Impact of changes in metabolic control on progression to photocoagulation for clinically significant macular oedema: a 20 year study of type 1 diabetes.

AIMS/HYPOTHESIS: Although increasing hyperglycaemia, arterial hypertension and longer duration of diabetes raise the risk of progression of diabetic retinopathy, short-term benefits in terms of improved metabolic control and lowered blood pressure have not been demonstrated. We therefore examined the effect of changes in glycaemia and arterial blood pressure on the incidence of clinically significant macular oedema in a population of diabetic patients. METHODS: We performed a retrospective review of all patients with type 1 diabetes who attended the retinopathy screening clinic at the Steno Diabetes Center from 1988 to 2008, using the endpoint referral to first photocoagulation treatment for clinically significant diabetic macular oedema. The analysis included 1,878 patients (median observation, 8 years). Changes were defined as the inter-visit change; in the case of an event the last event-free interval before referral, where the median screening interval was 6 months. RESULTS: Risk of progression to photocoagulation for macular oedema increased with duration of diabetes (p < 0.001), current HbA1c (p < 0.0001) and with the magnitude of changes in HbA1c (p = 0.0002) and systolic blood pressure (p < 0.0001) in a multiple regression model. A recent decrease of ≥ 0.5 percentage points or an increase in HbA1c of >0.5 percentage points per 6 months was associated with HRs of 3.04 and 1.28, respectively, compared with lesser changes in HbA1c. CONCLUSIONS/INTERPRETATION: In this study, large recent changes in metabolic control and systolic blood pressure, irrespective of direction, were independent risk factors for progression to photocoagulation for diabetic macular oedema. The effects of metabolic and haemodynamic stability on diabetic retinopathy should be examined in prospective studies.

Cumulative glycaemia as measured by lens fluorometry: association with retinopathy in type 2 diabetes.

AIMS/HYPOTHESIS: The aim of this study was to assess the association between lifelong cumulative glycaemia estimated by lens fluorometry and the presence of retinopathy in individuals with type 2 diabetes. METHODS: We carried out a cross-sectional population-based study of 970 participants aged between 30 and 60 years, of which 170 were diagnosed with diabetes on screening (WHO 1999 criteria) and 35 had known type 2 diabetes. Procedures included clinical and laboratory examinations, non-invasive assessment of the intrinsic fluorescence of the lens of the eye, and seven-field fundus photography. RESULTS: Retinopathy was found in 46 (22%) of 205 participants with type 2 diabetes. In a logistic regression analysis controlling for age, sex and diabetes status (screen-detected or known), a two-fold increase in lens fluorescence increased the odds for retinopathy by 3.46 (95% CI 1.25-9.55, p = 0.017). The association was marginally significant (OR 3.00 [95% CI 1.00-9.01], p = 0.050) when also adjusted for smoking, systolic blood pressure, body mass index and HbA(1c). CONCLUSIONS/INTERPRETATION: Diabetic retinopathy was related to cumulative lifelong glycaemia as estimated by lens fluorometry in participants with type 2 diabetes. This supports the hypothesis that retinopathy is a marker of lifelong elevated glycaemia as well as of the unknown, pre-diagnostic duration of type 2 diabetes. The powerful association between lens fluorescence and retinopathy underscores the importance of strict long-term glycaemic control in the prevention of retinopathy in people with diabetes.

Improved visual function in IDDM patients with unchanged cumulative incidence of sight-threatening diabetic retinopathy.

OBJECTIVE: To evaluate trends in visual acuity and the cumulative incidence of diabetic retinopathy in a clinic-based observational follow-up study. RESEARCH DESIGN AND METHODS: All patients visiting Hvidore Hospital in 1984 whose diagnosis of IDDM had been made before 41 years of age and between 1965 and 1979 (n = 356) were followed until 1994 or until their deaths. All patients were Caucasians and resided in Copenhagen. Patients were divided into three prevalence cohorts based on time of diabetes onset: group A, 1965-1969 (n = 113); group B, 1970-1974 (n = 130); and group C, 1975-1979 (n = 113). RESULTS: Fifteen years after diabetes onset, the visual acuity was significantly improved in patients with increasing calendar year of the disease onset. The median (interquartile range) visual acuity was 1.0 (0.8-1.0), 1.0(0.9-1.0), and 1.0 (1.0-1.0) in groups A, B, and C, respectively (P < 0.01 overall; P = 0.28 for group A vs. group B; and P < 0.01 for group A vs. group C) with 60, 66, and 93 having a visual acuity of 1.0 in groups A, B, and C, respectively. The cumulative incidence (+/-SEM), expressed as a percentage and calculated according to the life-table method, of proliferative retinopathy, maculopathy, and laser-treated retinopathy 15 years after onset of diabetes were, respectively, 13+/-3, 11+/-3, and 12+/-3 in group A; 16+/-3, 12+/-3, and 21+/-4 in group B; 11+/-3, 5+/-2, and 12+/-3 in group C, respectively (NS). The development of proliferative retinopathy was associated with the degree of retinopathy and albuminuria at baseline and the mean HbA1c during follow-up. CONCLUSIONS: The study revealed an improvement in visual acuity with increasing calendar year of diabetes onset but an unchanged cumulative incidence of diabetic retinopathy.

Vitreous fluorophotometry: mathematical analysis of the effect of peripheral leakage on axial scans.

Current instrumentation in vitreous fluorophotometry allows the determination of a fluorescein concentration profile along the optical axis of the eye. Based on an assumption of a uniform blood-retinal barrier permeability, several methods have been used for the determination of the permeability from an axial scan. The assumption of a uniform permeability is not realistic and it has been unknown to what extent the calculated common permeability reflects the local permeability in different areas of the retina. Using a mathematical model for a nonuniform permeability, we have investigated the effect of localized leakage on the axial concentrations and thereby on the calculated common permeability under the assumption of free diffusion in the vitreous body. It turns out that leakage outside the large temporal vessels has to be extremely strong to have a noticeable impact on 60 min axial scans. A 100-fold increase of the permeability in the region more than 30 degrees (central angle) from the optical center of the eye leads to just a 2-fold increase of the apparent common permeability. Thus, axial vitreous fluorophotometry almost exclusively measures the condition of the retina in the vicinity of the optical center.

Diabetic macular edema: passive and active transport of fluorescein through the blood-retina barrier.

PURPOSE: To investigate the passive bidirectional and active outward transport of fluorescein through the blood-retina barrier (BRB) in diabetic patients with clinically significant macular edema and in healthy controls. METHODS: The passive and active transport of fluorescein through the BRB was quantitated by vitreous fluorometry. A previously developed method was used to model passive transport. A new simulation model was developed and evaluated for estimation of active transport. The study included 10 eyes of 5 healthy controls and 31 eyes of 20 diabetic patients with clinically significant diabetic macular edema (CSME) in at least one eye, totalling 25 eyes with CSME. RESULTS: Passive permeability of fluorescein was increased by a factor of 12 in eyes with edema compared to healthy controls (edema, 23.7 nm/sec; healthy subjects, 1.9 nm/sec, P < 0.01), whereas the active transport was doubled (edema, 84.1 nm/sec; healthy subjects, 43.5 nm/sec, P < 0.01). Unlike active transport, passive permeability was related to the degree of retinopathy, in that eyes with severe non-proliferative diabetic retinopathy had a passive permeability that was significantly increased compared to moderate retinopathy (32.1 nm/sec and 14.6 nm/sec, respectively, P: < 0.05). The passive movement quantitated with vitreous fluorometry was larger for diffuse and mixed leakage compared to focal (P = 0.07). CONCLUSIONS: Insofar as the movement of fluorescein can be taken as a probe for the movement of electrolytes and water, the pathogenesis of diabetic macular edema seems to involve a disruption of the BRB, presumably its inner component. The active resorptive functions of the blood-retina barrier appear to be compensatorily increased to counteract edema formation, although the increase is too small to prevent edema in the face of severe leakage through the blood-retina barrier.

Effects of acetazolamide on passive and active transport of fluorescein across the normal BRB.

PURPOSE: To investigate the effect of the carbonic anhydrase inhibitor acetazolamide (AZM) on passive permeability and active transport of fluorescein across the blood-retina barrier in healthy subjects. The study may have implications for the understanding of the edema-reducing effect of AZM. METHODS: The effect of AZM on the blood-retina barrier function was assessed by differential vitreous spectrofluorometry using fluorescein as a tracer. The study included fourteen healthy subjects in a randomized double-masked crossover trial with 3 days' treatment with AZM (500 mg/d) and placebo, respectively. The two examinations were separated by at least 1 week. Fluorescein concentration was determined separately from its metabolite fluorescein glucuronide. The passive permeability of fluorescein was determined by computerized modeling and curve-fitting to the preretinal curve and the plasma concentration curve obtained at 30 to 60 minutes after the injection of fluorescein. The unidirectional permeability due to outward active transport from vitreous to blood was estimated from the preretinal gradient and the plasma concentration at 7 to 10 hours after injection. RESULTS: Treatment with AZM was associated with significant increases in passive permeability and unidirectional permeability of fluorescein. For the passive permeability the increase was on average 0.3+/-0.4 nm/s (mean+/-SD; range, -0.8-1.0 nm/s), and for the unidirectional permeability the increase was on average 7.4 nm/s+/-7.0 (mean+/-SD; range, -3.3-19.0 nm/s). CONCLUSIONS: Acetazolamide caused an increase in passive permeability. Unidirectional permeability was increased by AZM, indicating a stimulation of the outward active transport of fluorescein. It has been proposed that the edema-reducing effect of AZM is due to stimulated ion and fluid removal from the retina to the choroid. The results of this study are consistent with AZM affecting the blood-retina barrier with stimulation of at least one ion transport mechanism.

Quantitative vitreous fluorophotometry applying a mathematical model of the eye.

A slit-lamp fluorophotometric method is presented that permits calculation of a blood-retinal barrier permeability to fluorescein (P) and a diffusion coefficient for fluorescein in the vitreous body (D). The calculations are performed by relating the time course of the free--not protein bound--fluorescein concentration in the bloodstream with the fluorescein concentration profile in the vitreous body. The combination is performed automatically on a computer by applying a simplified mathematical model of the eye. P refers to the area of the barrier of the model eye. In a group of six normal persons, the mean P was (1.1 +/- 0.4) X 10(-7) cm/sec (mean +/- SD), while in six diabetic patients with background retinopathy and macular edema the mean P was (7.1 +/- 3.8 ) X 10(-7) cm/sec. The mean D was (7.4 +/- 3.4) X 10(-6) cm2/sec in the normal group and (9.6 +/- 2.0) X 10(-6) cm2/sec in diabetic patients, corresponding as a first approximation to free diffusion in water. Model calculations show that knowing the fluorescein concentration in the bloodstream is considerably significant for the calculation of the permeability, contributing factors up to 50%. For the low-permeation situation, subtraction of the preinjection scan contributes a factor of 50% for both permeability and diffusion coefficient. The exact placement in the vitreous body of the concentration profile, by applying a formalism that transforms slit-lamp movement to intraocular distance, contributes a factor of 20% on the diffusion coefficient. The permeability obtained with the model can be calculated as the ratio between area of vitreous and plasma fluorescein concentration curves within 20%. Active transport of fluorescein across the blood-retinal barrier in the direction of vitreous to blood does not seem to be significant within the first 2 hr after fluorescein injection.

Lens fluorescence in relation to metabolic control of insulin-dependent diabetes mellitus.

The correlation of blue-green lens fluorescence to the metabolic control of insulin-dependent diabetes mellitus was studied in 36 patients in whom the level of glycosylated hemoglobin A1c (HbA1c) had been followed from the onset of diabetes. Good metabolic control (22 patients, all with mean HbA1c levels, less than 7.0% and, thus, low blood glucose concentrations) was associated with less lens fluorescence and a higher lens transmittance than poor metabolic control (14 patients, all with mean HbA1c levels, greater than 9.7%). It appears that in diabetes, an increase in lens fluorescence and a decrease in lens transmittance are delayed by good metabolic control, and that the determination of lens fluorescence provides information about the long-term control of diabetes.

Cotton-wool spots and retinal light sensitivity in diabetic retinopathy.

In 14 eyes of 14 patients with diabetic retinopathy the light sensitivity of retinal cotton-wool spots was studied by computerised perimetry, and the visual field data were accurately correlated with the corresponding morphology as seen on fundus photographs and fluorescein angiograms. In 12 of the eyes the examinations were repeated within one year in order to follow changes in retinal light sensitivity during the evolution of the lesions. Retinal cotton-wool spots were in all eyes associated with localised non-arcuate scotomata in the visual field. In four eyes the cotton-wool spots disappeared within three months of the first examination, and in two of these cases the corresponding scotomata disappeared together with the morphological lesions. In eight eyes the cotton-wool spots (and the corresponding scotomata) had not resolved one year after the first examination. The mean blood pressure showed no significant difference between the patients in whom the lesions resolved within three months and the patients in whom the lesions persisted longer.

Localised blood-retinal barrier leakage and retinal light sensitivity in diabetic retinopathy.

Twenty patients with insulin dependent diabetes mellitus were selected on the basis of morphological signs of blood-retinal barrier leakage--namely, hard exudates seen on fundus photographs and/or localised leakage of fluorescein seen on fluorescein angiograms. Computerised perimetry was carried out in visual field areas that corresponded to the morphological lesions, and the visual field data were accurately correlated with the morphology as seen on fundus photographs and fluorescein angiograms. In addition, in seven of the patients who represented the range of leakage among the patients studied, the blood-retinal barrier leakage was quantitated by vitreous fluorophotometry. In 16 cases normal light sensitivity was found in retinal areas showing localised leakage as studied on fluorescein angiograms. In four cases with pronounced maculopathy, where scotomata occurred, there was no topographical correlation between the scotomata and barrier leakage. Furthermore hard exudates often, but not consistently, caused localised scotomata when arranged in dense conglomerates. The permeability values correlated with angiographically observed hyperfluorescence in the macular area. On the basis of the techniques employed in the present study it seems that breakdown of the blood-retinal barrier is an earlier event than disturbance of neurosensory function in the development of diabetic retinopathy. However, the findings give no evidence of a causal relationship between barrier leakage and damage to sensory cell function.

Interferon alfa-2a modifies the course of subfoveal and juxtafoveal choroidal neovascularisation.

The first double masked placebo controlled trial of interferon alfa-2a for the treatment of overt choroidal neovascular membranes is presented. A total of 43 consecutive patients were randomised to double masked treatment with either interferon alfa-2a, 3 million IU subcutaneously three times a week or matching placebo, for a period of 8 weeks. End of study changes from baseline in distance and near visual acuity, macular visual field, contrast sensitivity, and macular morphology (fluorescein angiography) were assessed. The between group difference in distance visual acuity, the primary efficacy variable, was significant in favour of interferon alfa-2a (p = 0.023). Fluorescein angiograms, macular visual fields, and near vision all showed a trend in favour of interferon alfa-2a. It was concluded that, at the dosage used in this study, interferon alfa-2a is a reasonably well tolerated and apparently effective short term treatment of subfoveal and juxtafoveal choroidal neovascularisations.

Passive permeability and outward active transport of fluorescein across the blood-retinal barrier in early ARM.

AIM: To study the passive and active transport of fluorescein across the blood-retina barrier in early age related maculopathy (ARM) (soft drusen > 63 microm, hyperpigmentation and/or hypopigmentation in patients above 50 years of age). METHODS: 15 patients and 10 healthy subjects were included. Morphological changes were graded from 30 degrees fundus photographs using a simplified version of the epidemiological ARM study group classification system. Differential vitreous spectrofluorophotometry was used to assess the transport properties of the blood-retina barrier (that is, passive permeability and unidirectional permeability caused by outward active transport from the vitreous to the blood). RESULTS: The passive permeability of the patient group was not significantly different from that of the control group. Four patients with passive permeability more than 3 SD above the mean of the control group (mean 1.8 (SD 0.7) nm/s, range 1.0-3.0 nm/s, data normally distributed) all had centrally located drusen > 500 microm and superjacent pigment clumps of 63-500 microm in diameter. There was no significant difference between the unidirectional permeabilities for the patient group and for the control group (mean 47.4 (29.3) nm/s, range 12.7-91.1 nm/s). CONCLUSION: There was no significant difference in the passive permeability and in the unidirectional permeability of fluorescein. However, the study may indicate that the combination of very large drusen and superjacent pigment clumps in ARM may be associated with a deterioration of the blood-retina barrier.

Diabetic macular oedema: the effect of photocoagulation on fluorescein transport across the blood-retinal barrier.

BACKGROUND/AIM: The visual loss secondary to diabetic macular oedema can be controlled to some extent by photocoagulation, though the mechanism of action is largely unknown. The purpose of the present study was to quantitate the effect of photocoagulation on the blood-retinal barrier using fluorescein as a tracer of passive and active transport. METHODS: A prospective study of 46 eyes in 34 patients with clinically significant macular oedema (CSMO) examined by vitreous fluorometry before and 6 months after macular photocoagulation treatment. RESULTS: In 23 eyes CSMO was not present at follow up (responding eyes), in another 23 other eyes CSMO was still present (non-responding eyes). With reference to the presence or absence of CSMO at follow up, the passive transport (permeability) for responding eyes decreased after photocoagulation in contrast with an increase in non-responding eyes; the difference between the groups at follow up was significant (p=0.03). The active transport for responding eyes decreased slightly at follow up, while it increased for non-responding eyes; the difference between the groups at follow up was not significant (p=0.09). CONCLUSION: Following photocoagulation a reduction of diabetic macular oedema, defined as disappearance of CSMO, is paralleled by a decrease of the passive permeability while the hypothesis of an increase in the active transport from the retina to the blood could not be supported by this study.

Diabetic macular oedema: a comparison of vitreous fluorometry, angiography, and retinopathy.

AIM: To evaluate the relation between the quantitative measurement of vitreous fluorescein with fluorescein angiography and retinopathy in diabetic patients with and without clinically significant macular oedema (CSMO). METHODS: In a prospective cross sectional study, passive permeability and active, outward transport of fluorescein across the blood-retinal barrier were quantitated with vitreous fluorometry in 61 eyes from 48 patients with CSMO and 22 fellow eyes without CSMO, after exclusion of eyes with previous macular laser treatment and vitreous liquification. All patients were recruited from the university hospital's outpatient clinic. Retinopathy and fluorescein angiograms were evaluated on 60 degree photographs. RESULTS: The passive permeability in CSMO was significantly correlated with the severity of leakage on fluorescein angiograms (r=0.73), the level of retinopathy (r=0.61), and visual acuity (r=0.45). Significant differences between eyes with CSMO and eyes without CSMO were found for passive permeability (p<0.001), fluorescein leakage (p<0.001), visual acuity (p=0.02), and retinopathy (p=0.002). CONCLUSION: Passive permeability of fluorescein quantitated with vitreous fluorometry was correlated both with semiquantitative fluorescein angiography and retinopathy, and a significant increase in passive permeability was found when comparing eyes with CSMO to eyes without CSMO. No such pattern was found for the active transport indicating that passive and not the outward, active transport is the factor of most importance in the development of CSMO.

Glycaemic threshold for diabetes-specific retinopathy among individuals from Saudi Arabia, Algeria and Portugal.

We studied the glycaemic threshold and prevalence of diabetic retinopathy in screen-detected diabetes in Saudi Arabia, Algeria and Portugal. The prevalence of diabetes-specific retinopathy started to increase at an HbA1c level of 6-6.4% (42-47 mmol/mol) and in individuals with HbA(1c) >7.0% the prevalence was 6.0%.

Diabetic macular oedema: a clinical overview.

Diabetic retinopathy is the leading cause of blindness in working aged-adults in westernised countries. Diabetic macular oedema (DMO) is a manifestation of diabetic retinopathy and is the leading cause of the visual impairment that occurs with diabetic retinopathy. There are multiple ways of classifying DMO; however, none appear to be wholly satisfactory. DMO occurs more frequently in type 2 diabetes mellitus, and appears to be more prevalent as the duration of diabetes increases, and as the severity of diabetic retinopathy worsens. There are multiple risk factors in common with diabetic retinopathy, such as hyperglycaemia, hypertension and dyslipidaemia; however, specific factors such as the presence of renal disease appear to be more significantly associated with DMO. Whereas the gold standard for diagnosis of DMO is via clinical examination, there is considerable variability involved, and hence, this has led to the advent of more objective methods of quantifying the degree of retinal thickness, such as optical coherence tomography. Laser photocoagulation appears to be the only universally acceptable treatment of choice to date; however, this is a destructive therapy, and its side effects coupled with the suboptimal efficacy has led to the advent of potential new therapies which will undoubtedly compliment the existing approaches, in the future management of a patient with DMO.

Endothelial dysfunction and low-grade inflammation and the progression of retinopathy in Type 2 diabetes.

AIMS: To study whether microalbuminuria, endothelial dysfunction and low-grade inflammation are associated with the presence and progression of diabetic retinopathy. METHODS: Patients with Type 2 diabetes (n = 328) attending a diabetes clinic were followed for 10 years and examined annually during the last 7 years. Retinopathy was assessed after pupillary dilatation by direct ophthalmoscopy (baseline) and two-field 60 degrees fundus photography (follow-up). Urinary albumin excretion, and markers of endothelial function (von Willebrand factor, tissue-type plasminogen activator, soluble E-selectin (sE-selectin), and soluble vascular cell adhesion molecule 1) and inflammatory activity (C-reactive protein and fibrinogen) were determined. RESULTS: The prevalence of retinopathy was 33.8%. The median diabetes duration at baseline was 7 years (interquartile range 2-12 years). The highest tertiles of baseline urinary albumin excretion and glycated haemoglobin (HbA(1c)) were associated with prevalent retinopathy: odds ratio (OR) 95% confidence interval (CI) 2.80 (1.44-5.46) and 2.19 (1.11-4.32), respectively. Progression of retinopathy occurred in 188 patients. The second and third tertiles of baseline sE-selectin were associated with progression of retinopathy [1.44 (1.04-2.01) and 1.61 (1.19-2.18)] but not independently of HbA(1c). None of the other markers was significantly associated with the presence or progression of retinopathy. High baseline HbA(1c) was significantly associated with progression of retinopathy: 1.65 (1.21-2.25). CONCLUSIONS: In this population of patients with Type 2 diabetes who attended a diabetes clinic, there was some evidence for a role of endothelial dysfunction in the progression of retinopathy. We could not demonstrate a role for low-grade inflammation. Our study emphasizes the importance of glycaemic control in the development and progression of retinopathy.