Smoking in pregnancy is associated with increased adiposity and retinal arteriolar wall-to-lumen ratio in adolescence: The Copenhagen Child Cohort Study 2000.

PURPOSE: To investigate the association between prenatal exposures and anthropometric data and cardiovascular risk factors including retinal arteriolar wall-to-lumen ratio in adolescence. METHODS: This longitudinal observational study included all 1445 adolescents from the Copenhagen Child Cohort 2000 who attended the 2016-2017 examination. Outcome measures included retinal arteriolar wall-to-lumen ratio, height, body mass index, waist-to-hip ratio, body composition measured by bioimpedance, and blood pressure. Information on prenatal exposures (birth weight, gestational age, maternal smoking during pregnancy) as well as sex, parental age, household income and parental educational levels were obtained from national registries. Associations between exposures and outcome measures were analyzed using general linear models. RESULTS: Maternal smoking during pregnancy was associated with a higher retinal arteriolar wall-to-lumen ratio (0.004 or 1.9%, P = 0.009) at age 16/17 years, an association driven exclusively by the female participants (0.008 or 3.7%, P < 0.0001). Maternal smoking during pregnancy was also associated to higher body-mass index (1.43 kg/m2, P < 0.0001), waist-to-hip ratio (0.02, P < 0.0001) and fat mass index (0.93 kg/m2, P < 0.0001). Birth weight, gestational age, and parental age had no detectable impact on retinal arteriolar wall-to-lumen ratios. CONCLUSION: Prenatal exposure to tobacco smoking is associated with a higher risk of obesity and, predominantly in girls, to a greater retinal arteriolar wall thickness, which suggests that maternal smoking may induce an unfavorable cardiovascular and metabolic risk profile in the child.

Progression Over 5 Years of Prelaminar Hyperreflective Lines to Optic Disc Drusen in the Copenhagen Child Cohort 2000 Eye Study.

BACKGROUND: The purpose of the study was to examine 5-year changes in eyes with optic disc drusen at baseline on optical coherence tomography (OCT) scans and the relation of incident drusen to hyperreflective prelaminar lines. METHODS: The study included children who presented at baseline, when participants were aged 11-12 years, and again 5 years later. Grading for optic disc drusen was made in all. Grading for prelaminar lines was made in all children at follow-up and in eyes with optic disc drusen at baseline. Analyses included associations with scleral canal diameter at baseline in all children with optic disc drusen and a nested control group of 115 children without optic disc drusen. Data are reported as the number of children having at least one drusen or at least one hyperreflective line per person. RESULTS: The analysis included 724 children who attended both rounds of the study. Of these, 11 (1.5%) had optic disc drusen at baseline. Five additional children had developed optic disc drusen at follow-up, whereas optic disc drusen had disappeared in none, so that 16 (2.2%) children had optic disc drusen in one or both eyes at follow-up. Children with optic disc drusen at the 5-year follow-up had had a mean scleral canal diameter of 1,364 µm (interquartile range [IQR] 81 µm), compared with 1,457 µm (IQR 197) µm in 115 nested controls without optic disc drusen (P < 0.001). Optic disc drusen at follow-up were associated with more hypermetropic refraction. All children who had optic disc drusen at follow-up also had prelaminar hyperreflective lines. In addition, such lines were found at follow-up in 24 of the remaining 708 children without optic disc drusen (P < 0.001). Prelaminar hyperreflective lines with or without optic disc drusen were associated with a narrower scleral canal (diameter 1,364 µm, IQR 119 µm) compared with absence of prelaminar lines (1,486 µm, IQR 206 µm; P < 0.0001). CONCLUSION: This study provides the first evidence from a prospective study that small optic discs and prelaminar hyperreflective lines on OCT are risk factors for the development of optic disc drusen. The association between prelaminar hyperreflective lines, hypermetropia, and a narrow scleral canal supports that a crowded disc is an essential predisposing factor for the development of optic disc drusen.

Optic Disc Drusen in Children: The Copenhagen Child Cohort 2000 Eye Study.

BACKGROUND: Optic disc drusen (ODD) are seen in up to 2.4% of the general population, but the etiology and pathophysiology of the condition is still unknown. The purpose of this study was to determine the prevalence of ODD in a population-based child cohort and to determine if scleral canal diameter and fetal birth and pubertal parameters are associated with the presence of ODD. METHODS: This observational, longitudinal population-based birth cohort study, with a nested case-control, included 1,406 children. Eye examinations were performed when the children were between 11 and 12 years of age. Assessment was performed of optical coherence tomography (OCT) scans from 1,304 children with gradable enhanced depth imaging scans of the optic disc. RESULTS: ODD in one or both eyes were found in 13 (1.0%) of all children. All but one of the cases were found in children with scleral canal diameter in the lowest quartile (1,182-1,399 µm) in the nested case-control study. Children with ODD had a mean disc diameter of 1,339 µm (interquartile range, 30 µm), whereas it was 1,508 µm (interquartile range, 196 µm) in the 130 controls without ODD (P < 0.001). No differences in sex, birth weight, refractive error, and Tanner stages (of puberty) were found between children with and without ODD. CONCLUSIONS: The prevalence of ODD was 1% in a large child cohort examined by OCT. ODD was found only in eyes with a narrow scleral canal, which is consistent with the hypothesis that ODD might arise as a consequence of retinal nerve fiber congestion in the scleral canal.

GUNN'S DOTS IN RETINAL IMAGES OF 2,286 ADOLESCENTS: Prevalence, Retinal Distribution and Associations.

PURPOSE: To investigate the epidemiology of Gunn's dots and their associations in a population-based cohort of children. METHODS: Red-free fundus photographs from 2,286 children aged 11 years to 14 years from the Sydney Myopia Study were graded. Gunn's dots were manually marked and counted within a 6 mm grid centered on the optic disc. RESULTS: One or more Gunn's dots were seen in at least one eye in 82.6% of children. The median number of Gunn's dots per eye was 46 (range 0-482). Most Gunn's dots were found inferior and superior of the optic disc (49.3% and 45.8%, respectively, of the total number of Gunn's dots in the population). The odds for having 1 or more Gunn's dots were 3-fold greater in children with dark brown irides compared with children with blue irides (odds ratio 2.99, 95% CI 1.81 to 4.94, P < 0.0001 adjusted for age, sex, retinal nerve fiber layer thickness, refraction, ethnicity, and axial length). In the same analysis, the presence of 1 or more Gunn's dots was less frequent in children with thin retinal nerve fiber layers (first quartile) compared with children with thick retinal nerve fiber layers (fourth quartile) (odds ratio 0.68, 95% CI 0.49-0.93, P = 0.016). No disease or disease-marker associations were identified. CONCLUSION: Gunn's dots were visible on fundus photographs in most of the school children, most of the dots being located inferiorly and superiorly to the optic disc. Fundus photographically visible Gunn's dots were associated with darker irides and thicker retinal nerve fiber layers. Gunn's dots are a common and apparently harmless finding in children. Assessment of their clinical significance will require long-term follow-up.

Cadherin 5 is regulated by corticosteroids and associated with central serous chorioretinopathy.

Central serous chorioretinopathy (CSC) is characterized by leakage of fluid from the choroid into the subretinal space and, consequently, loss of central vision. The disease is triggered by endogenous and exogenous corticosteroid imbalance and psychosocial stress and is much more prevalent in men. We studied the association of genetic variation in 44 genes from stress response and corticosteroid metabolism pathways with the CSC phenotype in two independent cohorts of 400 CSC cases and 1,400 matched controls. The expression of cadherin 5 (CDH5), the major cell-cell adhesion molecule in vascular endothelium, was downregulated by corticosteroids which may increase permeability of choroidal vasculature, leading to fluid leakage under the retina. We found a significant association of four common CDH5 SNPs with CSC in male patients in both cohorts. Two common intronic variants, rs7499886:A>G and rs1073584:C>T, exhibit strongly significant associations with CSC; P = 0.00012; odds ratio (OR) = 1.5; 95%CI [1.2;1.8], and P = 0.0014; OR = 0.70; 95%CI [0.57;0.87], respectively. A common haplotype was present in 25.4% male CSC cases and in 35.8% controls (P = 0.0002; OR = 0.61, 95% CI [0.47-0.79]). We propose that genetically predetermined variation in CDH5, when combined with triggering events such as corticosteroid treatment or severe hormonal imbalance, underlie a substantial proportion of CSC in the male population.

Multilayered pigment epithelial detachment in neovascular age-related macular degeneration.

PURPOSE: To describe the spectral domain optical coherence tomography findings in eyes with chronic fibrovascular pigment epithelial detachment (PED) receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. METHODS: Retrospective observational case series of patients with chronic fibrovascular PEDs receiving serial intravitreal anti-VEGF therapy. Corresponding spectral domain optical coherence tomography scans of chronic PEDs were studied in detail over multiple visits. The internal structure within the sub-PED compartment was analyzed, characteristic features were identified, and then correlated with visual outcome. RESULTS: Thirty-eight eyes of 34 patients with fibrovascular PEDs were included. Mean and median Snellen visual acuity was 20/50 (range, 20/20-20/400). Eyes received a mean of 28.2 intravitreal anti-VEGF injections (median, 23.0; range, 3-70) administered over a mean of 36.9 months (median, 37.5; range, 6-84). A fusiform, or spindle-shaped, complex of highly organized layered hyperreflective bands was noted within each PED. Nineteen eyes demonstrated heterogenous, dilated, irregular neovascular tissue adherent to the undersurface of the retinal pigment epithelium. Additionally, 25 eyes demonstrated a hyporeflective cavity separating the choroidal neovascularization complex from the underlying choroid. CONCLUSION: Chronic fibrovascular PEDs receiving serial anti-VEGF therapy demonstrate a characteristic fusiform complex of highly organized, layered, hyperreflective bands, termed a "multilayered PED," which is often seen in conjunction with neovascular tissue adherent to the undersurface of the retinal pigment epithelium monolayer. On the basis of previous histopathologic correlations, these bands may represent a fibrous tissue complex with contractile properties. An associated hyporeflective space, termed a "pre-choroidal cleft," separates the fusiform complex from the underlying choroid and may be due to contraction, the exudation of fluid, or both. Many of these eyes maintain good visual acuity, presumably because the neovascular and cicatricial process is suppressed within the sub-retinal pigment epithelium space by chronic anti-VEGF therapy, thus permitting the viability of the photoreceptor population through preservation of the retinal pigment epithelium.

Retinal arteriolar wall-to-lumen ratios at 16-17 years in the Copenhagen Child Cohort 2000 Study.

PURPOSE: To study the thickness of retinal arteriolar walls in a population-based cohort of adolescents. METHODS: This cross-sectional, observational study included 1217 participants aged 16-17 years from the Copenhagen Child Cohort 2000 Study. The wall thickness and lumen diameter of a major branch retinal arteriole were measured using adaptive optics imaging. The wall-to-lumen ratio was analyzed in relation to blood pressure and body composition variables using a general linear model. Overall in the study population, wall-to-lumen ratio was found to decrease by 0.49% per µm increase in arteriole diameter (P < 0.0001) and all subsequent analyzes were adjusted accordingly. RESULTS: The average outer and inner arteriole diameters were 117 ±â€Š19 and 96.6 ±â€Š18 µm (mean ±â€ŠSD), corresponding to a wall-to-lumen ratio of 0.21 ±â€Š0.024. There was no detectable difference between sexes. A higher wall-to-lumen ratio was associated with a higher BMI (+0.21% per kg/m, P = 0.0018), higher body fat percentage (+0.097% per 1% increase, P = 0.0052), wider hip circumference (+1.1% per 10 cm increase, P = 0.0006), wider waist circumference (+0.92% per 10 cm increase, P = 0.0009), higher SBP in girls (+1.1% per 10 mmHg increase, P = 0.0005), longer axial length (+0.70% per mm increase, P = 0.013), and younger age (+4.9% per year younger, P < 0.0001), adjusted for arteriole diameter, age, sex, and height. CONCLUSION: A higher retinal arteriolar wall-to-lumen ratio was associated with all registered indices of body fat proportion.

Heritability of cilioretinal arteries: a twin study.

PURPOSE: To determine whether the presence of one or more cilioretinal arteries, a distinct element of the pattern of fundus vessels, is genetically programmed, influenced by environmental factors, or the result of random mechanisms of vascular development. METHODS: The fundi of 112 pairs of healthy monozygotic and dizygotic twins were examined using digital fundus photography and visual assessment of grayscale fundus photographs and color transparencies to detect the presence of cilioretinal arteries. RESULTS: Cilioretinal arteries were present in 45.1% of participants and 28.8% of eyes. The majority of cilioretinal arteries, 88.2%, were located temporally, and 11.8% were located nasally. Monozygotic twins had higher concordance rates for cilioretinal arteries than dizygotic twins. Tetrachoric correlations and Mantel-Haenszel odds ratios demonstrated statistically significant evidence of a genetic effect underlying the presence of cilioretinal arteries (P < 0.01). Statistical analysis supported the hypothesis that additive genetic factors influenced the presence of cilioretinal arteries with a heritability of 71.4%, the remaining variance being attributable to nonshared or random environmental factors. CONCLUSIONS: The presence or absence of one or more cilioretinal arteries in healthy persons is markedly influenced by genetic factors.

Choroidal thickness in relation to birth parameters in 11- to 12-year-old children: the Copenhagen Child Cohort 2000 Eye Study.

PURPOSE: To examine choroidal thickness in a population-based child cohort in relation to birth parameters. METHODS: The Copenhagen Child Cohort 2000 Eye Study examined 1406 children aged 11 to 12 years using enhanced depth imaging spectral-domain optical coherence tomography (EDI-OCT), ocular biometry and measurement of height, weight, refraction, and self-reported pubertal development status. Birth parameters were obtained from the Danish Medical Birth Registry. RESULTS: The subfoveal choroid in low birth weight children (<2500 g, n = 51, mean 324 ± 76 µm) was thinner than in normal birth weight children (2500-4500 g, n = 1194, mean 361 ± 78 µm), the difference being -37 (CI95 -60 to -15) µm, P = 0.001 after adjusting for age, sex, height, Tanner stage by sex, axial length, anterior chamber depth, and spherical equivalent refractive error. The subfoveal choroid in high birth weight children (>4500 g, n = 48, mean 351 ± 63 µm) was comparable with normal birth weight children, P = 0.44. The subfoveal choroid was thinner in preterm children, however the difference was not significant (-18 [-37 to 2] µm, P = 0.08). Small for gestation children had thinner subfoveal choroid (-19 [-37 to -1] µm, P = 0.04) compared with appropriate for gestation children. Longer birth length was associated with a thicker subfoveal choroid (2 [1-4] µm/cm, P = 0.005). Macular choroidal thickness at 16 extrafoveal locations was measured in a subset of children and found to have the same associations with birth weight as the subfoveal choroidal thickness. CONCLUSIONS: In 11- to 12-year-old children, thinner choroids were associated with lower birth weight, lower birth length, and being small for the gestational age.

Flow patterns on spectral-domain optical coherence tomography reveal flow directions at retinal vessel bifurcations.

PURPOSE:   To study intravascular characteristics of flowing blood in retinal vessels using spectral-domain optical coherence tomography (SD-OCT). METHODS:   Examination of selected arterial bifurcations and venous sites of confluence in 25 healthy 11-year-old children recruited as an ad hoc subsample from the population-based, observational Copenhagen Child Cohort 2000 study. RESULTS:   The blood stream in retinal arteries maintains a figure-of-8 SD-OCT profile consistent with a laminar flow in concentric sheets and a parabolic velocity distribution up to the point of divergence at arterial bifurcations. In contrast, the blood stream at the site of confluence of two retinal veins remains divided into two parallel sets of sheets with separate velocity distribution for a downstream distance of at least four trunk vessel diameters. Consequently, retinal trunk vessels near bifurcations/confluences have distinctly different internal SD-OCT profiles, a figure-of-8 pattern in arteries and a figure figure-of-88 in veins that can be used to distinguish between the two vessel types. CONCLUSION:   This study verified the hypothesis that directions of blood flow at dichotomous vascular branchings can be determined using SD-OCT. This feature may assist the identification of flow reversal near sites of vascular occlusion, the analysis of blood flow near vascular malformations and the segmentation of retinal SD-OCT images.

Retinal and choroidal intravascular spectral-domain optical coherence tomography.

PURPOSE: To examine retinal and choroidal blood vessels using spectral-domain optical coherence tomography (SD-OCT). METHODS: Retrospective case series. RESULTS: Scans through retinal blood vessels in healthy subjects demonstrated vessel wall reflexes and a tri-layer profile of the blood column on longitudinal scans and a figure-of-eight configuration on cross-sectional scans. Intravascular reflectivity decreased with increasingly oblique angles of observation and was absent when blood flow was parallel to the line of sight. The high blood flow in the choroidal vessels in healthy subjects and the low flow in the retinal vessels in patients with ocular ischaemic syndrome and central retinal artery occlusion were both associated with lower reflectivity of the blood and an unstructured intravascular SD-OCT profile. DISCUSSION: This qualitative in vivo study found a characteristically structured SD-OCT profile of the blood column in retinal vessels with normal blood flow. Both structure and total reflectivity faded when blood flow was lower or higher than normal or at oblique angles to the line of sight. In conclusion, SD-OCT scans of the vessels in the posterior pole of the eye may assist the clinical assessment of gross abnormalities of ocular blood flow, e.g. in carotid artery stenosis.

Mechanism of retinal pigment epithelium tear formation following intravitreal anti-vascular endothelial growth factor therapy revealed by spectral-domain optical coherence tomography.

PURPOSE: To demonstrate the mechanism by which retinal pigment epithelium (RPE) tears occur in eyes with neovascular age-related macular degeneration (AMD) treated with intravitreal anti-vascular endothelial growth factor (VEGF) agents using spectral-domain optical coherence tomography (OCT). DESIGN: Retrospective observational case series. METHODS: OCT images of 8 eyes that developed RPE tears following the administration of intravitreal anti-VEGF agents for neovascular AMD were evaluated. Pretear and posttear images were compared in order to elucidate the mechanism by which RPE tears occur in this setting. RESULTS: In all eyes, pretear images revealed a vascularized pigment epithelial detachment (PED) containing hyperreflective material consistent with choroidal neovascularization (CNV). This CNV was adherent to the undersurface of the RPE and created contractile folds in the RPE contour. In 6 eyes, contractile neovascular tissue spanned the PED, causing outward bowing of the Bruch membrane and a peaked appearance to the overlying RPE monolayer. RPE tears occurred after the first anti-VEGF injection in 6 of 8 eyes. The posttear OCT images showed a discontinuity in the RPE with the CNV adherent to the retracted RPE. In all eyes, the RPE ruptured along a segment of bare RPE not in contact with the CNV or Bruch membrane. CONCLUSIONS: Eyes with vascularized PEDs secondary to AMD may show specific OCT findings that increase the risk for RPE tear following intravitreal anti-VEGF injection. Rapid involution and contraction of neovascular tissue adherent to the undersurface of the RPE may impart a substantial contractile force that tears this already-strained tissue layer.