Conventional photodynamic therapy (cPDT) is an effective treatment option for field cancerization and multiple actinic keratoses (AK). The main side effect of cPDT is pain during illumination which in severe cases might necessitate early termination of treatment. Modification of treatment parameters such as light dose and fluence rate is a promising approach to mitigate PDT-associated pain. The aim of this study was to compare the efficacy and tolerability of four different cPDT illumination protocols in the treatment of AK in the head region. Prospective, investigator-blinded, within-patient study on 67 patients with multiple AK in the head region. PDT treatment was performed on comparable target areas with four different settings of illumination: (A) standard light dose and standard fluence rate, (B) standard light dose and halved fluence rate, (C) halved standard light dose and standard fluence rate and (D) halved standard light dose and halved fluence rate. Pain and the intensity of the phototoxic skin reaction was recorded during and after illumination. The clearance rate of the target areas and target lesions was assessed at 12 weeks after PDT. Target areas with incomplete clearance were retreated, those with complete clearance were reassessed at 24 weeks after PDT. The mean and maximum pain level during illumination was significantly decreased at the lower fluence rates. The phototoxic skin reaction was most pronounced with the standard illumination setting. The overall clearance rate of AK and the clearance rate of the target lesions at 3 months after PDT as well as the number of recurrent or new AK at 6 months after PDT did not differ between four treatment protocols. Reduction of the fluence rate and/or light dose was associated with less PDT-induced pain and/or shorter exposures times without compromising the therapeutic efficacy of cPDT for AK in the head region.

Chronic venous insufficiency (CVI) is a global health concern with significant public health and individual impact. Currently available diagnostic methods cannot visualize microvenous pathologies that have shown to result in severe forms of CVI and also affect the skin. Optical coherence tomography angiography (OCTA) may close the CVI diagnostic gap by providing a fast, label-free, and non-invasive solution to visualize cutaneous microvasculature. The study enlisted 66 subjects, including 53 CVI patients spanning all clinical-etiology-anatomic-pathophysiologic (CEAP) C stages and 13 healthy controls. The high spatial resolution OCTA system used was specifically designed for skin imaging. Significant microangiographic pattern variations emerged, both in qualitative and quantitative terms. OCTA provided valuable insights into cutaneous microvascular changes among different CVI stages. Thereby, OCTA may enable the selection of patient populations at risk for disease progression in the future.

BackgroundConventional photodynamic therapy (cPDT) is an effective treatment option for field cancerization and multiple actinic keratoses (AK). The main side effect of cPDT is pain during illumination which in severe cases might necessitate early termination of treatment. Modification of treatment parameters such as light dose and fluence rate is a promising approach to mitigate PDT-associated pain.ObjectivesThe aim of this study was to compare the efficacy and tolerability of four different cPDT illumination protocols in the treatment of AK in the head region.MethodsProspective, investigator-blinded, within-patient study on 67 patients with multiple AK in the head region. PDT treatment was performed on comparable target areas with four different settings of illumination: (A) standard light dose and standard fluence rate, (B) standard light dose and halved fluence rate, (C) halved standard light dose and standard fluence rate and (D) halved standard light dose and halved fluence rate. Pain and the intensity of the phototoxic skin reaction was recorded during and after illumination. The clearance rate of the target areas and target lesions was assessed at 12 weeks after PDT. Target areas with incomplete clearance were retreated, those with complete clearance were reassessed at 24 weeks after PDT.ResultsThe mean and maximum pain level during illumination was significantly decreased at the lower fluence rates. The phototoxic skin reaction was most pronounced with the standard illumination setting. The overall clearance rate of AK and the clearance rate of the target lesions at 3 months after PDT as well as the number of recurrent or new AK at 6 months after PDT did not differ between four treatment protocols.ConclusionsReduction of the fluence rate and/or light dose was associated with less PDT-induced pain and/or shorter exposures times without compromising the therapeutic efficacy of cPDT for AK in the head region.

To find baseline predictors for subretinal fibrosis (SF) in neovascular age-related macular degeneration (nAMD). Forty-five eyes of 45 participants with treatment-naïve nAMD were consecutively enrolled and treated according to a standardized treat-and-extend protocol. Spectral-domain optical coherence tomography (OCT), color fundus photography and fluorescein angiography as well as novel imaging modalities polarization-sensitive OCT and OCT angiography (OCTA) were performed to detect SF after 1 year and find baseline predictors for SF development. Baseline OCTA scans were evaluated for quantitative features such as lesion area, vessel area, vessel junctions, vessel length, vessel endpoints and mean lacunarity. Additionally, the type of macular neovascularization, the presence of subretinal fluid, intraretinal fluid (IRF), subretinal hyperreflective material (SHRM), retinal hemorrhage as well as best-corrected visual acuity (BCVA) were evaluated. After 12 months 8 eyes (18%) developed SF. Eyes with SF had worse baseline BCVA (p = .001) and a higher prevalence of IRF (p = .014) and SHRM at baseline (p = .017). There was no significant difference in any of the evaluated quantitative OCTA parameters (p > .05) between eyes with and without SF. There were no quantitative baseline microvascular predictors for SF in our study. Low baseline BCVA, the presence of IRF and SHRM, however, are easily identifiable baseline parameters indicating increased risk.

PURPOSE:To identify correlations between the vascular characteristics of macular neovascularization (MNV) obtained by optical coherence tomography angiography (OCTA) and distinct retinal fluid volumes in neovascular age-related macular degeneration (nAMD). METHODS:In this prospective interventional study, 54 patients with treatment-naïve type 1 or 2 nAMD were included and treated with intravitreal aflibercept. At baseline and month 1, each patient underwent a SD-OCT volume scan and volumetric flow scan using a swept-source OCTA. A deep learning algorithm was used to automatically detect and quantify fluid in OCT scans. Angio Tool, a National Cancer Institute algorithm, was used to skeletonize MNV properties and quantify lesion size (LS), vessel area (VA), vessel density (VD), total number of endpoints (TNE), total number of junctions (TNJ), junction density (JD), total vessel length (TVL), average vessel length (AVL) and mean-e-lacunarity (MEL). Subsequently, linear regression models were used to investigate a correlation between OCTA parameters and fluid quantifications. RESULTS:The median amount of fluid within the central 6-mm EDTRS ring was 173.7 nl at baseline, consisting of 156.6 nl of subretinal fluid (SRF) and 2.3 nl of intraretinal fluid (IRF). Fluid decreased significantly in all compartments to 1.76 nl (SRF) and 0.64 nl (IRF). The investigated MNV parameters did not change significantly after the first treatment. There was no significant correlation between MNV parameters and relative fluid decrease after anti-VEGF treatment. Baseline fluid correlated statistically significant but weakly with TNE (p = 0.002, R2  = 0.17), SRF with TVL (p = 0.04, R2  = 0.08), VD (p = 0.046, R2  = 0.08), TNE (p = 0.001, R2  = 0.20) and LS (p = 0.033, R2  = 0.09). IRF correlated with VA (p = 0.042, R2  = 0.08).The amount of IRF at month 1 correlated significantly but weakly with VD (p = 0.036, R2  = 0.08), JD (p = 0.019, R2  = 0.10) and MEL (p = 0.005, R2  = 0.14). CONCLUSION:Macular neovascularization parameters at baseline and month 1 played only a minor role in the exudation process in nAMD. None of the MNV parameters were correlated with the treatment response.

Purpose To assess the signal composition of cone photoreceptors three-dimensionally in healthy retinas using adaptive optics optical coherence tomography (AO-OCT). Methods Study population. Twenty healthy eyes of ten subjects (age 23 to 67). Procedures. After routine ophthalmological assessments, eyes were examined using AO-OCT. Three-dimensional volumes were acquired at 2.5° and 6.5° foveal eccentricity in four main meridians (superior, nasal, inferior, temporal). Cone densities and signal compositions were investigated in four different planes: the cone inner segment outer segment junction (IS/OS), the cone outer segment combined with the IS/OS (ISOS+), the cone outer segment tips (COST) and full en-face plane (FEF) combining signals from all mentioned cone layers. Additionally, reliability of a simple semi-automated approach for assessment of cone density was tested. Main outcome measures. Cone density of IS/OS, IS/OS+, COST and FEF. Qualitative depiction and composition of each cone layer. Inter-rater agreement of cone density measurements. Results Mean overall cone density at all eccentricities was highest at the FEF plane (21.160/mm 2 ), followed by COST (20.450/mm 2 ), IS/OS+ (19.920/mm 2 ) and IS/OS (19.530/mm 2 ). The different meridians and eccentricities had a significant impact on cone density, with lower eccentricity resulting in higher cone densities (p≤.001), which were highest at the nasal, then temporal, then inferior and then superior meridian. Depiction of the cone mosaic differed between all 4 layers regarding signal size and packing density. Therefore, different cone layers showed evident but not complete signal overlap. Using the semi-automated technique for counting of cone signals achieved high inter-rater reliability (ICC > .99). Conclusions In healthy individuals qualitative and quantitative changes in cone signals are found not only in different eccentricities and meridians, but also within different photoreceptor layers. The variation between cone planes has to be considered when assessing the integrity of cone photoreceptors in healthy and diseased eyes using adaptive optics technology.

Purpose: To prospectively investigate the development of quantitative autofluorescence (qAF) during progression from intermediate to late age-related macular degeneration (AMD). Methods: Quantitative autofluorescence images from patients with intermediate AMD were acquired every three months with a Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany) using a built-in autofluorescence reference. The association between changes in longitudinal qAF and progression toward late AMD was assessed using Cox regression models with time-dependent covariates. Results: One hundred and twenty-one eyes of 71 patients were included, and 653 qAF images were acquired. Twenty-one eyes of 17 patients converted to late AMD (median follow-up: 21 months; 12 eyes: atrophic AMD; nine eyes: neovascular AMD). The converting patients' mean age was 74.6 ± 4.4 years. Eleven eyes in the converting group (52.4%) were pseudophakic. The presence of an intraocular lens did not affect the qAF regression slopes ( P > 0.05). The median change for atrophic AMD was −2.34 qAF units/3 months and 0.78 qAF units/3 months for neovascular AMD. A stronger decline in qAF was significantly associated with an increased risk of developing atrophic AMD (hazard ratio = 1.022, P < 0.001). This association, however, was not present in the group progressing toward neovascular AMD (hazard ratio = 1.001, P = 0.875). Conclusion: The qAF signal declines with progression to atrophy, contrary to developing neovascularization. Quantitative autofluorescence may allow identification of patients at risk of progressing to late AMD and benefits individualized patient care in intermediate AMD.

Purpose: To evaluate morphologic and microvascular differences between eyes with and without subretinal fibrosis (SF) caused by neovascular age-related macular degeneration (nAMD). Methods: Patients with nAMD with a minimum history of 12 months of anti-VEGF treatment were prospectively included in this cross-sectional study. Patients were imaged using standard imaging, swept-source optical coherence tomography angiography for quantitative microvascular analysis and polarization-sensitive OCT as an ancillary method for automated SF segmentation. The presence of reticular pseudodrusen, hyperreflective foci (HRF), and outer retinal tubulation (ORT) were also evaluated. Results: Sixty eyes of 60 participants (37 female) with nAMD and a mean 3.1 (±2.7)-year history of anti-VEGF treatment were included, 20 (33%) of which were diagnosed with SF. Eyes with SF had a higher prevalence of ORT (P < 0.001) and a lower prevalence of HRF (P = 0.004) than eyes without SF. Fifty eyes were analyzed quantitatively for microvascular biomarkers. Eyes with SF had a larger greatest vascular caliber (P = 0.001) and greatest linear diameter (P = 0.042), a larger microvascular neovascularization (MNV) area (P = 0.026), larger vessel area (P = 0.037), higher number of vessel junctions (P = 0.025), longer total vessel length (P = 0.027), higher number of vessel endpoints (P = 0.007), and higher endpoint density (P = 0.047). Conclusions: This multimodal imaging approach demonstrated in vivo microvascular and morphological differences in eyes with and without SF. Eyes with SF tend to have larger MNV lesions with thicker vessels and are often associated with the presence of ORT. Translational Relevance: This study points out imaging biomarkers in patients with SF, which may help identifying high-risk patients.

Purpose To investigate the impact of large choroidal vessels (LCV) on Choriocapillaris (CC) flow deficit (FD) analyses with swept-source optical coherence tomography angiography (SS-OCTA) Design Prospective, cross-sectional study. Methods Macular 6x6mm SS-OCTA scans were obtained from intermediate age-related macular degeneration (iAMD) and healthy eyes. Images were captured and processed according to most common standards and analyzed for percentage of flow-deficits (FD%) within four 1x1mm squares at the corners of each image. Choroidal thickness (CT), iris color and refraction error were considered as potential influential factors for LCV visibility. A linear mixed model and logistic regression models were calculated for statistical evaluation. Results Sixty-nine iAMD and 49 age-matched healthy eyes were enrolled. LCV were visible in at least one sector in 52% of iAMD and 47% of healthy eyes. Within the iAMD group FD% were significantly lower in areas containing LCV (p = 0.0029). Increasing CT resulted in an odds ratio decrease of LCV (OR: 0.94, p<0.0001). Below a CT value of ≤118μm LCV could be expected with a sensitivity of 86% and a specificity of 85%. Conclusions LCV can significantly affect CC FD analyses of SS-OCTA images. Their visibility is negatively associated with CT. The impact of LCV should be taken into account when performing CC FD assessments, especially in patients where reduced CT is to be expected and inclusion of affected areas should be considered carefully.