Monika Fleckenstein

High-Resolution Spectral Domain-OCT Imaging in Geographic Atrophy Associated with Age-Related Macular Degeneration

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.

Uveitis Subtypes in a German Interdisciplinary Uveitis Center—Analysis of 1916 Patients

Objective Studies on the epidemiology of uveitis are rare and cohorts are small. We analyzed the frequencies of classified forms of uveitis in all patients at our center. Methods We studied 1916 consecutive patients with inflammatory eye disease. Data were analyzed regarding associated systemic disease, infection, ocular syndromes, anatomic localization, age, and sex. Results In 59.1% of patients, a classified form of uveitis was observed: associated systemic diseases in 43.7%, the most frequent ones sarcoidosis (17.4%) and ankylosing spondylitis (16.8%); ocular syndromes in 34.3%, the most frequent HLA-B27-positive anterior uveitis (AU; 35.1%) and Fuchs uveitis syndrome (FUS; 34.3%); and infections in 22.4%, the most frequent herpetic infections (46.1%) and toxoplasmosis (31.5%). We found AU in 45.4% of patients (15.4% HLA-B27-positive AU and 11.3% FUS), intermediate uveitis in 22.9% (unclassified 53.7% and multiple sclerosis 10.3%), and posterior uveitis in 13.5% (24.7% toxoplasmosis). Panuveitis was diagnosed in 6.2% of cases (Behçet’s disease 12.6%; sarcoidosis 10.9%). The remaining 12.0% of cases showed extrauveal manifestations (scleritis, episcleritis, keratitis, optic neuritis, myositis, and orbital inflammation). Conclusion We describe the largest cohort to date of consecutive patients from a specialized uveitis center. The high frequency of classified disease, nearly 60% in our clinic, shows the usefulness of an interdisciplinary approach, oriented on anatomic presentation.

Fundus Autofluorescence and Progression of Age-related Macular Degeneration

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.

Combined Confocal Scanning Laser Ophthalmoscopy and Spectral-Domain Optical Coherence Tomography Imaging of Reticular Drusen Associated with Age-Related Macular Degeneration

PURPOSE To determine microstructural retinal alterations associated with reticular drusen in patients with age-related macular degeneration (AMD) using high-resolution in vivo imaging techniques. DESIGN Retrospective case series. PARTICIPANTS A total of 116 eyes of 78 AMD patients with reticular drusen were examined. METHODS Simultaneous spectral-domain optical coherence tomography (SD OCT; 870 nm, 40,000 A-scans/sec) and near-infrared confocal scanning laser ophthalmoscopy (cSLO; 830 nm) were performed using a combined imaging instrument (Spectralis HRA+OCT, Heidelberg Engineering, Heidelberg, Germany). Individual anatomic layers in SD OCT were evaluated and correlated to en face cSLO fundus imaging. MAIN OUTCOME MEASURES Description of corresponding structural changes in areas of reticular drusen. RESULTS Reticular drusen appeared as an interlacing network of round or oval irregularities by near-infrared cSLO reflectance imaging. On SD OCT, reticular drusen corresponded to marked changes at a level anterior to the retinal pigment epithelium (RPE) and Bruchs membrane complex to the interface of inner and outer photoreceptor segment layer (IPRL). Individual reticular drusen correlated to focal elevations of the IPRL, accumulation of highly reflective material below the IPRL, and an increased distance between the IPRL and RPE. CONCLUSIONS The findings indicate that the morphologic substrate of reticular drusen is the accumulation of highly reflective material within outer retinal layers anterior to the RPE. This is in contrast to previous assumptions pointing toward a localization of abnormal material at the level of the inner choroid. Although the origin of the material is unknown, the results may indicate a role for primary abnormalities in the neurosensory retina. Because reticular drusen represent high-risk markers for the progression of AMD, their ready identification is relevant both for natural history studies as well as for interventional trials.

Reticular Drusen Associated With Geographic Atrophy in Age-Related Macular Degeneration

PURPOSE To characterize reticular drusen (RDR) in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) in a prospective, multicenter, natural history study. METHODS Confocal scanning laser ophthalmoscopy (cSLO) three-field fundus autofluorescence (FAF; exc., 488; em., 500-700 nm), near-infrared reflectance (IR; 820 nm), and blue reflectance (BR; 488 nm) images as well as red-free (RF) and color fundus (CF) camera photographs were recorded in 458 GA patients. The digital images were evaluated by two independent readers with subsequent senior reader arbitration for prevalence and topographic distribution of RDR using a modified Early Treatment Diabetic Retinopathy Study grid. RESULTS RDR were detected with at least one cSLO modality in 286 of 458 (62%) patients in either eye (bilateral 207 [45%]) and were visible in fundus camera photographs in 66 of 371 (18%) patients (bilateral 48 [13%]). Prevalence of RDR by cSLO imaging was associated with increasing age (P = 0.007) and female sex (P = 0.007), but not with GA total lesion area (P = 0.38). Cohen kappa statistics showed good interobserver agreement for FAF (0.81) and IR (0.82) imaging modes, and moderate agreement was found for BR (0.48), RF (0.48), and CF (0.40). On three-field FAF images RDR were present most frequently superior to the fovea (99%). CONCLUSIONS RDR represent a common phenotypic hallmark in GA eyes. RDR are readily identified using cSLO imaging technology. These observations may explain the high prevalence determined herein, in contrast to previous reports based on fundus photographs. Incorporation of these novel imaging modalities in future natural history studies may facilitate efforts aimed at defining the role and predictive value of RDR in the progression of AMD. (ClinicalTrials.gov number, NCT00599846.)

Clinical evaluation of simultaneous confocal scanning laser ophthalmoscopy imaging combined with high‐resolution, spectral‐domain optical coherence tomography

Acta Ophthalmol. 2010: 88: 842–849

Semiautomated Image Processing Method for Identification and Quantification of Geographic Atrophy in Age-Related Macular Degeneration

PURPOSE To determine intraobserver and interobserver longitudinal measurement variability of novel semiautomated software for quantification of age-related macular degeneration-associated geographic atrophy (GA) based on confocal scanning laser ophthalmoscopy fundus autofluorescence (FAF) imaging. METHODS Three-field FAF (excitation 488 nm, emission 500-700 nm), near-infrared reflectance (820 nm), and blue reflectance (488 nm) images of 30 GA subjects were recorded according to a standardized protocol at baseline after 6 and 12 months. At all visits, the GA area was analyzed on central FAF images by seven independent readers using semiautomated software. The software allows direct export of FAF images from the database and semiautomated detection of atrophic areas by shadow correction, vessel detection, and selection of seed points. RESULTS The mean size of atrophy at baseline and the mean progression rate were 5.96 mm² (range, 1.80-15.87) and 1.25 mm²/year (0.42-2.93), respectively. Mean difference of interobserver agreement (Bland-Altman statistics) ranged from -0.25 to 0.30 mm² for the baseline visit and from -0.14 to 0.11 mm²/year for the atrophy progression rate. Corresponding reflectance images were helpful for lesion boundary discrimination, particularly for evaluation of foveal GA involvement and when image quality was poor. CONCLUSIONS The new image processing software offers an accurate, reproducible, and time-efficient identification and quantification of outer retinal atrophy and its progression over time. It facilitates measurements both in natural history studies and in interventional trials to evaluate new pharmacologic agents designed to limit GA enlargement.

CFH, C3 and ARMS2 are significant risk loci for susceptibility but not for disease progression of geographic atrophy due to AMD

Background Age-related macular degeneration (AMD) is a prevalent cause of blindness in Western societies. Variants in the genes encoding complement factor H (CFH), complement component 3 (C3) and age-related maculopathy susceptibility 2 (ARMS2) have repeatedly been shown to confer significant risks for AMD; however, their role in disease progression and thus their potential relevance for interventional therapeutic approaches remains unknown. Methodology/Principal Findings Here, we analyzed association between variants in CFH, C3 and ARMS2 and disease progression of geographic atrophy (GA) due to AMD. A quantitative phenotype of disease progression was computed based on longitudinal observations by fundus autofluorescence imaging. In a subset of 99 cases with pure bilateral GA, variants in CFH (Y402H), C3 (R102G), and ARMS2 (A69S) are associated with disease (P = 1.6×10−9, 3.2×10−3, and P = 2.6×10−12, respectively) when compared to 612 unrelated healthy control individuals. In cases, median progression rate of GA over a mean follow-up period of 3.0 years was 1.61 mm2/year with high concordance between fellow eyes. No association between the progression rate and any of the genetic risk variants at the three loci was observed (P>0.13). Conclusions/Significance This study confirms that variants at CFH, C3, and ARMS2 confer significant risks for GA due to AMD. In contrast, our data indicate no association of these variants with disease progression which may have important implications for future treatment strategies. Other, as yet unknown susceptibilities may influence disease progression.

Tracking Progression with Spectral-Domain Optical Coherence Tomography in Geographic Atrophy Caused by Age-Related Macular Degeneration

PURPOSE To investigate, with the use of spectral-domain optical coherence tomography (SD-OCT), microstructural alterations over time in eyes with progressive geographic atrophy (GA) due to age-related macular degeneration. METHODS Forty-six eyes of 26 patients (median age, 77.9 years [interquartile range (IQR), 71.8-81.0]) with GA without evidence of active or previous neovascular disease at baseline were examined by simultaneous confocal scanning laser ophthalmoscopy (cSLO) and SD-OCT. Serial examinations with alignment of follow-up to baseline scans were performed over a median period of 12.2 months (IQR, 10.2-15.3). Longitudinal SD-OCT variations were evaluated, including quantification of retinal thickness (RT) change and lateral spread of GA (LSGA) at a temporal, nasal, inferior, and superior GA border-section in each eye. RESULTS GA-enlargement was characterized by progressive loss of the outer hyperreflective SD-OCT bands and by thinning of the outer nuclear layer with subsequent approach of the outer plexiform layer toward Bruchs membrane. In the perilesional zone, various dynamic changes were recorded, including migration of hyperreflective material and changes in drusen height. At the borders, there was a median RT change of -14.09 microm/y (IQR -26.21 to -7.48 microm/y). The median LSGA was 106.90 microm/y (IQR, 55.44-161.70 microm/y). Both parameters showed only moderate intraocular agreement (RT change: intraclass correlation coefficient [ICC], 0.54; 95% CI, 0.39-0.67; LSGA: ICC, 0.49; 95% CI, 0.34-0.64) and no statistical significant difference for one location (RT change, P = 0.125; LSGA, P = 0.516; likelihood ratio test). CONCLUSIONS Combined cSLO and SD-OCT imaging provides unprecedented insight into dynamic microstructural changes of GA enlargement that may help to better understand the pathogenesis of the disease. Quantitative progression data indicate local factors may exist that drive progression in junctional areas (ClinicalTrials.gov number, NCT00393692).

Recent developments in the treatment of age-related macular degeneration

Age-related macular degeneration (AMD) is a common cause of visual loss in the elderly, with increasing prevalence due to increasing life expectancy. While the introduction of anti-VEGF therapy has improved outcomes, there are still major unmet needs and gaps in the understanding of underlying biological processes. These include early, intermediate, and atrophic disease stages. Recent studies have assessed therapeutic approaches addressing various disease-associated pathways, including complement inhibitors. Drug-delivery aspects are also relevant, as many agents have to be administered repeatedly. Herein, relevant pathogenetic factors and underlying mechanisms as well as recent and potential therapeutic approaches are reviewed.