Macular Degeneration: Scholl HP

Finger RP, Krohne TU, Charbel Issa P, Fleckenstein M, Scholl HP, Holz FG. · No affiliation provided · Retina. · Pubmed #19430277 No free full text.

This publication has no abstract.

Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, Holz FG. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Surv Ophthalmol. · Pubmed #19171212 No free full text.

Abstract: Fundus autofluorescence imaging is an imaging method that provides additional information compared to conventional imaging techniques. It permits to topographically map lipofuscin distribution of the retinal pigment epithelial cell monolayer. Excessive accumulation of lipofuscin granules in the lysosomal compartment of retinal pigment epithelium cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases including age-related macular degeneration (AMD). This comprehensive review contains an introduction in fundus autofluorescence imaging, including basic considerations, the origin of the signal, different imaging methods, and a brief overview of fundus autofluorescence findings in normal subjects. Furthermore, it summarizes cross-sectional and longitudinal fundus autofluorescence findings in patients with AMD, addresses the pathophysiological significance of increased fundus autofluorescence, and characterizes different fundus autofluorescence phenotypes as well as fundus autofluorescence alterations with disease progression.

Finger RP, Fleckenstein M, Scholl HP, Holz FG. · Centre for International Health, Curtin University of Technology, Perth, Australien. · Pharm Unserer Zeit. · Pubmed #17957685 No free full text.

Abstract: Bei der altersabhängigen Makuladegeneration (AMD) handelt es sich um eine komplexe Erkrankung des Netzhaut-/Pigmentepithel-/ Aderhaut-Komplexes, die typischerweise zu einem Verlust der Sehschärfe und des zentralen Gesichtsfeldes führt. Bei der häufigen neovaskulären Spätform kann ein Sehverlust mittels VEGF-Inhibitoren verhindert und bei einem Teil der Patienten sogar erstmals eine Sehverbesserung erreicht werden.

Scholl HP, Fleckenstein M, Charbel Issa P, Keilhauer C, Holz FG, Weber BH. · Department of Ophthalmology, University of Bonn, Bonn, Germany. <> · Mol Vis. · Pubmed #17327825 links to  free full text

Abstract: Age-related macular degeneration (AMD) is a genetically complex disorder of the photoreceptor-RPE-Bruch's membrane-choriocapillaris complex. Family and twin studies have shown that the susceptibility for this disease is genetically influenced. The heritability has been estimated to be up to 71%. Linkage and association studies have identified several chromosomal regions that are likely to contain susceptibility loci with strongest evidence found on chromosome 1q31 and 10q26. Variants in the complement factor H (CFH) gene have been shown by several independent studies to be associated with an increased risk for AMD in Caucasian populations. These findings imply that the innate immune system may play a significant role in AMD pathogenesis. The LOC387715/HTRA1 locus within 10q26 has been identified as a second major locus contributing to AMD pathogenesis. The two late forms of AMD, choroidal neovascularization and geographic atrophy, have not been found to be different in risk allele distribution. Variants within CFH and LOC387715/HTRA1 may contribute to the increased risk of late AMD largely through their impact on precursors, such as drusen and/or other RPE/Bruch's membrane changes. Considering variants at CFH, LOC387715/HTRA1 and complement component 2-complement factor B (C2-FB), high-risk homozygotes at all three loci may have a 250-fold increased risk compared to baseline. However, the identification of genetic factors has not resulted in therapeutic strategies to modify the disease so far and additional genetic and environmental factors are yet to be discovered in order to influence the onset and the progression of AMD.

Ladewig MS, Ziemssen F, Jaissle G, Helb HM, Scholl HP, Eter N, Bartz-Schmidt KU, Holz FG. · Augenklinik, Universität, Ernst-Abbe-Strasse 2, 53127 Bonn. · Ophthalmologe. · Pubmed #16763862 No free full text.

Abstract: The efficacy and safety of the therapeutic anti-VEGF concept has already been demonstrated for pegaptanib and ranibizumab. Bevacizumab acts as an antibody against all VEGF-A isoforms and has been developed for oncological indications with intravenous application. Initial reports on intravitreal administration in patients with neovascular age-related macular disease (AMD) have shown beneficial morphological and functional effects. In the meantime, bevacizumab has been used off-label in thousands of patients with AMD. However, data from prospective, controlled, randomized trials on both safety and efficacy are lacking. Herein recent experiences with bevacizumab are summarized and discussed. Furthermore, a web-based platform for online data registration and pooled analyses is presented.

Holz FG, Helb HM, Bindewald-Wittich A, Scholl HP. · Universitäts-Augenklinik, Bonn. · Internist (Berl). · Pubmed #16341677 No free full text.

Abstract: Age-related macular degeneration (AMD) is now the most common cause for blind registration in all developed countries. Epidemiologic data indicate that there are 4.5 millions affected in Germany with constant increase in incidence and prevalence with subsequent considerable health economic implications. Late manifestations of the disease result in the inability to read and to perform daily tasks. Therefore, there is an urgent need for efficacious prophylactic and therapeutic measures to prevent irreversible loss of central vision. Based on a better understanding of the underlying molecular mechanisms new therapeutic approaches have been brought forward and expand previous approaches such as thermal laser surgery or photodynamic therapy. Repeated intravitreal injection of anti-VEGF (vascular endothelial growth factor) agents as well as corticosteroids have a beneficial effect on growth and permeability of neovascular membranes. The risk for progression from early to late stages of AMD can be reduced with certain antioxidative preparations (AREDS medication) in presence of defined funduscopic signs. Early diagnosis is key for all currently available interventions since a beneficial effect can only be achieved in early stages of the disease process.

Charbel Issa P, Scholl HP, Holz FG, Knolle P, Kurts C. · Augenklinik, Universität, Bonn. · Ophthalmologe. · Pubmed #16215754 No free full text.

Abstract: The discovery of the complement factor H (CFH) polymorphism in age-related macular degeneration (AMD) strongly suggests a causative role of the complement system in the pathogenesis of this disease. The complement system is part of the innate immune system and is closely associated with the cellular response and the adaptive immune system. This article provides an overview of the complement system and, taking the new data into account, of possible immunopathogenetic processes in AMD.

Scholl HP, Weber BH, Nöthen MM, Wienker T, Holz FG. · Augenklinik, Universität, Bonn. · Ophthalmologe. · Pubmed #16170519 No free full text.

Abstract: Age-related macular degeneration is a complex genetic disorder. Recent data suggest that the additive genetic risk for late-stage disease is more than two-thirds. Comprehensive genetic studies (candidate gene approaches, linkage and association studies) have been performed in recent years to identity the genetic risk factors at the molecular lavel. Very recently, a significant risk allele, Y402H, has been discovered in the complement factor H (CFH) gene. The relative risk of developing AMD has been estimated between 2.4-4.6 for heterozygotes and 3.3-7.4 for homozygotes. This polymorphism accounts for approximately 20-50% of the overall risk of developing AMD. In this review the results from molecular genetic studies in AMD are summarized, with a special emphasis on the recent data obtained for the CFH gene.

Besch D, Jägle H, Scholl HP, Seeliger MW, Zrenner E. · University Eye Hospital, Schleichstr. 12-16, D-72076 Tübingen, Germany. · Vision Res. · Pubmed #14611947 No free full text.

Abstract: Alterations of retinoid cycle genes are known to cause retinal diseases characterized by focal white dot fundus lesions. Fundus appearances reveal circumscribed RPE-changes, although generalized metabolic defects and global functional abnormalities are present. As a possible explanation, topographic inhomogeneities of the human photoreceptor mosaic and the role of a cone specific visual cycle will be discussed. Due to particular characteristics of photoreceptor subtypes as well as different pathways for photopigment regeneration the metabolic demand of individual RPE cells might differ. In "flecked retina diseases" heterogeneity of metabolic demand in individual RPE cells could therefore be responsible for their multifocal appearance.

Fleckenstein M, Charbel Issa P, Helb HM, Schmitz-Valckenberg S, Scholl HP, Holz FG. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Arch Ophthalmol. · Pubmed #18852430 No free full text.

This publication has no abstract.

Pauleikhoff D, Scheider A, Wiedmann P, Gelisken F, Scholl HP, Roider I, Mohr A, Zlateva G, Xu X. · Augenabteilung am St. Franziskus-Hospital, Münster, Deutschland. · Ophthalmologe. · Pubmed #18709375 No free full text.

Abstract: BACKGROUND: Approximately 35,000 cases of neovascular age-related macular degeneration (AMD) occur annually in Germany. The neovascular form of AMD (NV-AMD) is responsible for severe vision loss associated with the disease in 90% of the cases. This study was conducted to assess the humanistic and economic burden of NV-AMD in the German population. METHODS: A cross-sectional, observational study of subject self-reported functional health, well-being, and disease burden among elderly subjects with (n=83) and without (n=93) NV-AMD in Germany was conducted. Patients participated in telephone surveys involving the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), the EuroQol (EQ-5D), the Hospital Anxiety and Depression Scale (HADS), and also reported history of falls, fractures, and healthcare resource utilization. Furthermore, the healthcare utilization and unit costs for the NV-AMD patients were calculated. RESULTS: The mean age of NV-AMD patients was 77.2 years and 64% were female. NV-AMD patients reported significantly worse vision-related function and overall well-being than controls (adjusted mean scores: NEI-VFQ-25 overall scale: 51.3 vs 96.3; p<0.0001) and significantly more depression symptoms than controls (HADS depression: 6.2 vs. 2.7; p<0.0001). NV-AMD patients also reported that the need for assistance with daily activities was more than 10 times greater compared to controls (26.5% vs. 2.2%; p<0.0001) and the prevalence of falls was 3 times that of the control group (13.3% vs 4.3%; p=0.031). Annual NV-AMD costs per patient were <euro> 9871, 6 times that of elderly patients without NV-AMD (<euro> 1559). Of the NV-AMD costs one-half were direct non-medical-related costs (assistance of ADL or social benefit) and one-third were direct medical costs. CONCLUSIONS: NV-AMD is associated with decreased functional abilities and quality of life, which result in an increase in healthcare resource utilization. Consequently, costs were higher for NV-AMD patients compared to controls. These findings emphasize the need for new NV-AMD treatments that will prevent vision loss and progression to blindness, and lessen the ensuing economic burden. Sponsored by Pfizer Inc. New York, US.

Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok-Kopp B, Börncke F, Fritsche LG, Chong NV, Fimmers R, Wienker T, Holz FG, Weber BH, Oppermann M. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · PLoS One. · Pubmed #18596911 links to  free full text

Abstract: Dysregulation of the alternative pathway (AP) of complement cascade has been implicated in the pathogenesis of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. To further test the hypothesis that defective control of complement activation underlies AMD, parameters of complement activation in blood plasma were determined together with disease-associated genetic markers in AMD patients. Plasma concentrations of activation products C3d, Ba, C3a, C5a, SC5b-9, substrate proteins C3, C4, factor B and regulators factor H and factor D were quantified in patients (n = 112) and controls (n = 67). Subjects were analyzed for single nucleotide polymorphisms in factor H (CFH), factor B-C2 (BF-C2) and complement C3 (C3) genes which were previously found to be associated with AMD. All activation products, especially markers of chronic complement activation Ba and C3d (p<0.001), were significantly elevated in AMD patients compared to controls. Similar alterations were observed in factor D, but not in C3, C4 or factor H. Logistic regression analysis revealed better discriminative accuracy of a model that is based only on complement activation markers Ba, C3d and factor D compared to a model based on genetic markers of the complement system within our study population. In both the controls' and AMD patients' group, the protein markers of complement activation were correlated with CFH haplotypes.This study is the first to show systemic complement activation in AMD patients. This suggests that AMD is a systemic disease with local disease manifestation at the ageing macula. Furthermore, the data provide evidence for an association of systemic activation of the alternative complement pathway with genetic variants of CFH that were previously linked to AMD susceptibility.

Fleckenstein M, Charbel Issa P, Helb HM, Schmitz-Valckenberg S, Finger RP, Scholl HP, Loeffler KU, Holz FG. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #18487363 No free full text.

Abstract: PURPOSE: To describe morphologic variations in outer retinal layers in eyes with atrophic age-related macular degeneration (AMD) using high-resolution, spectral-domain optical coherence tomography (SD-OCT). METHODS: SD-OCT scans were obtained with a combined confocal scanning laser ophthalmoscope (cSLO) and SD-OCT for simultaneous tomographic and topographic in vivo imaging. A total of 81 eyes of 56 patients (mean age, 77.8 +/- 7.4 years) with geographic atrophy (GA) were examined. Morphologic alterations were analyzed and classified in the perilesional zone, at the junction between GA and nonatrophic retina, and in the atrophic area itself. RESULTS: In the perilesional zone, distinct morphologic alterations included elevations of the outer retinal layers, thickening, and spikes of the outer hyperreflective band as well as clumps at different neurosensory retinal levels. At the junction, highly variable transitions of the outer retinal layers were present with different degrees of loss of the normal hyperreflective bands. Within the actual GA, hyperreflective clumps at different retinal levels, segmented plaques of the outer band and elevations with variable reflectivity were visualized. CONCLUSIONS: SD-OCT imaging in eyes with GA revealed a wide spectrum of morphologic alterations, both in the surrounding retinal tissue and in the atrophic area. These alterations may reflect different disease stages or, alternatively, heterogeneity on a cellular and molecular level. Longitudinal studies using in vivo SD-OCT imaging may allow evaluation of the relevance of these phenotypic changes as potential predictive markers for the progression of disease (i.e., enlargement rates of GA over time) and may be used for monitoring of future therapeutic interventions.

Finger RP, Fleckenstein M, Holz FG, Scholl HP. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Qual Life Res. · Pubmed #18365767 No free full text.

Abstract: PURPOSE: Age-related macular degeneration (AMD) has a considerable impact on older adults' independence and autonomy. Recently, patient reported outcomes (PROs) such as QoL have been met with increasing interest by the scientific community, healthcare payers and planners. Against this background, the multitude of psychometric tools used to measure QoL in AMD was reviewed. METHODS: A search of the literature from 1990 onwards yielded 355 results, out of which 58 publications were included in the review. Data regarding design, validation and extent of utilization were obtained where available. RESULTS: The National Eye Institute-Visual Function Questionnaire (NEI VFQ-25-item) was found to be the most often used (29% of studies) and best validated psychometric tool, followed by the Visual Function Questionnaire (VF-14; 17%), and the Impact of Vision Impairment Profile (IVI; 9%). Most tools that were identified have been validated for the use in AMD patients. CONCLUSION: Psychometric tools specifically designed to measure vision-related quality of life are well equipped and validated to measure QoL in AMD. More recent developments such as the Macular Disease-dependent Quality of Life (MacDQoL) questionnaire might be able to depict dimensions of vision-related QoL in greater depth. Future studies should endeavour to use a suggested standard when gathering data on vision related QoL, allowing for international comparisons.

Meyer CH, Scholl HP, Eter N, Helb HM, Holz FG. · Department of Ophthalmology, University of Bonn, Germany. · Acta Ophthalmol. · Pubmed #18221499 No free full text.

Abstract: PURPOSE: To assess the effectiveness of consecutive intravitreal injections of recombined tissue plasminogen activator (rtPA), expansile gas and bevacizumab in eyes with acute subretinal haemorrhage (SRH). METHODS: A retrospective, non-randomized consecutive case series included 19 eyes in 19 patients with SRH related to exudative age-related macular degeneration (AMD). The initial size of the subfoveal SRH was 1-3 disc diameters. Each patient received a triple procedure using 0.05 ml rtPA (50 microg), 0.3 ml of sulphur hexafluoride (SF6) gas and 0.05 ml bevacizumab (1.25 mg). Lesion size, location of the SRH and early treatment in diabetic retinopathy study (ETDRS) visual acuity were evaluated pretreatment as well as 1 and 3 months after the procedure. RESULTS: At the initial presentation, the patients' mean age was 77 years (range 63-88 years) and the mean duration of symptoms was 9.3 days (range 4-12 days). The mean visual acuity pretreatment (20/133) improved significantly to 20/86 at 1 month and to 20/74 at 3 months. The mean ETDRS visual acuity improved from baseline by 2.1 lines at 1 month (Wilcoxon ranks test; P < 0.005) and 3.7 lines at 3 months after treatment (Wilcoxon ranks test; P < 0.005). None of our patients had reading visual acuity prior to treatment, with visual acuity below 0.3. One month after the triple procedure, 25% of our patients had reading visual acuity (> or = 0.4); at 3 months, the figure was 35%. A successful inferior displacement of the SRH was achieved in 17/19 eyes. Eyes with elevated intraocular pressure were treated immediately by a corneal paracentesis. CONCLUSION: The intravitreal application of rtPA, gas and bevacizumab appears to be beneficial and well tolerated in the treatment of SRH in the short term. The triple approach seems a logical alternative to the current combined dual approach in limiting the progression of the underlying disease and achieving better visual outcome. Further randomized evaluations are warranted.

Ladewig MS, Karl SE, Hamelmann V, Helb HM, Scholl HP, Holz FG, Eter N. · Department of Ophthalmology, University of Bonn, Ernst-Abbe-Strasse 2, 53127, Bonn, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #17701197 No free full text.

Abstract: BACKGROUND: Our aim was to evaluate the short-term safety and efficacy of combined photodynamic therapy (PDT) with verteporfin and intravitreal bevacizumab in neovascular age-related macular degeneration (AMD). METHODS: A prospective non-randomized interventional case series of 30 eyes of 30 patients with choroidal neovascularization (CNV) caused by AMD was studied. All patients were treated with PDT followed by an intravitreal injection of bevacizumab (1.5 mg) on the same day. Ophthalmic evaluations included determination of best-corrected visual acuity by using ETDRS charts. CNV lesion characteristics were determined by fluorescein angiography, and retinal morphology by optical coherence tomography. Review examinations were performed 1, 4, and 12 weeks following treatment. RESULTS: The median ETDRS letter scores increased by 3 letters after 4 weeks and 4.3 letters after 12 weeks. Median central retinal thickness decreased from the baseline by 145 microm (week 1), 205 microm (week 4), and 171 microm (week 12), respectively (P < 0.0001, for all comparisons). One patient experienced a transient moderate vision loss after 4 weeks post treatment. Leakage on fluorescein angiography was resolved in all patients at week 12. No significant ocular or systemic side-effects were observed. CONCLUSIONS: Short-term results suggest that a single PDT in combination with intravitreal bevacizumab is safe and associated with stabilization of visual acuity and decrease of intraretinal and subretinal fluid accumulation in the macula. Further evaluation of this treatment strategy for neovascular AMD appears warranted.

Holz FG, Bindewald-Wittich A, Fleckenstein M, Dreyhaupt J, Scholl HP, Schmitz-Valckenberg S, Anonymous00266. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Am J Ophthalmol. · Pubmed #17239336 No free full text.

Abstract: PURPOSE: To test if fundus autofluorescence (FAF) patterns around geographic atrophy (GA) have an impact on GA progression rates over time in atrophic age-related macular degeneration (AMD). DESIGN: Prospective longitudinal multicenter natural history study. METHODS: Standardized digital FAF images were obtained from 195 eyes of 129 patients with GA using confocal scanning laser ophthalmoscopy (excitation 488 nm, emission >500 nm). Areas of GA were quantified and patterns of abnormal FAF in the junctional zone were classified. Repeated FAF images were obtained over a median follow-up period of 1.80 years (interquartile range [IQR], 1.28 to 3.34). RESULTS: Areas of GA (median, 7.04 mm(2) at baseline; IQR, 3.12 to 10.0) showed a median enlargement of 1.52 mm(2)/year (IQR, 0.81 to 2.33). Progression rates in eyes with the banded (median 1.81 mm(2)/year) and the diffuse FAF pattern (1.77 mm(2)/year) were significantly higher compared to eyes without FAF abnormalities (0.38 mm(2)/year) and focal FAF patterns (0.81 mm(2)/year, P < .0001). Within the group of the diffuse pattern, eyes with a diffuse trickling pattern could be identified that exhibited an even higher spread rate (median 3.02 mm(2)/year) compared to the other diffuse types (1.67 mm(2)/year, P = .001). CONCLUSIONS: The results indicate that distinct phenotypic FAF patterns have an impact on disease progression in eyes with atrophic AMD and may therefore serve as prognostic determinants. The findings underscore the relevance of FAF imaging and the pathogenetic role of excessive retinal pigment epithelium (RPE) lipofuscin (LF) accumulation in GA. Natural history data and identification of high-risk characteristics will be helpful to design interventional studies aiming at slowing the spread of atrophy.

Schmitz-Valckenberg S, Bindewald-Wittich A, Dolar-Szczasny J, Dreyhaupt J, Wolf S, Scholl HP, Holz FG, Anonymous00317. · Department of Ophthalmology, University of Bonn, Bonn, Germany, and First Eye Hospital, University of Lublin, Poland. · Invest Ophthalmol Vis Sci. · Pubmed #16723482 links to  free full text

Abstract: PURPOSE: To test the hypothesis that the extension of areas with increased fundus autofluorescence (FAF) outside atrophic patches correlates with the rate of spread of geographic atrophy (GA) over time in eyes with age-related macular degeneration (AMD). METHODS: The database of the multicenter longitudinal natural history Fundus Autofluorescence in AMD (FAM) Study was reviewed for patients with GA recruited through the end of August 2003, with follow-up examinations within at least 1 year. Only eyes with sufficient image quality and with diffuse patterns of increased FAF surrounding atrophy were chosen. In standardized digital FAF images (excitation, 488 nm; emission, >500 nm), total size and spread of GA was measured. The convex hull (CH) of increased FAF as the minimum polygon encompassing the entire area of increased FAF surrounding the central atrophic patches was quantified at baseline. Statistical analysis was performed with the Spearman's rank correlation coefficient (rho). RESULTS: Thirty-nine eyes of 32 patients were included (median age, 75.0 years; interquartile range [IQR], 67.8-78.9); median follow-up, 1.87 years; IQR, 1.43-3.37). At baseline, the median total size of atrophy was 7.04 mm2 (IQR, 4.20-9.88). The median size of the CH was 21.47 mm2 (IQR, 15.19-28.26). The median rate of GA progression was 1.72 mm2 per year (IQR, 1.10-2.83). The area of increased FAF around the atrophy (difference between the CH and the total GA size at baseline) showed a positive correlation with GA enlargement over time (rho=0.60; P=0.0002). CONCLUSIONS: FAF characteristics that are not identified by fundus photography or fluorescein angiography may serve as a prognostic determinant in advanced atrophic AMD. As the FAF signal originates from lipofuscin (LF) in postmitotic RPE cells and since increased FAF indicates excessive LF accumulation, these findings would underscore the pathophysiological role of RPE-LF in AMD pathogenesis.

Dandekar SS, Jenkins SA, Peto T, Scholl HP, Sehmi KS, Fitzke FW, Bird AC, Webster AR. · Moorfields Eye Hospital and Institute of Ophthalmology, London, England. · Arch Ophthalmol. · Pubmed #16286612 No free full text.

Abstract: OBJECTIVE: To describe the autofluorescence (AF) characteristics of choroidal neovascularization (CNV) in patients with age-related macular degeneration. METHODS: Autofluorescence images of 65 consecutive eyes with CNV at various stages of evolution were analyzed. Twenty images were of recent-onset CNV (group 1), 8 were of eyes 1 to 6 months after CNV diagnosis (group 2), and 37 were late-stage CNV (group 3). Autofluorescence images from groups 1 and 2 were compared with fundus fluorescein angiographic images. RESULTS: Group 1 showed areas of hyperfluorescence on fundus fluorescein angiography corresponding to areas of normal AF in 16 of 20 cases, with adjacent areas of increased AF in 13 cases. The main areas of abnormal AF were larger than the main areas of abnormal fluorescence on fundus fluorescein angiography in 18 of the 20 cases. Groups 2 and 3 showed areas of decreased AF corresponding to areas of previous leakage on fundus fluorescein angiography (in group 2) or atrophy. CONCLUSIONS: Preserved AF in group 1 indicates viable retinal pigment epithelium initially, which has implications for visual prognosis. Decreased AF in groups 2 and 3 indicates loss of retinal pigment epithelium and photoreceptors. Autofluorescence imaging may increase our understanding of CNV in age-related macular degeneration.

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.

Scholl HP, Dandekar SS, Peto T, Bunce C, Xing W, Jenkins S, Bird AC. · Institute of Ophthalmology and Moorfields Eye Hospital, London, United Kingdom. · Ophthalmology. · Pubmed #14711724 No free full text.

Abstract: OBJECTIVE: To compare 35-mm stereoscopic slide transparencies with digitized nonstereoscopic images (resolution 1024x768 pixels) for grading abnormalities in age-related maculopathy (ARM) and age-related macular degeneration (AMD). DESIGN: Comparative observational case series. PARTICIPANTS: Twenty-five patients (50 eyes) with ARM and/or AMD. METHODS: Twenty-five patients with ARM/AMD in at least 1 eye were randomly selected from a large ongoing collection of clinical data and DNA in a tertiary referral United Kingdom population. Retinal photography was performed with mydriasis using the Zeiss FF-series 30 degrees fundus camera on Ektachrome slide transparency film. The images were centered on the macula. The color transparencies were then digitized. The grading process has been set up based on the International ARM Epidemiology Study Group. All images were independently graded by 3 retinal specialists. Both kappa statistics and exact agreement were calculated to assess agreement between and within observers and between the 2 master copies derived from the gradings of the color slides and digitized images. MAIN OUTCOME MEASURE: Agreement between the 2 master copies derived from the gradings obtained from stereoscopic slide transparencies and digitized nonstereoscopic images. RESULTS: For small hard and intermediate soft drusen, agreement ranged between 77% and 91% (kappa, 0.56-0.72) and 83% and 93% (kappa, 0.31-0.64), respectively, for the 3 macular subfields. Agreement for the presence of hyperpigmentation was 12% to 56% (kappa, 0.00-0.27). Agreement was 94% to 96% (kappa, 0.80-0.82) for the presence of geographic atrophy and 93% (kappa, 0.78) for the area covered. For the presence of choroidal neovascularization (CNV), agreement was 94% to 98% (kappa, 0.81-0.88), and it was 95% (kappa, 0.83) for the area covered. For individual features of CNV, exact agreement was 88% to 96% (kappa, 0.22-0.49). In 3 cases of geographic atrophy and 2 cases of CNV, the lesion was missed on digitized images. CONCLUSIONS: Because of the close agreement for most categories between the grading of stereoscopic color slides and digitized images, digitized nonstereoscopic color images prove to be useful for grading ARM and AMD.

Scholl HP, Peto T, Dandekar S, Bunce C, Xing W, Jenkins S, Bird AC. · Institute of Ophthalmology, Moorfields Eye Hospital, 162 City Road, EC1 V2PD, London, UK. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #12545291 No free full text.

Abstract: PURPOSE. To introduce a revised version of the grading system established by the International ARM Epidemiological Study Group for identifying and quantifying abnormalities of age-related maculopathy (ARM) and age-related degeneration (AMD) and to investigate its reliability, specifically the inter- and intra-observer variability. METHODS. Fifty eyes of 25 patients with ARM or AMD in at least one eye were randomly selected from a large ongoing collection of clinical data and DNA in a tertiary referral UK population. Stereoscopic color fundus photographs were taken with a 30 degrees fundus camera and were centered on the macula. Presence and severity of fundus abnormalities in ARM and AMD were graded using a grid to define macular subfields and standard circles to define the size of lesions. Inter-observer variability was assessed by having three retinal specialists evaluate the color slides and intra-observer variability by re-grading the same set. RESULTS. The inter-observer agreement for all subfields was fair to substantial for small hard drusen (70-89%; kappa=0.26-0.63) and intermediate soft drusen (76-94%; kappa=0.27-0.69). Agreement ranged between 87% and 100%, between 50% and 92%, and between 78% and 100% for larger drusen, the presence of hyperpigmentation, and the presence of hypopigmentation, respectively. Agreement was moderate to almost perfect for the presence of geographic atrophy (88-98%; kappa=0.60-0.95) and substantial to almost perfect for the presence of choroidal neovascularization (84-100%; kappa=0.62-1.00). The intra-observer variability for the grading of drusen characteristics and pigmentary changes was similar in magnitude, but slightly greater for features of advanced AMD. CONCLUSION. Reproducibility was achieved using a revised version of the grading system established by the International ARM Epidemiological Study Group. This grading system may therefore be used for phenotyping of ARM and AMD.

Scholl HP, Schuster AM, Vonthein R, Zrenner E. · Department of Pathophysiology of Vision and Neuro-Ophthalmology, University Eye Hospital, Schleichstrasse 12-16, 72076 Tübingen, Germany. · Vision Res. · Pubmed #11934455 No free full text.

Abstract: In order to evaluate the function of the retina in Best macular dystrophy (BMD) 18 patients were examined by means of the multifocal electroretinogram (mfERG). The mfERG peak amplitudes of the central and pericentral responses were significantly reduced in the BMD patients (p<0.001). The ERG amplitude decrease of the central response was significantly correlated with visual acuity loss and with the funduscopic staging. The implicit times in more eccentric groups were slightly but significantly increased. The markedly reduced mfERG amplitudes with only slightly increased implicit times may indicate cone photoreceptor cell loss or damage to the cone outer segments.

Scholl HP, Besch D, Vonthein R, Weber BH, Apfelstedt-Sylla E. · Department of Pathophysiology of Vision and Neuroophthalmology, University Eye Hospital Tübingen, Tübingen, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #11923272 links to  free full text

Abstract: PURPOSE: To investigate the slow and fast rod signals of the scotopic 15-Hz flicker ERG in patients with molecularly confirmed Stargardt disease type I (STGD1). There is evidence that these slow and the fast rod ERG signals can be attributed to the rod bipolar-AII cell pathway and the rod-cone coupling pathway, respectively. METHODS: Twenty-seven patients with STGD1 with mutations in both alleles of the ABCA4 gene were included. Scotopic ERG response amplitudes and phases to flicker intensities ranging from -3.37 to -0.57 log scotopic troland x sec (log scot td x sec) were measured at a flicker frequency of 15 Hz. In addition, scotopic standard ERGs were obtained. Twenty-two normal subjects served as controls. RESULTS: The amplitudes of both the slow and fast rod ERG signals were significantly reduced in the STGD1 group. The phases of the slow rod signals lagged significantly, whereas those of the fast rod signals did not. The standard scotopic ERG did not reveal significant alterations. CONCLUSIONS: The results provide evidence that a defective ABCA4 transporter can functionally affect both the rod bipolar-AII cell pathway and the rod-cone coupling pathway. In STGD1, the scotopic 15-Hz flicker ERG may reveal subtle abnormalities at different sites within the rod system that remain undetected by standard ERG techniques.

Scholl HP, Kremers J, Wissinger B. · Laboratories of Electrophysiology, Department of Experimental Ophthalmology, University Eye Hospital Tübingen, Germany. · Curr Eye Res. · Pubmed #11462159 No free full text.

Abstract: PURPOSE: To determine the L- and M-cone driven ERG responses in a male patient with macular dystrophy and a protan phenotype. METHODS: We measured large field ERG thresholds to stimuli which modulated exclusively the L- or the M-cones or the two in various combinations (both in-phase and in counterphase). In none of the stimuli, the S-cones were modulated. Additionally, standard and multifocal ERGs were measured. Analysis of the L- and M-cone pigment genes was performed by means of PCR, RFLP analysis and DNA sequencing techniques. RESULTS: Macular dystrophy was revealed by the markedly abnormal multifocal ERGs in presence of near normal standard ERGs. The large field ERG responses were exclusively driven by the M-cones with enlarged thresholds when compared with otherwise normal protanopes. In addition, the M-cone driven ERG response phases were abnormal. Pigment gene analysis confirmed a protan genotype with the presence of a single 5'red/3'green hybrid pigment gene. CONCLUSIONS: Our novel stimulus technique allows a reliable analysis of the separate cone pathways even in cases with macular dysfunction. The increased thresholds and the abnormal phase behavior of the M-cone driven ERGs reflect altered mechanisms of the retinal physiology in this patient. The data strongly suggest that the macular dystrophy and the protanopia have independent origins.