Rachelle V. O'Connell

Validated Automatic Segmentation of AMD Pathology Including Drusen and Geographic Atrophy in SD-OCT Images

PURPOSE To automatically segment retinal spectral domain optical coherence tomography (SD-OCT) images of eyes with age-related macular degeneration (AMD) and various levels of image quality to advance the study of retinal pigment epithelium (RPE)+drusen complex (RPEDC) volume changes indicative of AMD progression. METHODS A general segmentation framework based on graph theory and dynamic programming was used to segment three retinal boundaries in SD-OCT images of eyes with drusen and geographic atrophy (GA). A validation study for eyes with nonneovascular AMD was conducted, forming subgroups based on scan quality and presence of GA. To test for accuracy, the layer thickness results from two certified graders were compared against automatic segmentation results for 220 B-scans across 20 patients. For reproducibility, automatic layer volumes were compared that were generated from 0° versus 90° scans in five volumes with drusen. RESULTS The mean differences in the measured thicknesses of the total retina and RPEDC layers were 4.2 ± 2.8 and 3.2 ± 2.6 μm for automatic versus manual segmentation. When the 0° and 90° datasets were compared, the mean differences in the calculated total retina and RPEDC volumes were 0.28% ± 0.28% and 1.60% ± 1.57%, respectively. The average segmentation time per image was 1.7 seconds automatically versus 3.5 minutes manually. CONCLUSIONS The automatic algorithm accurately and reproducibly segmented three retinal boundaries in images containing drusen and GA. This automatic approach can reduce time and labor costs and yield objective measurements that potentially reveal quantitative RPE changes in longitudinal clinical AMD studies. (ClinicalTrials.gov number, NCT00734487.).

Dynamics of Human Foveal Development after Premature Birth

PURPOSE To determine the dynamic morphologic development of the human fovea in vivo using portable spectral domain-optical coherence tomography (SD-OCT). DESIGN Prospective, observational case series. PARTICIPANTS Thirty-one prematurely born neonates, 9 children, and 9 adults. METHODS Sixty-two neonates were enrolled in this study. After examination for retinopathy of prematurity (ROP), SD-OCT imaging was performed at the bedside in nonsedated infants aged 31 to 41 weeks postmenstrual age (PMA) (= gestational age in weeks + chronologic age) and at outpatient follow-up ophthalmic examinations. Thirty-one neonates met eligibility criteria. Nine children and nine adults without ocular pathology served as control groups. Semiautomatic retinal layer segmentation was performed. Central foveal thickness, foveal to parafoveal (FP) ratio (central foveal thickness divided by thickness 1000 μm from the foveal center), and 3-dimensional thickness maps were analyzed. MAIN OUTCOME MEASURES In vivo determination of foveal morphology, layer segmentation, analysis of subcellular changes, and spatiotemporal layer shifting. RESULTS In contrast with the adult fovea, several signs of immaturity were observed in the neonates: a shallow foveal pit, persistence of inner retinal layers (IRLs), and a thin photoreceptor layer (PRL) that was thinnest at the foveal center. Three-dimensional mapping showed displacement of retinal layers out of the foveal center as the fovea matured and the progressive formation of the inner/outer segment band in the opposite direction. The FP-IRL ratios decreased as IRL migrated before term and minimally after that, whereas FP-PRL ratios increased as PRL subcellular elements formed closer to term and into childhood. A surprising finding was the presence of cystoid macular edema in 58% of premature neonates that appeared to affect inner foveal maturation. CONCLUSIONS This study provides the first view into the development of living cellular layers of the human retina and of subcellular specialization at the fovea in premature infant eyes using portable SD-OCT. Our work establishes a framework of the timeline of human foveal development, allowing us to identify unexpected retinal abnormalities that may provide new keys to disease activity and a method for mapping foveal structures from infancy to adulthood that may be integral in future studies of vision and visual cortex development. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Maturation of the Human Fovea: Correlation of Spectral-Domain Optical Coherence Tomography Findings With Histology

PURPOSE To correlate human foveal development visualized by spectral-domain optical coherence tomography (SDOCT) with histologic specimens. DESIGN Retrospective, observational case series. METHODS Morphology and layer thickness of retinal SDOCT images from 1 eye each of 22 premature infants, 30 term infants, 16 children, and 1 adult without macular disease were compared to light microscopic histology from comparable ages. RESULTS SDOCT images correlate with major histologic findings at all time points. With both methods, preterm infants demonstrate a shallow foveal pit indenting inner retinal layers (IRL) and short, undeveloped foveal photoreceptors. At term, further IRL displacement forms the pit and peripheral photoreceptors lengthen; the elongation of inner and outer segments (IS and OS, histology) separates the IS band from retinal pigment epithelium. Foveal IS and OS are shorter than peripheral for weeks after birth (both methods). By 13 months, foveal cone cell bodies stack >6 deep, Henle fiber layer (HFL) thickens, and IS/OS length equals peripheral; on SDOCT, foveal outer nuclear layer (which includes HFL) and IS/OS thickens. At 13 to 16 years, the fovea is fully developed with a full complement of SDOCT bands; cone cell bodies >10 deep have thin, elongated, and tightly packed IS/OS. CONCLUSIONS We define anatomic correlates to SDOCT images from normal prenatal and postnatal human fovea. OCT bands typical of photoreceptors of the adult fovea are absent near birth because of the immaturity of foveal cones, develop by 24 months, and mature into childhood. This validates the source of SDOCT signal and provides a framework to assess foveal development and disease.

Progression of Intermediate Age-related Macular Degeneration with Proliferation and Inner Retinal Migration of Hyperreflective Foci

PURPOSE Drusen and migrating retinal pigment epithelium have been associated with hyperreflective foci (HF) detected by spectral-domain optical coherence tomography (SD-OCT). This study sought to quantify the change in intraretinal HF distribution and its correlation with age-related macular degeneration (AMD) disease progression. DESIGN Prospective observational study from the multicenter Age-Related Eye Disease Study 2 (AREDS2) Ancillary SD-OCT Study. PARTICIPANTS Patients (n=299) with 1 enrolled eye with intermediate AMD and baseline SD-OCT, followed by SD-OCT imaging at 1-year and 2-year visits. METHODS The number and location of HF were scored in SD-OCT scans of all 299 eyes. The change in transverse (horizontal) and axial (vertical) distribution of HF in the macula were evaluated with pairwise signed-rank tests. Two-year inner retinal HF migration was determined by the change in HF-weighted axial distribution (AxD) score calculated for each eye. The correlation of HF with SD-OCT features of AMD progression was evaluated with logistic regression analysis. MAIN OUTCOME MEASURES The mean change in number of HF, transverse and axial distribution of HF in the macula, and AxD per eye. RESULTS In 299 study eyes, the 2-year increase in the number of HF (P<0.001) and the AxD (P<0.001) per eye represented longitudinal proliferation and shift to inner retinal layers, respectively. Eyes with geographic atrophy (GA) at 2 years were correlated with the presence of baseline HF (P<0.001; odds ratio [OR], 4.72; 95% confidence interval [CI], 2.43-9.80), greater number of baseline HF (P<0.001; OR, 1.61 per HF; 95% CI, 1.32-2.00), and greater baseline AxD (P<0.001; OR, 1.58 per AxD point; 95% CI, 1.29-1.95). CONCLUSIONS Proliferation and inner retinal migration of SD-OCT HF occurred during follow-up in eyes with intermediate AMD. These characteristics were associated with greater incidence of GA at year 2; therefore, SD-OCT HF proliferation and migration may serve as biomarkers for AMD progression. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Macular Features From Spectral Domain Optical Coherence Tomography as an Adjunct to Indirect Ophthalmoscopy in Retinopathy of Prematurity

Purpose: To compare vitreoretinal pathology imaged with portable handheld spectral-domain optical coherence tomography (SD-OCT) to conventional indirect ophthalmoscopic examination in neonates undergoing screening for retinopathy of prematurity. Methods: Spectral-domain optical coherence tomography images were collected from 76 eyes of 38 neonates during 118 routine retinopathy of prematurity examinations. Imaging sessions in the Neonatal Intensive Care Unit were performed immediately after the subjects underwent a standard ophthalmic examination with indirect ophthalmoscopic by a pediatric ophthalmologist. Masked certified SD-OCT graders evaluated scans for preretinal and retinal findings including material in the vitreous, epiretinal membrane, intraretinal cystoid structures and deposits, optic nerve and vascular features, and severity and location of retinopathy of prematurity. The frequency of detection of these features by clinical examination and evaluation of SD-OCT images was compared to determine potential clinical advantages for each modality. Results: Portable SD-OCT imaging characterized macular features of retinal cystoid structures in 39% of examinations and epiretinal membrane in 32% of examinations. Neither feature was visualized by indirect ophthalmoscopy in any cases. The clinician using indirect ophthalmoscopy detected stage of retinopathy of prematurity and the presence or absence of Plus or pre-Plus disease. These were not visualized with SD-OCT. Conclusion: Spectral-domain optical coherence tomography provides new information about the premature infant retina that is of unknown importance relative to visual development and acuity. As used in this study, SD-OCT does not replace indirect ophthalmoscopy for evaluation of retinopathy of prematurity.

Spatial correlation between hyperpigmentary changes on color fundus photography and hyperreflective foci on SDOCT in intermediate AMD.

PURPOSE Macular hyperpigmentation is associated with progression from intermediate to advanced age-related macular degeneration (AMD). The purpose of this study was to accurately correlate hyperpigmentary changes with spectral domain optical coherence tomography (SDOCT) hyperreflective foci in eyes with non-advanced AMD. METHODS A prospective cross-sectional analysis of 314 eyes (314 subjects) with intermediate AMD was performed in the multicenter Age-Related Eye Disease Study 2 (AREDS2) Ancillary SDOCT Study to correlate hyperpigmentary changes on color fundus photographs (CFP) with abnormal morphology on SDOCT. Spatial coregistration was performed with an automated algorithm in two nonoverlapping subsets of 20 study eyes, which permitted double-masked CFP and SDOCT grading by certified investigators. RESULTS Macular CFP hyperpigmentation was significantly associated with SDOCT intraretinal hyperreflective foci in the 314 study eyes (P < 0.001). In a substudy of 40 eyes, automated intermodality spatial coregistration was successfully achieved in all 136 (100%) retinal regions selected for CFP and SDOCT grading. In one subset of 20 study eyes, 28 of 39 (71.8%) retinal CFP regions with hyperpigmentation were correlated with focal hyperreflectivity on SDOCT, versus seven of 39 (17.9%) control regions (P < 0.001). In another subset of 20 eyes, 21 of 29 (72.4%) SDOCT regions with hyperreflective foci were correlated with hyperpigmentary changes on CFP, versus two of 29 (6.9%) control regions (P < 0.001). CONCLUSIONS A novel algorithm achieves automated intermodality spatial coregistration for masked grading of regions selected on CFP and SDOCT. In intermediate AMD, macular hyperpigmentation has high spatial correlation to SDOCT hyperreflective foci and often represents the same anatomical lesion. (ClinicalTrials.gov number, NCT00734487.).

Choroid Development and Feasibility of Choroidal Imaging in the Preterm and Term Infants Utilizing SD-OCT

PURPOSE To determine whether choroidal imaging is feasible in preterm and term infants using an 840-nm portable spectral domain optical coherence tomography (SD-OCT) system without the use of enhanced-depth imaging techniques and to assess choroidal development by comparing choroidal thickness of preterm infants, term infants, and adults. METHODS SD-OCT images were obtained from 86 preterm infants, 59 term infants, and nine adults using a portable SD-OCT system plus nine adults using a tabletop system. An unprocessed image across the macula from one randomly selected eye of each participant was selected for determination of whether the choroidal-scleral junction (CSJ) could be visualized and for measurement of choroidal thickness. RESULTS Subfoveal CSJ was visualized in 96% of young-preterm infants (imaged from 30-36 weeks postmenstrual age [PMA]); 78% of term-aged preterm infants (imaged from 37-42 weeks PMA); 49% of term infants; and 39% of adult subjects. Racial pigmentation did not affect CSJ visibility in young-preterm infants (P = 0.57). Subfoveal choroidal thickness (SFCT) in young-preterm infants, term-aged preterm infants, term infants, and adults was 176 ± 53 μm, 289 ± 92 μm, 329 ± 66 μm, and 258 ± 66 μm, respectively, and these were all statistically significantly different from one another except term-aged preterms to adults. CONCLUSIONS Infant choroid can be imaged with a portable SD-OCT system without enhanced depth imaging. Melanin in the RPE and choroid does not hinder outer choroidal imaging in young-preterm infants without advanced retinopathy of prematurity (ROP). In preterm infants, choroidal thickness increased with age but was thinner when compared to term infants suggesting delayed development due to ROP.

Racial variation in optic nerve head parameters quantified in healthy newborns by handheld spectral domain optical coherence tomography

PURPOSE To characterize optic nerve head (ONH) morphology and parameters, including vertical disk diameter, vertical cup diameter, and vertical cup/disk ratio in healthy, full-term newborns using a handheld spectral domain optical coherence tomography (SD-OCT) device. METHODS In this prospective observational case series, healthy white, black, and Hispanic full-term newborns delivered at the Duke Birthing Center between August 2010 and May 2011 underwent dilated fundus examination and SD-OCT imaging of the optic nerve in each eye. OCT parameters were calculated and compared for each group of infants. RESULTS A total of 58 consecutive newborns of white (n = 22), black (n = 15) and Hispanic (n = 21) ethnicity were included. Mean vertical disk diameter in white, black, and Hispanic newborns was 1.29 ± 0.15 mm (standard deviation), 1.38 ± 0.14 mm, and 1.38 ± 0.14 mm, respectively (white versus Hispanic, P = 0.02; white versus black, P = 0.07). Mean vertical cup diameter in white, black, and Hispanic newborns was 0.44 ± 0.15 mm, 0.56 ± 0.23 mm, and 0.46 ± 0.30 mm, respectively (white versus black, P = 0.03). Mean vertical cup/disk ratio was 0.34 ± 0.10 for white, 0.40 ± 0.17 for black, and 0.33 ± 0.20 for Hispanic newborns (P = 0.07 for white versus black). CONCLUSIONS Handheld SD-OCT is an effective means of imaging the ONH in newborns. Racial differences in cup/disk ratio are present at birth. These data may serve as the beginning of a normative dataset for characterizing development of the ONH as well as for comparison to the neonatal ONH in disease states.

Macular Findings in Healthy Full-term Hispanic Newborns Observed by Hand-held Spectral-Domain Optical Coherence Tomography

BACKGROUND AND OBJECTIVE To enhance understanding of ethnically diverse normal newborn retinal morphology, the authors report spectral-domain optical coherence tomography (SD-OCT) macular findings in healthy Hispanic newborns. PATIENTS AND METHODS In this IRB-approved prospective, observational case series, 20 full-term Hispanic newborns had dilated retinal examinations and imaging by hand-held SD-OCT without sedation at the Duke Birthing Center. RESULTS Of 20 newborns imaged (35% male; median gestational age: 39 weeks; range: 36 to 40 weeks), two (10%) had bilateral subfoveal fluid, including one case of bilateral double subretinal fluid pockets. Three eyes of two infants (10%) had retinal macular cystoid structures (one enlarged at 1.5 months, with resolution by 3 months). These SD-OCT findings were not visible by indirect ophthalmoscopy. CONCLUSION Some Hispanic newborns have subretinal fluid or macular cystoid structures on SD-OCT. This study expands our understanding of findings seen by SD-OCT in healthy full-term newborns of various races.