Fixation stability and implication for multifocal electroretinography in patients with neovascular age-related macular degeneration after anti-VEGF treatment.

PURPOSE: To quantify fixation stability in patients with neovascular age-related macular degeneration (nAMD) at baseline, 3 and 6 months after anti-vascular endothelial growth factor (anti-VEGF) treatment and furthermore asses the implications of an unsteady fixation for multifocal electroretinography (mfERG) measurements. METHODS: Fifty eyes of 50 nAMD patients receiving intravitreal anti-VEGF treatment with either bevacizumab or ranibizumab and eight eyes of eight control subjects were included. Fixation stability measurements were performed with the Eye-Link eyetracking system and the retinal area in degrees2 (deg2) containing the 68 % most frequently used fixation points (RAF68) was calculated. MfERG P1 amplitude and implicit time were analyzed in six concentric rings and as a summed response. Patients were examined at baseline, 3 and 6 months. Four different mfERG recordings were performed for the control subjects to mimic an involuntary unstable fixation: normal central fixation, 2.4°, 4.8°, and 7.1° fixation instability. RESULTS: For control subjects, a fixation instability of 2.4° (corresponding to the central hexagon) did not reduce mfERG ring amplitudes significantly, whereas 4.8° and 7.1° fixation instability reduced the amplitudes significantly in rings 1 and 2 (p < 0.001) as well as in the peripheral rings in the 7.1° instability condition (p < 0.001). Fixation stability improved non-significantly for patients at 3 and 6 months. The size of the retinal area of fixation was at baseline, 3 and 6 months negatively correlated to visual acuity (VA) (rbaseline = -0.65, r3 months = -0.60, and r6 months = -0.66 respectively, p < 0.001) and mfERG amplitudes of the three innermost rings (rbaseline = -0.29, p = 0.042, r3 months = -0.43, p = 0.003 and r6 months = -0.31, p = 0.042). The VA cutoff for a fixation area less than 5 deg2 (approximately the central hexagon) was 65, 77, and 68 ETDRS letters (corresponding a maximal Snellen equivalent of 0.31) at baseline, 3 and 6 months, respectively. CONCLUSIONS: MfERG amplitudes in recordings of nAMD patients are at substantial risk of being reduced due to poor fixation as a large number of patients may use a fixation area of more than 5 deg2. Fixation monitoring during recording as well as interpretation of results should be performed with care, especially in patients with poor visual acuity.

Retinal microaneurysm count predicts progression and regression of diabetic retinopathy. Post-hoc results from the DIRECT Programme.

OBJECTIVE: To study the association between baseline retinal microaneurysm score and progression and regression of diabetic retinopathy, and response to treatment with candesartan in people with diabetes. METHODS: This was a multicenter randomized clinical trial. The progression analysis included 893 patients with Type 1 diabetes and 526 patients with Type 2 diabetes with retinal microaneurysms only at baseline. For regression, 438 with Type 1 and 216 with Type 2 diabetes qualified. Microaneurysms were scored from yearly retinal photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Retinopathy progression and regression was defined as two or more step change on the ETDRS scale from baseline. Patients were normoalbuminuric, and normotensive with Type 1 and Type 2 diabetes or treated hypertensive with Type 2 diabetes. They were randomized to treatment with candesartan 32 mg daily or placebo and followed for 4.6 years. RESULTS: A higher microaneurysm score at baseline predicted an increased risk of retinopathy progression (HR per microaneurysm score 1.08, P < 0.0001 in Type 1 diabetes; HR 1.07, P = 0.0174 in Type 2 diabetes) and reduced the likelihood of regression (HR 0.79, P < 0.0001 in Type 1 diabetes; HR 0.85, P = 0.0009 in Type 2 diabetes), all adjusted for baseline variables and treatment. Candesartan reduced the risk of microaneurysm score progression. CONCLUSIONS: Microaneurysm counts are important prognostic indicators for worsening of retinopathy, thus microaneurysms are not benign. Treatment with renin-angiotensin system inhibitors is effective in the early stages and may improve mild diabetic retinopathy. Microaneurysm scores may be useful surrogate endpoints in clinical trials.

Exposure to candesartan during the first trimester of pregnancy in type 1 diabetes: experience from the placebo-controlled DIabetic REtinopathy Candesartan Trials.

AIMS/HYPOTHESIS: The teratogenic consequences of angiotensin-converting enzyme inhibitors angiotensin receptor blockers (ARBs) during the second and third trimesters of pregnancy are well described. However, the consequences of exposure during the first trimester are unclear, especially in diabetes. We report the experience from DIRECT (DIabetic REtinopathy and Candesartan Trials), three placebo-controlled studies designed to examine the effects of an ARB, candesartan, on diabetic retinopathy. METHODS: Over 4 years or longer, 178 normotensive women with type 1 diabetes (86 randomised to candesartan, 32 mg once daily, and 92 assigned to placebo) became pregnant (total of 208 pregnancies). RESULTS: More than half of patients were exposed to candesartan or placebo prior to or in early pregnancy, but all discontinued it at an estimated 8 weeks from the last menstrual period. Full-term pregnancies (51 vs 50), premature deliveries (21 vs 27), spontaneous miscarriages (12 vs 15), elective terminations (15 vs 14) and other outcomes (1 vs 2) were similar in the candesartan and placebo groups. There were two stillbirths and two 'sick babies' in the candesartan group, and one stillbirth, eight 'sick babies' and one cardiac malformation in the placebo group. CONCLUSIONS/INTERPRETATION: The risk for fetal consequences of ARBs in type 1 diabetes may not be high if exposure is clearly limited to the first trimester. Long-term studies in fertile women can be conducted with ARBs during pregnancy, provided investigators diligently stop their administration upon planning or detection of pregnancy. TRIAL REGISTRATION: ClinicalTrials.gov DIRECT-Prevent 1 NCT00252733; DIRECT-Protect 1 NCT00252720; DIRECT-Protect 2 NCT00252694. FUNDING: The study was funded jointly by AstraZeneca and Takeda.

Does renin-angiotensin system blockade have a role in preventing diabetic retinopathy? A clinical review.

Diabetes management has increasingly focused on the prevention of macrovascular disease, in particular for type 2 diabetes. Diabetic retinopathy, one of the main microvascular complications of diabetes, is also an important public health problem. Much of the care invested in retinopathy relates to treatment rather than prevention of disease. Tight glycaemic and blood pressure control helps to reduce the risk of retinopathy, but this is not easy to achieve in practice and additional treatments are needed for both primary and secondary prevention of retinopathy. A renin-angiotensin system (RAS) has been identified in the eye and found to be upregulated in retinopathy. This has led to specific interest in the role of RAS blockade in retinopathy prevention. The recent DIRECT programme assessed use of the angiotensin receptor blocker (ARB) candesartan in type 1 and type 2 diabetes. Although the primary trial end-points were not met, there was a clear trend to less severe retinopathy with RAS blockade. A smaller trial, RASS, reported reduced retinopathy progression in type 1 diabetes from RAS blockade with both the ARB losartan and the angiotensin converting enzyme (ACE) inhibitor enalapril. The clinical implications of these new data are discussed.

Prevalence and 25 year incidence of proliferative retinopathy among Danish type 1 diabetic patients.

AIMS/HYPOTHESIS: This study aimed to evaluate the prevalence of retinopathy in long-surviving type 1 diabetic patients. It also investigated the 25 year incidence of proliferative retinopathy and associated risk factors in a Danish population-based cohort. METHODS: A population-based cohort of 727 type 1 diabetic patients from Fyn County, Denmark, was identified in 1973. In 1981-1982, baseline retinopathy was graded and other risk factors were assessed in 573 patients. Twenty-five years later, 308 patients were still alive. Of these, 201 (65.3%) were re-examined at follow-up in 2007-2008. RESULTS: The median age and duration of diabetes at follow-up were 58.8 and 43 years, respectively. At follow-up, the prevalence of diabetic retinopathy was 97.0%. Non-proliferative retinopathy was found in 45.8%, and 51.2% had proliferative retinopathy. The 25 year incidence of proliferative retinopathy was 42.9% among patients at risk. In a multivariate analysis, baseline HbA(1) (OR 2.14 per 1% increase, 95% CI 1.06-4.31) and non-proliferative retinopathy (OR 4.61, 95% CI 1.94-11.0) were the only risk factors for incident proliferative retinopathy. The long-term incidence of proliferative retinopathy was not associated with baseline duration of diabetes, proteinuria, smoking, body mass index, maculopathy or systolic or diastolic blood pressure. CONCLUSIONS/INTERPRETATION: Retinopathy among long-surviving type 1 diabetic patients is almost universal. Proliferative retinopathy was found in half of these patients. In addition, the 25 year incidence of proliferative retinopathy was high. Baseline glycaemic regulation and non-proliferative retinopathy were identified as risk factors for incident proliferative retinopathy.

Retinal vessel calibre and micro- and macrovascular complications in type 1 diabetes.

AIMS/HYPOTHESIS: The purpose of the study was to evaluate the association between retinal vascular calibre and micro- and macrovascular complications in a population-based cohort of Danish type 1 diabetic patients. METHODS: This was a cross-sectional study of 208 long-surviving type 1 diabetic patients from a population-based Danish cohort. Retinal photographs were obtained at a clinical examination attended by each participant in 2007-2008, and retinal vascular calibre was measured and summarised as the central retinal artery or vein equivalent (CRAE or CRVE) using a computer-based program and a standardised protocol. Associations between retinal vascular calibre and micro- and macrovascular complications were examined after adjusting for confounding clinical characteristics. RESULTS: Retinal photographs were gradable for 188 of 208 patients (90.3%). The median age and duration of diabetes for patients with gradable photos were 57.9 and 42 years, respectively. After multivariate adjustments, individuals with narrower retinal arterioles were more likely to have nephropathy (OR 2.17, 95% CI 1.29-3.68, per SD decrease in CRAE) and macrovascular disease (OR 3.17, 95% CI 1.59-6.34, per SD decrease in CRAE), but not neuropathy (OR 1.10, 95% CI 0.70-1.71, per SD decrease in CRAE). Retinal venular calibre was not associated with any micro- or macrovascular complications. CONCLUSIONS/INTERPRETATION: In type 1 diabetic patients, retinal arteriolar narrowing is associated with nephropathy and macrovascular disease independently of other clinical characteristics. If supported by further prospective studies, measurement of retinal vessel diameter may allow a non-invasive evaluation of the risk of diabetes-related complications.

Proliferative retinopathy and proteinuria predict mortality rate in type 1 diabetic patients from Fyn County, Denmark.

AIMS/HYPOTHESIS: We evaluated the effect of diabetic retinopathy on 25 year survival rate among a population-based cohort of type 1 diabetic patients from Fyn County, Denmark. METHODS: In 1973 all diabetic patients from Fyn County, Denmark with onset before the age of 30 years as of 1 July 1973 were identified (n=727). In 1981, only 627 patients were still alive and resident in Denmark. Of these, 573 (91%) participated in a clinical baseline examination, in which diabetic retinopathy was graded and other markers of diabetes measured. Mortality rate was examined in a 25 year follow-up and related to the baseline examination. RESULTS: Of the 573 patients examined at baseline in 1981 and 1982, 297 (51.8%) were still alive in November 2006. Of the others, 256 (44.7%) had died, three (0.5%) had left Denmark and 17 (3%) were of unknown status. Age- and sex-adjusted HRs of mortality rate were 1.01 (95% CI 0.72-1.42) and 2.04 (1.43-2.91) for patients with non-proliferative and proliferative retinopathy respectively at baseline compared with patients with no retinopathy. After adjusting for proteinuria, HR among patients with proliferative retinopathy lost statistical significance, but still remained 1.48 (95% CI 0.98-2.23). The 10 year survival rate of patients who had proliferative retinopathy as well as proteinuria at baseline was 22.2% and significantly lower (p<0.001) than in patients with proteinuria only (70.3%), proliferative retinopathy only (79.0%) or neither (86.6%). CONCLUSIONS/INTERPRETATION: Proliferative retinopathy and proteinuria predict mortality rate in a population-based cohort of type 1 diabetic patients. In combination they act even more strongly. Non-proliferative diabetic retinopathy did not affect survival rate.

The contribution of microsaccades and drifts in the maintenance of binocular steady fixation.

BACKGROUND: The eye performs three types of eye movements during fixation: fast microsaccades are interrupted by slow drift movements, and tremor is superimposed on the drifts. The contribution of the microsaccades and drifts in maintaining fixation has been discussed since the late 1950s. Initially, microsaccades were thought to correct the misalignment from the optimal fixation locus induced by the drift movements, a theory still postulated in more recent work. The present study aimed to uncover to what extent each fixation movement contributes to maintain steady binocular fixation. METHOD: Binocular fixation during a 40-s fixation task was recorded using an infrared recording technique for ten normal test persons. Start and end point of each microsaccade and drift were superimposed on a fixation map, and the distance to the preferred retinal location of fixation (PRL) was measured. RESULTS: It was found that 32.6% of the microsaccades corrected the previous drift movement towards the PRL, whereas 53.1% of the drifts corrected the endpoint of the previous microsaccade towards the PRL. The overall mean post-microsaccadic and mean post-drift distance to the PRL for the ten normal test persons were 0.46 degrees and 0.41 degrees , respectively; the difference was not statistically significant. Interindividually, the mean post-microsaccadic distance to the PRL ranged between 0.21 degrees and 0.91 degrees and the mean post-drift distance to the PRL ranged between 0.20 degrees and 0.72 degrees . CONCLUSION: Neither the endpoints of the microsaccades nor the drifts bring the visual line to coincide with the centre of the PRL. Consequently, it must be the eye movements performed during the drifts ("slow control") that keep the visual line in the centre of the foveola.

Fixation topography in normal test persons.

BACKGROUND: The eye is moved so that the object of interest falls on the central fovea, where the spatial resolution is highest. In the present study we quantified eye movements of normal test persons during steady fixation and characterized the fixation using a 3D fixation plot (X horizontal eye position, Y vertical eye position, Z time in each eye position). METHOD: Fixation eye movements were quantified binocularly in ten normal test persons during a 40-s fixation task using an infrared recording technique. RESULTS: The fixation plot was characterized by a single preferred fixation locus in 17 eyes. One eye had two distinctly separated preferred fixation locations and in two eyes the configuration of fixation plot was flat with no single identifiable locus of fixation. The fixation plots were elliptical along the horizontal meridian in 9 eyes, elliptical along the vertical meridian in 8 eyes, and round in 3 eyes. The fixation area (RAF95) ranged between 1418 and 14182 arcmin(2), and a significant positive correlation was found between RAF95 and the mean microsaccadic amplitude (p<0.001). CONCLUSION: The fixation plots are often characterized by a single preferred fixation locus but may also be almost flat with no identifiable location of fixation. The individual fixations patterns resembles the cone density contour plots as found in histological studies, and it may be speculated, that the shape of the fixation plot is determined by the cone density topography.

Binocular fixation topography in patients with diabetic macular oedema: possible implications for photocoagulation therapy (3rd revision).

BACKGROUND: During retinal photocoagulation for diabetic maculopathy, there is a potential risk of foveal burns, and laser scars may later enlarge to be sight-threatening when involving retinal areas previously used during fixation. Since the retinal area used during binocular steady fixation has been found to vary considerably in the normal test person and central fixation may be even further compromised in patients with diabetic maculopathy, the sight-threatening side effects could possibly be reduced by taking into account the fixation area individually. However, no study has described and quantified the retinal area of fixation binocularly in patients with clinically significant macular oedema (CSME). METHODS: Sixteen diabetic patients with CSME in one or both eyes were examined. Each examination included visual acuity testing (ETDRS charts), a standard eye examination, central retinal thickness assessment by optical coherent tomography, fluorescein angiography and binocular quantification of fixational eye movements using an infrared recording technique. RESULTS: A negative correlation was found between visual acuity and mean microsaccadic amplitude (R=0.48, p=0.009). The maximal retinal extension of the fixation area ranged between 1.0 degrees and 3.0 degrees , and in two eyes with CSME, this area was estimated to exceed 800 mum on the retinal plane. No correlation was found between retinal thickness and visual acuity, retinal area of fixation, maximal extension of the fixation area or mean microsaccadic amplitude. CONCLUSION: Large interindividual differences in quantitative measures of binocular fixational eye movements were found. The mean amplitude of fixational eye movements was not correlated to central retinal thickness, and fixation area could only partly be predicted by visual acuity. Two eyes with CSME had an estimated maximal extension of the fixation area exceeding the central 800 mum on the retinal plane; thus, the possible benefit of individualising central photocoagulation according to precise measures of fixation area needs to be investigated on a larger population.

Medical management of diabetic retinopathy.

Although current treatment and prevention of diabetic retinopathy with laser photocoagulation, and tight metabolic and blood pressure control has reduced the risk of visual loss, there is still a need for additional therapies. A literature review on medical therapies for diabetic retinopathy has been performed, and the following classes of drugs are discussed: blockers of the renin-angiotensin system, protein kinase C-beta inhibitors, glitazones, somatostatin analogues, lipid-lowering drugs and anti-inflammatory drugs. There is experimental and clinical data suggesting beneficial effect from several classes of drugs on diabetic retinopathy, and results from large clinical trials are awaited within the next 3-4 years.

Binocular quantification and characterization of microsaccades.

BACKGROUND: The significance of microsaccades in the visual process has been discussed for more than 50 years. However, only a few studies have measured microsaccades binocularly, and detailed quantification and characterization of these small movements are needed in order to further understand their nature. METHOD: The amplitude, velocity, acceleration and direction of microsaccades were quantified binocularly in 10 normal test persons during a 40-s fixation task, using an infrared recording technique. RESULTS: All microsaccades for all test persons were performed simultaneously and individually with an almost identical amplitude in the right and left eye (a range of 0.003-0.042 deg between right and left eye mean values). The mean microsaccadic amplitude for the test persons was within a range of 0.223-1.079 deg. The directional difference between simultaneously-performed right and left eye microsaccades was less than 22.5 deg for 84.8% of the saccades, indicating that the majority of microsaccades are conjugated. Three different fixation patterns were identified and characterized: (1) a classic interplay between easily identified drifts and medium-sized microsaccades (mean amplitude range 0.328-0.413 deg); (2) long intersaccadic intervals (4-5 s) with almost absent drifts, followed by three or four large microsaccades (mean amplitude range 0.755-1.079 deg); and (3) low-amplitude drift movements interrupted by low-amplitude microsaccades (mean amplitude range 0.231-0.265 deg). CONCLUSION: Microsaccades are involuntary, predominantly conjugated, simultaneously performed, and of almost identical amplitude in the right and left eye, suggesting a central control mechanism for microsaccades at subcortical level.

The retinal renin-angiotensin system: implications for therapy in diabetic retinopathy.

Retinopathy is the most common complication of diabetes, and a leading cause of blindness in people of working age. Optimal blood pressure and metabolic control can reduce the risk of diabetic retinopathy, but are difficult to achieve in clinical practice. In the EUCLID Study, the angiotensin converting enzyme (ACE) inhibitor lisinopril reduced the risk of progression of retinopathy by approximately 50%, and also significantly reduced the risk of progression to proliferative retinopathy. These findings are consistent with extensive evidence that the renin-angiotensin system is expressed in the eye, and that adverse effects of angiotensin II on retinal angiogenesis and function can be inhibited by ACE inhibitors or angiotensin II-receptor blockers. However, in the EUCLID Study retinopathy was not a primary end-point and the study was not sufficiently powered for the eye-related outcomes. Hence, the Diabetic Retinopathy Candesartan Trials (DIRECT) programme has been established to determine whether AT(1)-receptor blockade with candesartan can prevent the incidence and progression of diabetic retinopathy. This programme comprises three studies, involving a total of 4500 patients recruited from about 300 centres worldwide. The patients are normotensive or treated hypertensive individuals, and so the DIRECT programme should assess the potential of an AT(1)-receptor blocker to protect against the pathological changes in the eye following diabetes.

The importance of genes and environment for ocular refraction and its determiners: a population based study among 20-45 year old twins.

AIMS: To estimate the heritability for ocular refraction and its determiners in a population based cohort of 20-45 years old twins. METHODS: 114 twin pairs (53 monozygotic and 61 dizygotic) participated. Refraction was determined in cycloplegia and eye dimensions were measured with ultrasound. Educational length was assessed. The heritability was estimated employing aetiological model fitting. Evidence of gene-environment interaction was analysed. Correlations between intrapairwise differences in educational length and in refraction were evaluated. RESULTS: The heritability was between 0.89 and 0.94 (95% CI: 0.82, 0.96) for refraction, total refraction, axial length, and radius of corneal curvature. Phenotypic variation was mostly due to additive genetic effects. Refraction revealed evidence of gene-environment interaction (r = -0.29 to -0.32; p <0.05). The heritability for anterior chamber depth and lens thickness was between 0.88 and 0.94 (95% CI: 0.81, 0.96) and dominant genetic effects were the most likely explanation. There was no correlation between age and intrapairwise differences in refraction. The dizygotic twins had significant larger intrapairwise differences in educational length (p <0.05), but the differences were not correlated with differences in refraction. CONCLUSIONS: The results indicate a high heritability for ocular refraction and its determiners and thus suggest that environmental impact on refraction is not significant. However, the epidemiological association between educational length (near work) and myopia, the evidence of increasing myopia prevalence within a few generations, and the theory of gene-environment interaction imply that some individuals might be genetically liable to develop myopia if exposed to certain environmental factors.

Is one 60 degrees fundus photograph sufficient for screening of proliferative diabetic retinopathy?

OBJECTIVE: To compare one 60 degrees fundus photograph to seven field stereo fundus photographs in identifying proliferative diabetic retinopathy. RESEARCH DESIGN AND METHODS: A total of 44 eyes in 23 patients with moderate/severe nonproliferative diabetic retinopathy were included. Evaluation of each eye was based on one 60 degrees fundus photograph. Eyes were re-examined using seven field 30 degrees stereo fundus photographs according to the protocol of the Early Treatment Diabetic Retinopathy Study, and the photographs were examined independently by three ophthalmologists to identify retinal neovascular lesions. In addition, fluorescein angiography was performed in all patients to verify the presence of the lesions. RESULTS: In four eyes of three patients (11.1% of eyes) evaluated based on seven field stereo photographs, retinal neovascularization was found. This condition was not found on examination of 60 degrees fundus photographs. CONCLUSIONS: Examination of one 60 degrees fundus photograph was found to be insufficient as a screening procedure in patients with moderate/severe nonproliferative diabetic retinopathy.

Metabolic control and prevalence of microvascular complications in young Danish patients with Type 1 diabetes mellitus. Danish Study Group of Diabetes in Childhood.

AIMS: After Danish nationwide investigations (1987, 1989) demonstrated unacceptable blood glucose control in unselected young diabetic patients, we set out to estimate the present glycaemic control and the prevalence of microvascular complications in a cohort of children and adolescents participating in the two previous studies. METHODS: This follow-up represents 339 patients (47% of the inception cohort), median age 21.1 years (range 12.0-26.9), median diabetes duration 13.2 years (range 8.9-24.5). A standardized questionnaire, fundus photographs (with central reading) and a physical examination were performed. HbA1c and overnight albumin excretion rate (AER) were analysed centrally. RESULTS: Although 88% (n= 309) of the young persons were treated with three or more daily insulin injections, HbA1c (nondiabetic range 4.3-5.8, mean 5.3%) was 9.7+/-1.7% (mean+/-SD). Males had higher HbA1c values than females (P < 0.015). Mean daily insulin dose was 0.92+/-0.25 IU.kg(-1).24h(-1). Microalbuminuria (AER > 20-150 microg/min) and macroalbuminuria (AER > 150 microg/min) were found in 9.0% and 3.7% of the patients, respectively, and was associated with increased diastolic blood pressure (P<0.01) and presence of retinopathy (P<0.01). Retinopathy was present in approximately 60% of the patients and was associated with age, diabetes duration, HbA1c, diastolic blood pressure and AER (all P<0.01). Subclinical neuropathy (vibration perception threshold by biothesiometry > 6.5 V) was found in 62% and showed a significant association with age, linear height, diastolic blood pressure (all P < 0.01) and diabetic retinopathy (P = 0.01). CONCLUSIONS: In spite of the majority of the patients being on multiple insulin injections, only 11% had HbA1c values below 8% and the prevalence of diabetic microvascular complications in kidneys, eyes and nerves was unacceptable high.

[Effect of lisinopril on progression of retinopathy and microalbuminuria in normotensive subjects with insulin-dependent diabetes mellitus]. / Effekt af lisinopril på progression af retinopati og mikroalbuminuri hos normotensive personer med insulinafhaengig diabetes mellitus. The EUCLID Study Group.

Effect of lisinopril on progression of retinopathy and microalbuminuria in normotensive subjects with insulin-dependent diabetes mellitus. Retinopathy and nephropathy are the most important microvascular complications in diabetes with hyperglycaemia and hypertension as important risk factors. Antihypertensive treatment with angiotensin-converting enzyme inhibitors has been shown to delay progression of nephropathy, but the effect on retinopathy has not been established. We, therefore, performed a trial of the effect of the ACE-inhibitor lisinopril on retinopathy and nephropathy in normotensive patients with IDDM. We performed a two year randomized double-blind placebo-controlled trial of the ACE-inhibitor lisinopril on 530 normotensive IDDM patients within the age group 20-59 years from 18 European centres. Patients were either normo- or microalbuminuric. Retinopathy was classified from retinal photographs into five levels (none to proliferative). The primary endpoint of the trial was progression of albuminuria. Mean albumin excretion rate (AER) was 8.0 micrograms/min at baseline in both treatment groups. After two years AER was 2.2. micrograms/min lower in the lisinopril than in the placebo group, a difference of 18.8% (p = 0.03). The difference in AER was 38.5 micrograms/min between treatment groups in patients with microalbuminuria at baseline (p = 0.001), and 0.23 microgram/min in patients with normoalbuminuria at baseline (p = 0.6). Retinopathy was a secondary endpoint. Patients treated with lisinopril had significantly lower Hb-A1c at baseline than the placebo group (6.9%-7.3%). Retinopathy progressed with at least one level in 13.2% of lisinopril treated and 23.4% of placebo treated patients (odds ratio 0.50, p = 0.02). Progression by two levels or progression to proliferative retinopathy were also significantly reduced in the lisinopril group compared to the placebo group (odds ratio 0.27 and 0.18, respectively). In conclusion, lisinopril delays progression of retinopathy and nephropathy in normotensive IDDM patients with micro- or normoalbuminuria.

Pneumatic retinopexy. A long term follow-up study.

PURPOSE: We have analysed the results of 48 consecutive cases of rhegmatogenous retinal detachment treated with pneumatic retinopexy in a long term follow-up study. RESULTS: Thirty six of the original 48 patients were available to follow-up. We had an average follow-up period of 8.1 years and a 75% 7 year follow-up. Single operation success was achieved in 83% of patients. Redetachment occurred in 3 patients at 11, 30 and 33 months. Complications found included new breaks in 14%,, cystoid macular oedema in 8%,, and proliferative vitreoretinopathy in 3% of patients. No previously unreported complications were found in spite of the long follow-up time. Final anatomic success (after 1 or more operations) at 6 months post operatively was found in 97% of patients. At follow-up we found final anatomic success in all patients. CONCLUSION: The use of pneumatic retinopexy instead of scleral buckling is discussed. We recommend the consideration of pneumatic retinopexy in uncomplicated selected cases of rhegmatogenous retinal detachment.

[Insulin-dependent diabetes in the county of Funen 1970-2020. An epidemiological description]. / Insulinkraevende diabetes i Fyns Amt 1970-2020. En epidemiologisk beskrivelse.

We present an epidemiological model applicable to insulin-dependent diabetes mellitus (IDDM), based on which prevalence rates are estimated from assumed rates of incidence and mortality of diabetes. The model is illustrated by analysing epidemiological data on IDDM in Fyn County, Denmark for the period 1970-1990, with predictions of prevalence rates during 1990-2020. The epidemiological model assumes known prevalence rates as well as incidence rates and mortality at a given point of time. Under assumed rates of incidence and mortality of IDDM and its complications, the prevalence rate is the dependent variable which is estimated as a function of calendar time. We used epidemiological data on IDDM (operationally defined as insulin-treated diabetes with onset before age 30 years), blindness and nephropathy as well as mortality as reported for the years 1973 and 1987 in Fyn County, Denmark. During 1970-1990 the prevalence of IDDM increased steadily, due to increasing incidence and decreasing risk of complications and mortality. The relative prevalence of patients with nephropathy increased whereas that of blind patients decreased considerably. Under specified assumptions regarding the future levels of incidence of disease, complications and of mortality, it is estimated that the prevalence rate of IDDM in the year 2020 will be 45-60% higher than the level in 1990. The relative prevalence of patients with nephropathy will increase further, whereas the relative prevalence of blind patients will remain constant at a low level. We conclude that IDDM will represent an increasing public health problem in Denmark over the next decades, with increasing overall prevalence rates and a rising proportion of patients with nephropathy. The major determinants of this trend are increasing incidence, combined with declining mortality and declining risk of complications. It is recommended that epidemiological modelling techniques be further developed to provide improved data for the planning of the future diabetes care.

Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus.

BACKGROUND: Retinopathy commonly occurs in people with type 1 diabetes. Strict glycaemic control can decrease development and progression of retinopathy only partially. Blood pressure is also a risk factor for microvascular complications. Antihypertensive therapy, especially with inhibitors of angiotensin-converting enzyme (ACE), can slow progression of nephropathy, but the effects on retinopathy have not been established. We investigated the effect of lisinopril on retinopathy in type 1 diabetes. METHODS: As part of a 2-year randomised double-blind placebo-controlled trial, we took retinal photographs at baseline and follow-up (24 months) in patients aged 20-59 in 15 European centres. Patients were not hypertensive, and were normoalbuminuric (85%) or microalbuminuric. Retinopathy was classified from photographs on a five-level scale (none to proliferative). FINDINGS: The proportion of patients with retinopathy at baseline was 65% (117) in the placebo group and 59% (103) in the lisinopril group (p = 0.2). Patients on lisinopril had significantly lower HbA1c at baseline than those on placebo (6.9% vs 7.3 p = 0.05). Retinopathy progressed by at least one level in 21 (13.2%) of 159 patients on lisinopril and 39 (23.4%) of 166 patients on placebo (odds ratio 0.50 [95% CI 0.28-0.89], p = 0.02). This 50% reduction was the same when adjusted for centre and glycaemic control (0.55 [0.30-1.03], p = 0.06). Lisinopril also decreased progression by two or more grades (0.27 [0.07-1.00], p = 0.05), and progression to proliferative retinopathy (0.18 [0.04-0.82], p = 0.03). Progression was not associated with albuminuric status at baseline. Treatment reduced retinopathy incidence (0.69 [0.30-1.59], p = 0.4). INTERPRETATION: Lisinopril may decrease retinopathy progression in non-hypertensive patients who have type 1 diabetes with little or no nephropathy. These findings need to be confirmed before changes to clinical practice can be advocated.