LASER FLARE PHOTOMETRY IN PRIMARY RHEGMATOGENOUS RETINAL DETACHMENT: An Evaluation of 2,487 Cases.

PURPOSE: Exploratory analysis associated with the prospective, multicenter, randomized PRIVENT trial. To characterize the associations between laser flare photometry and anatomical and epidemiological features of rhegmatogenous retinal detachment (RRD). METHODS: The authors measured laser flare values of all 3,048 prescreened patients excluding those with comorbidities. A mixed regression analysis evaluated the strength of the influencing factors like age, sex, lens status, and presence and extent of RRD on laser flare. RESULTS: Rhegmatogenous retinal detachment was more frequent in men (65.8%) than in women (34.2%, P < 0.001) and in right (52%) than in left eyes (48%, P = 0.045). Phakic RRD affected less quadrants and was less likely to be associated with macula-off status than pseudophakic RRD (48.4% vs. 58.0% macula off, 23% vs. 31% ≥3 quadrants, P < 0.001). Laser flare of affected eyes was significantly higher compared with fellow eyes (12.6 ± 15.2 vs. 8.3 ± 7.4 pc/ms, P < 0.001). The factors age, sex, lens status, presence of RRD, and the number of quadrants affected were independent influencing factors on laser flare. R 2 was 0.145 for phakic and 0.094 for pseudophakic eyes. CONCLUSION: The results indicate that there may be more factors affecting laser flare than previously assumed. This might limit flare as predictive value for PVR and retinal redetachment.

Intravitreal 5-Fluorouracil and Heparin to Prevent Proliferative Vitreoretinopathy: Results from a Randomized Clinical Trial.

PURPOSE: Proliferative vitreoretinopathy (PVR) is the major cause for surgical failure after primary rhegmatogenous retinal detachment (RRD). So far, no therapy has been proven to prevent PVR. Promising results for 5-fluorouracil (5-FU) and low-molecular weight heparin (LMWH) in high-risk eyes have been reported previously. The objective of this trial was to examine the effect of adjuvant intravitreal therapy with 5-FU and LMWH compared with placebo on incidence of PVR in high-risk patients with primary RRD. DESIGN: Randomized, double-blind, controlled, multicenter, interventional trial with 1 interim analysis. PARTICIPANTS: Patients with RRD who were considered to be at high risk for PVR were included. Risk of PVR was assessed by noninvasive aqueous flare measurement using laser flare photometry. METHODS: Patients were randomized 1:1 to verum (200 mg/ml 5-FU and 5 IU/ml dalteparin) and placebo (balanced salt solution) intravitreally applied during routine pars plana vitrectomy. MAIN OUTCOME MEASURES: Primary end point was the development of PVR grade CP (full-thickness retinal folds or subretinal strands in clock hours located posterior to equator) 1 or higher within 12 weeks after surgery. For grading, an end point committee assessed fundus photographs. Secondary end points included best-corrected visual acuity and redetachment rate. A group sequential design with 1 interim analysis was applied using the O'Brien and Fleming boundaries. Proliferative vitreoretinopathy grade CP incidence was compared using a Mantel-Haenszel test stratified by surgeon. RESULTS: A total of 325 patients in 13 German trial sites had been randomized (verum, n = 163; placebo, n = 162). In study eyes, mean laser flare was 31 ± 26 pc/ms. No significant difference was found in PVR rate. Primary analysis in the modified intention-to-treat population results were: verum 28% vs. placebo 23% (including not assessable cases as failures); odds ratio [OR], 1.25; 95% confidence interval [CI], 0.76-2.08; P = 0.77. Those in the per-protocol population were: 12% vs. 12%; OR, 1.05; 95% CI, 0.47-2.34; P = 0.47. None of the secondary end points showed any significant difference between treatment groups. During the study period, no relevant safety risks were identified. CONCLUSIONS: Rate of PVR did not differ between adjuvant therapy with 5-FU and LMWH and placebo treatment in eyes with RRD.

Test-Retest-Reliability of Computer-Based Metamorphopsia Measurement in Macular Diseases. / Test-Retest-Reliabilität der computergestützten Metamorphopsiemessung bei Makulaerkrankungen.

In this study, the test-retest-reliability as one aspect of reliability of metamorphopsia measurements using a computer-based measuring method was determined in patients with macular diseases. Metamorphopsia amplitude, position, and area were quantified using AMD - A Metamorphopsia Detector software (app4eyes GmbH & Co. KG, Germany) in patients with diabetic, myopic, or uveitic macular edema, intermediate or neovascular age-associated macular degeneration, epiretinal membrane, vitelliform maculopathy, Irvine-Gass syndrome, or macular edema due to venous retinal occlusion. The intraclass correlation coefficient (ICC) was calculated in order to determine the repeatability of two repeated measurements and was used as an indicator of the reliability of the measurements. In this study, metamorphopsia measurements were conducted on 36 eyes with macular diseases. Metamorphopsia measurements made using AMD - A Metamorphopsia Detector software were highly reliable and repeatable in patients with maculopathies. The intraclass correlation coefficient of all indices was excellent (0.95 - 0.97). For diseases of the vitreoretinal interface or macular diseases with intra- or subretinal edema, this metamorphopsia measurement represents a supplement for visual function testing in the clinic, as well as in clinical studies.

ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion.

PURPOSE: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. METHODS: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. RESULTS: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. CONCLUSION: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

Rupture of the Globe: What to Do, What not to Do. / Bulbusberstung: Vorgehen und Ergebnisse.

Due to their complexity, globe ruptures are highly compromising traumas for the patient. This is due on the one hand to the eye injury itself with the accompanying loss of vision and on the other hand due to the need for extended treatment with uncertain prognosis and the resulting psychological stress. Globe ruptures are among the prognostically most unfavorable injuries due to the force and peak pressure impacting the eye. Furthermore, contusional retinal necrosis may be of significance prognostically. In the present review, we discuss treatment of globe ruptures involving retinal surgery. We discuss the primary sugery, its chronological planning and extent as well as the necessity for follow-up interventions. We also discuss the origin of traumatic retinal detachment with differential diagnosis of giant retinal tear versus oradialysis as well as secondary sequelae of traumas such as formation of macular holes and their treatment. On this basis, the use of buckling surgery versus pars-plana vitrectomy is discussed. Further focus is set on the role of the iris lens diaphragm in surgery of globe ruptures.

[Evaluation of Ophthalmic Follow-up Care of Former Pre-term and Full-term Infants Aged from 4 to 10 Years in Germany - Results of the Wiesbaden Prematurity Study (WPS)]. / Evaluation der augenärztlichen Versorgung ehemaliger früh- und reifgeborener Kinder im Alter von 4 bis 10 Jahren in Deutschland ­ Ergebnisse der Wiesbaden Prematurity Study (WPS).

BACKGROUND: The purpose of this investigation was to analyse the ophthalmic follow-up care of former pre-term and full-term born infants aged 4 to 10 years in the clinical practice and the comparison to the recommendations of the national ophthalmic guidelines. METHODS: For the prospective Wiesbaden Prematurity Study (WPS), 503 infants were examined: 239 former pre-term infants (PT) with gestational age (GA) ≤ 32 weeks and 264 former full-term born infants (FT) with a GA ≥ 37 weeks aged 4 to 10 years. Ophthalmic examination was performed including refractive measurements and orthoptic examination. Anisometropia was defined as a difference of ≥ 1 D spherical equivalent. Data was assessed if an ophthalmological examination was performed after hospital discharge, and how many times the ophthalmologist was contacted within the last 12 months. RESULTS: Overall, strabismus and anisometropia were present in 18 and 10% of all PT, and in 2 and 5% of all FT infants, respectively. In infants aged 4 to 6 years, 65% of all former PT and 42% of all former FT had ophthalmological contacts within the last year (p = 0.002). 15% of the pre-term infants with strabismus did not have an ophthalmological examination within the last year. The parents of three former pre-term infants reported that they never had an ophthalmologic examination after hospital discharge. CONCLUSION: Two-thirds of the former pre-term infants participated in a screening examination at the age of 4 to 6 years in the last year according to their parents, which is recommended by the guidelines for the care of former pre-term infants. There is still room for improvement to provide best ophthalmological care for this vulnerable population that have high risk for strabismus and amblyopia.

Preexisting epiretinal membrane is associated with pseudophakic cystoid macular edema.

PURPOSE: The purpose of the present study was to evaluate whether preexisting epiretinal membrane (ERM) is a significant risk factor for developing pseudophakic cystoid macular edema (PCME). METHODS: Two hundred four consecutive eyes and 153 consecutive eyes without preexisting epiretinal membranes were retrospectively compared regarding PCME development following phacoemulsification with posterior chamber lens implantation. Patients with vascular retinal diseases, uveitis, trauma, neovascular macular degeneration, chronic inflammatory conditions, diabetic retinopathy, endophthalmitis, eventful cataract surgery, and combination of cataract surgery and vitrectomy during the observation period were excluded. Macular examination was performed using spectral-domain optical coherence tomography (SD-OCT) before as well as at 4, 8, 12, 16, 24, and 36 weeks after cataract surgery. Univariate and multivariate logistic regression analyses were calculated. RESULTS: PCME occurred in 32 of 204 eyes with preexisting ERM (15.7%), whereas 9 of 153 eyes without preexisting ERM (5.9%) developed PCME. The risk of PCME was significantly increased in eyes with ERM (p = 0.007). By multivariate logistic regression analysis, factors predictive of PCME included the history of previous pars plana vitrectomy for retinal detachment (odds ratio (OR) 3.619 [95% confidence interval (CI) 1.242 to 10.258]; p = 0.016) as well as the preexistence of ERM (OR 3.885 [95% CI 1.162 to 17.762]; p = 0.04). CONCLUSION: Preexisting ERM seems to be associated with an increased risk of PCME following cataract surgery. Therefore, this risk should be considered in surgery planning, preoperative medication, and follow-up care after surgery.

The influence of systemic renin-angiotensin-inhibition on ocular cytokines related to proliferative vitreoretinopathy.

PURPOSE: The renin-angiotensin system is involved in the pathogenesis of fibrosis in several organs via induction of transforming growth factor (TGF) beta. In the pathogenesis of proliferative vitreoretinopathy (PVR) TGF-beta plays a pivotal role, promoting transition of retinal pigment epithelial (RPE) cells into myofibroblasts. We studied the influence of angiotensin converting enzyme-inhibition (ACEI) on cytokines and growth factors, related to PVR in aqueous humor. METHODS: We performed a post hoc analysis of a prospectively conducted interventional case series. From patients with rhegmatogenous retinal detachment (RRD) aqueous humor was obtained during primary surgery and analyzed using multiplex bead analysis for interferon gamma, tumor necrosis factor alpha, CC-chemokine ligand (CCL) 2 / monocyte chemoattractant protein (MCP)-1, interleukin (IL)-1 beta, IL-2, IL-4, IL-6, IL-8, vascular endothelial growth factor (VEGF)-A, platelet derived growth factor (PDGF)-aa, TGF-beta 1, TGF-beta 2, TGF-beta 3, fibroblast growth factor (FGF)-aa, and FGF-bb. We recorded information about systemic ACEI from the medical history. RESULTS: In the primary study elevated levels of TGF-beta 1 and 2, IL 6 and 8 and CCL2/MCP-1 were a risk factor for later PVR development. Here, systemic ACEI neither influenced levels of these cytokines and growth factors, nor of any other tested in this study (p ≥ 0.438, respectively). Also the incidence of PVR development was unaffected (p = 0.201). CONCLUSION: The systemic intake of ACEI for arterial hypertension does not influence levels of profibrotic cytokines/growth factors in aqueous humor. Further studies need to clarify if relevant levels of ACEI accumulate in the eye, and if direct administration of ACEI in experimental PVR could be beneficial.

Macular morphology in former preterm and full-term infants aged 4 to 10 years.

OBJECTIVE: To analyse macular retinal and choroidal layer thickness in former preterm and full-term infants and to assess associated perinatal influence factors and functional correlation. METHODS: This prospective controlled, cross-sectional, hospital-based study in a tertiary center of maximum care examined former preterm infants with a gestational age (GA) ≤ 32 weeks and full-term neonates currently aged 4 to 10 years. We investigated data from 397 infants, analysing total foveal retinal thickness and six distinct macular retinal layer and choroidal layer measurements via spectral-domain optical coherence tomography. Multivariable linear regression analysis was performed to investigate associations of layer thickness with GA and retinopathy of prematurity (ROP). RESULTS: Total retinal thickness in the fovea was thicker in former preterm infants with GA ≤ 28 weeks and in those with GA between 29-32 weeks compared to full-term infants independently of ROP. Occurrence of ROP was also associated with increased foveal thickness. Ganglion cell layer together with inner plexiform layer (GCL+IPL) was thinner in infants with GA ≤ 28 weeks than in full-term infants at 1000 and 2000µm distance from the fovea, but no association with ROP was present. Similar results were found for the photoreceptor layer. Total foveal retinal thickness was associated with low visual function. CONCLUSION: This study identified low gestational age and ROP occurrence as main determinants for foveal thickening. Furthermore, thinned GCL+IPL measurements were associated with lower gestational age. This study highlights the prognostic value of these maturity parameters influencing retinal morphology, which may affect visual function.

Prevalence and associated factors of strabismus in former preterm and full-term infants between 4 and 10 Years of age.

BACKGROUND: Limited data exist collating most of the associated factors for strabismus in one analysis. The aim of this study was to assess the prevalence of strabismus and to analyse associated factors in former preterm and full-term infants. METHODS: In this cross-sectional study, 239 former preterm infants with gestational age (GA) ≤ 32 weeks and 264 former full-term born infants with GA ≥ 37 weeks underwent detailed ophthalmologic examination in the age of 4-10 years and perinatal data assessment for risk factor analysis. Ophthalmologic examinations included cover testing, best corrected visual acuity, cycloplegic objective refraction, slit lamp as well as fundus examinations. For association analysis with strabismus, the following data was collected and included in multivariable analysis: sex, age at examination, anisometropia, myopic and hyperopic refractive error (≥ 3 dioptres), astigmatism, birth weight percentile, gestational age, retinopathy of prematurity occurrence, maternal age at childbirth, mother smoking, breastfeeding < 3 months, artificial ventilation, intraventricular bleeding, and other perinatal adverse events. RESULTS: Overall, 4/264 (2%) full-term infants, 15/125 (12%) preterm-infants with GA 29-32 weeks without ROP, 13/59 (22%) preterm infants with GA ≤ 28 weeks without ROP and 14/55 (26%) with GA ≤ 32 weeks with retinopathy of prematurity were affected by strabismus. In the multivariable regression model strabismus was associated with GA (OR = 0.84 per week; p = 0.001), hyperopic refractive error (OR = 4.22; p = 0.002) and astigmatism (OR = 1.68; p = 0.02). CONCLUSION: This investigation highlights that low gestational age and refraction of the eye are independent risk factors for strabismus, while the other factors show less independent influence.

[Cell Transplantation in Age-related Macular Degeneration]. / Zelltransplantation zur Behandlung der altersabhängigen Makuladegeneration.

Robert Machemer offers a surgical approach to age-related macular degeneration with his retinal rotation. There is already considerable experimental and clinical knowledge available in Europe and the US on transplantation techniques for age-related macular degeneration. On average, initial visual acuity can be preserved. When photodynamic therapy was standard for exudative AMD, transplantation was superior. Photodynamic therapy could not stop, but was instead able to slow down visual loss. Currently, VEGF-blocker therapy has priority, because the visual acuity can be improved. However, this advantage does not last much longer than two years. Therefore, in the future, transplantation with new cells and less surgical risk may be reconsidered. At present, homologous RPE stem cells show promising results. They may be delivered as "sheets" or as single cells. For dry AMD only, a prophylactic approach seems reasonable, because, thus far, we are unable to reverse the atrophy on the retinal side.

HISTORY OF SUNLIGHT EXPOSURE IS A RISK FACTOR FOR AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate effects of current and past sunlight exposure and iris color on early and late age-related macular degeneration (AMD). METHODS: Of 3,701 individuals from the EUGENDA database, 752 (20.3%) showed early AMD, 1,179 (31.9%) late AMD, and 1,770 (47.8%) were controls. Information about current and past sunlight exposure, former occupation type, subdivided in indoor working and outdoor working, and iris color were obtained by standardized interviewer-assisted questionnaires. Associations between environmental factors adjusted for age, gender, and smoking and early and late AMD were performed by multivariate regression analysis. RESULTS: Current sunlight exposure showed no association with early AMD or late AMD, but past sunlight exposure (≥8 hours outside daily) was significantly associated with early AMD (odds ratio: 5.54, 95% confidence interval 1.25-24.58, P = 0.02) and late AMD (odds ratio: 2.77, 95% confidence interval 1.25-6.16, P = 0.01). Outside working was found to be associated with late AMD (odds ratio: 2.57, 95% confidence interval 1.89-3.48, P = 1.58 × 10). No association was observed between iris color and early or late AMD. CONCLUSION: Sunlight exposure during working life is an important risk factor for AMD, whereas sunlight exposure after retirement seems to have less influence on the disease development. Therefore, preventive measures, for example, wearing sunglasses to minimize sunlight exposure, should start early to prevent development of AMD later in life.

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.

Polymorphisms in vascular endothelial growth factor receptor 2 are associated with better response rates to ranibizumab treatment in age-related macular degeneration.

PURPOSE: Intravitreal anti-vascular endothelial growth factor (VEGF) injections are currently the standard treatment for neovascular age-related macular degeneration (AMD), but a broad range of response rates has been observed. We evaluated the association of single nucleotide polymorphisms (SNPs) in VEGF genes and their receptors (VEGFR) with the response rate to ranibizumab in 366 patients with neovascular AMD. DESIGN: Case series study. PARTICIPANTS: A total of 366 eyes of 366 patients with neovascular AMD. METHODS: Visual acuity (VA) was determined at baseline, after 3 monthly ranibizumab injections, and after 1 year of treatment. Genotyping of 126 SNPs in the genes encoding VEGF family members VEGFA, VEGFB, VEGFC, VEGFD (FIGF), and placental growth factor (PGF); VEGF receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4); and the gene encoding pigment epithelium-derived factor (PEDF) (SERPINF1) was performed. MAIN OUTCOME MEASURES: The changes in VA after 3 injections and after 1 year of treatment and their association with VEGF and VEGFR genotypes. RESULTS: Univariate analyses of variance (ANOVAs) revealed a significant effect of SNP rs4576072 in the VEGFR2 gene on VA change after 12 months (F[1,235] = 14.05; P = 0.02). A stepwise linear regression analysis returned a model (P = 0.01) with SNPs rs4576072 and rs6828477 in the VEGFR2 gene as independent predictors for VA change after 12 months, with a mean increase in VA of 0.26 on the logarithm of the minimum angle of resolution (logMAR) scale in patients with 3 contributing minor alleles compared with a loss of 0.03 logMAR in patients with no minor allele. CONCLUSIONS: Polymorphisms in the VEGFR2/KDR gene significantly influence visual outcome in patients receiving ranibizumab treatment for neovascular AMD. This study shows that genetic variation partially explains the wide range of response to ranibizumab treatment, which in the future might help clinicians tailoring medical interventions to individual needs.

Response to anti-VEGF therapy in patients with subretinal fluid and pigment epithelial detachment on spectral-domain optical coherence tomography.

PURPOSE: To analyse the long-term functional and morphological response of a specific choroidal neovascular membrane (CNV) phenotype to anti-vascular endothelial growth factor (VEGF) therapy. METHODS: Data from 30 eyes of 30 consecutive patients with subretinal fluid (SRF) and fibrovascular pigment epithelial detachment (PED) due to CNV on spectral-domain optical coherence tomography (SDOCT) with a follow-up of at least 20 months were retrospectively collected. Main outcome measures included change in visual acuity, quantitative and qualitative parameters on SDOCT [photoreceptor layer, outer nuclear layer (ONL), choroid, PED, SRF] and on fluorescein angiography (CNV activity). Subjects were divided into responders and non-responders based on morphological and functional aspects. RESULTS: An average number of 20.23 ± 9.9 anti-VEGF injections were administered during a mean follow-up of 40.25 ± 13.5 months. Fourteen eyes were categorized as morphological non-responders, 12 as functional non-responders and eight as complete non-responders. Complete non-responders were significantly younger than complete responders (68.5 ± 4.5 vs 74.3 ± 6.8 years; p < 0.05) and presented thinner baseline ONL values (68.43 ± 15.2 vs103.5 ± 32.8 µm; p < 0.05). Intermediate or large drusen as typical features for age-related macular degeneration (AMD) were less frequently present in complete non-responders; however, this was not statistically significant (62.5 % vs 91.7 %; p = 0.25). CONCLUSIONS: Our preliminary findings indicate that eyes with the specific SDOCT phenotype with isolated fibrovascular PED and SRF frequently demonstrate non-response to anti-VEGF therapy, and the underlying disease mechanism may be different from AMD. Larger prospective trials are required to validate those results, and to develop strategies to improve the morphological as well as functional outcome.