Half-dose photodynamic therapy versus 577 nm subthreshold pulse laser therapy in treatment-naive patients with central serous chorioretinopathy.

BACKGROUND: To compare real-life anatomical and functional outcomes of half-dose photodynamic therapy (HD-PDT) and 577 nm subthreshold pulse laser therapy (SPL) in treatment-naïve patients with central serous chorioretinopathy (CSC). METHODS: We retrospectively reviewed consecutive treatment-naïve CSC patients with non-resolving subretinal fluid (SRF) for more than 2 months who received either HD-PDT or SPL treatment. One repetition of the same treatment was allowed in patients with persistent SRF after first treatment. Functional and anatomical outcomes were assessed after first treatment and at final visit. RESULTS: We included 95 patients (HD-PDT group, n = 49; SPL group, n = 46). Complete resolution of SRF after a single treatment was observed in 42.9% of HD-PDT-treated patients (n = 21; median time to resolution 7.1 weeks) and in 41.3% of SPL-treated patients (n = 19; median time to resolution 7.0 weeks). In the HD-PDT-group, 44.9% of patients (n = 22) and in the SPL-group, 43.5% (n = 20) of patients, received a second treatment due to persistent SRF, while 12.2% (n = 6) and 15.2% (n = 7), respectively, opted against a second treatment despite persistent SRF. After the final treatment, complete SRF resolution was observed in 61.2% of all HD-PDT-treated patients (n = 30; median time to resolution 8.8 weeks) and 60.9% of all SPL-treated patients (n = 28; median time to resolution 13.7 weeks, p = 0.876). In the final visit, both groups showed significant improvement of BCVA in comparison to baseline (p < 0.001 for all). The change in BCVA from baseline to final visit was similar for the two groups (HD-PDT, median BCVA change 0.10 logMAR (IQR: 0.0-0.2); in SPL group, median BCVA change 0.10 logMAR (IQR: 0.0-0.2), P = 0.344). The CSC subclassification (simple versus complex) had no influence on the anatomical or functional outcome. CONCLUSIONS: High-density 577 nm SPL resulted in as good anatomical and functional treatment as HD-PDT and may thus represent a treatment alternative to HD-PDT in CSC.

Association between laser flare photometry and symptom duration in primary rhegmatogenous retinal detachment.

PURPOSE: The purpose of this study was to investigate preoperative blood-ocular barrier disruption via laser flare photometry (LFP) in patients diagnosed with rhegmatogenous retinal detachment (RRD), and to analyse possible associations with symptom duration and anatomical parameters. METHODS: We retrospectively analysed consecutive patients presenting with RRD at a single centre between January 2016 and March 2020. LFP was performed in both eyes after pupillary dilatation prior to RRD surgery. Symptom duration, extent of retinal detachment, and lens status were assessed. For statistical analysis, we carried out the unequal variances t test and Welch's analysis of variance (ANOVA). RESULTS: We included 373 eyes of 373 patients (mean age 63.96 years ± 10.29; female:male ratio 1:1.8). LFP values quantified in photon count per millisecond (pc/ms) increased with longer symptom duration when comparing patients with a symptom duration of 0-3 days (n = 158; 9.25 ± 6.21 pc/ms) and ≥ 4 days (n = 215; 11.97 ± 11.58 pc/ms; p = 0.004). LFP values also rose with the number of retinal quadrants affected by RRD (1 quadrant, 6.82 ± 4.08 pc/ms; 2 quadrants, 10.08 ± 7.28 pc/ms; 3 quadrants, 12.79 ± 7.9 pc/ms; 4 quadrants, 31.57 ± 21.27 pc/ms; p < 0.001), macula off status (macula on, 8.89 ± 6.75 pc/ms; macula off, 12.65 ± 11.66 pc/ms; p < 0.001), and pseudophakic lens status (pseudophakia, 12.86 ± 9.52 pc/ms; phakia: 9.31 ± 9.67 pc/ms; p < 0.001). CONCLUSION: In RRD patients, blood-ocular barrier disruption quantified by LFP is associated with the duration of symptoms and the disease's anatomical extent. These results warrant further investigation of the potential clinical use of LFP in RRD.

[Retinopathy of Prematurity - Update on Classification, Screening, and Therapy]. / Frühgeborenenretinopathie.

Retinopathy of prematurity (ROP) is a leading cause of preventable childhood blindness. This proliferative retinal vascular disease affects only prematurely born infants. Major risk factors include low gestational age and prolonged postnatal oxygen supplementation. ROP screening allows for timely identification of treatment-requiring infants and thus significantly reduces the risk of severe visual impairment and blindness from ROP. Current treatment options comprise retinal laser coagulation and intravitreal anti-vascular endothelial growth factor (VEGF) therapy. We provide a review of scientific data and current treatment recommendations, with special attention to the updated German guideline on ROP screening, the statement of the German ophthalmological societies on anti-VEGF therapy of ROP, and the new third edition of the International Classification of Retinopathy of Prematurity (ICROP3).

Oxalobacter formigenes treatment combined with intensive dialysis lowers plasma oxalate and halts disease progression in a patient with severe infantile oxalosis.

BACKGROUND: Infantile oxalosis, the most devastating form of primary hyperoxaluria type 1 (PH1), often leads to end-stage renal disease (ESRD) during the first weeks to months of life. CASE-DIAGNOSIS: Here, we report the outcome of the therapeutic use of Oxalobacter formigenes (Oxabact OC5; OxThera AB, Stockholm, Sweden) in a female infant with PH1 who exhibited severely elevated plasma oxalate (Pox) levels, pronounced nephrocalcinosis, anuretic end-stage renal disease, and retinal oxalate deposits. Following the diagnosis of PH1 at an age of 8 weeks, a combined regimen of daily peritoneal dialysis, daily pyridoxine treatment and hemodialysis (3 times a week) was unable to reduce the pronounced hyperoxalemia. After the addition of Oxalobacter formigenes therapy to the otherwise unchanged treatment regimen, Pox levels first stabilized and subsequently declined from 130 µmol/L to around 80 µmol/L. Nephrocalcinosis and retinal deposits stabilized. Oxalobacter formigenes treatment was well-tolerated and no related adverse events were observed. The patient showed nearly age-appropriate growth and development and received successful combined liver-kidney transplantation at the age of two years. CONCLUSIONS: Treatment with O. formigenes combined with intensive dialysis led to reduction of Pox, stabilization of systemic oxalosis, and improvement in the clinical disease course. O. formigenes treatment may be an option for reduction of oxalosis in infantile patients with insufficient response to conservative treatments until combined liver-kidney transplantation can be performed.

The Rise of Retinal Organoids for Vision Research.

Retinal degenerative diseases lead to irreversible blindness. Decades of research into the cellular and molecular mechanisms of retinal diseases, using either animal models or human cell-derived 2D systems, facilitated the development of several therapeutic interventions. Recently, human stem cell-derived 3D retinal organoids have been developed. These self-organizing 3D organ systems have shown to recapitulate the in vivo human retinogenesis resulting in morphological and functionally similar retinal cell types in vitro. In less than a decade, retinal organoids have assisted in modeling several retinal diseases that were rather difficult to mimic in rodent models. Retinal organoids are also considered as a photoreceptor source for cell transplantation therapies to counteract blindness. Here, we highlight the development and field's improvements of retinal organoids and discuss their application aspects as human disease models, pharmaceutical testbeds, and cell sources for transplantations.

Optical coherence tomography angiography (OCT-A) in an animal model of laser-induced choroidal neovascularization.

Aim of the study was to compare optical coherence tomography angiography (OCT-A) and conventional fluorescein angiography (FA) for quantitative analysis of the retinal and choroidal vasculature in the animal model of laser-induced choroidal neovascularization (CNV). Therefore, Dark Agouti rats underwent argon laser photocoagulation to induce CNV at D0. In vivo imaging using combined confocal scanner laser ophthalmoscopy (cSLO)-based FA and OCT-A (Heidelberg Engineering GmbH, Heidelberg, Germany) was performed before and immediately after laser treatment as well as at day 2, 7, 14 and 21. OCT-A en-face images were compared to cSLO images obtained by conventional FA topographic uptake recorded using a series of different pre-defined focus settings. For a quantitative comparison of CNV imaging by OCT-A and FA, CNV area, vessel density, number of vessel junctions, total vessel length and number of vessel end points were analyzed. Subsequent ex vivo analyses of the CNV included immunofluorescence staining of vessels in retinal and RPE/choroidal/scleral flatmount preparations. We found, that OCT-A allowed for high-resolution non-invasive imaging of the superficial, intermediate and deep retinal capillary plexus as well as the choroidal blood vessels in rats. Compared with OCT-A, visualization of CNV progression by invasive FA was less accurate, in particular the deep vascular plexus was visualized in more detail by OCT-A. The area of neovascularization was mainly detected in the deep retinal vascular plexus, outer nuclear layer (ONL), ellipsoid zone (EZ) and the choroid. Within the laser lesions, signs of CNV formation occurred at day 7 with progression in size and number of small vessels until day 21. Due to leakage and staining effects, CNV areas appeared significantly larger in FA compared to OCT-A images (p ≤ 0.0001 for all tested layers). Vessel density, number of vessel junctions, total vessel length and number of vessel end points were significantly higher in intermediate vascular plexus (IVP) and deep vascular plexus (DVP) in OCT-A compared to FA images. Overall, CNV area in flatmounts was similar to OCT-A results and much smaller compared to the area of dye leakage by FA. This study demonstrates that in vivo OCT-A imaging in small animals is feasible and allows for precise analysis of the formation of new blood vessel formation in the animal model of laser-induced CNV. Given its superior axial resolution, sensitivity and non-invasiveness compared to conventional FA imaging, OCT-A opens the door for a more detailed evaluation of CNV development in such a model and, thus, enables the analysis of the response to novel therapeutic interventions in longitudinal in vivo studies.

Correction to: Visual impairment and blindness in institutionalized elderly in Germany.

The original version of this article inadvertently contained a mistake. Authors incorrectly listed in PDF version while correctly presented in the html version.

Visual impairment and blindness in institutionalized elderly in Germany.

PURPOSE: To determine the prevalence of and identify factors associated with visual impairment and blindness in institutionalized elderly in Germany. METHODS: In this prospective multicenter cross-sectional study, ophthalmic health care need and provision were investigated in institutionalized elderly in 32 nursing homes in Germany. All participants underwent a standardized examination including medical and ocular history, refraction, visual acuity testing, tonometry, biomicroscopy, and dilated funduscopy. A standardized questionnaire was used to identify factors associated with eye healthcare utilization, visual impairment and/or blindness. RESULTS: Visual acuity of 566 (94.3%; 413 women and 153 men) of a total of 600 institutionalized elderly was determined. Mean age of the included patients was 82.9 years (± 9.8). Of all participants, 30 (5.3%; 95% CI 3.4-7.2%) were blind and 106 (18.7%; 95% CI 15.5-21.9%) were moderately or severely visually impaired according to the World Health Organization definition. The 136 blind and moderately or severely visually impaired participants were older (OR, Odds Ratio = 1.1, 95% CI 1.0-1.1; p < 0.001), and more likely to have reduced mobility (OR = 12.6, 95% CI 2.8-57.6; p = 0.001). CONCLUSION: A high proportion of blindness and visual impairment was found amongst nursing home residents. Age and reduced mobility were factors associated with an increased likelihood of blindness and visual impairment. Any surveys of blindness and visual impairment excluding nursing homes may considerably underestimate the prevalence of visual impairment and blindness.

MINIMAL OPTICAL COHERENCE TOMOGRAPHY B-SCAN DENSITY FOR RELIABLE DETECTION OF INTRARETINAL AND SUBRETINAL FLUID IN MACULAR DISEASES.

PURPOSE: To determine the minimal optical coherence tomography B-scan density for reliable detection of intraretinal and subretinal fluid. METHODS: Spectral domain optical coherence tomography raster scanning (Spectralis; Heidelberg Engineering, Heidelberg, Germany) using a scan field of 20° × 20° of 97 B-scans with an interscan distance (ISD) of 60 µm was performed in 150 eyes of 150 consecutive patients at monitoring visits for intravitreal anti-vascular endothelial growth factor therapy. Using custom software, every other B-scan was repeatedly deleted to generate additional data sets with an ISD of 120 µm (49 B-scans), 240 µm (25 B-scans), and 480 µm (13 B-scans). Two independent reviewers evaluated the data sets for the presence of cystoid spaces of intraretinal fluid and subretinal fluid. RESULTS: Treatment diagnoses were neovascular age-related macular degeneration (68.0%), macular edema secondary to retinal vein occlusion (20.7%), diabetic macular edema (10.7%), and other retinal diseases (4.0%). Using the source data sets with an ISD of 60 µm, intraretinal fluid was detected in 56.0%, subretinal fluid in 19.3%, and either/both in 68.7%. Compared with these results, the sensitivity of detection of intraretinal fluid and/or subretinal fluid using an ISD of 120 µm, 240 µm, and 480 µm was 99.0% (95% confidence interval, 94.7-100.0; P = 0.5), 97.1% (91.7-99.4; P = 0.1), and 87.4% (79.4-93.1; P = 0.0001), respectively. CONCLUSION: An increase of ISD up to 240 µm does not significantly impair the detection of treatment-relevant exudative retinal changes in monitoring during intravitreal therapy of macular diseases. These findings are relevant for the choice of optical coherence tomography B-scan density in both routine clinical care and interventional clinical studies.

RANIBIZUMAB IN PIGMENT EPITHELIAL TEARS SECONDARY TO AGE-RELATED MACULAR DEGENERATION: A Prospective Study.

PURPOSE: To assess efficacy of intravitreal ranibizumab in retinal pigment epithelium tears secondary to neovascular age-related macular degeneration. METHODS: The Ranibizumab In Pigment epithelial tears secondary to age-related macular degeneration (RIP) study is a prospective, single-arm, multicenter, investigator-initiated trial. Twenty four eyes of 24 patients with a retinal pigment epithelium tear secondary to age-related macular degeneration received monthly intravitreal injection of 0.5mg ranibizumab for 12 months, together with monthly assessments of morphologic and functional efficacy parameters. Primary outcome measure was mean best-corrected visual acuity at final visit compared with baseline. RESULTS: Mean best-corrected visual acuity remained stable over the 12-month study period with 50.3 Early Treatment of Diabetic Retinopathy Study letters (±18.7; Snellen equivalent 20/100) at baseline and 52.9 letters (±19.7; Snellen equivalent 20/100) at final visit (P = 0.39). One eye (4%) experienced a vision loss of ≥15 letters, and 2 eyes (8%) gained ≥15 letters. Mean central retinal thickness decreased from 571 µm (±185 µm) to 436 µm (±171 µm; P = 0.0001). Vision-related quality of life was stable with a mean VFQ-25 score of 79.0 (±10.8) at baseline and 74.3 (±13.9) at final visit (P = 0.12). CONCLUSION: In retinal pigment epithelium tears secondary to age-related macular degeneration, monthly intravitreal ranibizumab therapy results in stabilization of visual acuity over 12 months.

LONGITUDINAL CHANGE OF OUTER NUCLEAR LAYER AFTER RETINAL PIGMENT EPITHELIAL TEAR SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate longitudinal changes of outer nuclear layer (ONL) thickness in patients with retinal pigment epithelium tears secondary to neovascular age-related macular degeneration. METHODS: This is an institutional retrospective interventional case series. Twenty-six eyes of 22 patients with retinal pigment epithelium tears identified between April 2009 and March 2015. The patients underwent intravitreal injection of anti-vascular endothelial growth factor agents as needed. Volume scans of optical coherence tomography at first diagnosis of tear (baseline) and after 12 months were analyzed. Outer nuclear layer was segmented, and average ONL thickness inside the tear area, at the border of the tear, and in areas outside the tear was measured. Change of ONL thickness. We also explored several factors for their association with ONL thinning including tear area, number of treatments, and the duration with persistent subretinal fluid. RESULTS: Thinning of ONL was found in all the investigated areas (P < 0.01, respectively). Among the investigated factors, larger tear area was associated with greater ONL thinning outside the tear area (standardized ß = -0.37, P = 0.030), and younger age was associated with greater ONL thinning inside the tear area (standardized ß = 0.37, P = 0.041). CONCLUSION: After an retinal pigment epithelium tear, thinning of ONL occurs in the area devoid of retinal pigment epithelium and also in adjacent areas. Few factors were predictive for the degree of ONL thinning. These results provide new insight in disease progression of this particular neovascular age-related macular degeneration subphenotype.

Complement Component C5a Primes Retinal Pigment Epithelial Cells for Inflammasome Activation by Lipofuscin-mediated Photooxidative Damage.

Complement activation, oxidative damage, and activation of the NLRP3 inflammasome have been implicated in retinal pigment epithelium (RPE) pathology in age-related macular degeneration (AMD). Following priming of RPE cells, the NLRP3 inflammasome can be activated by various stimuli such as lipofuscin-mediated photooxidative damage to lysosomal membranes. We investigated whether products of complement activation are capable of providing the priming signal for inflammasome activation in RPE cells. We found that incubation of primary human RPE cells and ARPE-19 cells with complement-competent human serum resulted in up-regulation of C5a receptor, but not C3a receptor. Furthermore, human serum induced expression of pro-IL-1ß and enabled IL-1ß secretion in response to lipofuscin phototoxicity, thus indicating inflammasome priming. Complement heat-inactivation, C5 depletion, and C5a receptor inhibition suppressed the priming effect of human serum whereas recombinant C5a likewise induced priming. Conditioned medium of inflammasome-activated RPE cells provided an additional priming effect that was mediated by the IL-1 receptor. These results identify complement activation product C5a as a priming signal for RPE cells that allows for subsequent inflammasome activation by stimuli such as lipofuscin-mediated photooxidative damage. This molecular pathway provides a functional link between key factors of AMD pathogenesis including lipofuscin accumulation, photooxidative damage, complement activation, and RPE degeneration and may provide novel therapeutic targets in this disease.

Influence of ocular volume and lens status on pharmacokinetics and duration of action of intravitreal vascular endothelial growth factor inhibitors.

PURPOSE: To assess the effects of ocular axial length, refraction, and lens status on pharmacokinetics and duration of action of the vascular endothelial growth factor (VEGF) inhibitors ranibizumab and bevacizumab after intravitreal injection in humans. METHODS: In 119 eyes of 119 patients, aqueous humor was sampled at different time points after intravitreal injection of ranibizumab or bevacizumab, and either drug or VEGF concentrations were measured by enzyme-linked immunosorbent assays and Luminex multiplex bead technology, respectively. Relative deviation of the measured drug concentrations from the time-corrected mean values was calculated (n = 41). Repetitive VEGF measurements were preformed to identify the duration of complete suppression of ocular VEGF activity for individual eyes (n = 78). In addition, axial length, spherical equivalent refraction, and lens status were determined. RESULTS: For neither ranibizumab nor bevacizumab, a correlation between ocular pharmacokinetics (as measured by relative deviation of drug concentration from the mean) and axial length was detected in phakic eyes (Spearman's correlation coefficient, r = 0.084; P = 0.600). Similarly, the duration of action of intravitreal ranibizumab (as measured by VEGF suppression time) did not correlate with spherical equivalent refraction in phakic eyes (Spearman's correlation coefficient, r = 0.164; P = 0.301) and was not different between phakic and pseudophakic eyes (P = 0.694; Mann-Whitney U test). CONCLUSION: The results indicate that ocular volume and lens status have no relevant impact on ocular pharmacokinetics and duration of action of VEGF-inhibitory drugs and may, thus, be excluded as factors accounting for the high interindividual variability in morphologic and functional responses to intravitreal anti-VEGF therapy.

[Lamellar macular holes-In the center of vitreomacular interface diseases : Pathophysiology, spontaneous courses and treatment concepts]. / Makulaschichtforamen ­ im Zentrum der vitreomakulären Grenzflächenerkrankungen : Pathophysiologie, Spontanverläufe und Therapiekonzepte.

BACKGROUND: A lamellar macular hole (LMH) is characterized by a distinct morphologic configuration and can be distinguished from related entities such as macular pseudohole (MPH) and epiretinal membrane with foveoschisis (ERM-FS) by clear morphologic features. PURPOSE: Based on current knowledge, the pathophysiologic function of LMH in the spectrum of vitreomacular interface diseases will be described and therapeutic concepts will be presented. METHODS: Current studies are supplemented by case reports to provide a schematic overview of the natural history and therapeutic concepts at the vitreomacular interface. RESULTS: The LMH is as a retrospective marker for pathologic posterior vitreous detachment in adult patients and may be interpreted as the pathophysiologic center of tractional maculopathies. Various vitreomacular pathologies can result in LMH: a detached vitreomacular traction, a spontaneously closed penetrating macular hole, or an epiretinal membrane with foveoschisis. Pathophysiologically, a degenerative, progressive loss of the architecture of the foveal muller cell cone may be the underlaying mechanism, resulting in the typical undermining of the hole edges and occasionally in a full thickness macular hole. The optimal timing and the appropriate surgical method are the focus of current clinical studies. CONCLUSION: The pathophysiology of LMH indicates a smooth transition of tractive maculopathies. These should be prospectively evaluated in order to develop evidence-based treatment strategies for LMH.

[Macular hole: Differential diagnosis, treatment options and new guideline recommendations]. / Makulaforamen: Differenzialdiagnose, Behandlungsoptionen und neue Leitlinienempfehlungen.

Full-thickness macular holes (FTMH) usually result in a pronounced reduction of visual acuity and represent one of the most frequent indications for retinal surgery. If diagnosed and treatment is initiated at an early stage, surgery has a high success rate with respect to both hole closure and improvement of visual acuity. Optical coherence tomography (OCT)-based staging and sizing enables an estimation of the surgical outcome. The differential diagnostic distinction from clinically similar disorders, such as lamellar macular holes, macular pseudoholes, and foveoschisis is clinically relevant as the pathogenesis, prognosis and treatment are significantly different. While vitrectomy with peeling of the inner limiting membrane (ILM) and gas tamponade is established as the standard treatment for FTMH, some aspects of treatment are handled differently between surgeons, such as the timing of surgery, the choice of endotamponade and the type and duration of postoperative positioning. For FTMH associated with vitreomacular traction, alternative treatment options in addition to vitrectomy include intravitreal ocriplasmin injection and pneumatic vitreolysis. The current clinical guidelines of the German ophthalmological societies summarize the evidence-based recommendations for diagnosis and treatment of FTMH.

[Vitreomacular traction: diagnostics, natural course, treatment decision and guideline recommendations]. / Vitreomakuläre Traktion: Diagnostik, natürlicher Verlauf, Therapieentscheidung und Leitlinienempfehlungen.

Vitreomacular traction is a tractive foveolar adhesion of the posterior vitreous limiting membrane, resulting in pathological structural alterations of the vitreomacular interface. This must be differentiated from physiological vitreomacular adhesion, which exhibits a completely preserved foveolar depression. Symptoms depend on the severity of the macular changes and typically include reduced visual acuity, reading problems and metamorphopsia. High-resolution spectral domain optical coherence tomography (SDOCT) imaging enables classification of the sometimes only subtle morphological changes. If pronounced vitreomacular traction is accompanied by epiretinal gliosis and alterations to the outer retina, it is referred to as a vitreomacular traction syndrome. Vitreomacular traction has a high probability of spontaneous resolution within 12 months. Therefore, treatment should only be carried out in cases of undue suffering of the patient and with symptoms during bilateral vision and a lack of spontaneous resolution. In addition to pars plana vitrectomy, alternative treatment options, such as intravitreal injection of ocriplasmin and pneumatic vitreolysis are discussed for vitreomacular traction with an associated macular hole; however, ocriplasmin is no longer available in Germany. The best anatomical results in comparative investigations were achieved by vitrectomy. Pneumatic vitreolysis is controversially discussed due to the increased risk of retinal tears. In one of the current S1 guidelines of the German ophthalmological societies evidence-based recommendations for the diagnostics and treatment of vitreomacular traction are summarized.