[10 years of screening for retinopathy of prematurity (2009-2019) : Results analysis of two German level-1 neonatal intensive care units (NICUs) with university on-site screening and a telemedical approach in the non-university NICU]. / 10 Jahre Screening auf Frühgeborenenretinopathie (2009­2019) : Ergebnisanalyse zweier deutscher Level-1-Perinatalzentren mit universitärem Vor-Ort-Screening und telemedizinischem Ansatz in dem nicht universitären Zentrum.

BACKGROUND: Retinopathy of prematurity (ROP) is one of the most common causes of childhood blindness in Germany and worldwide and adequate screening is essential. The telemedical approach with objective documentation of retinal findings opens up the possibility of reliably diagnosing all ROP stages independent of the examiner, if a team of ophthalmologists specialized in ROP evaluates the images. OBJECTIVE: A 10-year comparison of ROP screening at two level­1 neonatal intensive care units (NICU): university and on-site vs. non-university and telemedical. MATERIAL AND METHODS: Retrospective analysis of screened premature infants by gestational age (GA), birth weight (BW), sex, multiple births, time of ROP occurrence, treatment needs and time as well as examination frequency. RESULTS: From 2009 to 2019, we screened 1191 infants of whom 29 had been screened before by an external clinic. The internal 1162 infants were screened on-site with 3713 retinal examinations. We diagnosed 34% with ROP and treated 5.4% (3.7% in Giessen, 7.2% in Siegen). Mean GA was 28.9 weeks (±â€¯2.5 weeks); mean BW 1155 g (±â€¯417.5 g). The number of ROP diagnoses increased by 227.3% in Giessen and by 111.1% in Siegen due to the increasing number of premature births in neonatal care. CONCLUSION: Comparative analysis confirmed nationally and internationally increasing ROP screening and children with acute ROP. Telemedical screening was equivalent to on-site screening and safe. Both screening methods identified infants requiring treatment on time. No child with GA > 29 weeks required treatment, analogous to Swedish ROP registry results; however, in the German ROP registry some premature babies with GA ≥ 30 weeks required treatment.

The Feasibility of Using Ultra-Widefield Retinal Imaging to Identify Ocular Pathologies amongst Those with Systemic Medical Disease Attending a Tertiary Healthcare Facility at a University Hospital.

AIMS: The aim of the study was to evaluate the feasibility of ultra-widefield (UWF) imaging to identify ocular pathologies amongst in- and out-patients in a tertiary university hospital. METHODS: We followed a prospective double-blinded multicenter clinical study. In total, 634 patients from a university hospital with pulmonary, cardiovascular, and endocrine diseases were examined by two teams by conventional slit-lamp biomicroscopy (CBM). UWF images with Optos Tx200 were taken and subsequently graded independently by two retina specialists and graders from two reading centers for the presence of pre-defined pathologies. Interrater reliability was calculated using Fleiss statistical software. An independent, trained and certified ophthalmologist with retinal subspecialty (BL) classified all UWF images with retinal hemorrhages by severity and interrater agreement. RESULTS: Complete data were available for 502 patients. The Moorfields Eye Hospital Reading Center, London, UK (RM), reported the highest number of cases with retinal pathologies (378), and the Reading Center GRADE Bonn, Germany (RB), did so for cases with optic disc cupping (466). Two retinal consultants (R1 and R2) from the Department of Ophthalmology, University Hospital Giessen and Marburg GmbH, Campus Giessen, Germany, noted optic disc pathologies. R1 reported 151 cases with optic disc pallor, while R2 reported only 39 disc pathologies. Both for clinical and for image readers, the early changes had equally low interrater reliability. The presence of at least 3 retinal hemorrhages had the highest interrater reliability (0.59). CONCLUSIONS: UWF imaging is convenient to identify overt retinal pathologies in patients at risk of ocular complications of their systemic disease who are attending hospital clinics. Imaging the eye allows for remote retinal assessment and for placing the patient into the appropriate clinical pathway for ophthalmology. PRECIS: UWF-imaging in a population of in- and out-patients at a university hospital who are at risk of retinal complications is effective to detect overt retinal pathologies and allows for tele-ophthalmology approaches to be enabled for placing the patients into the appropriate clinical pathways.

[Fluorescence Angiography-assisted Management of Recurrences in Aggressive Posterior Retinopathy of Prematurity (APROP) after Intravitreal Monotherapy with 0.312 mg Bevacizumab]. / Fluoreszenzangiografieassistiertes Management von Rezidiven bei aggressiver posteriorer Frühgeborenenretinopathie (APROP) nach intravitrealer Monotherapie mit 0,312 mg Bevacizumab.

BACKGROUND: In cases of aggressive posterior retinopathy of prematurity (APROP), recurrences can occur after intravitreal injection of bevacizumab (IVB), in spite of successful treatment of the acute stage. Therefore, long-term examinations in extremely premature patients are needed. We defined recurrences as a relapse of plus disease and leakage (with or without proliferation) at the vascularisation border, but also anterior and posterior to it. METHODS: RetCam wide-field colour images and fluorescein angiography were performed before the first IVB (0.312 mg bevacizumab in 0.025 ml per eye), before each further therapy, i.e. additional intravitreal injection, laser- or cryocoagulation or pars-plana vitrectomy, and at the end of the therapy. We analysed the images of 18 eyes with APROP of 9 extreme premature patients treated between 08/2007 and 12/2017 (GA 21 - 27 weeks, BW 430 - 890 g). RESULTS: Long-term therapeutic success was achieved in only 4 eyes/2 children (22%) with one single injection. In 2 eyes/2 children (11%), a second and third injection was given within 2 weeks because of an insufficient therapeutic effect. Up to 3 injections together with laser coagulation were needed in 12 eyes/6 children (67%), in order to achieve complete resolution of ROP activity. In 6 eyes/2 children (33%), resolution of leakage at the original vascularisation border was achieved only with further laser coagulation. In one single eye, retinal detachment occurred after unsuccessful retinal surgery. Before IVB, fluorescein angiography disclosed leakage due to proliferation in most of the patients (12 eyes/6 children). In recurrences after IVB, a posterior shift of the leakage site was found (14 eyes/4 children), whereas after laser photocoagulation proliferative changes were also detected anterior to the vascularisation border (5 eyes/3 children). Treatment was indicated based on angiographic findings in 14 eyes/4 children where wide-field colour images did not show plus disease or proliferation. CONCLUSIONS: Intravitreal injection of 0.312 mg bevacizumab has been shown to be an effective therapy for the acute stage of APROP. Long-term success required consequent monitoring and treatment of APROP recurrences. Fluorescein angiography was particularly useful to detect recurrences that were not evident in wide-field colour images.

Fundus-Controlled Dark Adaptometry in Young Children Without and With Spontaneously Regressed Retinopathy of Prematurity.

PURPOSE: We correlate dark adaptation course with foveal morphologic alterations in preterm and term-born children using a modified fundus-controlled perimeter and spectral domain-optical coherence tomography (SD-OCT) imaging. METHODS: We performed fundus-controlled chromatic dark adaptometry in premature children aged 6 to 13 years without retinopathy of prematurity (no-ROP; n = 61) and with spontaneously regressed ROP (sr-ROP, n = 29), and in 11 age-matched term-born children. The degree of macular developmental arrest (MDA), defined as a disproportion of the outer nuclear layer to inner retinal layers in the fovea (ONL+/IRL-ratio), was analyzed with the DiOCTA tool in SD-OCT scans. RESULTS: Children with MDA showed a flatter dark adaptation course progression with a significant rod-mediated sensitivity recovery delay (0.0113 vs. 0.0253 dB/s; P < 0.001). Preterm-born children with regular foveal morphology reached the final rod-mediated dark-adapted threshold at 12 minutes after bleach at 18.8 dB, compared to after 18.7 minutes at 17.6 dB in children with MDA (no significant difference in final threshold; P = 0.773). The cone-mediated dark adaptation progression showed a significant lower final threshold in children with MDA (6.0 vs. 8.1 dB; P = 0.004). CONCLUSIONS: Changes in dark adaptation were seen in the presence of MDA observed in premature children in the no-ROP and sr-ROP groups. MDA in former premature children is associated with functional deficits of cone and rod photoreceptor visual pathways. TRANSLATIONAL RELEVANCE: Morphologic alterations in the central retina of premature children, evident in SD-OCT, are associated with long-term functional deficits in the rod and cone pathways, particularly evident in the rod dark adaptation course measured at 12° eccentricity. This indicates a more widespread retinal functional pathology not limited to the fovea, but occurring together with foveal alterations best defined as MDA.

Cone-Mediated Function Correlates to Altered Foveal Morphology in Preterm-Born Children at School Age.

Purpose: To correlate cone- and rod-mediated function with morphology of the macula in preterm-born children without and with spontaneously regressed retinopathy of prematurity (ROP). Methods: We performed spectral-domain optical coherence tomography (SD-OCT) single scans in the macular center of preterm-born children aged 6 to 12 years (mean ± SD, 7.4 ± 1.8) without ROP (noROP; n = 59) and with spontaneously regressed ROP (srROP; n = 34), documented with wide-angle digital imaging during routine screening for acute ROP, and compared the data from 14 age-matched term-born children. SD-OCT data were compared to functional cone- and rod-mediated results of scotopic and photopic chromatic pupillometry (cP) and two-color fundus-controlled perimetry (2C-FCP). Results: SD-OCT showed a shallowed foveal pit with significantly reduced outer nuclear layer to inner retinal layer ratio, indicating macular developmental arrest (MDA). MDA was present in 44% of the srROP and 27% of the noROP children. Pupil reaction to photopic red stimuli on blue background showed significantly lower values in all preterm-born children with MDA. In accordance, photopic light increment sensitivity (LIS) to red stimuli in the foveal center on the 2C-FCP was also significantly reduced in children with MDA. Under scotopic conditions, no significant differences were apparent in both pupil reaction with cP and LIS with 2C-FCP. Conclusions: Both objective pupillary response to cone-mediated photopic red stimuli and subjective central cone-mediated results in fundus-controlled perimetry were reduced in preterm-born children with MDA. MDA was present in a significant number of patients with srROP, but also without ROP.

Choroidal Thickness with Swept-Source Optical Coherence Tomography versus Foveal Morphology in Young Children with a History of Prematurity.

AIM: Comparison of choroidal thickness (CT) and foveal morphology as seen with swept-source optical coherence tomography (SS-OCT) in children with a history of treated or spontaneously regressed retinopathy of prematurity (tROP or srROP) to assess the impact on best-corrected visual acuity (BCVA). METHODS: CT was measured by SS-OCT (DRI-OCT Triton; Topcon, USA) single scans of a 6-mm diameter around the fovea in 17 children with tROP or srROP (4-7 years of age) and compared to 25 controls (age-matched children and adults). The disproportion of the outer nuclear layer and inner retinal layers at the fovea (i.e., the ONL+/IRL ratio) as a measure of macular developmental arrest (MDA) was manually analyzed. BCVA was tested with ETDRS letter charts and correlated with the morphology. RESULTS: CT was significantly thinner in children with tROP and srROP compared to term-born healthy children (nKids) at all measurement marks (p < 0.001), and mostly affected in the subfoveal area. tROP showed the lowest CT. CT allowed no direct conclusion about ONL+/IRL, but correlated positively with BCVA. CONCLUSIONS: Reduced CT in children with a history of ROP is linked to ROP severity. These findings overlap with the degree of MDA. CT appears to be involved in ROP, but MDA showed a higher impact on the BCVA of the examined cohort.

OCT Angiography in Young Children with a History of Retinopathy of Prematurity.

PURPOSE: To describe the size and appearance of the foveal avascular zone (FAZ) in the superficial and deep plexus in young children with treated or spontaneously regressed retinopathy of prematurity (ROP), in comparison with age-matched controls and young adults, as seen with OCT angiography (OCTA), and to compare these parameters with foveal classic OCT images and visual function. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Twenty-five children with treated or spontaneously regressed ROP (mean 5.0±0.8 years) compared with 15 healthy term-born age-matched children and 20 healthy adults. METHODS: OCTA was performed using a DRI OCT Triton (Swept Source OCT, Topcon, Oakland, NJ). The best-quality images of 1 eye per patient were analyzed. Superficial FAZ and deep FAZ were analyzed separately. Single-scan OCTs were performed using a Spectralis SD-OCT (HRA+OCT, Heidelberg Engineering, Heidelberg, Germany). The foveal pit characteristics and the degree of macular developmental arrest (MDA), defined as the ratio of the outer nuclear layer + external limiting membrane (ONL+) and the inner retinal layers in the fovea (ONL+/IRL-ratio), were analyzed with a custom-made automated layer segmentation tool (DiOCTA, copyright by Justus-Liebig-University, Giessen, Germany). Visual acuity (VA) was tested with Early Treatment of Diabetic Retinopathy Study letter charts. MAIN OUTCOME MEASURES: The ONL+/IRL-ratio, superficial FAZ area, deep FAZ area, foveal parameters, and VA. RESULTS: Foveal pit depth and area were significantly reduced in both treated and spontaneously regressed ROP, whereas the foveal diameter was comparable in all groups. OCTA showed a significantly narrowed superficial FAZ in eyes with treated and spontaneously regressed ROP. In contrast, the deep FAZ was of comparable size in all groups. A reduced superficial FAZ significantly correlated with reduced ONL+/IRL-ratio, and thus the degree of MDA. In treated and spontaneously regressed ROP, reduced superficial FAZ and MDA correlated significantly with diminished VA. CONCLUSIONS: OCTA is feasible in young children with a history of ROP and without neurodevelopmental delay. It allows detecting a decreased superficial FAZ size noninvasively. A small superficial FAZ, reduced ONL+/IRL-ratio as a measure of MDA, and reduced VA are concurrent factors in preterm children who are otherwise neurologically normal.

[The Impact of Macular Development on Full-field and Multifocal ERG in Extremely Preterm-born Children with and without Acute Retinopathy of Prematurity]. / Einfluss der Makulareifung auf Ganzfeld- und multifokales ERG bei ehemaligen Extremfrühgeborenen mit und ohne akute Frühgeborenenretinopathie.

Introduction Retinal development is a complex process that can continue into early childhood and beyond. Prematurity can affect the maturation of the central retina, characterised by a flatter foveal pit and overlying inner retinal layers (IRL), leading to a disturbed ratio of outer retinal layers to IRL ("macular developmental arrest": MDA) and functional impairment (Bowl et al. 2016 18). The purpose of this study was to correlate functional results by electrophysiology with the morphological appearance of the fovea in children with spontaneously regressed and without ROP and term-born age-matched controls. Methods We investigated n = 60 preterm-born children with spontaneously regressed (srROP, n = 15) and without ROP (noROP, n = 50) as part of an extensive prospective cohort study and compared them to n = 10 term-born age-matched controls (Term). Full-field electroretinogram (ffERG) and multifocal ERG (mfERG) based on ISCEV-standards were performed in every child for functional evaluation. Foveal morphology was evaluated with optical coherence tomography (SD-OCT, Spectralis, Heidelberg Engineering, Germany). Results Analysis of the scotopic ffERG showed significantly modified b-wave amplitudes in srROP and noROP, especially when MDA was found on SD-OCT. The mfERG exhibited a modified P1-component of the central hexagon and the second concentric ring in children with MDA. No other parameters were significantly changed. Conclusions Electrophysiological changes can be found in extremely preterm-born children, especially with OCT-confirmed foveal maturation impairment (MDA), namely in children with spontaneously regressed ROP as well as in children without ROP. The reduced b-wave in the scotopic ffERG and the reduced P1-component in the mfERG indicate involvement of bipolar cells in extremely prematurely born children with MDA. In particular, the correlation of MDA with ffERG could be a sign of more global retinal maturation disturbance accompanying MDA, and this is seen even without acute ROP.

RETINAL VASCULAR DEVELOPMENT WITH 0.312 MG INTRAVITREAL BEVACIZUMAB TO TREAT SEVERE POSTERIOR RETINOPATHY OF PREMATURITY: A Longitudinal Fluorescein Angiographic Study.

PURPOSE: To report the outcome of intravitreal 0.312 mg bevacizumab (IVB) monotherapy in acute retinopathy of prematurity (ROP) and to describe the vascular development over time. METHODS: Seventeen prematurely born infants were treated with IVB (0.312 mg in 0.025 mL per eye) because of acute ROP in posterior Zone II or Zone I, including aggressive posterior ROP. Infants were examined by fluorescein angiography (FA) using RetCam II or III (Clarity Medical Systems Inc) before IVB (n = 21 eyes), within 6 weeks (n = 23 eyes), 8 to 13 weeks (n = 22 eyes), and up to 45 months (n = 10 eyes). RESULTS: Acute ROP regressed in 19 out of 27 analyzed eyes (70%), including 100% and 80% of posterior Zone II and Zone I eyes, respectively, but only 25% of aggressive posterior ROP eyes. Early recurrences (11%, all aggressive posterior ROP) and late reactivations (18%) were observed within 1 week and at 9 to 12 weeks, respectively. All eyes showed leakage at the junction of the vascularized zone and capillary malformation on FA before treatment. Vessel branching abnormalities and circumferential vessel formation were typical FA features after treatment. Vascular outgrowth after one IVB became complete in 87.5% of eyes for which FA was available up to at least 9 weeks after IVB. CONCLUSION: A single dose of 0.312 mg bevacizumab was efficient to induce regression of ROP in posterior Zone II and most of Zone I cases, but not in aggressive posterior ROP. FA describes vascular abnormalities, the importance of which warrants further investigation.

OCT-Based Macular Structure-Function Correlation in Dependence on Birth Weight and Gestational Age-the Giessen Long-Term ROP Study.

PURPOSE: To compare retinal layer thicknesses in preterm and term-born children using spectral-domain optical coherence tomography (SD-OCT) and to correlate structure with retinal function. METHODS: We performed SD-OCT single and volume scans in the foveal region of premature children aged 6 to 13 years without ROP (no-ROP, n = 100) and with spontaneously regressed ROP (sr-ROP, n = 50) documented with wide-angle digital imaging during routine screening for acute ROP, and 30 age-matched term-born children. Retinal layer segmentation and analysis was performed with custom-made software in single and volume-scans using an Early Treatment of Diabetic Retinopathy Study grid-based method, and compared to light increment sensitivity (LIS) data obtained with a microperimeter at eccentricity points of 0°, 2.8°, and 8°, as previously described. RESULTS: Overall, seven children had to be excluded due to poor image quality (n = 1 no-ROP; n = 2 sr-ROP; n = 4 term). Total retina, ganglion cell + inner plexiform layer (GCL+) and outer nuclear layer + external limiting membrane (ONL+) thickness at the foveal center in no-ROP and sr-ROP were significantly higher compared with term children. Gestational age (GA) and birth weight (BW) were inversely correlated with these layer thicknesses. Rod and cone outer segment length did not differ in either group. The ratio of ONL+ to the whole retina at 0° correlated significantly with reduced LIS. CONCLUSIONS: Increased thicknesses of the entire retina or specific layers at the fovea did not correlate with functional loss; but a thinner ONL in retinae without foveal pit did. This reduced ONL+ ratio is potentially caused by a reduced foveal cone density and may be the first morphologic functional correlate in prematurity and ROP.

Large deletions of the KCNV2 gene are common in patients with cone dystrophy with supernormal rod response.

Cone dystrophy with supernormal rod response (CDSRR) is considered to be a very rare autosomal recessive retinal disorder. CDSRR is associated with mutations in KCNV2, a gene that encodes a modulatory subunit (Kv8.2) of a voltage-gated potassium channel. In this study, we found that KCNV2 mutations are present in a substantial fraction (2.2-4.3%) of a sample of 367 independent patients with a variety of initial clinical diagnoses of cone malfunction, indicating that CDSRR is underdiagnosed and more common than previously thought. In total, we identified 20 different KCNV2 mutations; 15 of them are novel. A new finding of this study is the substantial proportion of large deletions at the KCNV2 locus that accounts for 15.5% of the mutant alleles in our sample. We determined the breakpoints and size of all five different deletions, which ranged between 10.9 and 236.8 kb. Two deletions encompass the entire KCNV2 gene and one also includes the adjacent VLDLR gene. Furthermore, we investigated N-terminal amino acid substitution mutations for its effect on interaction with Kv2.1 using yeast two-hybrid technology. We found that these mutations dramatically reduce or abolish this interaction suggesting a lack of assembly of heteromeric Kv channels as one underlying pathomechanism of CDSRR.

Phenotypes of 16 Stargardt macular dystrophy/fundus flavimaculatus patients with known ABCA4 mutations and evaluation of genotype-phenotype correlation.

PURPOSE: To determine the phenotypic variability in patients with compound heterozygous or homozygous ABCA4 mutations, and to correlate the phenotypes with the functional properties of the altered protein. METHODS: Sixteen patients from 13 families with signs of Stargardt macular dystrophy/fundus flavimaculatus and known mutations on both alleles of the ABCA4 gene (15 compound heterozygous, one homozygous) were characterized by clinical examination, fundus autofluorescence, psychophysics (color vision, kinetic and two-color dark- and light-adapted static threshold perimetry), and electrophysiology (Ganzfeld, multifocal ERG, EOG). RESULTS: The homozygous 5917delG mutation resulted in the earliest disease manifestation (at 5 years) and a general cone-rod dysfunction, whereas the compound heterozygous mother (5917delG, G1961E) exhibited a very mild phenotype. Compound heterozygotes for the IVS40+5G-->A and the C1488Y or Y362X mutation showed also an early age of onset but only a central dysfunction. The effect of the 2588G-->C mutation, the G1961E mutation, and the complex mutation L541P-A1038V depended on the mutation in the second allele. Genotype-phenotype correlation appeared possible in most instances. Psychophysics revealed a simultaneous yet not necessarily congruent cone and rod dysfunction. CONCLUSIONS: The type and combination of ABCA4 mutations in compound heterozygous patients determined were compatible with the severity of the phenotype as to age of onset and the functional consequences in the majority of patients. Unexplained phenotypic differences indicate the influence of other factors. ABCA4 mutations result in cone and rod dysfunction. Different disease durations limit the power of presently available genotype-phenotype correlations.