes with various pathologies.

A review of therapies for diabetic macular oedema and rationale for combination therapy.

Diabetic macular oedema (DMO) is responsible for significant visual impairment in diabetic patients. The primary cause of DMO is fluid leakage resulting from increased vascular permeability through contributory anatomical and biochemical changes. These include endothelial cell (EC) death or dysfunction, pericyte loss or dysfunction, thickened basement membrane, loss or dysfunction of glial cells, and loss/change of EC Glycocalyx. The molecular changes include increased reactive oxygen species, pro-inflammatory changes: advanced glycation end products, intracellular adhesion molecule-1, Complement 5-9 deposition and cytokines, which result in increased paracellular permeability, tight junction disruption, and increased transcellular permeability. Laser photocoagulation has been the mainstay of treatment until recently when pharmacological treatments were introduced. The current treatments for DMO target reducing vascular leak in the macula once it has occurred, they do not attempt to treat the underlying pathology. These pharmacological treatments are aimed at antagonising vascular endothelial growth factor (VEGF) or non-VEGF inflammatory pathways, and include intravitreal injections of anti-VEGFs (ranibizumab, aflibercept or bevacizumab) or steroids (fluocinolone, dexamethasone or triamcinolone) as single therapies. The available evidence suggests that each individual treatment modality in DMO does not result in a completely dry macula in most cases. The ideal treatment for DMO should improve vision and improve morphological changes in the macular (eg, reduce macular oedema) for a significant duration, reduced adverse events, reduced treatment burden and costs, and be well tolerated by patients. This review evaluates the individual treatments available as monotherapies, and discusses the rationale and potential for combination therapy in DMO. A comprehensive review of clinical trials related to DMO and their outcomes was completed. Where phase III randomised control trials were available, these were referenced, if not available, phase II trials have been included.

Defining response to anti-VEGF therapies in neovascular AMD.

The introduction of anti-vascular endothelial growth factor (anti-VEGF) has made significant impact on the reduction of the visual loss due to neovascular age-related macular degeneration (n-AMD). There are significant inter-individual differences in response to an anti-VEGF agent, made more complex by the availability of multiple anti-VEGF agents with different molecular configurations. The response to anti-VEGF therapy have been found to be dependent on a variety of factors including patient's age, lesion characteristics, lesion duration, baseline visual acuity (VA) and the presence of particular genotype risk alleles. Furthermore, a proportion of eyes with n-AMD show a decline in acuity or morphology, despite therapy or require very frequent re-treatment. There is currently no consensus as to how to classify optimal response, or lack of it, with these therapies. There is, in particular, confusion over terms such as 'responder status' after treatment for n-AMD, 'tachyphylaxis' and 'recalcitrant' n-AMD. This document aims to provide a consensus on definition/categorisation of the response of n-AMD to anti-VEGF therapies and on the time points at which response to treatment should be determined. Primary response is best determined at 1 month following the last initiation dose, while maintained treatment (secondary) response is determined any time after the 4th visit. In a particular eye, secondary responses do not mirror and cannot be predicted from that in the primary phase. Morphological and functional responses to anti-VEGF treatments, do not necessarily correlate, and may be dissociated in an individual eye. Furthermore, there is a ceiling effect that can negate the currently used functional metrics such as >5 letters improvement when the baseline VA is good (ETDRS>70 letters). It is therefore important to use a combination of both the parameters in determining the response.The following are proposed definitions: optimal (good) response is defined as when there is resolution of fluid (intraretinal fluid; IRF, subretinal fluid; SRF and retinal thickening), and/or improvement of >5 letters, subject to the ceiling effect of good starting VA. Poor response is defined as <25% reduction from the baseline in the central retinal thickness (CRT), with persistent or new IRF, SRF or minimal or change in VA (that is, change in VA of 0+4 letters). Non-response is defined as an increase in fluid (IRF, SRF and CRT), or increasing haemorrhage compared with the baseline and/or loss of >5 letters compared with the baseline or best corrected vision subsequently. Poor or non-response to anti-VEGF may be due to clinical factors including suboptimal dosing than that required by a particular patient, increased dosing intervals, treatment initiation when disease is already at an advanced or chronic stage), cellular mechanisms, lesion type, genetic variation and potential tachyphylaxis); non-clinical factors including poor access to clinics or delayed appointments may also result in poor treatment outcomes. In eyes classified as good responders, treatment should be continued with the same agent when disease activity is present or reactivation occurs following temporary dose holding. In eyes that show partial response, treatment may be continued, although re-evaluation with further imaging may be required to exclude confounding factors. Where there is persistent, unchanging accumulated fluid following three consecutive injections at monthly intervals, treatment may be withheld temporarily, but recommenced with the same or alternative anti-VEGF if the fluid subsequently increases (lesion considered active). Poor or non-response to anti-VEGF treatments requires re-evaluation of diagnosis and if necessary switch to alternative therapies including other anti-VEGF agents and/or with photodynamic therapy (PDT). Idiopathic polypoidal choroidopathy may require treatment with PDT monotherapy or combination with anti-VEGF. A committee comprised of retinal specialists with experience of managing patients with n-AMD similar to that which developed the Royal College of Ophthalmologists Guidelines to Ranibizumab was assembled. Individual aspects of the guidelines were proposed by the committee lead (WMA) based on relevant reference to published evidence base following a search of Medline and circulated to all committee members for discussion before approval or modification. Each draft was modified according to feedback from committee members until unanimous approval was obtained in the final draft. A system for categorising the range of responsiveness of n-AMD lesions to anti-VEGF therapy is proposed. The proposal is based primarily on morphological criteria but functional criteria have been included. Recommendations have been made on when to consider discontinuation of therapy either because of success or futility. These guidelines should help clinical decision-making and may prevent over and/or undertreatment with anti-VEGF therapy.

The effect of hyperglycaemia on permeability and the expression of junctional complex molecules in human retinal and choroidal endothelial cells.

Diabetic retinopathy is the leading cause of preventable blindness in the working population and its prevalence continues to increase as the worldwide prevalence of diabetes grows. Diabetic choroidopathy is less well studied and occurs in the late stages of diabetic eye disease. The main cause of visual loss in diabetic eye disease is diabetic macular oedema caused by an increase in microvascular endothelial permeability. Endothelial cell permeability is influenced by multiple factors which have not been fully elucidated, particularly in human models. In addition, the gene and protein expression between retinal and choroidal endothelial cells, even in humans, has been shown to be heterogeneous. The aim of this project was to determine, in vitro, the effect of high glucose (25 mM) on human paracellular permeability in retinal and choroidal endothelial cells. The expression of selected tight junction molecules (Occludin, Claudin-5, JAM-A and JAM-C) and adheren junction (VE-Cadherin) molecules was also compared between retinal and choroidal endothelial cells and with high glucose. High glucose conditions significantly increased the permeability in both retinal and choroidal endothelial cells monolayers although the increase was higher in retinal endothelial cells. Under normal glucose culture conditions microarray analysis determined that occludin and claudin-5 gene expression was higher in retinal endothelial cells than choroidal endothelial cells, and western blotting indicated that claudin-5 protein expression was also higher in retinal endothelial cells whilst JAM-A, and C and VE-Cadherin levels were similar. In retinal endothelial cells exposed to high glucose claudin-5, occludin and JAM-A was found to be reduced, whereas the expression of VE-Cadherin and JAM-C was unchanged when evaluated with western blotting, immunofluorescence and qPCR. None of the proteins were significantly decreased by high glucose in choroidal endothelial cells. The increase in retinal endothelial cell permeability is likely caused by a decrease in selective tight junction protein expression, leading to increased paracellular permeability. This may indicate differences in junctional molecule regulation of permeability in retinal compared to choroidal endothelial cells.

Quality of bevacizumab compounded for intravitreal administration.

AIM: To compare the quality and stability of unlicensed, repackaged bevacizumab intended for intravitreal injection, as provided by five licensed compounding pharmacies in the United Kingdom, with bevacizumab in its original glass vial. METHODS: Repackaged bevacizumab was obtained from five UK suppliers. Samples were analyzed at two time points (day 1 and day 14). Microflow imaging was performed to evaluate subvisible particle size, particle density, and particle size distribution. Protein concentration, immunoglobulin G (IgG) content, and molecular weight were also determined. RESULTS: A significant difference in subvisible particle density was observed between bevacizumab batches from the five suppliers on day 1 (P<0.001). An increase in subvisible particle density was observed between day 1 and 14 for repackaged bevacizumab from all suppliers (all P<0.05), but not the reference compound. Protein concentration, IgG content, and molecular weight were comparable between batches from each supplier and the reference bevacizumab. DISCUSSION: The study results indicate that the quality of bevacizumab repackaged into prefilled plastic syringes is variable among the different compounding pharmacies in the United Kingdom. Furthermore, particle density may increase with storage in repackaged syringes. It is noteworthy that particle size distribution in both the repackaged and reference bevacizumab fell outside of the range specified by the United States Pharmacopeia for injectable ophthalmic solutions. These data highlight the need for further research into the use of unlicensed, repackaged bevacizumab intended for intravitreal injection.

Intravitreal ranibizumab for the treatment of choroidal neovascularisation secondary to angioid streaks.

AIMS: To assess the medium to long-term efficacy and safety of intravitreal ranibizumab for the treatment of choroidal neovascularisation (CNV) secondary to angioid streaks (AS). METHODS: A total of 12 eyes of nine patients treated with intravitreal ranibizumab (0.5 mg in 0.05 ml) for CNV secondary to AS were retrospectively identified. Efficacy of treatment was determined by changes in best-corrected LogMAR visual acuity (BCVA) and optical coherence tomography. Changes with respect to baseline BCVA were defined as improved or reduced with a gain or loss of more than 10 letters, respectively, or stable if remaining within 10 letters. RESULTS: Over a mean follow-up of 21.75 months (range: 1-54), patients received mean 5.75 (range: 2-15) intravitreal ranibizumab injections per affected eye. BCVA improved in three eyes (25%), stabilised in eight eyes (66.67%), and deteriorated in one eye (8.33%). There was no significant change in central retinal thickness (CRT) over the follow-up period (P=0.1072). No drug-related systemic side effects were recorded. CONCLUSION: The long-term treatment of CNV secondary to AS with intravitreal ranibizumab showed a stabilisation in CRT and an improvement or stabilisation of BCVA. The absence of systemic side effects was reassuring. Further long-term prospective studies are required to validate these findings.

Central retinal artery occlusion following peribulbar anesthesia for pterygium excision.

Pterygium is a common ocular surface pathology in tropical environments. In the early stages, it may be managed medically with topical anti-inflammatory agents and ocular lubricants. However as the disease progresses, surgical excision becomes necessary and several anaesthetic methods may be used to assist this. We share our experience of a 30-year old woman who underwent uneventful pterygium excision using peribulbar lignocain injection with adrenaline. She developed sudden blindness due to central retinal artery occlusion with macular infarction. While peribulbar anaesthesia is generally safe, a remote risk of retinal vascular accident exists and its routine use should be done with caution. Where possible topical anaesthesia with or without intra-lesional injection be employed.

Causes and incidence of destructive eye procedures in north-eastern ghana.

OBJECTIVE: To determine the causes and incidence of destructive ophthalmic procedures as seen at a major reference eye centre in northern Ghana METHODS: Retrospective case series involving a review of surgical records of all evisceration and enucleation procedures done between January 2002 and December 2006 at the Bawku Hospital Eye Department. Information collected included basic demographic data, diagnosis, visual acuity at diagnosis and the eye affected. The aetiology responsible was determined from history, clinical examination and investigations as contained in the existing records. The primary clinical indications for evisceration were categorized into degenerative lesions, infections, trauma, neoplasms, and others. Statistical analysis was done using the Epi Info software. RESULTS: A total of 337 eyes of 336 patients made up of 217 (64.6%) males and 119 (35.4%) females were removed during the study period. Mean age was 36.4 with a range of 1-90 years. Children under 15 years constituted 25.1% of whom 9.3% were under 5 years. The elderly (>/=60 years) comprised 26.3%. The most common cause of destructive procedure was endophthalmitis /panophthalmitis (47.9%), ocular injuries (23.2%), degenerative lesions (8.9%) and neoplasms (5.1%). Regarding neoplasms, females were more likely to be enucleated while the reverse was so for traumas (p=0.04 and p=0.02, Chi(2) test, respectively). Compared to the total number of surgeries done each year the crude incidence was computed at 26.6% per 1000 cases per year. CONCLUSION: Most causes of destructive procedures in this part of Ghana are preventable and serious preventive strategies are needed to reverse this trend.

The effects of growth factors on the proliferation and in vitro angiogenesis of human macular inner choroidal endothelial cells.

AIM: To investigate the effect of VEGF(165), FGF2, IGF-1, PDGF-AA, PDGF-BB and IL-1 beta on the proliferation and angiogenic tube formation of human macular inner choroidal endothelial cells (ICEC). METHODS: The proliferation of human macular ICECs after exposure to the aforementioned growth factors was determined by using both a WST-1 colorimetric assay and a cell-counting technique. The effect of growth factors on ICEC angiogenesis was assessed by sprout formation using a three-dimensional in vitro Matrigel duplex assay. RESULTS: Using both the WST-1 assay and a cell-counting technique, VEGF(165) and FGF2 both significantly increased human macular ICEC proliferation. The effect of equimolar concentrations of VEGF(165) and FGF2 was additive. There was no significant effect for IGF-1, PDGF-AA, PDGF-BB or IL-1 beta on proliferation up to a growth factor concentration of 1000 pmol/l. The angiogenesis assay found a significant effect on sprout formation for VEGF(165) and FGF-2. Again, the effect of equimolar concentrations of VEGF(165) and FGF2 was additive. There was no significant effect for IGF-1, PDGF-AA, PDGF-BB or IL-1 beta on sprout formation at 1000 pmol/l. CONCLUSIONS: Both VEGF(165) and FGF2 significantly increase human macular ICEC proliferation and sprout formation in an angiogenesis assay. When present together, their effect was additive. IGF-1, PDGF-AA, PDGF-BB and IL-1 beta did not have any significant effect on proliferation or sprout formation in vitro. These results suggest that targeting other growth factors such as FGF2, in addition to VEGF, may be beneficial in the treatment of neovascular age-related macular degeneration.

Causes of childhood visual impairment and unmet low-vision care in blind school students in Ghana.

The purpose of this study was to determine the causes of childhood visual impairment and blindness in students of a school for blind children, to determine how many students had some residual vision, and to evaluate any unmet low-vision care. A survey of students in the blind school was conducted in two parts in May-June and then October 2003. The sample consisted of 201 students who became blind before the age of 16. Information was obtained from student interviews, doctors' referral notes and ophthalmic examination of all students who consented. Students with residual vision had low-vision assessments. These investigations were supplemented with active participation of the investigators in Parent-Teacher Association meetings and focus group discussions with parents. One hundred and ninety-nine students consented and were recruited, whereas two declined. Ninety-six became visually impaired within their first year of life and 33 by the age of 5 years. Pathology of the cornea and then the lens were the commonest causes of blindness. One hundred and eight students were totally blind, whereas 87 (43.7%) had some residual vision and formed the target for the second part of the study. Fifty-one out of 77 of this target group who turned up for low-vision examination had useful residual vision by the World Health Organisation (WHO) low-vision examination chart. Spectacle magnifiers aided two students to read normal print at N5 and N8, respectively. Different visual aids would help enhance the residual vision in some of the others. Emotional trauma was apparent in parents and teachers. Children who became blind later in life remained in shock for a longer time and adapted less well to their visual impairment. Visual impairment in the population is not uncommon. Some causes are preventable. There is a significant unmet need for low-vision care, particularly amongst children in Ghana, and perhaps many countries in the West Africa subregion. It is hoped that the findings from this study will help spur sustained interventions.

Syphilitic acute posterior placoid chorioretinitis in nonimmuno-compromised patients.

PURPOSE: To describe the clinical and angiographic features of three cases of secondary syphilis in immunocompetent patients, which presented as acute posterior placoid chorioretinitis (APPC) to the ophthalmologist. METHODS: Interventional case series. The aetiology of the APPC was confirmed by serology to be secondary syphilis. Optical coherence tomography, electrophysiology, fundus fluorescein, and indocyanine green (ICG) angiography were performed at presentation and after resolution. Appropriate treatment for secondary syphilis was instituted in each patient. RESULTS: The clinical features, fundus fluorescein and ICG angiography, multifocal electroretinography (mfERG), and optical coherence tomography findings of APPC are described. All three patients had a satisfactory resolution of the APPC with improvement in visual acuity. CONCLUSIONS: APPC in secondary syphilis can occur even in immunocompetent patients. A high index of suspicion is required for early diagnosis of this condition resulting in a good visual outcome with adequate treatment. mfERG and optical coherence tomography are useful in the diagnosis and follow-up of these patients.