Henrik Lund-Andersen

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes

BACKGROUND Intensified multifactorial intervention - with tight glucose regulation and the use of renin-angiotensin system blockers, aspirin, and lipid-lowering agents - has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria. We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes. METHODS In the Steno-2 Study, we randomly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy; the mean treatment period was 7.8 years. Patients were subsequently followed observationally for a mean of 5.5 years, until December 31, 2006. The primary end point at 13.3 years of follow-up was the time to death from any cause. RESULTS Twenty-four patients in the intensive-therapy group died, as compared with 40 in the conventional-therapy group (hazard ratio, 0.54; 95% confidence interval [CI], 0.32 to 0.89; P=0.02). Intensive therapy was associated with a lower risk of death from cardiovascular causes (hazard ratio, 0.43; 95% CI, 0.19 to 0.94; P=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI, 0.25 to 0.67; P<0.001). One patient in the intensive-therapy group had progression to end-stage renal disease, as compared with six patients in the conventional-therapy group (P=0.04). Fewer patients in the intensive-therapy group required retinal photocoagulation (relative risk, 0.45; 95% CI, 0.23 to 0.86; P=0.02). Few major side effects were reported. CONCLUSIONS In at-risk patients with type 2 diabetes, intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes. (ClinicalTrials.gov number, NCT00320008.)

A 4-Year Longitudinal Study of 555 Patients Treated with Ranibizumab for Neovascular Age-related Macular Degeneration

OBJECTIVE To investigate the visual outcome, pattern of discontinuation, ocular complications, and mortality of patients treated with a variable ranibizumab dosing regimen for neovascular age-related macular degeneration (AMD) for 4 years. DESIGN Retrospective chart review supplemented with clinical examination. PARTICIPANTS Six hundred eyes of 555 patients initiated intravitreal treatment with vascular endothelial growth factor inhibition for neovascular AMD in 2007 in a community-based hospital. METHODS Patient data from a database were retrieved from 2007 through 2011. Descriptive evaluation of the main outcome measures was carried out for the cohort of patients. A group of patients who had been discontinued because of apparent disease inactivity was reexamined. MAIN OUTCOME MEASURES Best-corrected visual acuity (BCVA; Snellen), number of intravitreal injections, causes of discontinuations, ocular complications, and standardized mortality rate. RESULTS One hundred ninety-two eyes (32%) were still receiving active treatment after 4 years. The mean BCVA in the 192 eyes was unchanged from the start (baseline, 0.30; 4-year follow-up, 0.32; P>0.3). Visual acuity after the third loading dose was associated significantly with the outcome (P<0.0001) and was a better predictor than baseline acuity. The mean number of injections was 5.5 per year. For 408 eyes (68%), discontinuation of treatment was motivated by the following 4 reasons: lack of apparent treatment response (28%), failure to appear at follow-up (11%), death (9%), and disease inactivity (20%, 120 eyes). Treatment was resumed later in 18% of patients discontinued because of inactivity. Sixty-seven eyes were reexamined in 2012 from the group of patients with disease inactivity. The final visual acuity by then had decreased significantly from the time of discontinuation, from 0.38 to 0.15 (P = 0.001). Endophthalmitis occurred in 2 eyes of 7584 injections. A total of 125 patients had died, corresponding to 75% of the mean mortality in the community. CONCLUSIONS One third of the eyes were still receiving active treatment after 4 years and had stable visual acuity. One third of fellow eyes (eyes at risk) started treatment during the 4 years. One fifth of discontinued eyes resumed treatment, indicating that close follow-up should be maintained for patients discontinued because of disease inactivity. The ocular complication rate was 0.2%, and the mortality rate was below expected.

THE BLOOD‐RETINAL BARRIER PERMEABILITY IN DIABETIC PATIENTS

By the of aid an extended corpus vitreum fluorophotometric technique, the blood‐retinal barrier permeability for fluorescein was studied in diabetologically well characterizied patients with insulin dependent diabetes mellitus. The method, which involves simultaneous determination of the fluorescein concentration in corpus vitreum and plasma, is described and discussed. A clear correlation was found between the degree of retinopathy and permeability (P). Patients with normal visus, ophthalmoscophy, fundus photo and fluorescence angiography exhibited P‐values of 1·10−7 cm·sec−1. This was similar to P‐values found in normal volunteers. Simplex retinopathy without macular oedema showed values of 2.5·10−7 cm·sec−1 while simplex retinopathy with macular oedema showed P‐values of 10·10−7 cm·sec−1.

The effect of acetazolamide on passive and active transport of fluorescein across the blood-retina barrier in retinitis pigmentosa complicated by macular oedema

Abstract · Background: The carbonic anhydrase inhibitor acetazolamide (AZM) reduces macular oedema in some patients with retinitis pigmentosa. To better understand the oedema-reducing effect of AZM, the effect of AZM on passive permeability and active transport of fluorescein across the blood-retina barrier was studied in patients with retinitis pigmentosa and varying degrees of macular oedema. · Method: The selection of patients was based on an introductory examination including vitreous fluorometry for qualitative assessment of the vitreous. Macular oedema was graded by fluorescein angiographic leakage. The effect of AZM on the transport properties of the blood-retina barrier was determined by differential spectrofluorometry, in a randomised, double-masked, cross-over study, comprising 2 weeks’ treatment with AZM (500 mg/day) and 2 weeks’ treatment with placebo. The penetration ratio, defined as the ratio between vitreous concentration 3 mm in front of the retina and the plasma integral, was determined for fluorescein and its metabolite fluorescein glucuronide at 30–60 min and at 120 min after fluorescein injection. Passive permeability and unidirectional permeability in the direction vitreous to blood, due to outward active transport of fluorescein, were determined in those cases where the curves for vitreous concentration of fluorescein could be fitted to a mathematical model. Visual acuity was tested by use of ETDRS standard logarithmic charts. · Results: Twenty-two patients volunteered to participate in the study. Signs of significant vitreous detachment/liquefaction caused the exclusion of ten patients after the introductory examination. Nine patients with approximately intact vitreous and varying degrees of oedema completed the cross-over study. AZM treatment was related to a decrease in the penetration ratio of 21% for fluorescein (P=0.01) and of 22% for fluorescein glucuronide (P=0.004). Passive permeability and unidirectional permeability were determined in seven patients. AZM caused a decrease of 27% in the passive permeability of fluorescein (from 1.1×101 nm/s, P=0.031), and a 95% increase in unidirectional permeability of fluorescein (from 1.2×102 nm/s, P=0.047). AZM led to a reduction in the grade of macular oedema as determined by fluorescein angiography in three out of seven patients. Only small improvements (≤5 letters) in visual acuity were noted. · Conclusion: The present study indicates that the oedema-reducing effect of AZM is due to decreased leakage and stimulated active transport across the blood-retina barrier.

Axonal loss occurs early in dominant optic atrophy

Purpose:  This study set out to investigate retinal nerve fibre layer (RNFL) thickness and best corrected visual acuity (BCVA) in relation to age in healthy subjects and patients with OPA1 autosomal dominant optic atrophy (DOA).

Test-retest repeatability of the pupil light response to blue and red light stimuli in normal human eyes using a novel pupillometer

In this study, we evaluated the repeatability of pupil responses to colored light stimuli in healthy subjects using a prototype chromatic pupillometer. One eye of 10 healthy subjects was tested twice in the same day using monochromatic light exposure at two selected wavelengths (660 and 470 nm, intensity 300 cd/m(2)) presented continuously for 20 s. Pupil responses were recorded in real-time before, during, and after light exposure. Maximal contraction amplitude and sustained contraction amplitude were calculated. In addition, we quantified the summed pupil response during continuous light stimulation as the total area between a reference line representing baseline pupil size and the line representing actual pupil size over 20 s (area under the curve). There was no significant difference in the repeated measure compared to the first test for any of the pupil response parameters. In conclusion, we have developed a novel prototype of color pupillometer which demonstrates good repeatability in evoking and recording the pupillary response to a bright blue and red light stimulus.

Predictors of 1-year visual outcome in neovascular age-related macular degeneration following intravitreal ranibizumab treatment.

Purpose:  To describe predictors of visual outcome in patients treated with intravitreal ranibizumab for choroidal neovascularisation (CNV) in age‐related macular degeneration (AMD).

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 hospitals 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.

Intrinsically photosensitive retinal ganglion cell function in relation to age: A pupillometric study in humans with special reference to the age-related optic properties of the lens

BackgroundThe activity of melanopsin containing intrinsically photosensitive ganglion retinal cells (ipRGC) can be assessed by a means of pupil responses to bright blue (appr.480 nm) light. Due to age related factors in the eye, particularly, structural changes of the lens, less light reaches retina. The aim of this study was to examine how age and in vivo measured lens transmission of blue light might affect pupil light responses, in particular, mediated by the ipRGC.MethodsConsensual pupil responses were explored in 44 healthy subjects aged between 26 and 68 years. A pupil response was recorded to a continuous 20 s light stimulus of 660 nm (red) or 470 nm (blue) both at 300 cd/m2 intensity (14.9 and 14.8 log photons/cm2/s, respectively). Additional recordings were performed using four 470 nm stimulus intensities of 3, 30, 100 and 300 cd/m2. The baseline pupil size was measured in darkness and results were adjusted for the baseline pupil and gender. The main outcome parameters were maximal and sustained pupil contraction amplitudes and the postillumination response assessed as area under the curve (AUC) over two time-windows: early (0–10 s after light termination) and late (10–30 s after light termination). Lens transmission was measured with an ocular fluorometer.ResultsThe sustained pupil contraction and the early poststimulus AUC correlated positively with age (p = 0.02, p = 0.0014, respectively) for the blue light stimulus condition only.The maximal pupil contraction amplitude did not correlate to age either for bright blue or red light stimulus conditions.Lens transmission decreased linearly with age (p < 0.0001). The pupil response was stable or increased with decreasing transmission, though only significantly for the early poststimulus AUC to 300 cd/m2 light (p = 0.02).ConclusionsAge did not reduce, but rather enhance pupil responses mediated by ipRGC. The age related decrease of blue light transmission led to similar results, however, the effect of age was greater on these pupil responses than that of the lens transmission. Thus there must be other age related factors such as lens scatter and/or adaptive processes influencing the ipRGC mediated pupil response enhancement observed with advancing age.

FLUORESCEIN IN HUMAN PLASMA IN VITRO

A method to determine fluorescein in human plasma is described. By aid of ultrafiltration a separation between fluorescein bound to plasma proteins and fluorescein free in the water is obtained. Both fractions are quantitated. Fluorescein is bound to plasma proteins. The protein binding is reversible, not sensitive to practically appearing changes in pH, temperature and gas tensions. For a normal person it appeared that at a total plasma concentration between (10‐6–10‐4) g·ml‐1 approximately 15% was free while at a total concentration of 10‐3 g·ml‐1 45% was free, pointing towards a limited amount of protein binding sites.