Retinal vascular calibre and response to light exposure and serial imaging.

PURPOSE: To investigate whether retinal vessel calibre measurements on optical retinal photography are affected by light and dark exposure prior to photography and whether the vessel calibre changes during an imaging sequence of several images. METHODS: Digital optical retinal photographs were obtained from 32 healthy adults in two separate image sequences of six images during 1 min; one sequence with 10 min of dark exposure and one with 10 min of light exposure prior to imaging. Retinal arteriolar and venular calibres were measured computer-assisted and summarized as central retinal artery and vein equivalents (CRAE and CRVE). Outcome measures were difference in calibres after prior light versus prior dark exposure and difference in calibre during each of the two imaging sequences. RESULTS: CRVE was wider with prior light exposure (2.7%, p = 0.0001), comparing the first image in each image sequence. Within each sequence, there was a venular dilatation from first to last image, both with prior light exposure (1.7%, p = 0.0003) and prior dark exposure (3.1%, p < 0.0001), with the change less pronounced with prior light exposure (p = 0.0164). CRAE showed no significant change in either outcome. CONCLUSIONS: Retinal venular calibre was wider with light exposure prior to imaging and increased slightly during the imaging sequences, less pronounced after prior light than dark exposure. Measurement error due to these effects will probably be reduced by avoiding dark prior to imaging, and a possible bias effect of endothelial dysfunction may possibly be reduced by measuring calibre on an image taken early in the image sequence.

Sex differences in risk factors for retinopathy in non-diabetic men and women: the Tromsø Eye Study.

PURPOSE: To determine the prevalence and risk factors for retinopathy in a nondiabetic population. METHODS: The study population included 5869 participants without diabetes aged 38-87 years from the Tromsø Eye Study, a substudy of the population-based Tromsø Study in Norway. Retinal images from both eyes were graded for retinopathy. We collected data on risk factors from self-report questionnaires, clinical examinations, laboratory measurements and case note reviews. The cross-sectional relationship between potential risk factors and retinopathy was assessed using logistic regression analysis. RESULTS: The overall prevalence of retinopathy was 14.8%. Men had a higher prevalence of retinopathy compared with women (15.9% versus 14.0%, p=0.04). In men, retinopathy was associated with hypertension (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.24-2.04) and HbA1c (OR per %, 1.41; 95% CI, 1.01-1.96). In women, retinopathy was associated with age (OR per 10 years, 1.32; 95% CI, 1.14-1.52), log-transformed urinary albumin excretion (OR per log unit, 1.46; 95% CI, 1.14-1.87) and hypertension (OR, 1.36; 95% CI, 1.08-1.71). In women, retinopathy was associated with very low levels of urinary albumin excretion (urinary albumin/creatinine ratio >0.43 mg/mmol). CONCLUSION: This study confirms results from previous studies on the strong association between blood pressure and retinopathy. A novel finding is the sex differences in risk factors for retinopathy, suggesting a sex difference in the pathogenesis leading to retinopathy.

Is smoking a risk factor for proliferative diabetic retinopathy in type 1 diabetes?

AIM: The aim was to evaluate if smoking was a risk factor for proliferative retinopathy (PDR) in a 25-year follow-up study. METHODS: 201 persons from a population-based cohort of Danish type 1 diabetic patients were examined at baseline and again 25 years later. At both examinations the patients were asked about their smoking habits. The level of retinopathy was evaluated by ophthalmoscopy at baseline and by nine 45-degree colour field fundus photos at the follow-up. RESULTS: In multivariate analyses there was a trend that current smokers at baseline were more likely to develop PDR at the follow-up (odds ratio 1.90, 95% confidence interval 0.88-4.11, p = 0.10). Neither smoking status at the follow-up nor pack-years of smoking were associated with PDR. CONCLUSIONS: We found neither a beneficial nor a harmful effect of smoking on long-term incidence. Selective mortality among smokers and patients with PDR at baseline might provide at least part of the explanation for this.

Long-term associations between serum lipids and panretinal photocoagulation in type 1 diabetes.

AIMS: To examine the predictive value of serum lipids on the need for panretinal photocoagulation (PRP) treatment in a long-term follow-up of a cohort of Danish type 1 diabetic patients. METHODS: A total of 243 type 1 diabetic patients were included from a population-based cohort. Of these, 25 patients (10.3%) were excluded due to proliferative diabetic retinopathy (PDR) at baseline. The remaining 218 patients were followed from January 1993 to November 2006. Serum levels of lipids were collected at baseline. PRP treatment was considered as indicative of PDR during follow-up, and the date of PRP was documented from the Danish National Patients Registry. RESULTS: At baseline, the median age and duration of diabetes were 45.9 years (range 23.9-78.4 years) and 30 years (range 20-72 years), respectively. In the crude analysis, serum triglyceride was associated with incident PRP. However, after adjustments for baseline age, sex, duration of diabetes and HbA1c, this was no longer statistically significant, although a clear trend was found (hazard ratio 1.40, 95% confidence interval 0.97-2.03, p = 0.07, for each 1 mmol/L increase in serum triglyceride). Total cholesterol, HDL cholesterol and LDL cholesterol were not associated with a higher risk of incident PRP. CONCLUSIONS: In a 13-year follow-up of a population-based cohort of long-term type 1 diabetic patients, there was a trend of an association between serum triglyceride and subsequent need of PRP treatment, which was used as a surrogate endpoint of PDR. This identifies triglycerides as a potential risk factor of PDR in type 1 diabetes.

Long-term outcomes of photorefractive keratectomy for low to high myopia: 13 to 19 years of follow-up.

PURPOSE: To evaluate long-term outcomes after photorefractive keratectomy (PRK). METHODS: A retrospective follow-up study of patients who received PRK at 5.0- to 6.5-mm optical zones, using the Summit broad beam excimer laser (Summit Technology, Inc., Waltham, MA) at Odense University Hospital, Odense, Denmark, between 1992 and 1998. One randomly selected eye of each patient was used in the statistical analyses. Re-treated eyes were excluded. RESULTS: One hundred sixty eyes were included. Mean follow-up time was 16 years (range: 13 to 19 years). Mean preoperative spherical equivalent was -4.84 ± 2.95 diopters (D) (range: -20.25 to -1.25 D). At last follow-up examination, achieved refraction was -1.00 ± 1.56 D (range: -10.75 to +1.00 D) from attempted refraction, and the change in mean refractive error from 6 months postoperatively was less than 1.00 D. Results from a subgroup of unilateral treated patients indicated that myopic progression was the main reason for the residual refractive error. For eyes with low myopia (n = 124), the proportion of eyes within ± 1.0 D of attempted refraction was 72%, and for eyes with high myopia (-6.00 D or more, n = 36) it was 47%. Forty-five percent had uncorrected distance visual acuity of 20/20 or better at last follow-up examination. Three eyes (2%) lost two or more lines and 13 eyes (8%) gained two or more lines of corrected distance visual acuity. Fourteen percent had haze (grade 0.5 to 2). Eighty-one percent were satisfied with the surgery. CONCLUSION: PRK for low degrees of myopia seemed safe and effective up to 19 years after surgery with conventional broad beam laser ablation. Refractive predictability was significantly lower and the occurrence of haze was higher in eyes with high myopia.

Tromsø eye study: prevalence and risk factors of diabetic retinopathy.

PURPOSE: To determine the prevalence of visual impairment, retinopathy and macular oedema, and assess risk factors for retinopathy in persons with diabetes. METHODS: The present study included 514 participants with diabetes aged 46-87 years from the Tromsø Eye Study, a sub-study of the population-based Tromsø Study in Norway. Visual acuity was measured using an auto-refractor. Retinal images from both eyes were graded for retinopathy and macular oedema. We collected data on risk factor exposure from self-report questionnaires, clinical examinations, laboratory measurements and case note reviews. Regression models assessed the cross-sectional relationship between potential risk factors and diabetic retinopathy. RESULTS: The prevalence of visual impairment (corrected Snellen visual acuity <20/60 in the better-seeing eye) was 1.6%. The prevalence of diabetic retinopathy was 26.8% and macular oedema 3.9%. In a multivariable logistic regression model, retinopathy was associated with longer diabetes duration (odds ratio, OR 1.07, 95% CI 1.03-1.11), insulin use (OR 2.14, 95% CI 1.19-3.85), nonfasting glucose (OR 1.07, 95% CI 1.00-1.15) and microalbuminuria (OR 1.89, 95% CI 1.28-2.81). Sub-group analyses showed association between retinopathy and even low levels of microalbuminuria (1.16 mg/mmol). CONCLUSION: The findings suggest that low levels of microalbuminuria may be a useful risk predictor for identifying individuals with diabetes at high risk of retinopathy. The study confirms previous findings that insulin use, longer diabetes duration and higher levels of blood glucose are associated with retinopathy in persons with diabetes. The prevalence of diabetic retinopathy was similar as reported in other studies.

Associations between diabetic retinopathy and plasma levels of high-sensitive C-reactive protein or von Willebrand factor in long-term type 1 diabetic patients.

PURPOSE: To evaluate high-sensitive C-reactive protein (hs-CRP) and von Willebrand factor as possible plasma markers of diabetic retinopathy in a population-based cohort of type 1 diabetic patients. MATERIALS AND METHODS: This was a cross-sectional study of 201 type 1 diabetic patients from a population-based cohort from Fyn County, Denmark. Plasma levels of hs-CRP and von Willebrand factor antigen were measured and related to the level of diabetic retinopathy (DR) as evaluated by dilated nine-field 45 degree monoscopic fundus photos captured by Topcon TRC-NWS6 and graded according to the Early Treatment Diabetic Retinopathy Study (ETDRS) adaptation of the modified Airlie House classification of DR. RESULTS: Median age and duration of diabetes were 58.7 and 43 years, respectively. Median levels (10th-90th percentile) of hs-CRP and von Willebrand factor antigen were 1.31 mg/l (0.37-13.3 mg/l) and 1.27 IU/ml (0.79-2.07 IU/ml), respectively. No or minimal DR (ETDRS-levels 10-20) was found in 16.4%, mild DR (ETDRS-level 35) in 19.4%, moderate DR (ETDRS-levels 43-47) in 11.0%, and 53.2% had proliferative diabetic retinopathy (PDR) corresponding to ETDRS-level 60 or more. In an age- and sex-adjusted model, patients in the highest quartile of hs-CRP were more likely to have PDR than patients in the lowest quartile (odds ratio: 2.59; 95% confidence interval: 1.09-6.12). However, this was no longer statistically significant in a multivariate model. Von Willebrand factor was not associated with PDR in any model. CONCLUSIONS: Even though patients with higher levels of hs-CRP were more likely to have PDR in an age- and sex-adjusted model, this was no longer statistically significant in a multivariate model. This indicates the importance of other risk factors like duration of diabetes, glycemic regulation, and smoking. We did not find any association between von Willebrand factor and diabetic retinopathy.

Proliferative retinopathy predicts nephropathy: a 25-year follow-up study of type 1 diabetic patients.

We wanted to examine proliferative retinopathy as a marker of incident nephropathy in a 25-year follow-up study of a population-based cohort of Danish type 1 diabetic patients and to examine cross-sectional associations between nephropathy and retinopathy in long-term surviving patients of the same cohort. All type 1 diabetic patients from Fyn County, Denmark, were identified as of 1 July 1973. One hundred and eighty four patients were examined in 1981-1982 (baseline) and in 2007-2008 (follow-up). The level of retinopathy was graded by ophthalmoscopy at baseline and nine-field digital colour fundus photographs at follow-up. Single spot urine was used to evaluate nephropathy at both examinations. Proliferative retinopathy was present in 29 patients (15.8%) at baseline. At follow-up, these patients were more likely to macroalbuminuria (20.7% vs. 6.5%) than patients without proliferative retinopathy at baseline. In a multivariate logistic regression adjusted for baseline age, sex, duration of diabetes, smoking, HbA(1,) systolic and diastolic blood pressure, odds ratio of nephropathy (micro- and macroalbuminuria combined) was 2.98 (95% confidence interval 1.18-7.51, p = 0.02) for patients with proliferative retinopathy at baseline as compared to those without. At follow-up, there was a close relation between retinopathy and nephropathy. The level of macroalbuminuria was 4.3, 4.6 and 13.0% for patients with no or mild non-proliferative retinopathy, moderate non-proliferative retinopathy and proliferative retinopathy, respectively. In conclusion, proliferative retinopathy is an independent marker of long-term nephropathy in type 1 diabetes. Upcoming studies should examine whether these microvascular complications are also causally linked in type 1 diabetes.

[Endophthalmitis is an acute disease which threatens the vision]. / Endoftalmitis er en akut synstruende øjensygdom.

Endophthalmitis is one of the most serious and most dreaded complications in ophthalmology. It is most often seen as a complication to intraocular surgery and especially after cataract surgery. Approximately 90% of the cases of endophthalmitis are caused by bacteria. Symptoms and signs may include pain, blurred vision, and hypopyon. Intravitreal injection of antibiotics in combination with vitrectomy or vitreous tap is the mainstay in the treatment of endophthalmitis. Prompt recognition and intervention are essential in preserving the vision of the affected eye in the case of endophthalmitis.

Electrophysiological assessment of retinal function during 6 months of bevacizumab treatment in neovascular age-related macular degeneration.

PURPOSE: The purpose of this study was to assess the alteration of retinal function by multifocal electroretinography and full-field electroretinography in patients with age-related macular degeneration treated with bevacizumab. METHODS: We performed a prospective pilot study of 26 eyes of 26 previously treatment-naïve patients with neovascular age-related macular degeneration receiving intravitreal injections with 1.25 mg bevacizumab. Patients were examined with multifocal electroretinography, full-field electroretinography, optical coherence tomography, and visual acuity. Follow-up was performed at 1 week, 6 weeks, 3 months, and 6 months. RESULTS: Mean multifocal electroretinography P1 amplitudes were significantly improved at 1 week in the central zone and after 3 and 6 months, improvement was seen in all 6 concentric rings corresponding to +/-25 degrees of the central visual field. Full-field electroretinography results indicated a decrease in cone photoreceptor function at 3 months, which was normalized at 6 months compared with baseline. Furthermore, 2 of 3 of the combined rod-cone responses showed signs of decreased retinal function at 6 months. CONCLUSION: Our results indicate passing signs of an altered retinal cone photoreceptor function assessed by full-field electroretinography. The results do not show any conclusive signs of global retinal toxicity after 6 months. Multifocal electroretinography results show improved photoreceptor function with no sign of focal toxicity in the central retina.

Retinal vascular fractals and microvascular and macrovascular complications in type 1 diabetes.

PURPOSE: Fractal analysis is a method to quantify the geometric pattern and complexity of the retinal vessels. This study examined the association of retinal fractal dimension (D(f)) and microvascular and macrovascular complications in a population-based cohort of Danish patients with type 1 diabetes. DESIGN: Cross-sectional study. PARTICIPANTS: This was a cross-sectional study of 208 long-term surviving type 1 diabetes patients from a population-based Danish cohort identified in 1973. METHODS: Retinal photographs were obtained at a clinical examination in 2007 or 2008. D(f) was measured with a semiautomatic computer-based program (International Retinal Imaging Software; National University of Singapore, Republic of Singapore; University of Sydney, Sydney, and University of Melbourne, Melbourne, Australia). D(f) of the retinal vasculature was measured within a predefined circular region of 3.5 optic disc radii centered on the optic disc. Line tracing of the vasculature was provided by the program. Any artifacts were removed by the grader, and the box-counting method then was used by the program to calculate D(f). MAIN OUTCOME MEASURES: The association of D(f) with proliferative retinopathy, nephropathy, neuropathy, and macrovascular disease (coronary heart disease, stroke, peripheral artery disease) was examined. RESULTS: Retinal fractals were gradable in at least 1 eye in 178 (86.6%) of 208 patients. Median age and duration of diabetes for these patients were 57.8 years and 42 years, respectively. Median D(f) was 1.4610 (range, 1.3774-1.5188). After adjustments for age, gender, duration of diabetes, systolic blood pressure, and smoking, persons with lower D(f) were more likely to have proliferative retinopathy (odds ratio [OR], 1.45 per standard deviation [SD] decrease in D(f); 95% confidence interval [CI], 1.04-2.03) and neuropathy (OR, 1.42 per SD decrease in D(f); 95% CI, 1.01-2.01). There was also a trend of an association between lower D(f) and nephropathy (OR, 1.39 per SD decrease in D(f); 95% CI, 0.97-2.01) but not macrovascular disease. Furthermore, persons with lower D(f) were older. CONCLUSIONS: This study adds to the evidence that D(f) may have some role as a global measure of retinal vasculature and its association with systemic disease. Prospective studies clarifying this role are needed. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Risk factors for mortality and ischemic heart disease in patients with long-term type 1 diabetes.

AIMS: The purpose of this study is to evaluate the effect of glycemic regulation, dyslipidemia, and renal dysfunction on mortality (all-cause and cardiovascular) and ischemic heart disease (IHD) in a long-term follow-up of a population-based cohort of Danish type 1 diabetic patients with at least 20 years of diabetes. METHODS: A population-based cohort of type 1 diabetic patients was identified as of July 1, 1973 (n=727). In 1993 to 1996, the cohort was reassessed and baseline data were collected from blood and urine samples in 389 patients. Mean (glycemic regulation and lipids) and highest values (creatinine and albuminuria) of the baseline period were used to predict mortality and IHD between baseline and 2006. Data of mortality and morbidity were provided by the Danish Civil Registration System, the Danish Causes of Death Registry, and the Danish National Patient Registry. RESULTS: At the follow-up in 2006, 256 patients (65.8%) were still alive. In a statistical model adjusted for age, sex and duration of diabetes, the following parameters were related to all-cause mortality and cardiovascular mortality: glycemic regulation, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (inversely), total cholesterol, creatinine, and macroalbuminuria. Furthermore, all markers except macroalbuminuria were associated with IHD. Microalbuminuria at baseline was not related to any of the endpoints. CONCLUSIONS: Glycemic regulation, dyslipidemia, and renal dysfunction were all related to mortality and IHD in a 13-year follow-up of long-term Danish type 1 diabetic patients. These results underscore the better outcome for tightly regulated type 1 diabetic patients, even in long-term survivors.

Retinal arterioles have impaired reactivity to hyperoxia in type 1 diabetes.

PURPOSE: Diabetes has adverse effects on the retinal microvasculature. The purpose of this study was to compare the effects of inhalation of hypoxic, hyperoxic and normoxic-hypercapnic gas mixtures on retinal vessel diameter in people with and without diabetes. METHODS: Sixty-one participants (aged 24-50 years) 29 with (male : female ratio 2.6 : 1) and 32 without (male : female ratio 0.7 : 1) diabetes, inhaled hypoxic, hyperoxic and normoxic-hypercapnic gas mixtures for 3-5 mins. The diameters of arterioles and venules were measured using digital retinal images taken before and after gas inhalation. RESULTS: There was no significant difference in the diameters of arterioles and venules prior to gas inhalation in people with and without diabetes. Inhalation of the hyperoxic gas mixture caused a statistically significant decrease in arteriolar and venular diameters without altering mean arterial pressure significantly. Arteriolar vasoconstriction in response to the hyperoxic gas mixture was significantly reduced in people with diabetes (3.95% versus 7.75%; p = 0.04), but venular vasoconstriction did not differ significantly. A hypoxic gas mixture caused increased arteriolar and venular diameter and a normoxic-hypercapnic gas mixture had no significant effect on vessel diameter. Responses to hypoxic and normoxic-hypercapnic gas did not differ significantly between diabetes and non-diabetes subjects. CONCLUSIONS: Type 1 diabetes impairs retinal arteriolar responses to hyperoxia. Abnormalities in retinal arteriolar reactivity in response to oxygen may play a role in the development of diabetic retinopathy and this technique may represent a simple means of identifying early abnormalities in the reactivity of retinal arterioles in diabetes.

Major diabetes-related vascular events do not improve glycaemic control in a population-based cohort of type 1 diabetic individuals.

OBJECTIVE: It is known that sudden serious events alter life styles related to treatment efficiency, as for example in cancer patients. However, it has not been specifically addressed if a first-time diabetes-related clinical event has impact on glycaemic regulation. We therefore assessed this in a population-based cohort of patients with long-term type 1 diabetes. METHODS: This study was based on a cohort of type 1 diabetes patients with at least 20 years duration of diabetes. Of the 460 patients from the original cohort still alive at 1 January 1994, all patients with a major first-time diabetes-related clinical event (limb amputation, blindness, stroke, cardiac event, or panretinal photocoagulation) and glycated haemoglobin (HbA(1c)) measurements before, 3 and/or 12 months after the event were included. Differences in HbA(1c) measurements before and after the event were tested with Wilcoxon's test. RESULTS: A total of 64 patients with a major clinical event between 1994 and 2006 entered the study. Mean HbA(1c) measurements decreased from 8.8% at baseline to 8.6% at 3 months and 8.7% after 12 months, a non-significant decrease. In all event groups, glycaemic regulation was unaltered in the majority of the patients. Only a minority worsened or improved their regulation, and in all groups only non-significant changes were seen. CONCLUSIONS: Surprisingly, complication-related events did not improve glycaemic regulation in long-term type 1 diabetes patients. This is in contrast with the experience from other patient categories and shows how difficult it can be to alter glycaemic regulation in diabetes patients with stabilized disease.

Blindness in a 25-year follow-up of a population-based cohort of Danish type 1 diabetic patients.

PURPOSE: To assess the long-term incidence of blindness and to evaluate risk factors for blindness in a population-based cohort of type 1 diabetic patients. DESIGN: Retrospective cohort study. PARTICIPANTS: A population-based cohort of 573 type 1 diabetic patients, all of whom participated in a clinical ophthalmologic examination in 1981 and 1982 and were followed up for 25 years. METHODS: At the baseline examination in 1981 and 1982, visual acuity, level of retinopathy, maculopathy, hemoglobin A(1) (HbA(1)), proteinuria, smoking habits, and blood pressure were evaluated and related to the subsequent development of blindness. Blindness was defined as present in patients who were registered as members of the Danish Association of the Blind between baseline and January 2007. The Danish Association of the Blind is a voluntary organization open for all patients with a best-corrected visual acuity in the best eye of

Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials.

BACKGROUND: Microalbuminuria in diabetes is strongly predictive of nephropathy, end-stage renal disease, and premature cardiovascular morbidity and mortality. Effective preventive therapies are therefore a clinical priority. OBJECTIVE: To determine whether the angiotensin-receptor blocker candesartan compared with placebo affects microalbuminuria incidence or rate of change in albuminuria in type 1 and type 2 diabetes. DESIGN: 3 randomized trials of the DIRECT (Diabetic Retinopathy Candesartan Trials) Program. SETTING: 309 secondary care centers. PATIENTS: 3326 and 1905 patients with type 1 and type 2 diabetes, respectively. Most were normotensive, and all had normoalbuminuria (median urinary albumin excretion rate, 5.0 microg/min). INTERVENTION: Candesartan, 16 mg/d increasing to 32 mg/d, versus placebo. Assignment was done centrally using an interactive voice-response system. Patients, caregivers, and researchers were blinded to treatment assignment. During a median follow-up of 4.7 years, 793 patients discontinued therapy and 63 were lost to follow-up. MEASUREMENTS: Urinary albumin excretion rate, assessed annually by 2 overnight collections; if it was 20 microg/min or greater, then 2 further collections were done. The primary end point was new microalbuminuria (3 or 4 collections of urinary albumin excretion rate >or=20 microg/min). The secondary end point was rate of change in albuminuria. RESULTS: Individual and pooled results of the 3 trials showed that candesartan had little effect on risk for microalbuminuria (pooled hazard ratio, 0.95 [95% CI, 0.78 to 1.16]; P = 0.60). Pooled results showed that the annual rate of change in albuminuria was 5.53% lower (CI, 0.73% to 10.14%; P = 0.024) with candesartan than with placebo. LIMITATIONS: Investigators recruited mainly normotensive patients or patients with well-controlled hypertension who were at low overall vascular risk, which resulted in a low rate of microalbuminuria. Studies were powered for retinal and not renal end points. CONCLUSION: Candesartan, 32 mg/d, for 4.7 years did not prevent microalbuminuria in mainly normotensive patients with type 1 or type 2 diabetes.

Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration in treatment-naive patients.

PURPOSE: To report the effects of intravitreal bevacizumab (Avastin) in treatment-naive patients with exudative age-related macular degeneration (ARMD) assessed by visual acuity (VA), optical coherence tomography (OCT) and contrast sensitivity. METHODS: A prospective, uncontrolled, pilot study of 26 eyes of 26 patients, all previously treatment-naive to photodynamic therapy, argon laser or anti-vascular endothelial growth factor (VEGF), were treated with one or more intravitreal injections of 1.25 mg bevacizumab. Of the 26 patients, 15 (57.7%) had occult choroidal neovascularization (CNV), 6 (23.1%) had predominantly classic CNV and 5 (19.2%) had minimally classic CNV. Ophthalmic outcome measures included changes in standardized Early Treatment Diabetic Research Study (ETDRS) VA, contrast sensitivity and OCT. The patients were examined at baseline and 1 week, 6 weeks, 3 months and 6 months after the first injection. Re-treatment was given on an 'as needed' basis. RESULTS: Twenty-four eyes of 24 patients completed 6 months of follow-up. Two patients chose to discontinue the study. Mean ETDRS VA score improved from 55 letters at baseline to 60 letters at 1 week (P < 0.01) and to 61 letters at 6 weeks (P < 0.01). No significant improvement in VA from baseline was found after 3 and 6 months. Patients with pigment epithelial detachment (PED) had a significantly worse outcome in VA at 6 months. Contrast sensitivity improved from baseline to 3 or 6 months, but this improvement was not statistically significant. Mean macular thickness decreased significantly from baseline to all follow-up examinations (P < 0.01). CONCLUSION: Mean ETDRS VA improved significantly after 1 and 6 weeks; thereafter, it remained stable throughout the study period. Macular thickness improved significantly at all time points. The results indicate that 1.25 mg intravitreal bevacizumab is associated with functional as well as morphological improvement among treatment-naive ARMD patients.

Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials.

BACKGROUND: Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden of diabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme to assess whether candesartan could reduce the incidence and progression of retinopathy in type 1 diabetes. METHODS: Two randomised, double-blind, parallel-design, placebo-controlled trials were done in 309 centres worldwide. Participants with normotensive, normoalbuminuric type 1 diabetes without retinopathy were recruited to the DIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1, and were assigned to candesartan 16 mg once a day or matching placebo. After 1 month, the dose was doubled to 32 mg. Investigators and participants were unaware of the treatment allocation status. The primary endpoints were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively. These trials are registered with ClinicalTrials.gov, numbers NCT00252733 for DIRECT-Prevent 1 and NCT00252720 for DIRECT-Protect 1. FINDINGS: 1421 participants (aged 18-50 years) were randomly assigned to candesartan (n=711) or to placebo (n=710) in DIRECT-Prevent 1, and 1905 (aged 18-55 years) to candesartan (n=951) or to placebo (n=954) in DIRECT-Protect 1. Incidence of retinopathy was seen in 178 (25%) participants in the candesartan group versus 217 (31%) in the placebo group. Progression of retinopathy occurred in 127 (13%) participants in the candesartan group versus 124 (13%) in the placebo group. Hazard ratio (HR for candesartan vs placebo) was 0.82 (95% CI 0.67-1.00, p=0.0508) for incidence of retinopathy and 1.02 (0.80-1.31, p=0.85) for progression of retinopathy. The post-hoc outcome of at least a three-step increase for incidence yielded an HR of 0.65 (0.48-0.87, p=0.0034), which was attenuated but still significant after adjustment for baseline characteristics (0.71, 0.53-0.95, p=0.046). Final ETDRS level was more likely to have improved with candesartan treatment in both DIRECT-Prevent 1 (odds 1.16, 95% CI 1.05-1.30, p=0.0048) and DIRECT-Protect 1 (1.12, 95% CI 1.01-1.25, p=0.0264). Adverse events did not differ between the treatment groups. INTERPRETATION: Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression.

Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial.

BACKGROUND: Diabetic retinopathy remains a leading cause of visual loss in people of working age. We examined whether candesartan treatment could slow the progression and, secondly, induce regression of retinopathy in people with type 2 diabetes. METHODS: We did a randomised, double-blind, parallel-group, placebo-controlled trial in 309 centres worldwide. We recruited normoalbuminuric, normotensive, or treated hypertensive people with type 2 diabetes with mild to moderately severe retinopathy and assigned them to candesartan 16 mg once a day or placebo. After a month, the dose was doubled to 32 mg once per day. Investigators and patients were unaware of the treatment allocation status. Progression of retinopathy was the primary endpoint, and regression was a secondary endpoint. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00252694. FINDINGS: 1905 participants (aged 37-75 years) were randomised to candesartan (n=951) or placebo (n=954). 161 (17%) patients in the candesartan group and 182 (19%) in the placebo group had progression of retinopathy by three steps or more on the Early Treatment Diabetic Retinopathy Study scale. The risk of progression of retinopathy was non-significantly reduced by 13% in patients on candesartan compared with those on placebo (hazard ratio [HR] 0.87, 95% CI 0.70-1.08, p=0.20). Regression on active treatment was increased by 34% (1.34, 1.08-1.68, p=0.009). HRs were not attenuated by adjustment for baseline risk factors or changes in blood pressure during the trial. An overall change towards less severe retinopathy by the end of the trial was observed in the candesartan group (odds 1.17, 95% CI 1.05-1.30, p=0.003). Adverse events did not differ between the treatment groups. INTERPRETATION: Treatment with candesartan in type 2 diabetic patients with mild to moderate retinopathy might induce improvement of retinopathy.