Diagnosis of retinopathy in children younger than 12 years of age: implications for the diabetic eye screening guidelines in the UK.

AimTo assess whether the current starting age of 12 is suitable for diabetic retinopathy (DR) screening and whether diabetes duration should be taken into account when deciding at what age to start screening patients.Materials and methodsA retrospective analysis of 143 patients aged 12 years or younger who attended diabetic eye screening for the first time in the Birmingham, Solihull and Black Country Diabetic Eye Screening Programme was performed.ResultsThe mean age of the patients was 10.7 (7-12) years with 73 out of 143 aged below 12 years and 70 were 12 years of age. 98% had type 1 diabetes and mean diabetes duration was 5 (1 month-11 years) years. For those younger than 12 years, 7/73 (9.6%) had background DR (BDR), of these mean diabetes duration was 7 years (6-8). The youngest patient to present with DR was aged 8 years. In those aged 12 years, 5/70 (7.1%) had BDR; of these mean diabetes duration was 8 years (6-11). No patient developed DR before 6 years duration in either group.ConclusionsThe results show that no patient younger than the age of 12 had sight-threatening DR (STDR), but BDR was identified. Based on the current mission statement of the Diabetic Eye Screening Programme to identify STDR, 12 years of age is confirmed as the right age to start screening, but if it is important to diabetic management to identify first development of DR, then screening should begin after 6 years of diabetes diagnosis.

Does microvascular disease predict macrovascular events in type 2 diabetes?

AIM: Population studies suggest a link between albuminuria, reduced glomerular filtration rate (GFR) and retinopathy and macrovascular events in type 2 diabetes. The aim of this review was to investigate whether this association extended to the presence of any diabetic microvascular complication. METHOD AND RESULTS: PUBMED was searched from 1999 to 2010 using the terms 'albuminuria', 'nephropathy', 'chronic kidney disease', 'estimated GFR', 'retinopathy', 'autonomic neuropathy', 'peripheral neuropathy', or 'microvascular' and 'cardiovascular disease', 'stroke', 'coronary heart disease' or 'peripheral vascular disease' and 'type 2 diabetes' and MESH equivalents. Prospective studies with at least 200 type 2 diabetes subjects that evaluated hard cardiovascular endpoints were selected. In 25 studies (n=54,117) included in the review there was evidence of an association between microvascular complications (notably retinopathy or nephropathy) and cardiovascular events. Diabetic retinopathy was associated with ∼ 1.7-fold increased risk for cardiovascular events, and albuminuria or reduced GFR associated with ∼ two-fold increased risk for cardiovascular events. In the presence of more than one complication, this risk was accentuated. These associations remained even after adjustment for conventional cardiovascular risk factors, diabetes duration and glycaemic control. These data suggest that similar mechanisms may be relevant to the pathogenesis of both micro- and macrovascular disease in type 2 diabetes. It is likely that endothelial dysfunction, low-grade inflammation and rheological abnormalities are common mechanistic denominators. CONCLUSIONS: This review highlights the association between micro- and macrovascular disease in type 2 diabetes, underlining the importance of early detection of microangiopathy for vascular risk assessment in type 2 diabetes.

Medical management of diabetic retinopathy: fenofibrate and ACCORD Eye studies.

The approach of all ophthalmologists, diabetologists and general practitioners seeing patients with diabetic retinopathy should be that good control of blood glucose, blood pressure and plasma lipids are all essential components of modern medical management. The more recent data on the use of fenofibrate in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye studies is reviewed. In FIELD, fenofibrate (200 mg/day) reduced the requirements for laser therapy and prevented disease progression in patients with pre-existing diabetic retinopathy. In ACCORD Eye, fenofibrate (160 mg daily) with simvastatin resulted in a 40% reduction in the odds of retinopathy progressing over 4 years, compared with simvastatin alone. This occurred with an increase in HDL-cholesterol and a decrease in the serum triglyceride level in the fenofibrate group, as compared with the placebo group, and was independent of glycaemic control. We believe fenofibrate is effective in preventing progression of established diabetic retinopathy in type 2 diabetes and should be considered for patients with pre-proliferative diabetic retinopathy and/or diabetic maculopathy, particularly in those with macular oedema requiring laser.

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 (P

Management of diabetic retinopathy: could lipid-lowering be a worthwhile treatment modality?

Diabetic eye disease confers substantial burden on the patient quality of life. Current therapeutic strategies indicate an unmet clinical need for preventive therapy. Tight control of blood pressure and glycaemia are mandatory components of primary prevention strategies, but are insufficient to eliminate risk in all patients. A body of evidence supports a role for lipid-modifying therapy in reducing the diabetic retinopathy endpoints. Although inconclusive for statin therapy, results from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study show beneficial effects of fenofibrate in reducing the requirement for laser therapy, and particularly in preventing disease progression in patients with pre-existing diabetic retinopathy. However, there is a need for confirmation of these findings in large prospective studies with progression of retinopathy as the primary endpoint, such as the ACCORD-EYE (Action to Control Cardiovascular Risk in Diabetes-EYE) study, and in a clinical trial specifically conducted for diabetic maculopathy. In addition, elucidation of the mechanism(s) of effect of fenofibrate is indicated.

Homocysteine, folates, and the eye.

Plasma homocysteine has been identified as a risk factor for arterial disease, retinal artery and vein occlusions, and other common eye diseases. The value of treating an elevated plasma homocysteine with folic acid for preventing further vascular disease has not been proven. Although secondary prevention of coronary artery disease using this approach has been unsuccessful, trials on primary prevention of stroke and loss of cognitive function with folic acid supplementation appear to be successful. Further trial data are awaited. In patients with premature retinovascular disease, the measurement of plasma homocysteine is suggested and reduction of elevated homocysteine with folic acid for secondary prevention of retinal arterial and venous occlusion. Meanwhile, the debate on fortification of flour for primary prevention of neural tube defects, which has already taken place in North America, continues in European countries. Such fortification could have an impact on primary and secondary prevention of vascular disease.

Pain response and follow-up of patients undergoing panretinal laser photocoagulation with reduced exposure times.

PURPOSE: We performed a study of laser panretinal photocoagulation in 20 patients with proliferative retinopathy. We compared short exposure, high-energy laser settings with conventional settings, using a 532 nm, frequency doubled, Neodymium-Yag laser and assessed the patients in terms of pain experienced and effectiveness of treatment. METHODS: Twenty patients having panretinal photocoagulation for the first time underwent random allocation to treatment of the superior and inferior hemi-retina. Treatment A used 'conventional' parameters: exposure time 0.1 s, power sufficient to produce a visible grey-white burns, spot size 300 microm. The other hemi- retina was treated with treatment B using exposure 0.02 s, 300 microm and sufficient power to have similar endpoint. All patients were asked to evaluate severity of pain on a visual analogue scale. (0=no pain, 10=most severe pain). All patients were masked as to the type of treatment and the order of carrying out the treatment on each patient was randomised. Patients underwent fundus photography and were followed up for 6-45 months. RESULTS: Seventeen patients had proliferative diabetic retinopathy, two had ischaemic central retinal vein occlusion and one had ocular ischaemic syndrome. The mean response to treatment A was 5.11, compared to 1.40 treatment B, on the visual analogue scale, which was statistically significant (P=0.001). All patients preferred treatment B. Further treatments, if required, were performed with treatment B parameters and long-term follow-up has shown no evidence of undertreatment. CONCLUSIONS: Shortening exposure time of retinal laser is significantly less painful but equally effective as conventional parameters.

Is measurement of blood pressure worthwhile in the diabetic eye clinic?

PURPOSE: The UK Prospective Diabetic Study has confirmed the importance of blood pressure (BP) as a major risk factor for diabetic retinopathy (DR). We wanted to investigate whether measuring the BP in the diabetic eye clinic could identify new hypertensive patients and monitor control in existing ones. PATIENTS AND METHODS: We compared BP in patients attending the diabetic eye clinic with home blood pressure measurement (HBPM) and ambulatory BP measurement (ABPM). In all, 106 patients attending a diabetic eye clinic were selected at random from clinic attendees. BP measurement (on an Omron 705 CP) was performed in the eye clinic and also compared to HBPM three times per day with an Omron 705 CP machine, and was compared to diabetic clinic measurements. In addition, 11 randomly chosen patients had 24 h ABPM to validate the above techniques. RESULTS: In all, 106 patients (70 male and 36 female) were recruited for the study, of which 71 were known to be hypertensive on antihypertensive medication. Of the total, 75 patients (70.8%) had BP > 140/85 in the eye clinic, of which 51 (68%) were known to be hypertensive on treatment and this was confirmed in 46 (90%) on HBPM. A total of, 24 patients (22.6%) were newly diagnosed as hypertensive in the eye clinic, which was confirmed by HBPM in 22 patients (92%). The mean BP of the measurements performed in the eye clinic was significantly higher than that carried out in the diabetic clinic (P < 0.01). Tropicamide 1% and phenylephrine 2.5% eye drop instillation had no effect on BP. In 11 randomly chosen patients, 24 h ABPM validated both diabetic eye clinic and home BP measurements. CONCLUSION: Attendance at the diabetic eye clinic is an important chance to detect both new patients with systemic hypertension and those with inadequate BP control. Ophthalmologists should be encouraged to measure BP in their diabetic patients attending diabetic eye clinics, as it is an important risk factor for DR. On the basis of our findings, good BP control is a goal yet to be achieved in diabetic patients with retinopathy.

Does cardiovascular therapy affect the onset and recurrence of preretinal and vitreous haemorrhage in diabetic eye disease?

AIMS: To review the role of cardiovascular disease and therapy in the onset and recurrence of preretinal/vitreous haemorrhage in diabetic patients. METHODS: Retrospective case note analysis of diabetic patients with vitreous haemorrhage from the Diabetic Eye Clinic at Birmingham Heartlands Hospital. RESULTS: In total, 54 patients (mean age 57.1, 37 males, 20 type I vs 34 type II diabetic patients) were included. The mean (SD) duration of diagnosed diabetes at first vitreous haemorrhage was significantly longer, 21.9 (7.6) years for type I and 14.8 (9.3) years for type II diabetic patients (P < 0.01, unpaired t-test, two-tailed).Aspirin administration was not associated with a significantly later onset of vitreous haemorrhage. Four episodes were associated with ACE-inhibitor cough. There was a trend towards HMGCoA reductase inhibitor (statin) use being associated with a delayed onset of vitreous haemorrhage: 21.4 years until vitreous haemorrhage (treatment group) vs 16.2 years (nontreatment group) (P = 0.09, two-tailed, unpaired t-test, not statistically significant). During follow-up 56 recurrences occurred, making a total of 110 episodes of vitreous haemorrhage in 79 eyes of 54 patients. The mean (range) follow-up post haemorrhage was 1067 (77-3842) days, with an average of 1.02 recurrences. Age, gender, diabetes type (I or II) or control, presence of hypertension or hypercholesterolaemia, and macrovascular complications were not associated with a significant effect on the 1-year recurrence rate. Aspirin (and other antiplatelet or anticoagulant agents) and ACE- inhibitors appeared to neither increase nor decrease the 1-year recurrence rate. However, statin use was significantly associated with a reduction in recurrence (Fisher exact P < 0.05; two-tailed) with an odds ratio (95% CI) of 0.25 (0.1-0.95). CONCLUSION: In this retrospective analysis, the onset of preretinal/vitreous haemorrhage was not found to be accelerated by gender, hypertension, hypercholesterolaemia, evidence of macrovascular disease, or HbA1c. Neither aspirin nor ACE-inhibitor administration accelerated the onset or recurrence of first vitreous haemorrhage. Statins may have a protective role, both delaying and reducing the recurrence of haemorrhage.

The platelet glycoprotein Ia/IIa gene polymorphism C807T/G873A: a novel risk factor for retinal vein occlusion.

Retinal vein occlusion (RVO) is associated with hyperhomocysteinaemia and the antiphospholipid syndrome-disorders known to contribute to both arterial and venous thrombosis. In both of these conditions and RVO, platelet activation occurs. Aspirin, not warfarin, is the most effective antithrombotic agent in RVO and, taken together, these observations suggest an important role for platelets in this common ocular thrombotic condition. Platelet glycoprotein Ia/IIa (GpIa/IIa) is an adhesion molecule mediating platelet-collagen interactions and is key to the initiation of thrombosis. Recently, the cellular density of this molecule was shown to be determined by two silent, linked polymorphisms (C807T/G873A) within the GpIa/IIa gene. There is evidence that some of the resulting genotypes are associated with thrombo-embolic disease. This study therefore aimed to establish the prevalence of the GpIa/IIa polymorphisms and the three commonest hereditary thrombophilic disorders (prothrombin gene G20210A (PT) mutation, Factor V Leiden (FVL), and the thermolabile methylene tetrahydrofolate reductase C677T (MTHFR) mutation) in patients with RVO and normal controls. The GpIa/IIa polymorphisms and thrombophilic abnormalities were all identified using the polymerase chain reaction.Our results show that the frequency of the GpIa/IIa polymorphisms was similar in our normal control population to previously published series. Patients with RVO, however, had only a 10% (4/40) frequency of the lowest risk subtype (CC/GG) compared to 37.5% (15/40) in the control group-P 0.0039. The incidence of the PT, FVL, and MTHFR thrombophilic mutations was not different between the two groups, but interestingly none of the 7/40 RVO cases with a PT, FVL, or MTHFR mutation had the low-risk GpIa/IIa genotype while all but one of the controls did-P<0.05. Thus, 17.5% of RVO patients harboured more than one prothrombotic abnormality. The principal difference between the RVO and control group was the very high incidence of the intermediate-risk GpIa/IIa subtype (CT/GA)-82.5 vs 50%, P&<0.05. These results suggest a major role for GpIa/IIa polymorphisms in the pathogenesis of RVO.

The role of serum lipids in exudative diabetic maculopathy: is there a place for lipid lowering therapy?

Diabetic maculopathy is a common complication of diabetes mellitus, characterised by macular oedema and frequently accompanied by lipid exudation. It is the major cause of loss of vision from diabetic retinopathy. There is some evidence to implicate serum lipids in exudative maculopathy; cross-sectional studies suggest that higher serum lipid levels are found in patients with macular exudates, and prospective studies have shown an increased risk of exudative maculopathy if baseline cholesterol is higher. The treatment for diabetic maculopathy is laser photocoagulation of the pigment epithelium. With the advent of systemic lipid lowering therapy over the last decade, there may be potential for medical therapy also. There is some anecdotal evidence of the effect of lipid lowering agents (particularly statins) in reducing exudate, and a number of studies have shown that lipid lowering therapy may reduce macular exudates, but numbers in these trials are small. A randomised controlled trial is now required to investigate whether the use of systemic lipid lowering therapy is of benefit in patients with exudative maculopathy, even in the absence of dyslipidaemia.

Hypertension and diabetes.

Hypertension is common in people with diabetes with an estimated prevalence using the new criteria (> or = 140/90) at 70%. The recent large randomized controlled studies in diabetic subjects has clearly shown the benefit of blood pressure lowering with reduction in cardiovascular endpoints and microvascular disease. ACE inhibitors, calcium antagonists, thiazide diuretics and beta-blocking agents have been the agents validated by the trials. The challenge now is to implement antihypertensive therapy to achieve tight blood pressure targets (< or = 140/80), usually requiring dual or even triple therapeutic regimens.

MHC class II region, CTLA4 gene, and ophthalmopathy in patients with Graves' disease.

Up to half of patients with Graves' hyperthyroidism have signs of thyroid associated ophthalmopathy, but the factors that cause this disorder are unknown. We investigated two major genetic susceptibility loci for Graves' disease in ophthalmopathy; the MHC class II region and the cytotoxic T lymphocyte antigen-4 (CTLA4) gene. Allelic frequencies of these genes in patients with Graves' disease who did and did not have concurrent thyroid-associated ophthalmopathy did not differ, and are, therefore, unlikely to contribute to its development.

Plasma total homocysteine and retinal vascular disease.

PURPOSE: Hyperhomocysteinaemia has been linked to macrovascular disease. Our aim was to investigate whether there is a relationship between fasting plasma total homocysteine levels and retinal vascular disease. METHODS: We measured the homocysteine levels in 70 patients with arterial or venous retinal vessel occlusion and compared them with the levels in 85 controls without evidence of ischaemic heart disease. Homocysteine levels were determined by high-performance liquid chromatography with electrochemical detection and compared after logarithmic transformation. RESULTS: Homocysteine levels were found by univariate analysis (unpaired two-tailed t-test) to be significantly higher in the group with retinal artery occlusion than the group with retinal vein occlusion (p = 0.045) and in both groups compared with controls (18.4 and 13.8 vs 9.5 mumol/l; p = 0.0002 and < 0.0001, respectively). The controls, however, were significantly younger than the subjects (51.5 +/- 15.4 vs 66.2 +/- 11.9 years; p < 0.0001), but analysis of the results by age revealed significant differences between the groups and controls for the seventh decade (vein occlusions, p = 0.05) and for the eighth decade (artery occlusions, p = 0.037). Subgroup analysis of the retinal vessel occlusion group revealed significant differences in mean blood pressure between those with branch retinal vein occlusions (175/100 mmHg) and both those with central retinal vein occlusions (155/88 mmHg) and those with retinal artery occlusions (157/86 mmHg). Both vein occlusion subgroups also differed significantly with regard to homocysteine levels, branch < central (12.2 +/- 1.3 vs 15.0 +/- 1.6 mumol/l, p = 0.03). Multiple linear regression analysis revealed significant relationships between homocysteine levels and the presence of retinal vessel occlusion (p = 0.0002), serum creatinine (p = 0.001) and age (p = 0.003), but not gender. CONCLUSIONS: We conclude that homocysteine may be a risk factor for retinal vascular disease and could be simply and cheaply treated with folate and vitamins B6 and B12.