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Despite the success of antiangiogenic therapy in controlling exudation in neovascular age-related macular degeneration (nAMD), the involvement of the outer retina in fibrosis results in gradual vision loss over time. The development of drugs that prevent or ameliorate fibrosis in nAMD requires that it is accurately detected and quantified with reliable endpoints and identification of robust biomarkers. Achievement of such an aim is currently challenging due to the lack of a consensus definition of fibrosis in nAMD. As a first step towards the establishment of a clear definition of fibrosis, we provide an extensive overview of the imaging modalities and criteria used to characterize fibrosis in nAMD. We observed variety in the selection of individual and combinations of imaging modalities, and criteria for detection. We also observed heterogeneity in classification systems and severity scales for fibrosis. The most commonly used imaging modalities were color fundus photography (CFP), fluorescence angiography (FA) and optical coherence tomography (OCT). A multimodal approach was frequently utilized. Our review suggests that OCT offers a more detailed, objective and sensitive characterization than CFP/FA. Thus, we recommend it as a primary modality for fibrosis evaluation. This review provides a basis for future discussions to reach a consensus definition using standardized terms based on a detailed characterization of fibrosis, its presence and evolution, and taking into consideration impact on visual function. Achieving this goal is of paramount importance for the development of antifibrotic therapies.

In this work we evaluated a postprocessing, customized automatic retinal OCT B-scan enhancement software for noise reduction, contrast enhancement and improved depth quality applicable to Heidelberg Engineering Spectralis OCT devices. A trained deep neural network was used to process images from an OCT dataset with ground truth biomarker gradings. Performance was assessed by the evaluation of two expert graders who evaluated image quality for B-scan with a clear preference for enhanced over original images. Objective measures such as SNR and noise estimation showed a significant improvement in quality. Presence grading of seven biomarkers IRF, SRF, ERM, Drusen, RPD, GA and iRORA resulted in similar intergrader agreement. Intergrader agreement was also compared with improvement in IRF and RPD, and disagreement in high variance biomarkers such as GA and iRORA.

Background To investigate anterior scleral thickness in a cohort of healthy subjects using enhanced depth imaging anterior segment optical coherence tomography. Methods Observational case series. The mean scleral thickness in the inferonasal, inferotemporal, superotemporal, and superonasal quadrant was measured 2 mm from the scleral spur on optical coherence tomography in healthy volunteers. Results Fifty-three eyes of 53 Caucasian patients (25 male and 28 female) with an average age of 48.6 years (range: 18 to 92 years) were analysed. The mean scleral thickness was 571 μm (SD 84 μm) in the inferonasal quadrant, 511 μm (SD 80 μm) in the inferotemporal quadrant, 475 (SD 81 μm) in the superotemporal, and 463 (SD 64 μm) in the superonasal quadrant. The mean scleral thickness was significantly different between quadrants (p

Fifty-five degree wide-field spectral domain optical coherence tomography provides an alternative to standard 30° optical coherence tomography lens with comparable thickness values with a greater field of view., Purpose: To assess whether retinal thickness measurements with a standard 30° spectral domain optical coherence tomography (SD-OCT) are comparable with wide-field 55° SD-OCT. Methods: Thirty-three healthy individuals were scanned using 55° as well as 30° SD-OCT according to a standardized protocol. Automated retinal layer segmentation of standard and wide-field SD-OCTs was assessed using customized software. Results: Both lenses showed a high correlation when analyzing total retinal thickness within the central, the inner, and the outer retinal ring (r = > 0.9). Automated thickness measurements with the 55° system were marginally higher compared with the 30° lens. The thickness of each separate retinal layer using automated segmentation showed excellent correlations within the inner and outer rings (range: r = 0.6—r = 0.9 for the inner ring and range: r = 0.9—r = 1.0 for the outer ring). Conclusion: Fifty-five degree wide-field SD-OCT provides a good overview of the posterior pole and presents similar quantitative values as a standard 30° OCT lens. Therefore, thickness values are comparable when switching between these two lenses.

This study confirms that fluorescence lifetime imaging ophthalmoscopy is able to identify and quantify macular alterations after surgical reattachment of macula-off rhegmatogenous retinal detachment that relate to visual acuity. Fluorescence lifetime imaging ophthalmoscopy could be a useful noninvasive diagnostic tool to assess eyes after rhegmatogenous retinal detachment repair., Purpose: The purpose of this study was to investigate fluorescence lifetime imaging ophthalmoscopy lifetimes after macula-off rhegmatogenous retinal detachment (RRD) repair. Methods: Fifty-eight patients with successful macula-off RRD reattachment surgery were included. Retinal autofluorescence was excited with 470 nm, and amplitude-weighted mean fluorescence lifetimes (Tm) were measured in a short spectral channel (SSC, 498–560 nm) and a long spectral channel (LSC, 560–720 nm). Tm were obtained within a standardized Early Treatment Diabetic Retinopathy Study grid and correlated with Tm. The unaffected fellow eye served as control. Results: Fifty-eight patients (age: 65 ± 1.6 years, 11 women) were imaged at median 1.5 months postoperatively. Tm were significantly prolongxxxed within areas of previously detached retina in the long spectral channel and particularly in the central subfield in the short spectral channel. Short lifetimes in the center of the Early Treatment Diabetic Retinopathy Study grid correlated with better visual acuity (short spectral channel; r2 = 0.18, P = 0.001, long spectral channel; r2 = 0.08, P = 0.03). Areas of residual subretinal fluid pockets in four RRD eyes displayed short fluorescence lifetimes. Conclusion: Areas of previously detached retina exhibit significant fluorescence lifetime changes. We found a significant correlation of fluorescence lifetimes within the fovea with visual acuity after successful RRD repair. Our data suggests that the prolongation of fluorescence lifetimes in the fovea is mainly driven by loss of macular pigment. Therefore, fluorescence lifetime imaging ophthalmoscopy may be useful in the prediction of long-term functional outcomes after macula-off RRD surgery.

AimTo report long-term outcomes on best-corrected visual acuity (BCVA) and treatment intervals with a treat-and-extend (T&E) regimen in patients with neovascular age-related macular degeneration (nAMD).MethodsThis observational study included treatment-naïve patients with nAMD, treated with aflibercept. A specific T&E protocol without a loading phase and predefined exit criteria was administered. After reaching predefined ‘exit-criteria’, the treatment period was complete, and patients were observed three monthly.ResultsEighty-two patients with a follow-up period of ≥2 years were included. BCVA (mean±SD, ETDRS letters) increased from 51.9±25.2 at baseline to 63.7±17.7 (pConclusionsAfter 4 years of treatment, initial vision gains were maintained with a reasonable treatment burden, even without an initial loading phase. Our results on functional outcomes are comparable with large controlled studies.

More than 15 years ago, the results of the pivotal trials supporting the intravitreal use of ranibizumab were published [...]

We aimed to evaluate the neuroprotective efficacy of rasagiline in pseudophakic patients who had surgery for macula-off rhegmatogenous retinal detachment (RRD). This was a 6-month, prospective, randomized, double-blind, placebo-controlled pilot study. Patients presenting with acute macula-off RRD were recruited and randomized 1:1 to receive rasagiline 1 mg/day or placebo for 7 days. Best-corrected visual acuity (BCVA) and optical coherence tomography were acquired 1 day before as well as 2 days, 3 weeks, 3 months and 6 months after surgery. We screened 26 patients with RRD whereof 23 were eventually included and randomized. The primary outcome was final BCVA. Secondary outcomes included central retinal thickness (CRT) and adverse events (AE). We evaluated photoreceptor cells (prc) recovery through morphological measurements. The baseline characteristics were comparable between groups. BCVA significantly improved in both groups (letters gained: rasagiline 61.5 ± 18.1 vs placebo 55.3 ± 29.2, p = 0.56), but no significant inter-group difference was found at any visit. CRT was stable 3 weeks after surgery onwards, with no inter-group difference. No treatment-emergent AE occurred. Significant prc restoration was observed from 3 weeks to 6 months after surgery, without inter-group difference at either visit. Ellipsoid zone integrity (β = 0.517, p = 0.008) and foveal bulge (β = 0.387, p = 0.038) were significant predictors of good final BCVA. In conclusion, perioperative oral treatment with rasagiline 1 mg/day for 7 days did not show significant benefits on visual or anatomical outcomes in macula-off RRD patients.

The aim of this observational study was to assess the use and outcome of intravitreal aflibercept in a treat and extend regimen in treatment-naïve neovascular AMD patients in routine practice. This both retrospective and prospective study was conducted in four larger Swiss retina clinics (ASTERIA study). The primary endpoint was the mean change in best-corrected visual acuity (BCVA) in ETDRS letters from baseline to 12 months. Between December 2017 and August 2018, 160 patients were included. For patients with available data, the mean change in BCVA was + 8.4 (± 14.4) letters at month 12 (n = 139) and + 5.0 (± 11.4) letters at month 24 (n = 95). A mean number of 8.3 (± 2.4) injections were administered within the first year and 5.4 (± 2.9) injections during the second year. On average, the observed treatment interval at month 12 was 63.3 (± 22.0) days and increased to 69.1 (± 28.6) days at month 24. For 37% of the patients, a treatment interval ≥ 12 weeks was attained at month 24. In conclusion, intravitreal aflibercept in a Swiss real-life treat and extend regimen resulted in comparable anatomic and functional outcomes as were observed in the prospective registration trials of aflibercept for nAMD treatment.

The role of microglia in retinal inflammation is still ambiguous. Branch retinal vein occlusion initiates an inflammatory response whereby resident microglia cells are activated. They trigger infiltration of neutrophils that exacerbate blood–retina barrier damage, regulate postischemic inflammation and irreversible loss of neuroretina. Suppression of microglia‐mediated inflammation might bear potential for mitigating functional impairment after retinal vein occlusion (RVO). To test this hypothesis, we depleted microglia by PLX5622 (a selective tyrosine kinase inhibitor that targets the colony‐stimulating factor‐1 receptor) in fractalkine receptor reporter mice (Cx3cr1 gfp/+) subjected to various regimens of PLX5622 treatment and experimental RVO. Effectiveness of microglia suppression and retinal outcomes including retinal thickness as well as ganglion cell survival were compared to a control group of mice with experimental vein occlusion only. PLX5622 caused dramatic suppression of microglia. Despite vein occlusion, reappearance of green fluorescent protein positive cells was strongly impeded with continuous PLX5622 treatment and significantly delayed after its cessation. In depleted mice, retinal proinflammatory cytokine signaling was diminished and retinal ganglion cell survival improved by almost 50% compared to nondepleted animals 3 weeks after vein occlusion. Optical coherence tomography suggested delayed retinal degeneration in depleted mice. In summary, findings indicate that suppression of cells bearing the colony‐stimulating factor‐1 receptor, mainly microglia and monocytes, mitigates ischemic damage and salvages retinal ganglion cells. Blood–retina barrier breakdown seems central in the disease mechanism, and complex interactions between different cell types composing the blood–retina barrier as well as sustained hypoxia might explain why the protective effect was only partial., Main points Microglia have been depleted in ischemic retina by colony‐stimulating factor‐1 receptor inhibition (PLX5622).Three weeks after branch vein occlusion, depleted retinas showed increased retinal ganglion cell survival and delayed inner retina atrophy.

To compare drusen volume between Heidelberg Spectral Domain (SD-) and Zeiss Swept-Source (SS) PlexElite Optical Coherence Tomography (OCT) determined by manual and automated segmentation methods. Thirty-two eyes of 24 patients with Age-Related Macular Degeneration (AMD) and drusen maculopathy were included. In the central 1 and 3 mm ETDRS circle drusen volumes were calculated and compared. Drusen segmentation was performed using automated manufacturer algorithms of the two OCT devices. Then, the automated segmentation was manually corrected and compared and finally analyzed using customized software. Though on SD-OCT, there was a significant difference of mean drusen volume prior to and after manual correction (mean difference: 0.0188 &plusmn, 0.0269 mm3, p &lt, 0.001, corr. p &lt, 0.001, correlation of r = 0.90), there was no difference found on SS-OCT (mean difference: 0.0001 &plusmn, 0.0003 mm3, p = 0.262, corr. p = 0.524, r = 1.0). Heidelberg-acquired mean drusen volume after manual correction was significantly different from Zeiss-acquired drusen volume after manual correction (mean difference: 0.1231 &plusmn, 0.0371 mm3, p &lt, 0.001, r = 0.68). Using customized software, the difference of measurements between both devices decreased and correlation among the measurements improved (mean difference: 0.0547 &plusmn, 0.0744 mm3, p = 0.02, corr. p = 0.08, r = 0.937). Heidelberg SD-OCT, the Zeiss PlexElite SS-OCT, and customized software all measured significantly different drusen volumes. Therefore, devices/algorithms may not be interchangeable. Third-party customized software helps to minimize differences, which may allow a pooling of data of different devices, e.g., in multicenter trials.

Background To evaluate retinal ganglion cell (RGC) loss and axonal affection in branch retinal vein occlusion (BRVO).Methods 13 eyes of 12 non-glaucomatous BRVO patients were included. Thickness of peripapillary and macular retinal nerve fiber layer (pRNFL, mRNFL), ganglion cell-inner plexiform layer (GCIPL), inner nuclear layer, outer and total retina were measured at baseline and after a mean follow-up of 14 months. We compared the thickness between the affected and their internal reference regions. Additionally, pRNFL thickness was compared between the occluded and the healthy fellow eyes in the 11 unilateral cases.Results Significant degeneration of the pRNFL was observed in the affected sector of the BRVO eyes (P < 0.01 versus reference sector and versus fellow eye). In contrast, mRNFL and GCIPL thickness showed no difference between affected and reference regions and no correlation with pRNFL thickness. Degenerative microcystic macular edema (MME) was present in 25% of the eyes with macular edema following BRVO.Conclusion Axonal degeneration occurs in pRNFL, which suggests that anterograde degeneration is the mechanism of RGC affection in BRVO. Our results emphasized the importance of pRNFL monitoring in BRVO treatment, and considering degenerative MME in persistent edema following BRVO.

PURPOSE To investigate the prevalence and impact of ganglion cell layer cysts (GCLC) in patients with diabetic macular oedema (DME) under continuous anti-vascular endothelial growth factor (VEGF) therapy. METHODS The clinical findings and spectral domain optical coherence devices of baseline visits and follow-up after 12-24 and 36 months of DME patients under continuous anti-VEGF therapy were retrospectively collected and analysed for the impact of GCLC cysts. Previously established prognostic parameters were also assessed. RESULTS A total of 110 eyes of 110 DME patients (mean age 64 ± 10 years) were included. At baseline, 17% eyes had GCLC. With GCLC, the best-corrected visual acuity (BCVA) improvement was in mean 8.4 ± 2.4 Early-Treatment-Diabetic-Retinopathy-Study (ETDRS) letters less over the course of 36 months compared to the group lacking GCLC (p = 0.0009). Eyes with GCLC showed 68 ± 23.4 μm less central retinal thickness (CRT) decrease than eyes lacking GCLC (p

PURPOSE To identify the prevalence and progression of macular atrophy (MA) in neovascular age-related macular degeneration (AMD) patients under long-term anti-vascular endothelial growth factor (VEGF) therapy and to determine risk factors. METHOD This retrospective study included patients with neovascular AMD and ≥30 anti-VEGF injections. Macular atrophy (MA) was measured using near infrared and spectral-domain optical coherence tomography (SD-OCT). Yearly growth rate was estimated using square-root transformation to adjust for baseline area and allow for linearization of growth rate. Multiple regression with Akaike information criterion (AIC) as model selection criterion was used to estimate the influence of various parameters on MA area. RESULTS Forty-nine eyes (47 patients, mean age 77 ± 14) were included with a mean of 48 ± 13 intravitreal anti-VEGF injections (ranibizumab:37 ± 11, aflibercept:11 ± 6, mean number of injections/year 8 ± 2.1) over a mean treatment period of 6.2 ± 1.3 years (range 4-8.5). Mean best-corrected visual acuity improved from 57 ± 17 letters at baseline (= treatment start) to 60 ± 16 letters at last follow-up. The MA prevalence within and outside the choroidal neovascularization (CNV) border at initial measurement was 45% and increased to 74%. Mean MA area increased from 1.8 ± 2.7 mm(2) within and 0.5 ± 0.98 mm(2) outside the CNV boundary to 2.7 ± 3.4 mm(2) and 1.7 ± 1.8 mm(2) , respectively. Multivariate regression determined posterior vitreous detachment (PVD) and presence/development of intraretinal cysts (IRCs) as significant factors for total MA size (R(2) = 0.16, p = 0.02). Macular atrophy (MA) area outside the CNV border was best explained by the presence of reticular pseudodrusen (RPD) and IRC (R(2) = 0.24, p = 0.02). CONCLUSION A majority of patients show MA after long-term anti-VEGF treatment. Reticular pseudodrusen (RPD), IRC and PVD but not number of injections or treatment duration seem to be associated with the MA size.

PURPOSE To evaluate macular retinal ganglion cell thickness in patients with neovascular age-related macular degeneration (AMD) and intravitreal anti-vascular endothelial growth factor (VEGF) therapy. DESIGN Retrospective case series with fellow-eye comparison METHODS: Patients with continuous unilateral anti-VEGF treatment for sub- and juxtafoveal neovascular AMD and a minimum follow-up of 24 months were included. The retinal nerve fiber (RNFL) and retinal ganglion cell layer (RGCL) in the macula were segmented using an ETDRS grid. RNFL and RGCL thickness of the outer ring of the ETDRS grid were quantified at baseline and after repeated anti-VEGF injections, and compared to the patients' untreated fellow eye. Furthermore, best-corrected visual acuity (BCVA), age, and retinal pigment epithelium (RPE) atrophy were recorded and correlated with RNFL and RGCL. RESULTS Sixty eight eyes of 34 patients (23 female and 11 male; mean age 76.7 (SD±8.2) with a mean number of 31.5 (SD ±9.8) anti-VEGF injections and a mean follow-up period of 45.3 months (SD±10.5) were included. Whereas the RGCL thickness decreased significantly compared to the non-injected fellow eye (p=0.01) the decrease of the RNFL was not significant. Visual acuity gain was significantly correlated with RGCL thickness (r=0.52, p

PURPOSE To identify individual retinal layer thickness changes associated with visual acuity gain in diabetic macular edema treated with ranibizumab using layer segmentation on high-resolution optical coherence tomography scans. METHODS Retrospective observational case series. Thirty-three treatment-naive eyes with diabetic macular edema were imaged by spectral domain optical coherence tomography at monthly visits while receiving intravitreal ranibizumab treatment as needed, guided by visual acuity. Thickness changes of individual layers after 1 year were quantitatively analyzed and correlated with visual acuity gain. RESULTS The mean best-corrected visual acuity improvement at 1 year was 6.2 (SEM ± 1.5) Early Treatment Diabetic Retinopathy Study letters, and central retinal thickness decreased by 66 ± 18 μm. In the central subfield, there was a significant decrease of thickness for all layers (P < 0.05) except the outer nuclear layer. Multiple linear regression analysis revealed that thickness decrease of the inner retina was associated with better visual acuity, whereas for the outer retina the opposite was true. The best estimate of final visual acuity (R = 0.817, P < 0.001) was obtained, by including baseline visual acuity and thickness change of the inner and outer plexiform layers in the model. CONCLUSION Whereas thickness decrease of the inner retina was positively associated with visual acuity gain, the opposite was found for the outer retina. This might be indirect evidence for recovery of the outer retina during ranibizumab treatment.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

Although sutureless techniques for 20-gauge vitrectomy had previously been described, it was not until the advent of 25-gauge vitrectomy that transconjunctival sutureless vitrectomy became popular. The development of less invasive methods had been motivated by the desire to avoid typical complications of 20-gauge pars plana vitrectomy, spare the conjunctiva from scarring, and shorten procedural time. During the early stages of small gauge vitrectomy, the lack of stiffness and the limited range of the instruments provoked skepticism among retina specialists and dampened initial enthusiasm. However, ingenious design, improved materials and adaptation of operating techniques lately led to rapid progress and much improved performance of small gauge vitrectomy systems. In fact, some surgeons now use 27-gauge systems almost exclusively for nearly the entire spectrum of vitreoretinal pathology. This chapter discusses performance characteristics and limitations of some popular small gauge vitrectomy platforms. Handling techniques and tricks to avoid common complications specific to minimally invasive pars plana vitrectomy are explained.

In ophthalmology, retinal biological markers, or biomarkers, play a critical role in the management of chronic eye conditions and in the development of new therapeutics. While many imaging technologies used today can visualize these, Optical Coherence Tomography (OCT) is often the tool of choice due to its ability to image retinal structures in three dimensions at micrometer resolution. But with widespread use in clinical routine, and growing prevalence in chronic retinal conditions, the quantity of scans acquired worldwide is surpassing the capacity of retinal specialists to inspect these in meaningful ways. Instead, automated analysis of scans using machine learning algorithms provide a cost effective and reliable alternative to assist ophthalmologists in clinical routine and research. We present a machine learning method capable of consistently identifying a wide range of common retinal biomarkers from OCT scans. Our approach avoids the need for costly segmentation annotations and allows scans to be characterized by biomarker distributions. These can then be used to classify scans based on their underlying pathology in a device-independent way.

IMPORTANCE: Despite the unquestionable effectiveness of anti–vascular endothelial growth factor therapy (VEGF), there is ongoing controversy about potential systemic adverse effects. Besides the direct adverse effects of anti-VEGF agents, other factors associated with the injection itself, such as perioperative blood pressure fluctuations, may contribute to adverse events. OBJECTIVE: To determine blood pressure fluctuations during intravitreal injections. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study at a tertiary referral center (Department of Ophthalmology, University Hospital Bern, Bern, Switzerland). Consecutive patients scheduled for intravitreal injections were recruited. Data were analyzed between October 2017 and January 2018. MAIN OUTCOMES AND MEASURES: Systolic and diastolic blood pressure, pulse rate, and oxygen saturation were recorded before, during, and after the intravitreal injection. An anxiety questionnaire was completed by all participants. Multivariate regression analysis was used to investigate potential factors associated with blood pressure rise during injections. RESULTS: Two hundred one patients (92 women and 109 men) were included in this study, with a mean age of 68 years (range, 18-93 years). Mean (SD) systolic blood pressure increased from a baseline of 150 (20) mm Hg to 162 (24) mm Hg following the preparation procedure to 168 (24) mm Hg during the injection (P

PURPOSE To evaluate the outcome of an exit strategy in a treat-and-extend regimen for neovascular age-related macular degeneration. METHODS Five hundred and ninety-eight eyes of 488 patients with neovascular age-related macular degeneration receiving intravitreal anti-vascular endothelial growth factor injections according to a treat-and-extend regimen were included in this retrospective study. A treat-and-extend regimen with either interval extension by 2 weeks or shortening by 1 week was used. "Exit criteria" were defined as 3 consecutive injections 16 weeks apart with stable findings after which the patient was exited from treatment and followed up at 3 to 4 monthly intervals without therapy. Best-corrected visual acuity, central retinal thickness at treatment initiation and termination, incidence of recurrence after treatment termination, presence of characteristics in the optical coherence tomography, duration of therapy, number and intervals of injections were analyzed. RESULTS Seventeen percent of all included eyes met the exit criteria. The mean number of anti-vascular endothelial growth factor injections was 23.7 ± 14.7 with a mean treatment duration of 4.5 ± 2.5 years. Twelve percent reached exit with the minimal number of injections. Thirteen percent had recurrent disease after a mean of 37 ± 16 weeks. In the subgroup with recurrent disease, rate of pigment epithelial detachment at treatment termination was significantly higher than without recurrence (77% vs. 30%, P = 0.0018) with a significant higher proportion of serous pigment epithelial detachment (31% vs. 7%, P = 0.0247). CONCLUSION The high percentage of patients meeting the exit criteria and the relatively low incidence of recurrences underline the usefulness of a predefined exit strategy. However, in a subgroup of patients, continuation of therapy may be advisable.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Neovascular age-related macular degeneration is one of the leading causes of blindness. Microglia and macrophages play a critical role in choroidal neovascularization (CNV) and may, therefore, be potential targets to modulate the disease course. This study evaluated the effect of the colony-stimulating factor-1 receptor inhibitor PLX5622 on experimental laser-induced CNV. A 98% reduction of retinal microglia cells was observed in the retina 1 week after initiation of PLX5622 treatment, preventing accumulation of macrophages within the laser site and leading to a reduction of leukocytes within the choroid after CNV induction. Mice treated with PLX5622 had a significantly faster decrease of the CNV lesion size, as revealed by in vivo imaging and immunohistochemistry from day 3 to day 14 compared with untreated mice. Several inflammatory modulators, such as chemokine (C-C motif) ligand 9, granulocyte-macrophage colony-stimulating factor, soluble tumor necrosis factor receptor-I, IL-1α, and matrix metallopeptidase-2, were elevated in the acute phase of the disease when microglia were ablated with PLX5622, whereas other cytokines (eg, interferon-γ, IL-4, and IL-10) were reduced. Our results suggest that colony-stimulating factor-1 receptor inhibition may be a novel therapeutic target in patients with neovascular age-related macular degeneration.

Purpose: We evaluated the repeatability of wide-field en face swept-source optical coherence tomography angiography (SS-OCTA) in healthy subjects. Methods: Healthy subjects underwent two imaging sessions, on average 8 days apart, with a 100 kHz SS-OCTA instrument. The imaging protocol included a central 3 × 3 and 12 × 12 mm scans of the four quadrants resulting in more than a 70° wide-field OCTA of the posterior pole. Quantitative analysis was performed using the inbuilt Macular Density Algorithm Version v0.6.1 and AngioTool software. Consistency for the foveal avascular zone (FAZ), vessel density, and perfusion density of the superficial and deep capillary plexus slabs and the wide-field OCTA superficial slab, and the number of artefacts on the wide-field images were assessed. Results: A total of 21 healthy volunteers (seven men and 14 women; mean age 32 years; range, 18-61; standard deviation, 10.28 years) were included in this analysis. Internal consistency was highest for FAZ area with an intraclass correlation (ICC) = 0.998 (95% confidence interval [CI], 0.997-0.999), a FAZ perimeter with an ICC = 0.995 (95% CI, 0.990-0.997), a FAZ circularity with an ICC= 0.976 (95% CI, 0.956-0.987), followed by the vessel density of the inner ring in the superficial slab with an ICC = 0.834 (95% CI, 0.691-0.911), and a vessel density of the inner ring in the deep slab with an ICC = 0.523 (95% CI, 0.113-0.744).The reproducibility of the average vessels length of the wide-field OCTA cropped images was strong (ICC = 0.801; 95% CI, 0.624-0.895), followed by the reproducibility of total number of junctions (ICC = 0.795; 95% CI, 0.613-0.892) and the vessels percentage area (ICC = 0.662; 95% CI, 0.361-0.821). Conclusions: The level of reproducibility for assessing the microvascular anatomy in wide-field OCTA is strong and can be used to quantify microvascular changes over time. Refinements in analysis strategies and a consensus of which parameters are most useful for quantitative assessment of wide-field OCTA images would be useful in the future. Translational Relevance: These findings bridge the gap between basic imaging research and clinical use for quantitative wide-field OCTA.

Purpose: We investigate which spectral domain-optical coherence tomography (SD-OCT) setting is superior when measuring subfoveal choroidal thickness (CT) and compared results to an automated segmentation software. Methods: Thirty patients underwent enhanced depth imaging (EDI)-OCT. B-scans were extracted in six different settings (W+N = white background/normal contrast 9; W+H = white background/maximum contrast 16; B+N = black background/normal contrast 12; B+H = black background/maximum contrast 16; C+N = Color-encoded image on black background at predefined contrast of 9, and C+H = Color-encoded image on black background at high/maximal contrast of 16), resulting in 180 images. Subfoveal CT was manually measured by nine graders and by automated segmentation software. Intraclass correlation (ICC) was assessed. Results: ICC was higher in normal than in high contrast images, and better for achromatic black than for white background images. Achromatic images were better than color images. Highest ICC was achieved in B+N (ICC = 0.64), followed by B+H (ICC = 0.54), W+N, and W+H (ICC = 0.5 each). Weakest ICC was obtained with Spectral-color (ICC = 0.47). Mean manual CT versus mean computer estimated CT showed a correlation of r = 0.6 (P = 0.001). Conclusion: Black background with white image at normal contrast (B+N) seems the best setting to manually assess subfoveal CT. Automated assessment of CT seems to be a reliable tool for CT assessment. Translational Relevance: To define optimized OCT analysis settings to improve the evaluation of in vivo imaging.

AIMS To investigate the prognostic significance of macular capillary drop-out and previous panretinal laser photocoagulation in diabetic macular oedema treated with intravitreal ranibizumab. METHODS Retrospective observational case series. Treatment-naive patients with diabetic macular oedema that had been treated with intravitreal ranibizumab as per the RESTORE study protocol for at least 12 months were included. Some patients (n=15) had previous panretinal laser photocoagulation. Best-corrected visual acuity and central retina thickness were recorded monthly. The foveal avascular zone and the perifoveal capillaries were quantitatively and qualitatively assessed on fluorescein angiography on two occasions during the observational period. RESULTS From the 46 eyes (46 patients) in this study, 13 (28%) had evidence of perifoveal capillary drop-out. Central retinal thickness was significantly thinner at baseline (p=0.02) and throughout the study period in these eyes compared with those with normal perifoveal capillaries. Both groups responded with a significant gain of best-corrected visual acuity to ranibizumab treatment (7.6±3.3 and 6.3±1.3 ETDRS letters, respectively). Eyes with previous panretinal laser photocoagulation displayed a comparable final outcome regarding function and morphology, requiring a similar intensity of intravitreal injections. CONCLUSIONS Perifoveal capillary drop-out did not limit the gain of visual acuity from intravitreal ranibizumab treatment. The reduction of central retina thickness was similar to that seen in eyes with normal perifoveal capillaries. Central retinal thickness in eyes with perifoveal capillary drop-out was generally reduced. However, this did not affect their benefit from treatment. Ranibizumab did not increase the amount of perifoveal capillary loss.

Purpose Selective retina therapy (SRT) has shown great promise compared to conventional retinal laser photocoagulation as it avoids collateral damage and selectively targets the retinal pigment epithelium (RPE). Its use however is challenging in terms of therapy monitoring and dosage because an immediate tissue reaction is not biomicroscopically discernibel. To overcome these limitations real time optical coherence tomography (OCT) might be useful to monitor retinal tissue during laser application. We have thus evaluated a proprietary OCT system for its capability of mapping optical changes introduced by SRT in retinal tissue. Methods Freshly enucleated porcine eyes covered in DMEM upon collection were utilized and a total of 175 scans from ex vivo porcine eyes were analyzed. The porcine eyes were used as an ex vivo model and results compared to two time resolved OCT scans recorded from a patient undergoing SRT treatment (SRT Vario Medical Laser Center Lübeck). In addition to OCT fluorescin angiography and fundus photography were performed on the patient and OCT scans were subsequently investigated for optical tissue changes linked to laser application. Results Biomicroscopically invisible SRT lesions were detectable in OCT by changes in the RPE / Bruch's complex both in vivo and the porcine ex vivo model. Laser application produced clearly visible optical effects such as hyper reflectivity and tissue distortion in the treated retina. Tissue effects were even discernible in time resolved OCT imaging when no hyper reflectivity persisted after treatment. Data from ex vivo porcine eyes showed similar to identical optical changes while effects visible in OCT appeared to correlate with applied pulse energy leading to an additional reflective layer when lesions became visible in indirect ophthalmoscopy. Conclusions Our results support the hypothesis that real time high resolution OCT may be a promising modality to obtain additional information about the extent of tissue damage caused by SRT treatment. Data shows that our ex vivo porcine model adequately reproduces the effects occurring in vivo and thus can be used to further investigate this promising imaging technique.

Spectral domain optical coherence tomography (SD-OCT) and scanning laser ophthalmoscopy (SLO) are extensively used in experimental ophthalmology. In the present protocol, mice expressing green fluorescent protein (gfp) under the promoter of Cx3cr1 (BALB/c-Cx3cr1gfp/gfp) were used to image microglia cells in vivo in the retina. Microglia are resident macrophages of the retina and have been implicated in several retinal diseases1,2,3,4,5,6. This protocol provides a detailed approach for generation of retinal B-scans, with SD-OCT, and imaging of microglia cell distribution in Cx3cr1gfp/gfp mice with SLO in vivo, using an ophthalmic imaging platform system. The protocol can be used in several reporter mouse lines. However, there are some limitations to the protocol presented here. First, both SLO and SD-OCT, when used in the high-resolution mode, collect data with high axial resolution but the lateral resolution is lower (3.5 µm and 6 µm, respectively). Moreover, the focus and saturation level in SLO is highly dependent on parameter selection and correct alignment of the eye. Additionally, using devices designed for human patients in mice is challenging due to the higher total optical power of the mouse eye compared to the human eye; this can lead to lateral magnification inaccuracies7, which are also dependent on the magnification by the mouse lens among others. However, despite that the axial scan position is dependent upon lateral magnification, the axial SD-OCT measurements are accurate8.

This report provides sound evidence that the small molecule pharmaceutical PLX5622, a highly selective CSF-1R kinase inhibitor, crosses the blood-retina barrier and suppresses microglia activity. Members of this class of drug are in advanced clinical development stages and may represent a novel approach to modulate ocular inflammatory processes.

Purpose To validate widefield autofluorescence (AF) in vivo imaging of the retina in mice expressing green fluorescent protein (gfp) in microglia, and to monitor retinal microglia reconstitution in vivo after lethal irradiation and bone marrow transplantation. Methods Transgenic Cx3cr1gfp/gfp and wildtype Balb/c mice were used in this study. A confocal scanning laser ophthalmoscope was used for AF imaging with a 55° and a widefield 102° lens. Intrasession reproducibility was assessed for each lens. To investigate reconstitution in vivo, bone marrow from Cx3cr1gfp/gfp mice was used to rescue lethally irradiated wildtype mice. Data were compared to confocal microscopy of retinal flat mounts. Results Both the 55° and the 102° lens produced high resolution images of retinal microglia with similar microglia density. However, compared to the 55° lens, the widefield 102° lens captured approximately 3.6 times more microglia cells (1515 ± 123 cells versus 445 ± 76 cells [mean ± SD], for 102° and 55°, respectively, P < 0.001). No statistical difference in the number of gfp positive cells within corresponding areas was observed within the same imaging session. Imaging of microglia reconstitution showed a similar time course compared to flat mount preparations with an excellent correlation between microglia cell numbers in AF and gfp-stained flat mounts (R = 0.92, P < 0.0001). Conclusions Widefield AF imaging of mice with gfp expressing microglia can be used to quantify retinal microglia. In vivo microglia counts corresponded very well with ex vivo counts on retinal flat mounts. As such, AF imaging can largely replace ex vivo quantification.

Purpose To investigate the effect of topical glucose on visual parameters in individuals with primary open-angle glaucoma (POAG). Design Double-blind, randomized, crossover study. Participants Nondiabetic pseudophakic patients with definite POAG were recruited; 29 eyes of 16 individuals participated in study 1. A follow-up study (study 2) included 14 eyes of 7 individuals. Intervention Eyes were randomly allocated to receive 50% glucose or saline eye drops every 5 minutes for 60 minutes. Main Outcome Measures The contrast sensitivity and best-corrected logarithm of the minimum angle of resolution (logMAR). Results The 50% glucose reached the vitreous in pseudophakic but not phakic individuals. Glucose significantly improved the mean contrast sensitivity at 12 cycles/degree compared with 0.9% saline by 0.26 log units (95% confidence interval [CI], 0.13–0.38; P P Conclusions Topical glucose temporarily improves psychophysical visual parameters in some individuals with POAG, suggesting that neuronal energy substrate delivery to the vitreous reservoir may recover function of "sick" retinal neurons.

Background The occurrence rate of adverse events (AEs) in hospitalised cancer patients in Switzerland remains unknown. The Institute for Healthcare Improvement (IHI) Global Trigger Tool (GTT) is among the most used methods to identify AEs. However, the GTT lacks oncology-specific triggers. Therefore, we developed a GTT-based Swiss Oncology Trigger Tool (SOTT), which included two modified GTT modules (“Cares” and “Medication”) and a new “Oncology” module. Objective We applied the SOTT to describe the occurrence rate, nature, level of harm and preventability of AEs reported in health records of four Swiss inpatient oncology and haemato-oncology units. Methods We reviewed records of discharged patients over a 6-week period using the method recommended by the IHI for the GTT. To identify documented AEs, two nurse reviewers analysed records using the SOTT. Identified AEs were subsequently validated by physician reviewers, and those occurring during hospitalisation were classified regarding the incurred level of harm and their preventability. Results We reviewed 224 records, 150 for oncology and 74 for haemato-oncology. Ninety-four of them (42%) contained at least one AE. In total we identified 169 AEs 100 for oncology and 69 haemato-oncology. Overall, we calculated a rate of 76 AEs/100 admissions and 108 AEs/1000 patients-days. “Pain related to care” was the most frequent AE reported (n = 29), followed by “Constipation” (n = 17) and “Anaemia” (n = 9). Most AEs were categorized as having caused temporary harm, either requiring an intervention (n = 98) or prolonging the hospital stay (n = 25). Two required an intervention to sustain the patient’s life. Exactly 78/125 (61%) were considered non-preventable, 28/125 (22%) preventable and 19/125(15%) undetermined. Conclusions This is the first Swiss study to identify and categorise AEs in the oncology setting. The application of the SOTT showed a relatively high rate of harm related to care, but only 22% were considered as preventable. The description of AEs with the SOTT might be an opportunity to prioritize the development of novel interventions to avoid or limit the impact of AEs on cancer patients’ lives. Legal entity responsible for the study Manuela Eicher. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Recent studies have demonstrated the safety and efficacy of ocular gene therapy based on adeno-associated viral vectors (AAVs). Accordingly, a surge in promising new gene therapies is entering clinical trials, including the first optogenetic therapy for vision restoration. To date, optogenetic therapies for vision restoration target either the retinal ganglion cells (GCs) or presynaptic ON-bipolar cells (OBCs). Initiating light responses at the level of the OBCs has significant advantages over optogenetic activation of GCs. For example, important neural circuitries in the inner retina, which shape the receptive fields of GCs, remain intact when activating the OBCs. Current drawbacks of AAV-mediated gene therapies targeting OBCs include (1) a low transduction efficiency, (2) off-target expression in unwanted cell populations, and (3) a poor performance in human tissue compared to the murine retina. Here, we examined side-by-side the performance of three state-of-the art AAV capsid variants, AAV7m8, AAVBP2, and AAV7m8(Y444F) in combination with the 4xGRM6-SV40 promoter construct in the healthy and degenerated mouse retina and in human post-mortem retinal explants. We find that (1) the 4xGRM6-SV40 promoter is not OBC specific, (2) that all AAV variants possess broad cellular transduction patterns, with differences between the transduction patterns of capsid variants AAVBP2 and AAV7m8 and, most importantly, (3) that all vectors target OBCs in healthy tissue but not in the degenerated rd1 mouse model, potentially limiting the possibilities for an OBC-targeted optogenetic therapy for vision restoration in the blind.

Anterior ischemic optic neuropathy (AION) is a relatively common cause of visual loss and results from hypoperfusion of the small arteries of the anterior portion of the optic nerve. AION is the leading cause of sudden optic nerve related vision loss with approximately 10 cases per 100′000 in the population over 50 years. To date there is no established treatment for AION and therefore a better understanding of the events occurring at the level of the optic nerve head (ONH) would be important to design future therapeutic strategies. The optical properties of the eye allow imaging of the optic nerve in vivo, which is a part of the CNS, during ischemia. Experimentally laser induced optic neuropathy (eLiON) displays similar anatomical features as anterior ischemic optic neuropathy in humans. After laser induced optic neuropathy we show that hyperreflective dots in optical coherence tomography correspond to mononuclear cells in histology. Using fluorescence-activated flow cytometry (FACS) we found these cells to peak one week after eLiON. These observations were translated to OCT findings in patients with AION, where similar dynamics of hyperreflective dots at the ONH were identified. Our data suggests that activated macrophages can be identified as hyperreflective dots in OCT.

AIM We acquired age-matched and sex-matched Sprague-Dawley rats from 2 independent breeding establishments. Serendipitously, we observed that constitutive, and bacterial toxin-induced, expression of major histocompatibility complex (MHC) class II RT1B chain in the uveal tract was much lower in one of the cohorts. Activated microglia are known to upregulate MHC II RT1B expression during optic nerve (ON) degeneration induced by raised intraocular pressure (IOP). We investigated whether, in a model of experimental glaucoma, microglial upregulation of MHC II RT1B was less efficacious and ON degeneration correspondingly less severe in the cohort of rats with low MHC II RT1B expression. METHODS Experimental glaucoma was induced by lasering the trabecular meshwork using a standard protocol. After 2 weeks of elevated IOP, retinal ganglion cells (RGC) survival, ON degeneration, and microglial responses were determined in both cohorts of rats. RESULTS Raised IOP-induced expression of MHC II RT1B by microglia was muted in the "Low" cohort compared with the "High" cohort. Axonal degeneration, RGC loss, and microgliosis were all significantly lower in the cohort of rats with low basal and induced expression of MHC II RT1B, despite both cohorts displaying IOP responses that were indistinguishable in terms of peak IOP and IOP exposure. CONCLUSIONS Expression of MHC II RT1B by activated microglia in the ON during experimental glaucoma was associated with more severe RGC degeneration. Further studies are needed to elucidate the role of MHC II during experimental glaucoma.

Purpose: To compare conventional 30° spectral domain optical coherence tomography (SD-OCT) with 55° wide-field SD-OCT for the assessment of diabetic macular edema (DME). Methods: This study included 50 DME patients. Both 55° and 30° SD-OCT was conducted. Two readers evaluated scans according to a standardized grading protocol. Intergrader agreement as well as agreement between 30° and 55° SD-OCT were assessed. Results: Intergrader agreement (κ) was strong and ranged from 0.79 to 1.0. Perfect interdevice agreement (κ = 1.0) was found for the detection of intra- and subretinal fluid. Excellent agreement (κ ≥ 0.9) was found for the presence of epiretinal membrane (κ = 0.92) and cotton-wool spots (κ = 0.92). A strong agreement was found for the presence of hard exudates (κ = 0.89) and microaneurysms (κ = 0.81). A moderate correlation was found for ellipsoid zone integrity (κ = 0.69) and configuration of the vitreomacular interface (VMI) (κ = 0.69). A weak agreement was found for retinal pigment epithelium atrophy (κ = 0.51) and external limiting membrane integrity (κ = 0.35). Conclusion: Wide-field OCT imaging may be beneficial for evaluating DME, particularly for assessing the VMI and the integrity of hyperreflective bands.

PURPOSE To compare outcomes between an as-needed and a treat-and-extend regimen in managing diabetic macular edema with intravitreal ranibizumab. METHODS This was a retrospective, single-centre, comparative case series on 46 treatment naive patients with diabetic macular edema. Twenty-two patients were treated following an optical coherence tomography guided treat-and-extend protocol (OCTER), and 24 patients were treated according to a visual acuity guided pro re nata regimen (VAPRN) at a tertiarry referral centre. The main outcome measures were best-corrected visual acuity, central retinal thickness, and the number of ranibizumab injections, as well as visits after 12 months of treatment. RESULTS After 12 months, the mean gain in best-corrected visual acuity (± standard deviation) was 8.3 ± 6.7 versus 9.3 ± 8.9 letters in the VAPRN and OCTER group, respectively (p = 0.3). The mean decrease in central retinal thickness was 68.1 ± 88.0 μm in the VAPRN group and 117.6 ± 114.4 μm in the OCTER group (p = 0.2). The mean number of ranibizumab injections was significantly different between the VAPRN (5.9 ± 1.8) and the OCTER protocol (8.9 ± 2.0) (p

The maintenance of vision, through prevention and attenuation of neuronal injury in glaucoma, forms the basis of current clinical practice. Currently, the reduction of intraocular pressure is the only proven method to achieve these goals. Although this strategy enjoys considerable success, some patients progress to blindness; hence, additional management options are highly desirable. Several terms describing treatment modalities of neuronal diseases with potential applicability to glaucoma are used in the literature, including neuroprotection, neurorecovery, neurorescue and neuroregeneration. These phenomena have not been defined within a coherent framework. Here, we suggest a set of definitions, postulates and principles to form a foundation for the successful translation of novel glaucoma therapies from the laboratory to the clinic.

To determine in vivo whether a pharmacologically induced change in intraocular pressure (IOP) leads to measurable changes in axial eye length and whether there is a difference between glaucoma patients and control subjects.42 subjects (19 patients with primary open angle glaucoma and 23 control patients matched for age and gender) underwent axial eye length measurement using partial coherence laser interferometry and measurement of IOP using dynamic contour tonometry before and 2 h after oral intake of 500 mg acetazolamide. Student's t-test was used to compare differences in the means.An identical drop in IOP was induced in both the glaucoma (mean+/-SEM: 2.90+/-0.44 mmHg, n=19) and the control group (mean+/-SEM: 3.17+/-0.32 mmHg, n=23). The change in axial eye length was significantly smaller (P=0.026) in the glaucoma group (mean+/-SEM: -14.2+/-3.2 microm, n=19) compared with the control group (mean+/-SEM: -23.0+/-2.98 microm, n=23).Our results strongly suggest that the ocular rigidity is increased in patients with established glaucoma in comparison to control subjects. Ocular rigidity could play a role in the pathogenesis and pathophysiology of glaucoma. Determination of ocular rigidity could be helpful in detection of glaucoma.