Macular Degeneration: Bellmann C

Bellmann C, Kabanarou SA, Sahel JA, Rubin GS, Fitzke FW. · Institute of Ophthalmology, University College London, UK. · Aging Clin Exp Res. · Pubmed #16485860 No free full text.

Abstract: Age-related macular disease (AMD) is the leading cause of legal blindness among the elderly in Western nations. The magnitude of the problem will undoubtedly grow, as age is a significant risk factor and the number of people aged 65 and over is projected to increase. The most frequent cause of severe visual loss associated with AMD is irreversible degeneration of the overlying neurosensory retina, caused by the growth of choroidal neovascularization or, alternatively, the development of geographic atrophy of the retinal pigment epithelium. Today, we are able to image the human retina in vivo. Recently developed imaging techniques provide better assessment of retinal pathology than conventional ophthalmoscopy alone. This overview presents the most recent devices available for retinal imaging, which mainly exploit laser technology such as scanning laser ophthalmoscopy. Its basic principles, as well as its characteristics for imaging and functional assessment of the retina, are described. Lastly, potential benefits for clinical routine, rehabilitation strategies in AMD, and future research aspects are discussed.

Bellmann C, Unnebrink K, Rubin GS, Miller D, Holz FG. · Department of Ophthalmology, University of Heidelberg, INF 400, 69120 Heidelberg, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #13680248 No free full text.

Abstract: BACKGROUND: Patients with advanced age-related macular degeneration (AMD) suffer not only from impairment in central visual acuity (VA), but also from reduction in contrast sensitivity (CS). We examined VA and CS changes over time in patients with subfoveal choroidal neovascularizations (CNV) as well as the correlation between the two parameters. METHODS: VA was determined according to a standardized protocol with the Early Treatment Diabetic Retinopathy (ETDRS) chart. CS was measured with Pelli-Robson charts. The angiographic characteristics of CNV and the presence of CNV in the fellow eye as well as gender and age were evaluated as possible prognostic factors of VA and CS progression. Two hundred and five patients with neovascular AMD were recruited within the Radiation Therapy for Age-Related Macular Degeneration (RAD) Study and were reviewed over 2 years. The treatment and control groups showed no significant difference for VA or for CS ( P>0.05), and both groups were considered together. RESULTS: At baseline, mean VA was 55.6+/-14.5 SD letters (EDTRS chart), and mean CS was 22.8+/-6.9 letters (Pelli-Robson chart). Spearman Correlation Coefficient ( r(s)) between VA and CS was r(s)=0.60, P=0.0001. Over 2 years the mean VA loss was 23.6+/-21.4 letters and mean CS reduction was 9.0+/-9.7 letters. Agreement between change of VA and change of CS was moderate ( r(s)=0.65, P=0.0001; kappa coefficient (grouped into VA loss < or =15, >15, >30 letters; CS loss < or =6, >6, >15 letters) kappa=0.43, 95% CI [0.32;0.54]). Proportional hazard models did not show any apparent influence of type of CNV, or CNV in the fellow eye, on change in VA and CS. CONCLUSION: The results indicate that VA and CS do not always show the same progression in visual function loss although they show a moderate correlation in eyes with neovascular AMD. Both parameters provide important information about visual disability and should be evaluated as outcome in interventional studies.

Kabanarou SA, Crossland MD, Bellmann C, Rees A, Culham LE, Rubin GS. · Institute of Ophthalmology, London, United Kingdom. · Ophthalmology. · Pubmed #16996593 No free full text.

Abstract: PURPOSE: To determine and explain gaze changes during binocular versus monocular viewing in patients with age-related macular degeneration (AMD). DESIGN: Cross-sectional study. PARTICIPANTS: Twenty-nine patients with bilateral late-stage AMD. METHODS: Distance acuity and fundus pathologic features were evaluated. Eye position was recorded while viewing a circular fixation target under monocular and binocular viewing conditions using an infrared eye tracker (SMI Gazetracker, SensoMotoric, Germany; Eyelink Software 2.04). Gaze changes were quantified by calculating the mean x-coordinate and y-coordinate eye position of the center of the bivariate contour ellipse area for a 30-second fixation task under both viewing conditions. Retinal loci used for monocular fixation for each eye were determined using the scanning laser ophthalmoscope (SLO; SLO 101, Rodenstock, Munich, Germany). MAIN OUTCOME MEASURE: Gaze position. RESULTS: Nine patients showed no shift in gaze position from monocular to binocular viewing. Three patients demonstrated a shift in both eyes, and 17 patients demonstrated a shift in only 1 eye. The mean shift was 4.7+/-5 degrees (standard deviation). The shift in gaze position in the worse eye was predictive of the distance between the 2 monocular preferred retinal loci (PRLs; better and worse eye; r(2) = 0.59; P<0.0001), whereas there was no association between the shift in gaze position in the better eye and distance (r(2) = 0.00; P = 0.91). CONCLUSIONS: Most AMD patients shift gaze position in 1 or both eyes when viewing binocularly compared with monocularly. These changes suggest that different retinal locations are used for fixation under the 2 viewing conditions. The SLO data showed that these patients are likely to demonstrate monocular PRLs that fall on noncorresponding areas. These results may have implications for the effective development of eccentric viewing and binocular behavior of AMD patients.

Bellmann C, Feely M, Crossland MD, Kabanarou SA, Rubin GS. · Institute of Ophthalmology, London, United Kingdom. · Ophthalmology. · Pubmed #15582084 No free full text.

Abstract: PURPOSE: To determine fixation stability for central and pericentral fixation targets in patients with age-related macular degeneration (AMD). DESIGN: Comparative study. PARTICIPANTS: Twelve patients having late-stage AMD involving the fovea and 10 age-matched controls having no other eye diseases and visual acuity better than 20/25. METHODS: Six different fixation targets (1 degrees cross; 1 degrees filled circle; 1 degrees letter x; small 4-point diamond; large 4-point diamond using dimensions as in a field analyzer; large-crossover whole-image diagonal with open 1 degrees center) were presented on a high-resolution monitor. Before examination, subjects were given verbal instructions to move their eye to see the center of the target best. Fixation stability was measured for the preferred eye, with the fellow eye occluded, using a gaze tracker. Fixation stability was quantified by calculating the bivariate contour ellipse area (BCEA) over 30 seconds for each target. For statistical analysis, BCEA values (minutes of arc2) were converted into their logarithms. The absolute retinal scotoma for the study eye was determined using a scanning laser ophthalmoscope. MAIN OUTCOME MEASURE: Bivariate contour ellipse area. RESULTS: Visual acuity in patients (age range, 57-87 years) ranged from 20/32 to 20/600. The lowest BCEA values were found for the 1 degrees letter x in patients (mean, 12052.2%+/-254.0%) and for the 1 degrees cross in normal subjects (mean, 1286.9%+/-47.8%); the highest BCEA values were found for the small 4-point diamond in patients (mean, 23109.5%+/-298.3%) and for the large 4-point diamond in normals (age range, 62-79 years) (mean, 3229.2%+/-105.4%). The difference between the targets was significant for normal subjects (analysis of variance [ANOVA], P<0.01) but not for patients (ANOVA, P>0.05). In normals, BCEA values were significantly lower for central fixation targets than for pericentral fixation targets (P<0.01). CONCLUSION: Fixation is significantly less stable for pericentral fixation targets in normal subjects, indicating an advantage for central fixation targets. These results are particularly significant for any clinical and experimental testing method that requires the patient to maintain stable fixation.

Scholl HP, Bellmann C, Dandekar SS, Bird AC, Fitzke FW. · Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom. · Invest Ophthalmol Vis Sci. · Pubmed #14744901 links to  free full text

Abstract: PURPOSE: To investigate photopic and scotopic sensitivity of retinal areas that show increased fundus autofluorescence (FAF) in patients with age-related maculopathy (ARM). METHODS: FAF was imaged with a modified confocal scanning laser ophthalmoscope (cSLO). Fine matrix mapping (FMM) was performed with a modified field analyzer. Photopic and scotopic thresholds were obtained at 100 locations on a 9 degrees x 9 degrees matrix with 1 degrees spacing, centered on a macular area of increased FAF. Inclusion criteria included ARM fundus changes, areas of increased FAF, central and stable fixation, and visual acuity of 20/40 or better. RESULTS: FAF images were reviewed in 436 patients with age-related maculopathy (ARM), of whom 38 met the inclusion criteria. FMM was performed in seven eyes of seven patients. Areas of increased FAF in patients with late ARM (choroidal neovascularization or geographic atrophy) showed normal or only mildly abnormal photopic, but severely reduced scotopic, sensitivity. The central area of increased FAF corresponding to a large foveal druse in a patient with ARM showed moderately reduced photopic and severely reduced scotopic sensitivity. In the other patients with ARM with drusen, areas of increased FAF showed normal or near-normal photopic sensitivity, but moderately reduced scotopic sensitivity. CONCLUSIONS: In retinal areas of increased FAF in patients with ARM, scotopic sensitivity loss considerably exceeded photopic sensitivity loss. This finding is in line with histologic data that have demonstrated a preferential loss of rods in ARM, but does not explain the magnitude of sensitivity loss. The study shows that increased FAF in ARM has a functional correlate.

Bellmann C, Rubin GS, Kabanarou SA, Bird AC, Fitzke FW. · Institute of Ophthalmology, University College London, UK. Moorfields Eye Hospital, London, UK. · Br J Ophthalmol. · Pubmed #14609839 links to  free full text

Abstract: BACKGROUND: With the advent of confocal scanning laser ophthalmoscopes (cSLO), fundus autofluorescence (FAF) resulting mainly from lipofuscin accumulation on the level of the retinal pigment epithelium can be visualised in vivo. Various cSLOs are available to document FAF. The authors analysed and compared results of FAF using three different instruments. METHODS: Eight eyes of eight normal volunteers and 18 eyes of 12 patients with different retinal diseases (age related macular degeneration, macular dystrophy, central serous retinopathy) were examined. FAF images were recorded from each subject with the Heidelberg retina angiograph (HRA), the Rodenstock cSLO (RcSLO) and the Zeiss Prototype SM 30-4024 (ZcSLO). For excitation an argon laser (488 nm) was used (barrier filter: HRA 500 nm; RcSLO 515 nm; ZcSLO 521 nm). 32 FAF images were aligned and averaged using the same software for all cSLOs. FAF distribution was measured and grey scale values as well as root mean square (RMS) contrast were compared. RESULTS: Mean age of all subjects was 55.5 (SD 21.4) years. The maximum grey scale value averaged across all eyes was 76.19 (39.34) for the HRA, 61.44 (22.12) for the ZcSLO and 37.0 (9.97) for the RcSLO. The RMS contrast was 0.46 (0.20) for the ZcSLO, 0.40 (0.12) for the HRA, and 0.13 (0.05) for the RcSLO. The differences between the cSLOs were statistically significant with higher grey scale levels and more contrast for the HRA and ZcSLO than the RcSLO (repeated measures ANOVA; p<0.0001). The differences between the HRA and the ZcSLO were not significant (post hoc comparisons; p<0.05). CONCLUSIONS: All cSLOs allow clinically useful FAF imaging in retinal diseases. However, grey scale levels and contrast were much lower on the RcSLO. Therefore, RcSLO images appear much darker than HRA or ZcSLO images. Furthermore, not all cSLOs have a fixed photodetector gain and a standardised value for the argon laser amplification, which is mandatory for an absolute comparison of FAF imaging results.

Bellmann C, Miller DW, Mehltretter K, Schütt F, Jorzik J, Unnebrink K, Holz FG. · Department of Ophthalmology, University of Heidelberg, Germany. · Br J Ophthalmol. · Pubmed #12812893 links to  free full text

Abstract: BACKGROUND/AIMS: To document the natural history and to assess the efficacy of interventional therapies in neovascular age related macular degeneration (AMD), an accurate and reproducible method is required for analysis of consecutive fluorescence angiograms. The development and evaluation of an image analysis software for this purpose is described here. It allows for the quantitative analysis of changes in CNV and/or leakage area over time. METHODS: In digitised angiograms, a mouse driven arrow was used to delineate the CNV border. The ratio of the CNV area to the square of the distance between two vessels was automatically calculated by pixel count to compensate for variation in image sizes at different examination times. These results were directly transferred and stored in a database. To assess reproducibility, CNV areas in 20 patients with occult and 20 patients with classic CNV were determined independently by two readers. RESULTS: There was only marginal variability between observers with this method: the mean deviation was 0.01 pixels for classic CNV (95% CI -0.17 to +0.15, SD 0.35) and 0.55 pixels for occult CNV (95% CI -1.06 to -0.04, SD 1.14). CONCLUSIONS: This practical PC based method allows for quantification of angiographic features such as CNV size in early frames and area of leakage in late frames. Limitations include non-readily defined borders in angiograms of poor image quality or indistinct borders of the hyperfluorescent areas of interest. The software is applicable to future clinical trials where the analysis of neovascular complex changes is required, for example, following therapeutic intervention.

Michaelides M, Johnson S, Tekriwal AK, Holder GE, Bellmann C, Kinning E, Woodruff G, Trembath RC, Hunt DM, Moore AT. · Institute of Ophthalmology, University College London, London, United Kingdom. · Invest Ophthalmol Vis Sci. · Pubmed #12714659 links to  free full text

Abstract: PURPOSE: To characterize the phenotype of an autosomal dominant macular dystrophy and identify the chromosomal locus. METHODS: Thirteen members of a four-generation, nonconsanguineous British family were examined clinically and also underwent automated perimetry, fundus fluorescein angiography, and fundus autofluorescence imaging. After informed consent was obtained, blood samples were taken for DNA extraction, and genetic linkage analysis was performed. RESULTS: The retinal changes have an early age of onset and are confined to the macular region. The macular abnormalities vary from mild retinal pigment epithelium (RPE) pigmentary change to atrophy. Drusen-like deposits are present to various degrees and are characteristic of the phenotype. Subretinal neovascular membrane (SRNVM) is an established complication. Genetic linkage analysis established linkage to chromosome 5, region p13.1-p15.33 with a maximum LOD score of 3.61 at a recombination fraction of 0.00 for marker D5S630. The locus for this autosomal dominant macular dystrophy lies between flanking markers D5S1981 and D5S2031. CONCLUSIONS: A novel locus has been identified for early-onset autosomal dominant macular dystrophy on chromosome 5.

Michaelides M, Johnson S, Poulson A, Bradshaw K, Bellmann C, Hunt DM, Moore AT. · Institute of Ophthalmology, University College London, London, United Kingdom. · Invest Ophthalmol Vis Sci. · Pubmed #12657606 links to  free full text

Abstract: PURPOSE: To describe the phenotype of an autosomal dominant macular dystrophy and identify the chromosomal locus. METHODS: Eleven members of a five-generation, nonconsanguineous British family were examined clinically and also underwent automated perimetry, electrodiagnostic testing, fundus fluorescein angiography, and fundus autofluorescence imaging. Blood samples were taken for DNA extraction and linkage analysis was performed. RESULTS: The phenotype is characterized by bull's-eye macular dystrophy first evident in the first or second decade of life. There is mild visual impairment, central scotomata, and electrophysiological testing indicates that most affected individuals have disease confined to the central retina but older subjects have more widespread rod and cone abnormalities, demonstrated by flash ERG. Genetic linkage analysis established linkage to chromosome 4 at p15.2-16.3 with a maximum lod score of 3.03 at a recombination fraction of 0.00 for marker D4S391. The locus for this autosomal dominant macular dystrophy lies between flanking markers D4S3023 and D4S3022, and overlaps the Stargardt 4 locus. CONCLUSIONS: A new locus was identified for a bull's-eye macular dystrophy on the short arm of chromosome 4.

Bellmann C, Jorzik J, Spital G, Unnebrink K, Pauleikhoff D, Holz FG. · Department of Ophthalmology, University of Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany. · Arch Ophthalmol. · Pubmed #12003606 No free full text.

Abstract: BACKGROUND: As a cause for severe visual loss, geographic atrophy of the retinal pigment epithelium is about half as common as choroidal neovascularization in patients with advanced age-related macular degeneration. To assess symmetry, we determined intraindividual variations of various features of bilateral geographic atrophy in patients with atrophic age-related macular degeneration in a cross-sectional study. METHODS: Patients were examined with the use of a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph; Heidelberg Engineering, Heidelberg, Germany). Digital infrared reflection images (excitation, 830 nm) and fundus autofluorescence images (excitation, 488 nm) were recorded. The eyes of each patient were compared regarding number, size, and convex hull of the atrophic areas with the use of image analysis software and with respect to fundus autofluorescence changes in the junctional zone. RESULTS: Seventy-two patients (mean +/- SD age, 76.3 +/- 7.9 years) were examined. The number of atrophic areas ranged from 1 to 23 (mean +/- SD, 4.9 +/- 4.6); the size of geographic atrophy, from 0.18 to 30.20 (mean +/- SD, 7.0 +/- 6.6) mm(2); and the size of the convex hull, from 0.18 to 39.20 (mean +/- SD, 11.7 +/- 8.4) mm(2). No statistically significant difference was found when comparing these variables between each left and right eye: number, P =.62; size, P =.81; and convex hull, P =.78. Identical patterns of fundus autofluorescence were observed in 43 (80%) of 54 patients. CONCLUSIONS: There is intraindividual symmetry in eyes with bilateral geographic atrophy in the presence of a wide range of interindividual variability. The findings are in accordance with the view that age-related macular degeneration is not merely the result of a nonspecific aging process. Symmetric manifestations, rather, reflect specific individual determinants in the pathogenesis and manifestation of the disease.

Holz FG, Bellmann C, Margaritidis M, Schütt F, Otto TP, Völcker HE. · Department of Ophthalmology, University of Heidelberg, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #9987631 No free full text.

Abstract: PURPOSE: To determine in vivo lipofuscin (LF)-induced topographic variations of fundus autofluorescence in eyes with geographic atrophy (GA) of the retinal pigment epithelium (RPE) associated with age-related macular degeneration (ARMD). METHODS: Fundus autofluorescence was examined with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph) after excitation with an argon laser (488 nm) and detection of the emitted light above 500 nm. Fifty-seven eyes of 38 patients with uni- or multifocal GA associated with ARMD were studied. The findings were compared with 43 eyes with GA secondary to other etiologies, including juvenile macular dystrophies. RESULTS: An increased autofluorescence outside the GA was observed in 47 (82.5%) of 57 eyes with GA associated with ARMD in contrast to 4 (9.3%) of 43 eyes with GA of other causes (P < 0.001). Three different patterns were noted: a continuous band at the margin with variable peripheral extension in 36 eyes (76.6%), a diffusely increased autofluorescence at the entire posterior pole in 6 eyes (12.8%), and small focal spots of increased autofluorescence in the junctional zone in 3 eyes (6.4%). Of 19 patients with bilateral GA, 17 (89.5%) had an identical pattern in both eyes. CONCLUSIONS: The different patterns of autofluorescence in the presence of GA associated with ARMD may reflect variable forms of reactive changes in the surrounding RPE cells, and may indicate the extend of compromised RPE secondary to ageing changes in the outer retina, Bruch's membrane and choriocapillaris. Since GA spreads over time, increased LF accumulation in the junctional zone may precede cell death and may, therefore, be of prognostic value. Knowledge of the topographic variation in LF accumulation is important because heterogeneity may reflect underlying differences in cell kinetics, metabolism and biochemistry.