Sex-Specific Differences in the Relationship Between Prematurity and Ocular Geometry.

Purpose: To explore differences in the relationship between gestational age (GA) and birth weight (BW) percentile and ocular geometry between males and females. Methods: The Gutenberg Prematurity Eye Study involved a prospective ophthalmic examination of adults, aged 18 to 52 years, who were born preterm or at term, in Germany. The associations between GA and BW percentile on the main outcome measures were evaluated by uni- and multivariable linear regression analyses. The main outcome measures were central corneal thickness, corneal radius, anterior chamber depth, lens thickness, posterior segment length, and central foveal thickness. Potential sex-specific differences and an effect modification by sex were analyzed. Results: This study involved 438 participants (245 females, 193 males) with an average age of 28.6 ± 8.7 years. In female participants, central foveal thickness was negatively associated with a higher GA (B = -2.99; P < 0.001). Similarly, male participants also demonstrated a negative association between central foveal thickness and GA (B = -4.27; P < 0.001). The multivariable model with effect modification revealed that the central foveal thickness was thicker with lower GA. There was an association between the effect modification of GA with sex and central foveal thickness, demonstrating a more pronounced effect of GA on central foveal thickness in male participants (B = 1.29; P = 0.04). Conclusions: This study identified a sex-specific correlation between lower GA and thicker central foveal thickness, suggesting differences in the developmental trajectory of this biometric parameter concerning GA. A thicker central foveal thickness might affect the visual acuity of individuals born preterm in adulthood, with a more pronounced impact in males and a potential predisposition to age-related diseases later in life. Sex did not influence the association of GA or BW percentile to other ocular geometric parameters.

FOVEAL AVASCULAR ZONE IN ADULTS BORN PRETERM WITH AND WITHOUT RETINOPATHY OF PREMATURITY: Results From The Gutenberg Prematurity Eye Study.

PURPOSE: To examine potential changes in the foveal avascular zone (FAZ) during adulthood due to prematurity and retinopathy of prematurity (ROP), as assessed by measurements of the FAZ area and circularity. METHODS: The Gutenberg Prematurity Eye Study is a retrospective German cohort study with a prospective ophthalmologic examination of adults aged 18 years to 52 years, born either preterm or full-term, using spectral-domain optical coherence tomography angiography. Participants were categorized into groups based on gestational age and postnatal ROP status. The study conducted multivariable linear regression analyses to explore associations with the FAZ. RESULTS: The study cohort comprised 380 right eyes from individuals born both preterm and full-term, with an average age of 28.4 years ± 8.6 years, including 214 women. The FAZ area decreased as gestational age decreased: FAZ was 0.28 mm 2 ± 0.12 mm 2 in the control group, 0.21 ± 0.10 mm 2 at GA 33 weeks to 36 weeks, 0.18 mm 2 ± 0.10 mm 2 at GA 29 weeks to 32 weeks, 0.11 mm 2 ± 0.10 mm 2 at GA ≤28 weeks, 0.11 mm 2 ± 0.10 mm 2 in ROP without treatment, and 0.11 mm 2 ± 0.10 mm 2 in those requiring ROP treatment. In the multivariable analyses, smaller FAZ was independently associated with gestational age ( P < 0.05), increased foveal retinal thickness ( P < 0.05), and foveal hypoplasia ( P < 0.05). Moreover, no association was seen between visual acuity and FAZ. CONCLUSION: The main perinatal factor associated with a smaller FAZ in this German cohort is preterm birth, while ROP, ROP treatment, or other perinatal factors do not affect FAZ observed in adulthood. A smaller FAZ shape in preterm individuals might be an indicator of foveal hypoplasia.

Prevalence of strabismus and risk factors in adults born preterm with and without retinopathy of prematurity: results from the Gutenberg Prematurity Eye study.

AIM: The purpose of this study was to assess the prevalence of strabismus and nystagmus and to analyse associated factors in preterm and full-term infants in adulthood. METHODS: The Gutenberg Prematurity Eye Study is a retrospective cohort study with a prospective ophthalmological examination of participants born preterm and full-term (aged 18-52 years). Perinatal data were carefully assessed for risk factors and comprehensive ophthalmological examinations were conducted. The association between strabismus and nystagmus was assessed by analysing 16 different perinatal and actual risk factors in multivariable analysis. Participants were grouped into full-term controls (gestational age (GA) at birth ≥37 weeks), preterm participants without retinopathy of prematurity (ROP) and GA 33-36 weeks (group 2), GA 29-32 weeks (group 3), GA ≤28 weeks (group 4), non-treated ROP (group 5) and treated ROP (group 6). RESULTS: In total, 892 eyes of 450 preterm and full-term individuals (mean age: 28.6 years, SD: ± 8.6 years, 251 females) were included. Strabismus was observed in 2.1% (3/140), 6.6% (9/137), 17.4% (16/92), 11.1% (2/18), 27.1% (13/48) and 60% (9/15) of participants and nystagmus in 0.7% (1/140), 1.5% (2/137), 4.3% (4/92), 5.6% (1/18), 10.4% (5/48) and 26.7% (4/15) of participants in the respective groups. In the multivariable regression model, strabismus was associated with GA (OR=0.90; p=0.046), anisometropia ≥1.5 diopter (OR=3.87; p=0.003), hypermetropia ≥2 diopter (OR=9.89; p<0.001) and astigmatism ≥1.5 diopter (OR=2.73; p=0.017). Esotropia was more frequent than exotropia and hypermetropia/hypometropia. Most strabismus cases occurred within the first 10 years of life. The strongest predictor associated with nystagmus was perinatal adverse events (OR=15.8; p=0.002). CONCLUSION: Low GA and refraction of the eye are independent risk factors for strabismus, which typically occurs in the first 10 years of life. Perinatal adverse events are the most important factors for the presence of nystagmus in adulthood.

Macular Curvature in Adults Born Preterm With and Without ROP: Results from the Gutenberg Prematurity Eye Study.

Purpose: This study investigated the effects of prematurity and retinopathy of prematurity (ROP) as well as the associations of the ocular geometry with macular curvature in adults. Methods: The Gutenberg Prematurity Eye Study is a retrospective cohort study of preterm and full-term participants aged 18 to 52 years with a prospective ophthalmologic examination. The main outcome measure was the macular curvature in the central foveal optical coherence tomography (OCT) scan and its associations with gestational age (GA), birth weight and birth weight percentile, ROP occurrence, ROP treatment, and other perinatal factors were evaluated in univariable and multivariable linear regression analyses. Furthermore, a second model assessed the association of ocular geometry with macular curvature. Results: In the present study, 550 eyes of 284 adults born preterm and 277 eyes of 139 adults born full-term were examined (aged = 28.7 ± 8.7 years, 240 female subjects). In multivariable analyses for perinatal parameters, ROP treatment (B = -52.44, P = 0.023) and maternal smoking during pregnancy (B = 26.41, P = 0.019) showed an association with macular curvature. Regarding ocular geometric parameters, posterior segment length (B = 9.07, P < 0.001) and subfoveal choroidal thickness (B = -0.26, P < 0.001) were associated with macular curvature, central corneal thickness, anterior chamber depth, lens thickness, and foveal retinal thickness were not associated. Conclusions: Adults treated for ROP had relatively more negative curvature values compared to the full-term group, indicating a macular protrusion toward the vitreous cave. A thicker subfoveal choroidal thickness was associated with a flatter macular curvature, whereas a longer posterior segment length was associated with a steeper macular curvature indicating the characteristics of the myopic elongation of the eye.

Fetal Growth Restriction Leads to an Enlarged Cup-to-Disc Ratio in Adults Born at Full Term.

PURPOSE: This study explores associations between fetal growth restriction or excessive fetal growth, along with perinatal factors on the optic nerve head morphology in adulthood. DESIGN: Retrospective cohort study. METHODS: This retrospective cohort study involved a prospective ophthalmological examination of individuals born at full term (with a gestational age of ≥37 weeks) from 1969 to 2002. Each participant underwent nonmydriatic fundus camera photography to capture images of the optic discs, followed by manual measurements. The vertical cup-to-disc ratio (VCDR) and optic disc area were examined and analyzed in relation to the baby's birth weight relative to the gestational age. These categories included those with former moderate (birth weight percentile between the 3rd and <10th), severe SGA (below the third percentile), normal (AGA, 10th-90th percentile), and moderately (birth weight >90th-97th percentile) and severely (birth weight >97th percentile) large for gestational age (LGA) adults within the age range of 18 to 52 years. RESULTS: Overall, 535 eyes of 280 individuals (age 29.7 ± 9.2 years, 144 females) born at full term were included. Multivariable analysis showed a significant association between a larger VCDR and the severe SGA group (B = 0.05, 95% CI 0.01-0.10; P = .02). In the univariable model, placental insufficiency was associated with VCDR (B = 0.10, 95% CI 0.01-0.19; P = .03). Other perinatal factors did not demonstrate an association with VCDR. Furthermore, there was an indication of an association suggesting a smaller optic disc area in individuals born moderately SGA at full term (B = -0.17, 95% CI -0.33 to -0.001; P = .05). CONCLUSIONS: This study provides evidence that individuals born at-term with severe SGA have an increased VCDR, suggesting that fetal growth restriction has a lasting impact on optic disc morphology independent of prematurity throughout adulthood.

Effects of Resveratrol on Vascular Function in Retinal Ischemia-Reperfusion Injury.

Ischemia-reperfusion (I/R) events are involved in the development of various ocular pathologies, e.g., retinal artery or vein occlusion. We tested the hypothesis that resveratrol is protective against I/R injury in the murine retina. Intraocular pressure (IOP) was elevated in anaesthetized mice to 110 mm Hg for 45 min via a micropipette placed in the anterior chamber to induce ocular ischemia. In the fellow eye, which served as control, IOP was kept at a physiological level. One group received resveratrol (30 mg/kg/day p.o. once daily) starting one day before the I/R event, whereas the other group of mice received vehicle solution only. On day eight after the I/R event, mice were sacrificed and retinal wholemounts were prepared and immuno-stained using a Brn3a antibody to quantify retinal ganglion cells. Reactivity of retinal arterioles was measured in retinal vascular preparations using video microscopy. Reactive oxygen species (ROS) and nitrogen species (RNS) were quantified in ocular cryosections by dihydroethidium and anti-3-nitrotyrosine staining, respectively. Moreover, hypoxic, redox and nitric oxide synthase gene expression was quantified in retinal explants by PCR. I/R significantly diminished retinal ganglion cell number in vehicle-treated mice. Conversely, only a negligible reduction in retinal ganglion cell number was observed in resveratrol-treated mice following I/R. Endothelial function and autoregulation were markedly reduced, which was accompanied by increased ROS and RNS in retinal blood vessels of vehicle-exposed mice following I/R, whereas resveratrol preserved vascular endothelial function and autoregulation and blunted ROS and RNS formation. Moreover, resveratrol reduced I/R-induced mRNA expression for the prooxidant enzyme, nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2). Our data provide evidence that resveratrol protects from I/R-induced retinal ganglion cell loss and endothelial dysfunction in the murine retina by reducing nitro-oxidative stress possibly via suppression of NOX2 upregulation.

Effects of Postoperative Atropine Eye Drops on Visual Quality in Patients Undergoing Trabeculectomy.

The aim of this study was to investigate the effects of atropine on patients' perception of visual quality after trabeculectomy. Forty patients undergoing standard trabeculectomy with mitomycin C were enrolled in this prospective randomized study. All surgeries were conducted at the ophthalmology department of the University Medical Center of Mainz, Germany. All patients received the same postoperative treatment with ofloxacin and dexamethasone eye drops. Following randomization of patients into two groups of 20 patients, the intervention group also received atropine eye drops three times daily for the first 2 days after surgery to stabilize the anterior chamber. All patients completed a visual quality questionnaire before surgery and 2 and 6 weeks after surgery. Results were compared using the Wilcoxon test. After surgery, there was a reduction in visual quality in all patients. Patients who received atropine eye drops described a greater and longer-lasting reduction in visual quality than those who did not receive atropine eye drops. Trabeculectomy often leads to a transient reduction in visual quality. This reduction was greater in severity and duration in patients who received postoperative atropine eye drops. Thus, unless there is an underlying medical necessity, we would discourage the application of atropine as a standard therapy for trabeculectomy surgery.

Betulinic Acid Protects from Ischemia-Reperfusion Injury in the Mouse Retina.

Ischemia/reperfusion (I/R) events are involved in the pathophysiology of numerous ocular diseases. The purpose of this study was to test the hypothesis that betulinic acid protects from I/R injury in the mouse retina. Ocular ischemia was induced in mice by increasing intraocular pressure (IOP) to 110 mm Hg for 45 min, while the fellow eye served as a control. One group of mice received betulinic acid (50 mg/kg/day p.o. once daily) and the other group received the vehicle solution only. Eight days after the I/R event, the animals were killed and the retinal wholemounts and optic nerve cross-sections were prepared and stained with cresyl blue or toluidine blue, respectively, to count cells in the ganglion cell layer (GCL) of the retina and axons in the optic nerve. Retinal arteriole responses were measured in isolated retinas by video microscopy. The levels of reactive oxygen species (ROS) were assessed in retinal cryosections and redox gene expression was determined in isolated retinas by quantitative PCR. I/R markedly reduced cell number in the GCL and axon number in the optic nerve of the vehicle-treated mice. In contrast, only a negligible reduction in cell and axon number was observed following I/R in the betulinic acid-treated mice. Endothelial function was markedly reduced and ROS levels were increased in retinal arterioles of vehicle-exposed eyes following I/R, whereas betulinic acid partially prevented vascular endothelial dysfunction and ROS formation. Moreover, betulinic acid boosted mRNA expression for the antioxidant enzymes SOD3 and HO-1 following I/R. Our data provide evidence that betulinic acid protects from I/R injury in the mouse retina. Improvement of vascular endothelial function and the reduction in ROS levels appear to contribute to the neuroprotective effect.

[Removal of higher viscosity oil through a hybrid 2-port 23/25 gauge pars plana vitrectomy]. / Hybrid-2-Port-23/25-G-Pars-plana-Vitrektomie zur Entfernung von Öl höherer Viskosität.

This article presents a new hybrid method of a combined 2­port 23/25G pars plana vitrectomy for removal of silicone oil (5700 centistokes) compared to a 25G vitrectomy. In this hybrid technique the infusion is performed through a 25G cannula and the oil removal through a 23G cannula. The duration of the surgery and the intraocular pressure (IOP) in both groups were compared. The oil removal using the hybrid technique was performed significantly faster with a reduction of the time by 32.2% but there was no difference in the IOP. In conclusion, silicone oil removal through a 25G cannula is generally possible but oil removal with the new hybrid technique is much faster.

Outcome of Bleb Revision With Autologous Conjunctival Graft Alone or Combined With Donor Scleral Graft for Late-onset Bleb Leakage With Hypotony After Standard Trabeculectomy With Mitomycin C.

PRCIS: Treatment of leakage with ocular hypotony after trabeculectomy with mitomycin C (MMC) can be safely achieved through conjunctival patch alone or combined with donor scleral graft in cases of melted underlying sclera. PURPOSE: To report outcomes of 2 surgical approaches for treating ocular hypotony in eyes with blebs with late-onset leakage after standard trabeculectomy with MMC. METHODS: Thirty consecutive cases with bleb leakage and hypotony underwent bleb revision surgery between 2009 and 2014 by the same surgeon (J.W.) at the Department of Ophthalmology of the Mainz University Medical Center, Germany. In 18 patients, an autologous conjunctival patch graft was applied. In 12 patients, the underlying sclera was found melted and an additional scleral donor graft was sutured in place. The authors analyzed intraocular pressure, visual acuity, and optical coherence tomography of the macula preoperatively at 1 day, 1 week, 4 weeks, and 6 months after surgery. RESULTS: The mean IOP was 6.2±3.5 mm Hg preoperatively and 21.7±16.4 mm Hg at 1 day, 13.7±6.7 at 1 week, 13.1±5.1 mm Hg at 4 weeks, and 12.1±4.7 mm Hg at 6 months after surgery. Visual acuity (logMar) increased from 0.57±0.49 preoperatively to 0.49±0.40 at 6 months. Optical coherence tomography showed flattening of macular folds that were present before treatment. No serious adverse event was reported. CONCLUSIONS: This revision technique with conjunctival patch and/or additional donor scleral graft is an effective and safe method for treating late bleb leakage and hypotony maculopathy after trabeculectomy with MMC.

Apolipoprotein E Deficiency Causes Endothelial Dysfunction in the Mouse Retina.

OBJECTIVE: Atherogenic lipoproteins may impair vascular reactivity consecutively causing tissue damage in multiple organs via abnormal perfusion and excessive reactive oxygen species generation. We tested the hypothesis that chronic hypercholesterolemia causes endothelial dysfunction and cell loss in the retina. METHODS: Twelve-month-old apolipoprotein E-deficient (ApoE-/-) mice and age-matched wild-type controls were used in this study (n = 8 per genotype for each experiment). Intraocular pressure, blood pressure, and ocular perfusion pressure were determined. Retinal arteriole responses were studied in vitro, and reactive oxygen and nitrogen species were quantified in the retinal and optic nerve cryosections. The expression of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and the NADPH oxidase isoforms, NOX1, NOX2, and NOX4, were determined in retinal cryosections by immunofluorescence microscopy. Pro- and antioxidant redox genes were quantified in retinal explants by PCR. Moreover, cell number in the retinal ganglion cell layer and axon number in the optic nerve was calculated. RESULTS: Responses to the endothelium-dependent vasodilator, acetylcholine, were markedly impaired in retinal arterioles of ApoE-/- mice (P < 0.01). LOX-1 (P = 0.0007) and NOX2 (P = 0.0027) expressions as well as levels of reactive oxygen species (P = 0.0022) were increased in blood vessels but not in other retinal structures. In contrast, reactive nitrogen species were barely detectable in both mouse genotypes. Messenger RNA for HIF-1α, VEGF-A, NOX1, and NOX2, but also for various antioxidant redox genes was elevated in the retina of ApoE-/- mice. Total cell number in the retinal ganglion cell layer did not differ between ApoE-/- and wild-type mice (P = 0.2171). Also, axon number in the optic nerve did not differ between ApoE-/- and wild-type mice (P = 0.6435). CONCLUSION: Apolipoprotein E deficiency induces oxidative stress and endothelial dysfunction in retinal arterioles, which may trigger hypoxia in the retinal tissue. Oxidative stress in nonvascular retinal tissue appears to be prevented by the upregulation of antioxidant redox enzymes, resulting in neuron preservation.

Correction: Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium.

[This corrects the article DOI: 10.1371/journal.pone.0220143.].

Genetic variants linked to myopic macular degeneration in persons with high myopia: CREAM Consortium.

PURPOSE: To evaluate the roles of known myopia-associated genetic variants for development of myopic macular degeneration (MMD) in individuals with high myopia (HM), using case-control studies from the Consortium of Refractive Error and Myopia (CREAM). METHODS: A candidate gene approach tested 50 myopia-associated loci for association with HM and MMD, using meta-analyses of case-control studies comprising subjects of European and Asian ancestry aged 30 to 80 years from 10 studies. Fifty loci with the strongest associations with myopia were chosen from a previous published GWAS study. Highly myopic (spherical equivalent [SE] ≤ -5.0 diopters [D]) cases with MMD (N = 348), and two sets of controls were enrolled: (1) the first set included 16,275 emmetropes (SE ≤ -0.5 D); and (2) second set included 898 highly myopic subjects (SE ≤ -5.0 D) without MMD. MMD was classified based on the International photographic classification for pathologic myopia (META-PM). RESULTS: In the first analysis, comprising highly myopic cases with MMD (N = 348) versus emmetropic controls without MMD (N = 16,275), two SNPs were significantly associated with high myopia in adults with HM and MMD: (1) rs10824518 (P = 6.20E-07) in KCNMA1, which is highly expressed in human retinal and scleral tissues; and (2) rs524952 (P = 2.32E-16) near GJD2. In the second analysis, comprising highly myopic cases with MMD (N = 348) versus highly myopic controls without MMD (N = 898), none of the SNPs studied reached Bonferroni-corrected significance. CONCLUSIONS: Of the 50 myopia-associated loci, we did not find any variant specifically associated with MMD, but the KCNMA1 and GJD2 loci were significantly associated with HM in highly myopic subjects with MMD, compared to emmetropes.

Suture Removal After Trabeculectomy With Fornix-based Conjunctival Flap Leads to Faster Visual Recovery but Not Reduced Astigmatism.

PRéCIS:: The closing limbal suture after trabeculectomy with a fornix-based conjunctival flap plays no critical role in the development of corneal astigmatism and intraocular pressure (IOP). A standard removal is not recommended. PURPOSE: To investigate the effect of removal of the conjunctival suture after trabeculectomy with fornix-based conjunctival flap on corneal astigmatism, visual acuity, and IOP. METHODS: Eighty-seven cases of trabeculectomy with mitomycin C with a fornix-based conjunctival flap performed in the eyes of 82 patients (5 patients underwent bilateral trabeculectomy) were enrolled in a prospective randomized study. All surgeries were conducted by the same surgeon (J.W.) in the Ophthalmology Department of the University Medical Center of Mainz, Germany. All eyes received a corneal-conjunctival, continuous, mattress, interlocked suture for closing the conjunctiva at the limbus. After randomization, in 46 cases the suture was removed 6 weeks postoperatively; in 41 patients, the suture was left in place. All patients were examined preoperatively, and at 6 weeks, 3 months, 6 months, and 12 months after surgery. Astigmatism was measured using objective refraction and corneal topography, IOP and visual acuity were also assessed. Results were compared using a Wilcoxon test or Mann-Whitney U test for single time-points. RESULTS: During follow-up, no significant differences between the 2 study groups regarding refractive or topographic values were found. Patients in the suture removal group had a significantly higher visual acuity than controls at 3 months, 6 months, and 1 year after surgery. IOP was similar in both groups throughout the study. CONCLUSIONS: Removal of the conjunctival suture in trabeculectomy with a fornix-based conjunctival flap leads to a faster rehabilitation of visual acuity but does not significantly affect corneal astigmatism or IOP.

The M1 muscarinic acetylcholine receptor subtype is important for retinal neuron survival in aging mice.

Muscarinic acetylcholine receptors have been implicated as potential neuroprotective targets for glaucoma. We tested the hypothesis that the lack of a single muscarinic receptor subtype leads to age-dependent neuron reduction in the retinal ganglion cell layer. Mice with targeted disruption of single muscarinic acetylcholine receptor subtype genes (M1 to M5) and wild-type controls were examined at two age categories, 5 and 15 months, respectively. We found no differences in intraocular pressure between individual mouse groups. Remarkably, in 15-month-old mice devoid of the M1 receptor, neuron number in the retinal ganglion cell layer and axon number in the optic nerve were markedly reduced. Moreover, mRNA expression for the prooxidative enzyme, NOX2, was increased, while mRNA expression for the antioxidative enzymes, SOD1, GPx1 and HO-1, was reduced in aged M1 receptor-deficient mice compared to age-matched wild-type mice. In line with these findings, the reactive oxygen species level was also elevated in the retinal ganglion cell layer of aged M1 receptor-deficient mice. In conclusion, M1 receptor deficiency results in retinal ganglion cell loss in aged mice via involvement of oxidative stress. Based on these findings, activation of M1 receptor signaling may become therapeutically useful to promote retinal ganglion cell survival.