Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor

Aberrant blood vessel growth in the retina that underlies the pathology of proliferative diabetic retinopathy and retinopathy of prematurity is the result of the ischemia-driven disruption of the normally antiangiogenic environment of the retina. In this study, we show that a potent inhibitor of angiogenesis found naturally in the normal eye, pigment epithelium-derived growth factor (PEDF), inhibits such aberrant blood vessel growth in a murine model of ischemia-induced retinopathy. Inhibition was proportional to dose and systemic delivery of recombinant protein at daily doses as low as 2.2 mg/kg could prevent aberrant endothelial cells from crossing the inner limiting membrane. PEDF appeared to inhibit angiogenesis by causing apoptosis of activated endothelial cells, because it induced apoptosis in cultured endothelial cells and an 8-fold increase in apoptotic endothelial cells could be detected in situ when the ischemic retinas of PEDF-treated animals were compared with vehicle-treated controls. The ability of low doses of PEDF to curtail aberrant growth of ocular endothelial cells without overt harm to retinal morphology suggests that this natural protein may be beneficial in the treatment of a variety of retinal vasculopathies.

Novelties in Diabetic Retinopathy

Although diabetic retinopathy (DR) remains a leading cause of vision loss, the last decade has brought significant advances in the diagnosis and treatment of this common complication of diabetes mellitus. First, optical coherence tomography allows for noninvasive imaging of the retina, in particular, the macula, with very high resolution, thus facilitating the management of diabetic macular edema. In addition, recent advances in the understanding of the pathophysiology of DR, in particular, the key role of cytokines, such as vascular endothelial growth factor (VEGF), have led to the development of anti-VEGF antibodies for intraocular use. Anti-VEGF therapies have largely replaced laser photocoagulation for the treatment of diabetic macular edema. The benefit of intravitreal anti-VEGF in diabetic macular edema has been proven in numerous large randomized controlled trials. Moreover, a role of inflammation in DR has been recognized, and several mainly steroid-based, anti-inflammatory agents for intravitreal treatment have been shown to be effective. Despite these recent advances, strict systemic control of glycemia remains the cornerstone of the management of DR, significantly reducing ocular complications. This chapter will provide an overview of current and novel concepts of DR and will allude to promising novel therapeutic options for this sight-threatening disease.

The Diabetic Retinopathy Vitrectomy Study : an explanation for patients, group N.

Mode of access: Internet.

Telepaediatrics and diabetic retinopathy screening of young people with diabetes in Queensland

We have examined the feasibility of a telemedicine-enabled screening service for children and adolescents with diabetes in Queensland. There are approximately 1400 young people with diabetes in Queensland and only about two-thirds of them are screened in accordance with international guidelines. A regional retinal screening service was established using a non-mydriatic digital retinal camera. Seven centres volunteered to participate in the study. During a five-month pilot trial, 83 of the young people with diabetes who attend these centres underwent digital retinal screening (3.7%). Retinal images were sent via email to a paediatric ophthalmologist for review and results were returned via email. A copy of each participant's results was forwarded by mail to the referring diabetes doctor and the participant and family. The majority of the image files (96%) were rated as excellent or good. Only one participant was identified as having an abnormal result. Participants and their families expressed satisfaction with the digital retinal screening process.

Evaluating digital diabetic retinopathy screening in people aged 90 years and over

Introduction: The English National Screening Programme determines that all people with diabetes aged 12 and over should be screened annually for diabetic retinopathy (DR) until they die. Purpose: This study aimed to evaluate digital DR screening in patients aged 90 and over to establish whether it is appropriate to cease screening at age 90. Methods: A retrospective analysis of 200 randomly selected patients with diabetes aged 90 and over within the Birmingham and Black Country Screening Programme. Results: 179 (90%) patients attended screening at least once after turning 90 years of age. To date, the mean number of screens per person 90+ was two (range 1–6) and the mean age of the first of these screens was 91 years (range 90–98 years). 133 (74%) were put on annual recall after their first screen in their 90’s, of which 58% had no visible DR bilaterally. 38 (21%) were referred to ophthalmology - 35 (92%) for non-DR reasons and three for maculopathy. Of the 133 patients put on annual recall, 75 (56%) were screened at least once more. Seven improved, 36 remained stable, three became unsuitable and 29 deteriorated. Of the latter, 18 patients were referred to ophthalmology; one of these for DR. Conclusion: Patients with diabetes aged 90 and over are at low risk of sight threatening DR and annual screening in this age group may be unnecessary. However, annual screening does provide opportunistic identification.

Is twelve years old an acceptable age at which to begin Diabetic Retinopathy Screening?

Introduction: The English National Screening Programme for diabetic retinopathy (ENSPDR) states that “all people with diabetes aged 12 years and over should be offered screening” Purpose: The audit aims to assess whether the current guideline is suitable and whether diabetes duration should be taken into account when deciding at what age to start screening patients. Method: Retrospective analysis of 143 randomly selected patients aged twelve years or younger who have attended diabetic retinopathy (DR) screening in the Birmingham and Black Country Screening Programme. Results: 98% had Type 1 diabetes and mean visual acuity (VA) was 6/5 (6/4-6/36). 73 were under 12 with 7 the youngest age and 70 were aged 12. Both groups had mean diabetes duration of 5 years (1month-11years). For those under 12, 7/73 (9.6%) had background DR, of these mean diabetes duration was 7 years (6-8) and the youngest aged 8. In those aged 12, 5/70 (7.1%) had background DR; of these mean diabetes duration was 8 years (6-11). In total 12 (8.4%) patients aged 12 years or under developed DR. No patients had retinopathy worse than background changes. One patient was referred to ophthalmology for VAs of 6/12, 6/18 and was diagnosed with optic atrophy so returned to annual screening. Conclusion: The results suggest that the current guideline on when to begin screening should be readdressed as more patients under twelve developed DR than those aged 12. Diabetes duration may help when deciding what age to start screening adolescent patients as DR was not seen in those with disease duration.

Neurodegeneration is an early event in diabetic retinopathy:therapeutic implications

Diabetic retinopathy (DR) remains the leading cause of blindness among working-age individuals in developed countries. Current treatments for DR are indicated in advanced stages of the disease and are associated with significant adverse effects. Therefore, new pharmacological treatments for the early stages of DR are needed. DR has been classically considered to be a microcirculatory disease of the retina. However, there is growing evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR, which participates in the microcirculatory abnormalities that occur in DR. Therefore, the study of the underlying mechanisms that lead to neurodegeneration will be essential for identifying new therapeutic targets. From the clinical point of view, the identification of those patients in whom retinal neurodegeneration appears will be crucial for implementing early treatment based on neuroprotective drugs. When the early stages of DR are the therapeutic target, it would be inconceivable to recommend an aggressive treatment such as intravitreous injections. By contrast, topical administration of neuroprotective drugs by using eye drops is a possible option. However, clinical trials to determine the safety and effectiveness of this non-invasive route, as well as a standardisation of the methods for monitoring neurodegeneration, are needed.

Diabetic retinopathy and blockade of the renin–angiotensin system:new data from the DIRECT study programme

The pathogenesis and medical management of diabetic retinopathy is reviewed. The importance of good control of blood glucose and blood pressure remain key elements in the prevention and treatment of diabetic retinopathy, and a number of specific metabolic pathways have been identified that may be useful additional targets for therapeutic intervention. Trial data, however, aimed specifically to answer the questions of optimum medical management are limited, so the DIRECT study of renin-angiotensin blockade using oral candesartan 32 mg daily is a welcome addition to our knowledge. This arose from the promising improvement of retinopathy outcomes in the EUCLID study of lisinopril in type I diabetes. In DIRECT, 5 years of candesartan treatment in type I diabetes reduced the incidence of retinopathy by two or more steps (EDTRS) in severity by 18% (P = 0.0508) and, in a post hoc analysis, reduced the incidence of retinopathy by three-step progression by 35% (P = 0.034). In type I diabetes patients there was no effect on progression of established retinopathy. In contrast, in type II diabetes, 5 years of candesartan treatment resulted in 34% regression of retinopathy (P ≤0.009). Importantly, an overall significant change towards less-severe retinopathy was noted in both type I and II diabetes (P0.03). Although there is still no absolute proof that these effects were specific to RAS blockade, or just an effect of lower blood pressure, it is reasonable to conclude that candesartan has earned a place in the medical management of diabetic retinopathy, to prevent the problem in type I diabetes and to treat the early stages in type II diabetes. © 2010 Macmillan Publishers Limited All rights reserved.

Improving the cost-effectiveness of photographic screening for diabetic macular oedema:a prospective, multi-centre, UK study

Background/aims: Retinal screening programmes in England and Scotland have similar photographic grading schemes for background (non-proliferative) and proliferative diabetic retinopathy, but diverge over maculopathy. We looked for the most cost-effective method of identifying diabetic macular oedema from retinal photographs including the role of automated grading and optical coherence tomography, a technology that directly visualises oedema. Methods: Patients from seven UK centres were recruited. The following features in at least one eye were required for enrolment: microaneurysms/dot haemorrhages or blot haemorrhages within one disc diameter, or exudates within one or two disc diameters of the centre of the macula. Subjects had optical coherence tomography and digital photography. Manual and automated grading schemes were evaluated. Costs and QALYs were modelled using microsimulation techniques. Results: 3540 patients were recruited, 3170 were analysed. For diabetic macular oedema, England's scheme had a sensitivity of 72.6% and specificity of 66.8%; Scotland 's had a sensitivity of 59.5% and specificity of 79.0%. When applying a ceiling ratio of £30 000 per quality adjusted life years (QALY) gained, Scotland's scheme was preferred. Assuming automated grading could be implemented without increasing grading costs, automation produced a greater number of QALYS for a lower cost than England's scheme, but was not cost effective, at the study's operating point, compared with Scotland's. The addition of optical coherence tomography, to each scheme, resulted in cost savings without reducing health benefits. Conclusions: Retinal screening programmes in the UK should reconsider the screening pathway to make best use of existing and new technologies.

Evaluating digital diabetic retinopathy screening in people aged 90 years and over

To evaluate the effectiveness of digital diabetic retinopathy screening in patients aged 90 years and over.MethodsThis is a retrospective analysis of 200 randomly selected patients eligible for diabetic retinopathy screening aged 90 years and over within the Birmingham, Solihull, and Black Country Screening Programme.ResultsOne hundred and seventy-nine (90%) patients attended screening at least once. 133 (74%) annual screening after their first screen, of whom 59% had no detectable diabetic retinopathy; 38 (21%) were referred for ophthalmology clinical assessment-36 for nondiabetic retinopathy reasons and two for diabetic maculopathy. Cataract accounted for 50% of all referrals for ophthalmology clinical assessment. Of the 133 patients placed on annual screening, 93 (70%) were screened at least once more. In terms of level of diabetic retinopathy, assessability or other ocular pathologies, 8 improved, 51 remained stable, and 31 deteriorated. Of the latter, 19 patients were referred for ophthalmology clinical assessment; none of these for diabetic retinopathy.ConclusionsScreening provides opportunistic identification of important nondiabetic retinopathy eye conditions. However, in view of the low identification rate of sight-threatening diabetic retinopathy in patients aged 90 years and over, and the current mission statement of the NHS Diabetic Eye Screening Programme, systematic annual diabetic retinopathy screening may not be justified in this age group of patients, but rather be performed in optometric practice.

Is it safe to increase diabetic retinopathy screening intervals in patients with no/background diabetic retinopathy?

Patients who present with background DR should continue to be screened annually as a high prportion of these patients develop sight threatening DR (12%). A low prportion of patients with no DR at baseline were referred for STDR (1.3%). Out of the 51 patients in this category referred only 1 required laser. The authors suggest that patients graded R0M0 could be screened biannually.

Is it safe to increase diabetic retinopathy screening intervals in patients with no background diabetic retinopathy?

Introduction. A 4 year retrospective follow up of 996 patients who pre-sented with no DR and 500 with background DR at baseline digital DR screening in 2006. Purpose. To evaluate the safety of increasing screening intervals in patients with no diabetic retinopathy (DR) or with background DR.Methods. A 4 year retrospective follow up of 996 patients who presented with no DR and 500 with background DR at baseline digital DR screening in 2006.results. Background DR Group: Of the 500 subjects that had back-ground DR in 2006, 231 were referred for DR, with an average DR routine referral rate of 12% (46 subjects) per year. nodrgrouP. Of the 996 patients who had no DR at baseline, 51 were referred over the 4 years for sight threatening DR (STDR), of these 45 patients have definite STDR confirmed by ophthalmological examination. 78% of these had type 2 diabetes and mean age at referral was 60 years (25-87). Mean diabetes duration was 10.7 years (3-32), with a mean HbA1c of 7.8% (5.7-11.3%). Eight patients (0.9%) were referred in the first year, 9 (0.9%) in the second year, 19 (1.9%) in the third year and 15 (1.5%) in the fourth year. 86% of referrals were for maculopathy, and all had observable retinopathy and none required ophthalmology clinic assessment or laser treatment.If biannual screening was adopted for patients with no DR at baseline, allowing for patients who subsequently develop background DR and would then revert to annual screening, a total of 7 (0.7%) patients would not have been appropriately referred for STDR and would have waited a further year for identification. None of the 51 referrals across the 4 years required laser treatment apart from just one patient who developed PDR in year 4 (2010) and had background since 2007.conclusIons. It could be recommended that it is safe to screen pa-tients with no DR biannually due to the low risk of developing STDR. However, patients who present with background DR should continue to be screened annually as there is a significant proportion developing STDR and would not be identified at an appropriate screening interval.