Impact of segmentation density on spectral domain optical coherence tomography assessment in Stargardt disease.

PURPOSE: Automated spectral domain optical coherence tomography (SD-OCT) segmentation algorithms currently do not perform well in segmenting individual intraretinal layers in eyes with Stargardt disease (STGD). We compared selective B-scan segmentation strategies for generating mean retinal layer thickness and preserved area data from SD-OCT scans in patients with STGD1. METHODS: Forty-five eyes from 40 Stargardt patients were randomly selected from the ongoing Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study. All eyes underwent SD-OCT using a standard macular volume consisting of 1024 × 49 equally spaced B-scans within a 20 × 20 degree field centered on the fovea. All 49 B-scans were segmented manually to quantify total retina, outer nuclear layer (ONL), photoreceptor inner segments, photoreceptor outer segments (OS), and retinal pigment epithelial layer (RPE). Mean thickness and total area were generated using all 49 B-scans (spaced 122 µm apart), 25 B-scans (every other B-scan, spaced 240 µm apart), 17 B-scans (every third scan, 353 µm apart), and 13 B-scans (every fourth scan, 462 µm apart), as well as by using an "adaptive" method where a subset (minimum 25 B-scans) of B-scans that the grader deemed as significantly different from adjacent B-scans were utilized. Mean absolute and percentage errors were calculated for macular thickness and area of different retinal layers for the different B-scan subset selection strategies relative to using all 49 B-scans, which was considered the reference or ground truth. RESULTS: Mean thickness and area measurements were significantly different for any regularly spaced reduction in B-scan density relative to the ground truth. When an adaptive approach was applied using a minimum of half the scans, the differences relative to ground truth were no longer significantly different. The mean percent differences for the area and thicknesses of the various layers ranged from 0.02 to 33.66 (p < 0.05 for all comparisons) and 0.44 to 7.24 (p > 0.05) respectively. CONCLUSION: Manual segmentation of a subset of B-scans using an adaptive strategy can yield thickness and area measurements of retinal sublayers comparable to the reference ground truth derived from using all B-scans in the volume. These results may have implications for increasing the efficiency of SD-OCT grading strategies in clinical trials for STGD and other related macular degenerative disorders.

[Unmet research and developmental needs in ophthalmology : A consensus-based road map of the European Vision Institute for 2019-2025]. / Forschungs- und Entwicklungsbedarf in der Augenheilkunde ("Unmet needs") : Ein konsensbasierter Fahrplan des European Vision Institute (EVI) für die Jahre 2019 bis 2025.

PURPOSE: To define unmet needs in ophthalmology which can realistically be addressed in the next years (2019-2025) and to describe potential avenues for research to address these challenges. METHODS: Outcomes of a consensus process within the European Vision Institute (EVI, Brussels) are outlined. Disease areas which are discussed comprise glaucoma, retinal dystrophies, diabetic retinopathy, dry eye disease, corneal diseases, cataract and refractive surgery. RESULTS: Unmet needs in the mentioned disease areas are discussed and realistically achievable research projects outlined. CONCLUSION: Considerable progress can be made in the field of ophthalmology and patient-relevant outcomes in the near future.

[Patient reported outcomes. Relevance and application in ophthalmology]. / "Patient reported outcomes" - Relevanz und Anwendung in der Augenheilkunde.

The use of patient-reported outcomes (PROs) - standardized assessments by the patient of the impact of illness or therapy - has been met with increasing interest over the last years. Evidence generated from PROs is used not only to support claims in the drug regulatory process but is also used in political decision making and activities by the pharmaceutical industry. PROs can reflect the benefits of a treatment very well because the patient's quality of life is a central variable, and its preservation or improvement is certainly the main objective of any therapeutic intervention. The routine use of PROs is still hampered by several methodological problems. However, there are a number of advantages, such as improved interaction between physicians and patients and shared decision making, that may result in increased compliance.

[Establishing ophthalmology in the research framework programs of the European Union]. / Verankerung der Augenheilkunde in den Forschungsrahmenprogrammen der Europäischen Union.

The framework programmes (FP) of the European Commission have substantially contributed to the funding of research within the European countries. The contribution of the funding provided by the EU relative to the funding available on the national level has steadily increased. European ophthalmology and vision research has benefited from this support provided by the EU. This review introduces the European funding policies and the European Research Area (ERA) and provides a list of all projects in ophthalmology and vision research that have been funded within FP1 to FP6. As an example for new instruments within FP6, Integrated Projects, the EVI-GENORET project is introduced. Finally an outlook for FP7 is provided.

[The European Vision Institute. Opening up new frontiers?]. / Das "European Vision Institute". Aufbruch zu neuen Ufern?

The European Vision Institute EEIG (EVI) creates a new legal entity based on Community law to facilitate and encourage cross-border co-operation in vision research. Its major objectives are to conduct and support research, training, health information dissemination and other programmes with respect to blinding eye diseases, visual disorders, mechanisms of visual function, preservation of sight and the special health problems and requirements of the blind and visually disabled. EVI aims to foster centres in the EU in capacity building for innovative projects, to increase the flexibility, attractiveness and competitiveness of research careers, especially for young researchers. In addition, EVI will serve to co-ordinate activities with patient organisations and to build a pan-European platform for clinical trials.

[Intravitreal bevacizumab for neovascular age-related macular degeneration]. / Intravitreales Bevacizumab bei der neovaskulären altersabhängigen Makuladegeneration.

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.

[Pseudoxanthoma elasticum]. / Pseudoxanthoma elasticum: Genetische Grundlagen, Manifestationen und therapeutische Ansätze.

Pseudoxanthoma elasticum (PXE) is an inherited disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vessel walls, and Bruch's membrane. Clinically, patients exhibit characteristic lesions of the skin (soft, ivory-colored papules in a reticular pattern that predominantly affect the neck), the posterior segment of the eye (peau d'orange, angioid streaks, choroidal neovascularizations), and the cardiovascular system (peripheral arterial occlusive disease, coronary occlusion, gastrointestinal bleeding). There is no causal therapy. Recent studies suggest that PXE is inherited almost exclusively as an autosomal recessive trait. Its prevalence has been estimated to be 1:25,000-100,000. The ABCC6 gene on chromosome 16p13.1 is associated with the disease. Mutations within the ABCC6 gene cause reduced or absent transmembraneous transport that leads to accumulation of substrate and calcification of elastic fibers. Although based on clinical features the diagnosis appears readily possible, variability in phenotypic expressions and the low prevalence may be responsible that the disease is underdiagnosed. This review covers current knowledge of PXE and presents therapeutic approaches.

[Classification of biomedical research reports as a reference for evidence-based medicine in ophthalmology. A survey considering as example the journal Der Ophthalmologe]. / Klassifikation biomedizinischer Forschungsberichte als Grundlage evidenzbasierter Medizin in der Augenheilkunde. Eine Untersuchung am Beispiel der Zeitschrift Der Ophthalmologe.

BACKGROUND: Evidence-based medicine requires careful appraisal of published data derived from experimental and clinical studies. Based on classification of biomedical research reports, evidence levels can be determined and recommendations for therapeutic decisions can be made. METHODS: A classification system for clinical studies was developed. It was evaluated in classifying the reports published in Der Ophthalmologe during 2003-2004 (study design: descriptive cross-sectional study, case series). RESULTS: In the 2-year interval, 70 longitudinal and 95 cross-sectional studies were published. The vast majority of the longitudinal studies were interventional cohort studies. Not considering case reports, 73% of the original articles were longitudinal prospective studies, 1% were retrospective (case-control) studies, and 26% were cross-sectional studies. CONCLUSIONS: The study design of all published articles could be classified using the classification system. This classification system proves to be applicable in the context of clinical studies in ophthalmology and may be helpful in the process of critical appraisal of the literature and synthesis of clinical evidence and an evidence-based recommendation.

[The complement system and its possible role in the pathogenesis of age-related macular degeneration (AMD)]. / Das Komplementsystem und dessen mögliche Beteiligung an der Pathogenese der altersabhängigen Makuladegeneration (AMD).

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.

[Y402H polymorphism in complement factor H and age-related macula degeneration (AMD)]. / Y402H-Polymorphismus im Komplementfaktor H und altersabhängige Makuladegeneration (AMD).

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.

Large phase differences between L-cone- and M-cone-driven electroretinograms in retinitis pigmentosa.

PURPOSE: To study the dynamics and interactions of the signals originating in the long- (L-) and middle (M)-wavelength-sensitive cone pathways in patients with retinitis pigmentosa (RP). METHODS: Twenty-six patients with RP and 29 normal subjects participated in the study. Electroretinographic (ERG) responses were measured to stimuli that modulated exclusively the L- or the M-cones or the two simultaneously (both in-phase and in counter-phase) with varying ratios of L- to M-cone contrasts. S-cones were not modulated. RESULTS: The data of the normal subjects and of the patients can be described by a model in which the amplitudes and the phases of the signals originating in the L- and M-cones are vector summed. In the RP patients, there was a general reduction in ERG sensitivity. The L-cone-driven ERG response was significantly delayed, whereas the M-cone-driven ERG response was phase advanced. CONCLUSIONS: Large dynamic differences between L- and M-cone-driven ERGs can be detected in RP. As a result, the interaction between the L- and M-cone systems, when modulated simultaneously at 30 Hz, is subtractive in RP patients and additive in normal subjects. Our data show that the use of only a standard white flicker ERG might lead to a misinterpretation of the mechanisms involved in retinal disorders, because the phases of different cone-driven responses are not considered.

Cone signal contributions to electroretinograms [correction of electrograms] in dichromats and trichromats.

PURPOSE: To find out how the different cone types contribute to the electroretinogram (ERG) by quantifying the contribution of the signal pathways originating in the long (L-) and the middle (M-) wavelength-sensitive cones to the total ERG response amplitude and phase. METHODS: ERG response amplitudes and phases were measured to cone-isolating stimuli and to different combinations of L- and M-cone modulation. Conditions were chosen to exclude any contribution of the short wavelength-sensitive (S-) cones. The sensitivity of the ERG to the L and the M cones was defined as the cone contrast gain. RESULTS: In the present paper, a model is provided that describes the ERG contrast gains and ERG thresholds in dichromats and color normal trichromats. For the X-chromosome-linked dichromats, the contrast gains of only one cone type (either the L or the M cones) sufficed to describe the ERG thresholds for all stimulus conditions. Data suggest that the M-cone contrast gains of protanopes are larger than the L-cone contrast gains of deuteranopes. The response thresholds of the trichromats are modeled by assuming a vector summation of signals originating in the L and the M cones. Their L- and M-cone contrast gains are close to a linear interpolation of the data obtained from the dichromats. Nearly all trichromats had larger L- than M-cone contrast gains. Data from a large population of trichromats were examined to study the individual variations in cone weightings and in the phases of the cone pathway responses. CONCLUSIONS: The data strongly suggest that the missing cone type in dichromats is replaced by the remaining cone type. The mean L-cone to M-cone weighting ratio in trichromats was found to be approximately 4:1. But there is a substantial interindividual variability between trichromats. The response phases of the L- and the M-cone pathways can be reliably quantified using the response phases to the cone-isolating stimuli or using a vector addition of L- and M-cone signals.

Slow and fast rod ERG pathways in patients with X-linked complete stationary night blindness carrying mutations in the NYX gene.

PURPOSE: To study the slow and fast rod signals of the scotopic 15-Hz flicker ERG in patients carrying mutations in the NYX gene, which has been recently identified as the cause of the complete form of congenital stationary night blindness, CSNB1. METHODS: Twenty eyes of 11 patients with CSNB1 who had nondetectable standard ERG rod b-waves were involved in the study. Scotopic ERG response amplitudes and phases to flicker intensities ranging from -3.37 to -0.57 log scotopic trolands. sec (scot td. sec) were measured at a flicker frequency of 15 Hz. ERG signals to flicker intensities between -3.37 and -1.97 and between -1.17 and -0.57 log scot td. sec were considered to represent primarily the slow and fast rod ERG pathway, respectively. Additionally, standard ERGs were performed. Twenty-two normal volunteers served as control subjects. RESULTS: For the slow rod ERG pathway, all patients exhibited ERG signals that were indistinguishable from noise. Accordingly, there was no systematic phase behavior for the slow rod signals. For the fast rod ERG pathway, the signals were significantly above noise, but they were significantly reduced in amplitude and advanced in phase. CONCLUSIONS: There is evidence that the slow and the fast rod ERG signals can be attributed to the rod bipolar-AII cell pathway and the rod-cone-coupling pathway, respectively. The current study provides evidence to suggest that a defective NYX gene product (nyctalopin) prevents detectable signal transmission through ON rod bipolar cells, but there is a residual transmission through rod-cone gap junctions in CSNB1, possibly through the OFF cone pathway.

L- and M-cone-driven electroretinograms in Stargardt's macular dystrophy-fundus flavimaculatus.

PURPOSE: To study the dynamics of the long (L)- and middle (M)-wavelength-sensitive cone-driven pathways and their interactions in patients with Stargardt's macular dystrophy-fundus flavimaculatus (SMD-FF) and to correlate them with other clinical parameters and individual genotypes. METHODS: Forty-seven patients with SMD-FF participated in the study. In addition to standard 30-Hz flicker electroretinograms (30-Hz fERG), ERG responses were measured to stimuli that modulated exclusively the L or the M cones (L/M cones) or the two simultaneously. Blood samples were screened for mutations in the 50 exons of the ABCA4 gene. RESULTS: Patients with SMD-FF did not show a decrease in the mean L/M-cone-driven ERG sensitivity, but there was a significant increase in the interindividual variability. The mean L-/M-cone weighting ratio was normal. However, the L-cone-driven ERG was significantly phase delayed, whereas the M-cone-driven ERG was significantly phase advanced. These phase changes were significantly correlated with disease duration. The amplitude and implicit time of the standard 30-Hz fERG both correlated significantly with the L/M-cone-driven ERG sensitivity and with the phase difference between the L/M-cone-driven ERGs, indicating the complex origin of the standard 30-Hz fERG. Probable disease-associated mutations in the ABCA4 gene were found in 40 of 45 patients, suggesting that they form a genetically fairly uniform SMD-FF study group. There was no correlation between the genotype and the L/M-cone-driven ERGS: CONCLUSIONS: The changes in L/M-cone-driven ERG sensitivity and phase possibly represent two independent disease processes. The phase changes are similar to those found in patients with retinitis pigmentosa and possibly are a general feature of retinal dystrophies.

Electrophysiology in the investigation of acquired retinal disorders.

Electrophysiological research on acquired retinal disorders, both common and rare, is reviewed. Age is a major factor influencing electroretinogram (ERG) and electro-oculogram (EOG) findings. Bipolar or Müller cell death in the aging retina could account for much of the amplitude decline that is observed with age. In diabetic retinopathy, the oscillatory potentials can monitor the progression of the disease and indicate neuronal alterations rather than diabetic angiopathy of the retina. Human ERG studies on glaucoma concentrated on ERG measures that are dominated by inner retinal contributions. It has been shown that the pattern ERG can serve as a predictor of ocular hypertension's progression to glaucoma. In retinal disorders caused by endogenous intoxication, such as hepatic retinopathy, or exogenous intoxication from chronic lead exposure, ERG changes give an objective measure of the damage and allow to study the pathophysiological mechanisms that are involved. Inflammations of the choroid and the retina affect the standard ERG when they are diffuse. In central serous chorioretinopathy, functional disturbances can be revealed not only in the photoreceptors but also in the middle and inner retinal layers with the use of focal stimuli. Choroidal melanoma leads to large reductions of the EOG light peak-to-dark trough ratio through its influence on the transepithelial potential of the retinal pigment epithelium (RPE). In cancer-associated retinopathy, both the rod and cone ERGs are reduced. However, selective cone dysfunction has been described. In melanoma-associated retinopathy, the long flash ERG may reveal a specific pathophysiological mechanism, namely the affection of the ON-pathway with preservation of the OFF-pathway. ERG measurements can reveal vitamin A deficiency and are altered in cases with a mutation in the gene for the retinol binding protein in which other organs are not affected. Photochemical damage to the retina from light emission by the operating microscope can be assessed by electrophysiological methods.

L- and M-cone driven ERGs are differently altered in Best's macular dystrophy.

To study the L- and M-cone pathways and their interactions in patients with Best's macular dystrophy (BMD), ERG response thresholds were measured to stimuli which modulated exclusively the L- or the M-cones, or both in various combinations. The ERG threshold data could be described with a vector addition model. Compared with normals, BMD patients showed generally larger amplitudes of the L-cone driven ERGs. However, the M-cone driven ERGs were similar in amplitude but significantly phase advanced. The data confirm our previous observations that L- and M-cone pathways can be affected differently by retinal degeneration, despite their large physiological and biochemical similarities.

Macular dystrophy with protan genotype and phenotype studied with cone type specific ERGs.

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.

[Methods for estimating personal costs of disease using retinal diseases as an example]. / Methoden zur Ermittlung persönlicher Krankheitskosten am Beispiel retinaler Erkrankungen.

PURPOSE: Age-related macular degeneration (AMD) and other retinal diseases, such as diabetic retinopathy (DRP) and hereditary retinal dystrophy can not only lead to a loss of visual function but also to a higher psychological and financial burden for the affected persons. Against this background a quantification of personal cost and vision-related quality of life was performed. METHODS: A total of 66 patients (mean age 69 years, SD 13 years) with clinically confirmed diagnoses of AMD, DRP or retinal dystrophy were interviewed regarding costs for medicines, aids and equipment, support in everyday life and social benefits. Vision-related quality of life was recorded using the Impact of Vision Impairment profile (IVI). RESULTS: The average total annual cost was 751 per patient, out of which the largest amount was cost of support in everyday life (506). Costs as well as dependence on other persons or social services increased with decreasing visual acuity (p=0.013). Vision-related quality of life decreased with increasing visual disability especially in the IVI subscales mobility and independence as well as reading and accessing information (p=0.002). CONCLUSIONS: Prevention or delay of visual disability and blindness caused by AMD or other retinal diseases and thus ensuring independence is not only relevant from a medical perspective but also from a health economic perspective. Against the background of a relative shortage of resources, costs should be reduced regardless of whether they are personal or societal costs.