Levels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression.

Dysregulation of the alternative pathway (AP) of the complement system is a significant contributor to age-related macular degeneration (AMD), a primary cause of irreversible vision loss worldwide. Here, we assess the contribution of the liver-produced complement factor H-related 4 protein (FHR-4) to AMD initiation and course of progression. We show that FHR-4 variation in plasma and at the primary location of AMD-associated pathology, the retinal pigment epithelium/Bruch's membrane/choroid interface, is entirely explained by three independent quantitative trait loci (QTL). Using two distinct cohorts composed of a combined 14,965 controls and 20,741 cases, we ascertain that independent QTLs for FHR-4 are distinct from variants causally associated with AMD, and that FHR-4 variation is not independently associated with disease. Additionally, FHR-4 does not appear to influence AMD progression course among patients with disease driven predominantly by AP dysregulation. Modulation of FHR-4 is therefore unlikely to be an effective therapeutic strategy for AMD.

[Prospective noninterventional BLUE SKY study evaluating the efficacy of brolucizumab in treatment-naïve and previously treated patients with neovascular AMD]. / Prospektive nichtinterventionelle BLUE SKY-Studie zur Beurteilung der Wirksamkeit von Brolucizumab bei unbehandelten und vorbehandelten Patienten mit neovaskulärer AMD.

Intravitreal injection of anti-vascular endothelial growth factor (VEGF) is the standard treatment for patients with neovascular age-related macular degeneration (nAMD). In addition to the approved substances ranibizumab (Lucentis®, Novartis) and aflibercept (Eylea®, Bayer), bevacizumab (Avastin®, Roche) is also available. Furthermore, brolucizumab (Beovu®, Novartis) has been approved and has been available in Germany since April 2020. The multicenter, noninterventional prospective BLUE SKY study investigates brolucizumab treatment with different schemes in 600 treatment-naive and pretreated nAMD patients in routine clinical practice over a 24-month period. Besides general patient data, visual acuity and treatment data will be documented. Fluorescein angiography, fundus photography, spectral domain optical coherence tomography and swept-source optical coherence tomography angiography will be performed and analyzed by reading centers. The focus of the analysis will be on the intraretinal and subretinal fluid distribution as well as morphological MNV changes and injection frequency. Also, safety and adverse drug effects of brolucizumab, with a specific focus on inflammatory complications, particularly retinal (occlusive) vasculitis will be evaluated.

[YAG laser vitreolysis for treatment of symptomatic vitreous opacities]. / YAG-Laser-Vitreolyse zur Behandlung von störenden Glaskörpertrübungen.

YAG laser vitreolysis is an innovative procedure to treat symptomatic vitreous floaters. The treatment decision is based on taking a comprehensive patient history, thorough clinical examination, realistic expectations, and detailed patient information including risk of the procedure. Manifestation of vitreous opacities and possible subjective impairments are considerably variable. Dynamic changes over time are possible. Therefore, not all vitreous opacities are suitable for laser treatment. A classification according to histoanatomical origin can aid the treatment decision. In comparison to other ophthalmic YAG laser applications, YAG laser vitreolysis differs predominantly by its specific technical equipment requirements. In addition, treatment is more complex and time consuming, requires appropriate experience and knowledge of the surgeon, and should be carried out with utmost care and accuracy.

Comparison of the horizontal diameter to a modeled area of traction in eyes with vitreomacular traction: is the diameter close enough to the truth?

PURPOSE: In daily practice, vitreomacular traction (VMT) is described by the horizontal diameter of its attachment site implying a regular round shape of VMT. We investigated the deviation from this circular area of vitreous traction in patients with VMT. METHODS: A retrospective analysis of optical coherence tomography (OCT) scans was performed. The area of vitreomacular attachment was determined using six radial OCT scans (Ameasured). The assumed circular area of traction was calculated based on measuring the maximal horizontal diameter for comparison (Acircular). RESULTS: Thirty-seven eyes of 37 patients with pure VMT were included. Patients' mean age was 72.8 ± 8.2 years. Mean horizontal VMT diameter was 400.8 ± 230.5 µm (median 361 µm; range 44-991 µm). While there was no difference between mean areas of traction for Acircular and Ameasured (P = 0.93), the individual difference (|Acircular - Ameasured|) was 0.042 (± 0.044) mm2 in mean or relative 73.0% (± 135.8%). A difference of ≥ 30% of Ameasured to Acircular was found in 16 eyes (43.2%) and ≥ 100% in 7 eyes (18.9%), respectively. CONCLUSION: Vitreous attachment sites possess an irregular non-circular shape in a significant number of eyes with VMT. Consequently, the area of traction appears inaccurately described by its horizontal VMT diameter alone. As the area of traction is important for therapeutic recommendation, our results emphasize the need for a more precise description of the area of traction in eyes with VMT.

[Pitfalls in retinal optical coherence tomography imaging]. / Fallstricke in der Netzhautbildgebung mittels optischer Kohärenztomographie.

Optical coherence tomography (OCT) imaging now plays an important role in the management of macular and retinal diseases. In addition to the many advantages of this noninvasive imaging modality, limitations and pitfalls should be taken into consideration. The aim of this review is to discuss several possible sources of error in the conduct and interpretation of OCT imaging. Ultimately, this article should add to a meaningful and focused use in clinical practice.

[Optical coherence tomography angiography (OCT­A) in rats]. / Optische-Kohärenztomographie-Angiographie (OCT­A) bei Ratten.

PURPOSE: Optical coherence tomography angiography (OCT­A) allows for the non-invasive, three-dimensional visualization of retinal and chorioidal vascular structures. In this study, this new imaging modality was evaluated in rats. METHODS: In vivo imaging in Dark Agouti rats was performed using confocal scanning laser ophthalmoscopy (cSLO) and OCT­A (Spectralis prototype, Heidelberg Engineering) after adjusting the length of the reference arm. The OCT­A en-face images were compared to conventional fluorescein angiography cSLO images. The histological examination allowed for correlation of retinal and chorioidal plexus. RESULTS: While the diagnostic device was developed for use in humans, OCT­A and cSLO imaging can be applied in rodents after only minor hardware modifications. High-resolution and contrast-enhanced images enable a depth-selective visualization of the three retinal plexus and the inner and outer chorioidal vascular networks. In comparison to fluorescein angiography (FA), OCT­A is characterized by higher resolution and more accurate three-dimensional localization of vascular structures, particularly in deep layers. A current limitation includes the relatively small area imaged by OCT­A. DISCUSSION: The recently developed OCT­A imaging technology also allows for three-dimensional detection of retinal and chorioidal vascular changes in vivo without dye injection in rodents. OCT may potentially replace invasive FA for specific questions and will be useful in animal models for research of retinal and chorioidal angiogenic processes physiologically and during pharmacological interventions.

[Retinal imaging of the macula and optic disc in neurodegenerative diseases]. / Retinale Bildgebung von Makula und Papille bei neurodegenerativen Erkrankungen.

BACKGROUND: Due to current demographic trends, the prevalence of mild cognitive impairment and dementia is expected to increase considerably. For potential new therapies it is important to identify patients at risk as early as possible. Currently, there is no population-based screening. Therefore, identification of biomarkers that will help screen the population at risk is urgently needed. Thus, a literature review on retinal pathology in neurodegenerative diseases was performed. METHODS: PubMed was searched for studies published up to August 2016 using the following keywords: "mild cognitive impairment", "dementia", "eye", "ocular biomarkers", "OCT" and "OCT angiography". Relevant publications were selected and summarized qualitatively. RESULTS: Multiple studies using noninvasive in vivo optical coherence tomography (OCT) imaging showed nonspecific retinal pathological changes in patients with neurodegenerative diseases such as mild cognitive impairment, Alzheimer's and Parkinson's disease. Pathological changes in macular volume, optic nerve fiber layer thickness and the ganglion cell complex were observed. However, based on available evidence, no ocular biomarkers for neurodegeneration which could be integrated in routine clinical diagnostics have been identified. CONCLUSION: The potential use of OCT in the early diagnostic workup and monitoring of progression of neurodegenerative diseases needs to be further explored in longitudinal studies with large cohorts.

[Design of the ORCA module in the OCEAN study : Evaluation of SD-OCT results in daily routine practice]. / Design des ORCA-Moduls der OCEAN-Studie : Evaluierung der SD-OCT-Befunderhebung in der täglichen Praxisroutine.

BACKGROUND: The prevalence of blindness as defined by law could be reduced by the introduction of anti-vascular endothelial growth factor (VEGF) therapy. Because the treatment is governed by patient needs, mostly using morphological criteria, imaging diagnostics are of particular importance. The non-interventional OCEAN study investigates the treatment with ranibizumab in the clinical routine practice. In a subgroup of patients the interpretation of spectral domain optical coherence tomography (SD-OCT) scans by the treating physicians will be analyzed (ORCA module). METHODS: Over a period of 24 months data from patients with exudative age-related macular degeneration (AMD), macular edema due to retinal vein occlusion or diabetes mellitus, who are receiving intravitreal injections of ranibizumab, will be assessed. Information on examinations, visual acuity, treatment and recordings from imaging techniques will be documented using a questionnaire. The SD-OCT scans, fluorescence angiography and fundus photography will be independently analyzed by the ophthalmologist of the study center and by three reading centers (CIRCL Cologne, GRADE Bonn and M3 Münster). Automated measurements of retinal thickness by the manufacturers' software will be checked and if necessary manually corrected. A qualitative interpretation in terms of morphological criteria for (further) treatment will be performed. CONCLUSION: A thorough assessment of SD-OCT images during anti-VEGF therapy provides the basis for the best possible needs-oriented treatment regimen. The control of the quality of data from daily routine practice may indicate possible weaknesses allowing explicit training and therefore optimization of patient treatment.

[Delayed treatment initiation of more than 2 weeks. Relevance for possible gain of visual acuity after anti-VEGF therapy under real life conditions (interim analysis of the prospective OCEAN study)]. / Verzögerung des Behandlungsbeginns um mehr als 2 Wochen. Relevanz für möglichen Visusgewinn nach Anti-VEGF-Therapie unter Real-Life-Bedingungen (Interimanalyse der prospektiven OCEAN-Studie).

BACKGROUND: The largest German prospective non-interventional ophthalmological study OCEAN (NCT02194803) investigates the treatment of retinal diseases with ranibizumab in routine patient care. A feature of this study is the participation of ophthalmic surgeons in surgical centers as well as general ophthalmologists who do not perform intravitreal injections themselves. OBJECTIVES: The functional outcome following administration of three intravitreal injections was analyzed with respect to the time from initial examination to the first injection (defined as treatment delay) as well as potentially confounding factors. MATERIAL AND METHODS: This interim analysis included only data from therapy naïve patients participating in the OCEAN study, who received at least three ranibizumab injections. The potential impact of various factors on treatment delay was analyzed by the χ(2)-test. RESULTS: Data of 1333 patients were analyzed. The median delay before treatment was 15 days (range 0-90 days). Patients with a delay of more than 28 days showed a significantly lower gain in visual acuity than patients with a delay of less than 14 days. Age, gender and baseline visual acuity did not show an association with the treatment delay; however, referral from a primary care ophthalmologist, undertaking fluorescein angiography in an external practice and the underlying indications did affect the observed treatment delays. CONCLUSION: Every patient should be treated within 14 days, following recent recommendations of the ophthalmological societies. Liability issues have to be considered as the statistical evaluation of real life data showed unambiguous results.

[Fundus Autofluorescence Imaging]. / Fundusautofluoreszenz-Imaging.

Fundus autofluorescence (FAF) imaging allows for non-invasive mapping of changes at the level of the retinal pigment epithelium/photoreceptor complex and of alterations of macular pigment distribution. This imaging method is based on the visualisation of intrinsic fluorophores and may be easily and rapidly used in routine patient care. Main applications include degenerative disorders of the outer retina such as age-related macular degeneration, hereditary and acquired retinal diseases. FAF imaging is particularly helpful for differential diagnosis, detection and extent of involved retinal areas, structural-functional correlations and monitoring of changes over time. Recent developments include - in addition to the original application of short wavelength light for excitation ("blue" FAF imaging) - the use of other wavelength ranges ("green" or "near-infrared" FAF imaging), widefield imaging for visualisation of peripheral retinal areas and quantitative FAF imaging.

[Reticular drusen over time with SD-OCT]. / Retikuläre Drusen über die Zeit mittels SD-OCT.

AIM: The aim of the study was the analysis of reticular drusen (RDR) in patients with age-related macular degeneration using simultaneous confocal scanning laser ophthalmoscopy (cSLO) and spectral domain optical coherence tomography (SD-OCT) at different time points. METHODS: Included in this retrospective analysis were 47 eyes from 32 patients (median age 80.1 years, range 66-89 years) with RDR at baseline and at least one follow-up visit. Registration of the cSLO near-infrared reflectance image and the SD-OCT B-scan (Spectralis HRA + OCT, Heidelberg Engineering, Heidelberg) at different time points was carried out using the AutoRescan tool. RESULTS: While either no alterations or increase in the RDR area (n=19 eyes) or RDR density (n=15) were seen by cSLO imaging, the analysis of the SD-OCT B-scans at different time points revealed a more complex picture. An increase in two well visible lesions at the baseline visit was detected in 8 eyes at the first follow-up and in 3 eyes at the second follow-up examination. A regression was seen in 5 eyes at the first follow-up and in 3 eyes at the second follow-up visit. In most eyes (n=23), an increase of one with a parallel decrease of the second RDR lesion in the identical B-scan was identified at the first follow-up visit, whereas individual RDR showed an increase at the second follow-up examination that had initially shown a decrease in size at the first follow-up visit. CONCLUSIONS: The results indicate underlying dynamic processes in the development and changes of RDR over time. For a more accurate analysis, the exact registration of SD-OCT B-scans at different time points and the use of high-resolution very dense volume scans would be helpful in order to assess such discrete changes of miniscule intraretinal lesions over time.

[Predictive near-infrared SLO signs for tears of the retinal pigment epithelium due to age-related macular degeneration]. / Prädiktive nahinfrarot-SLO-merkmale für risse des retinalen pigmentepithels bei altersabhängiger makuladegeneration.

PURPOSE: The aim of this study was to identify potential predictive markers in confocal scanning laser ophthalmoscopy (cSLO)-based imaging for tears of the retinal pigment epithelium (RPE) in the presence of pigment epithelial detachments (PED) due to age-related macular degeneration (AMD). METHODS: Fifteen eyes of 15 patients (mean age 77 years, SD ± 6) with RPE tears and pre-existing PEDs were retrospectively analysed for the presence of increased signals on near-infrared imaging (NIR) using confocal scanning laser ophthalmoscopy (cSLO). RESULTS: In 87 % of the cases increased reflectance signals on NIR in the area of the PED were noted prior to the development of an RPE tear. On average, these signals were recorded 58 days (SD ± 40) before the rip was diagnosed. In 62 % of the patients these signals were localised opposite to the rip location at the rim of the PED. CONCLUSION: Increased reflectance signals on NIR imaging may serve as a predictive marker for RPE tears in patients with PED in AMD. These signals recordable with a non-invasive imaging method should be prospectively validated in a larger cohort of patients with PEDs. It may be useful in the management of patients exhibiting this manifestation of exudative AMD.

[Clinical characteristics, progression and risk factors of geographic atrophy]. / Klinische Merkmale, Progression und Risikofaktoren bei geographischer Atrophie.

Geographic atrophy (GA) as the late stage manifestation of age-related macular degeneration (AMD) is a progressive disease process afflicting the retinal pigment epithelium, choriocapillaris and the outer neurosensory retina. GA represents a complex, multifactorial disease governed by the interdependence of genetic, endogenous and exogenous factors. Diagnosis and monitoring of GA progression is largely based on various retinal imaging modalities. After the breakthrough in the treatment of wet AMD GA represents a large clinical challenge. Recent studies have contributed to a better understanding of the pathophysiological pathways, natural history and predictive markers for progression.

[Imaging diagostics of geographic atrophy]. / Bildgebende Diagnostik bei geographischer Atrophie.

The development of imaging technologies has contributed to the understanding of the genesis and pathophysiological mechanisms of geographic atrophy (GA) secondary to age-related macular degeneration (AMD). Fundus autofluorescence (FAF) imaging allows accurate discrimination of the boundaries of atrophic patches. Furthermore, predictive markers for disease progression can be identified. Non-invasive FAF imaging now represents the gold standard for evaluating progressive enlargement of atrophic areas. By means of high resolution optical coherence tomography (OCT) microstructural retinal changes in GA can be identified. Anatomical endpoints are now being used in interventional GA trials and represent meaningful outcome parameters as surrogate markers in an overall slowly progressive disease which may not affect the fovea until later stages of the disease.

[Therapy approaches for geographic atrophy]. / Therapieansätze bei geographischer Atrophie.

Geographic atrophy, the dry form and late manifestation of age-related macular degeneration, is the next challenge following the breakthrough in the treatment of neovascular age-related macular degeneration (AMD). Various interventional pharmacologic approaches with different targets are already being tested in clinical interventional trials. These include reduction of retinal toxins, anti-inflammatory agents, complement inhibition, neuroprotection and alleviation of oxidative stress. Until efficacy and safety is demonstrated, aids for poor vision and further rehabilitative measures remain essential for patients with advanced dry AMD.

[In vivo imaging of retinal cell apoptosis following acute light exposure]. / In-vivo-Imaging retinaler Zellapoptose nach akuter Lichtexposition.

PURPOSE: Outer nuclear apoptosis following acute light exposure has previously only been shown histologically. This study investigated whether in vivo detection with DARC (detection of apoptosing retinal cells) technology could identify cells undergoing apoptosis. METHODS: Acute blue light damage (lambda=405 nm; 3.2 mW/cm(2)) was applied to eyes of dark Agouti rats over 2 h. In vivo retinal imaging using confocal scanning laser ophthalmoscopy was performed before and directly after light exposure as well as after 24 h of dark adaptation. Development of retinal cell apoptosis was then assessed using intravitreal fluorescent-labeled annexin-5 with DARC technology in vivo. RESULTS: Directly after light exposure, no pathological retinal changes were observed by in vivo imaging. However, retinal flattening and the development of apoptosis within the irradiated retina occurred 1 day later and following dark adaptation. Confocal live scanning through the exposed retina revealed hyperfluorescent apoptotic cells at the level of the outer retina. Histological analysis confirmed the occurrence of photoreceptor cell death and the development of cellular damage at the outer retina. DISCUSSION: This study confirms acute light-induced outer nuclear apoptosis using in vivo DARC technology. This may open new and promising ways to assess programmed cell death of the photoreceptor cells, which - until now - was possible only with postmortem analysis.

Lower limits of fluorescein and indocyanine green dye for digital cSLO fluorescence angiography.

BACKGROUND: With the advent of digital confocal scanning laser ophthalmoscopy it is possible to detect low levels of fluorescence. Here we used a novel confocal scanning laser ophthalmoscope (cSLO) to determine lower limits of dye required for fluorescein (FL) and indocyanine green (ICG) angiography. METHODS: A cSLO (Heidelberg retina angiograph 2, Heidelberg Engineering, Dossenheim, Germany) with an optically pumped solid state laser (488 nm) for FL and a diode laser (790 nm) for ICG angiography (FL/ICG-A) was used. 62 FL-As were performed in 53 patients and 45 ICG-As were performed in 39 patients with neovascular age related macular degeneration. The volume and overall dye content of bolus injections was gradually tapered (FL: 500 mg, 250 mg, 200 mg, 166 mg, 100 mg; ICG: 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, 2.5 mg), while dye concentrations were kept constant at 100 mg/ml for FL and at 5 mg/ml for ICG. Images were obtained 1, 5, 15, and 30 minutes after dye injection. Image quality was evaluated by two independent readers using standardised criteria. RESULTS: For amounts down to 166 mg for FL and to 5 mg for ICG, sufficient image quality was achieved during all phases following injection. Only late phase images showed less contrast compared to typically used dye amounts, which was irrelevant for interpretation and clinical management. CONCLUSIONS: With the increased sensitivity of this novel cSLO system, amounts of injected dye during FL-A can be reduced to one third for FL and to one fifth for ICG without relevant loss of image quality or information compared to conventionally used dye levels. These amounts can be used for routine angiography and allow relevant savings for units performing FL-A.

Classification of abnormal fundus autofluorescence patterns in the junctional zone of geographic atrophy in patients with age related macular degeneration.

AIM: To describe and classify patterns of abnormal fundus autofluorescence (FAF) in the junctional zone of geographic atrophy (GA) in patients with age related macular degeneration. METHODS: Digital FAF images were recorded in 164 eyes of 107 patients using a confocal scanning laser ophthalmoscope (cSLO; excitation 488 nm, detection above 500 nm) as part of a prospective multicentre natural history study (FAM Study). FAF images were obtained in accordance with a standardised protocol for digital image acquisition and generation of mean images after automated alignment. RESULTS: Image quality was sufficient for classification of FAF patterns in 149 eyes (90.9%) with lens opacities being the most common reason for insufficient image quality. Abnormal FAF outside GA in 149 eyes was classified into four patterns: focal (12.1%), banded (12.8%), patchy (2.0%), and diffuse (57.0%), whereby 12.1% had normal background FAF in the junctional zone. In 4% there was no predominant pattern. The diffuse pattern was subdivided into four groups including reticular (4.7%), branching (27.5%), fine granular (18.1%), and fine granular with peripheral punctate spots (6.7%). CONCLUSIONS: Different phenotypic patterns of abnormal FAF in the junctional zone of GA can be identified with cSLO FAF imaging. These distinct patterns may reflect heterogeneity at a cellular and molecular level in contrast with a non-specific ageing process. A refined phenotypic classification may be helpful to identify prognostic determinants for the spread of atrophy and visual loss, for identification of genetic risk factors as well as for the design of future interventional trials.