P Score: A Reference Image-Based Clinical Grading Scale for Vascular Change in Retinopathy of Prematurity.

PURPOSE: The International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), acknowledged that plus-like retinopathy of prematurity (ROP) vascular changes occurs along a spectrum. Historically, clinician-experts demonstrate variable agreement for plus diagnosis. We developed a 9-photograph reference image set for grading plus-like changes and compared intergrader agreement of the set with standard grading with no plus, preplus, and plus disease. DESIGN: Retinal photographic grading and expert consensus opinion. PARTICIPANTS: The development set included 34 international ICROP3 committee members. The validation set included 30 ophthalmologists with ROP expertise (15 ICROP3 committee members and 15 non-ICROP3 members) METHODS: Nine ROP fundus images (P1 through P9) representing increasing degrees of zone I vascular tortuosity and dilation, based on the 34 ICROP3 committee members' gradings and consensus image reviews, were used to establish standard photographs for the plus (P) score. Study participants graded 150 fundus photographs 2 ways, separated by a 1-week washout period: (1) no plus, preplus, or plus disease and (2) choosing the closest P score image. MAIN OUTCOME MEASURES: Intergrader agreement measured by intraclass correlation coefficient. RESULTS: Intergrader agreement was higher using the P score (intraclass correlation coefficient, 0.75; 95% confidence interval, 0.71-0.79) than no plus, preplus, or plus disease (intraclass correlation coefficient, 0.67; 95% confidence interval, 0.62-0.72). Mean ± standard deviation P scores for images with mode gradings of no plus, preplus, and plus disease were 2.5 ± 0.7, 4.8 ± 0.8, and 7.4 ± 0.8, respectively. CONCLUSIONS: Intergrader agreement of plus-like vascular change in ROP using the P score is high. We now incorporate this 9-image reference set into ICROP3 for use in clinician daily practice alongside zone, stage, and plus assessment. P score is not yet meant to replace plus diagnosis for treatment decisions, but its use at our institutions has permitted better comparison between examinations for progression and regression, communication between examiners, and documentation of vascular change without fundus imaging. P score also could provide more detailed ROP classification for clinical trials, consistent with the spectrum of plus-like change that is now formally part of the International Classification of Retinopathy of Prematurity. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

A differential proteomics study of cerebrospinal fluid from individuals with Niemann-Pick disease, Type C1.

Niemann-Pick, type C1 (NPC1) is a fatal, neurodegenerative disease, which belongs to the family of lysosomal diseases. In NPC1, endo/lysosomal accumulation of unesterified cholesterol and sphingolipids arise from improper intracellular trafficking resulting in multi-organ dysfunction. With the proximity between the brain and cerebrospinal fluid (CSF), performing differential proteomics provides a means to shed light to changes occurring in the brain. In this study, CSF samples obtained from NPC1 individuals and unaffected controls were used for protein biomarker identification. A subset of these individuals with NPC1 are being treated with miglustat, a glycosphingolipid synthesis inhibitor. Of the 300 identified proteins, 71 proteins were altered in individuals with NPC1 compared to controls including cathepsin D, and members of the complement family. Included are a report of 10 potential markers for monitoring therapeutic treatment. We observed that pro-neuropeptide Y (NPY) was significantly increased in NPC1 individuals relative to healthy controls; however, individuals treated with miglustat displayed levels comparable to healthy controls. In further investigation, NPY levels in a NPC1 mouse model corroborated our findings. We posit that NPY could be a potential therapeutic target for NPC1 due to its multiple roles in the central nervous system such as attenuating neuroinflammation and reducing excitotoxicity.

MULTIMODAL ASSESSMENTS OF DRUSENOID PIGMENT EPITHELIAL DETACHMENTS IN THE AGE-RELATED EYE DISEASE STUDY 2 ANCILLARY SPECTRAL-DOMAIN OPTICAL COHERENCE TOMOGRAPHY STUDY COHORT.

PURPOSE: To identify features correlating with drusenoid pigment epithelial detachment (DPED) progression in the Age-Related Eye Disease Study 2 Ancillary spectral-domain optical coherence tomography study cohort. METHODS: In this retrospective analysis of a prospective longitudinal study, eyes with intermediate age-related macular degeneration and DPEDs were followed longitudinally with annual multimodal imaging. RESULTS: Thirty-one eyes of 25 participants (mean age 72.6 years) in the Age-Related Eye Disease Study 2 Ancillary spectral-domain OCT substudy (A2A study) had DPED identified in color fundus images. Spectral-domain optical coherence tomography inspection confirmed a subretinal pigment epithelium drusenoid elevation of ≥433 µm diameter in 25 eyes (80.6%). Twenty-four of these eyes were followed longitudinally (median 4.0 years), during which 7 eyes (29.2%) underwent DPED collapse (with 3/7 further progressing to geographic atrophy), 6 (25.0%) developing neovascular age-related macular degeneration, and 11 (45.8%) maintaining DPED persistence without late age-related macular degeneration. On Kaplan-Meier analysis, mean time to DPED collapse was 3.9 years. Both DPED collapse and progression to neovascular age-related macular degeneration were preceded by the presence of hyperreflective foci over the DPED. CONCLUSION: The natural history of DPED comprises collapse (sometimes followed by the development of atrophy), vascularization followed by exudation, or DPED persistence. Spectral-domain optical coherence tomography can confirm retinal pigment epithelial elevation caused by drusenoid accumulation and facilitate the identification of high-risk features that correlate with progression.

International Classification of Retinopathy of Prematurity, Third Edition.

PURPOSE: The International Classification of Retinopathy of Prematurity is a consensus statement that creates a standard nomenclature for classification of retinopathy of prematurity (ROP). It was initially published in 1984, expanded in 1987, and revisited in 2005. This article presents a third revision, the International Classification of Retinopathy of Prematurity, Third Edition (ICROP3), which is now required because of challenges such as: (1) concerns about subjectivity in critical elements of disease classification; (2) innovations in ophthalmic imaging; (3) novel pharmacologic therapies (e.g., anti-vascular endothelial growth factor agents) with unique regression and reactivation features after treatment compared with ablative therapies; and (4) recognition that patterns of ROP in some regions of the world do not fit neatly into the current classification system. DESIGN: Review of evidence-based literature, along with expert consensus opinion. PARTICIPANTS: International ROP expert committee assembled in March 2019 representing 17 countries and comprising 14 pediatric ophthalmologists and 20 retinal specialists, as well as 12 women and 22 men. METHODS: The committee was initially divided into 3 subcommittees-acute phase, regression or reactivation, and imaging-each of which used iterative videoconferences and an online message board to identify key challenges and approaches. Subsequently, the entire committee used iterative videoconferences, 2 in-person multiday meetings, and an online message board to develop consensus on classification. MAIN OUTCOME MEASURES: Consensus statement. RESULTS: The ICROP3 retains current definitions such as zone (location of disease), stage (appearance of disease at the avascular-vascular junction), and circumferential extent of disease. Major updates in the ICROP3 include refined classification metrics (e.g., posterior zone II, notch, subcategorization of stage 5, and recognition that a continuous spectrum of vascular abnormality exists from normal to plus disease). Updates also include the definition of aggressive ROP to replace aggressive-posterior ROP because of increasing recognition that aggressive disease may occur in larger preterm infants and beyond the posterior retina, particularly in regions of the world with limited resources. ROP regression and reactivation are described in detail, with additional description of long-term sequelae. CONCLUSIONS: These principles may improve the quality and standardization of ROP care worldwide and may provide a foundation to improve research and clinical care.

Evaluating the association of clinical factors and optical coherence tomography retinal imaging with axial length and axial length growth among preterm infants.

PURPOSE: To study the association of clinical factors and optical coherence tomography (OCT) retinal imaging with axial length (AL) and AL growth in preterm infants METHODS: Among a subgroup of infants from the prospective BabySTEPS study who were screened for retinopathy of prematurity (ROP) and had both AL measured and OCT imaging performed, we analyzed data collected prior to 42 weeks postmenstrual age (PMA) and prior to ROP treatment. Using linear mixed effects models, we evaluated associations between AL and AL growth with gestational age (GA), birthweight, PMA, sex, race, multiparity, maximum ROP stage, and OCT features. RESULTS: We included 66 infants (132 eyes), mean GA = 27.6 weeks (SD = 2.3; range: 23.0-34.4) and mean birthweight = 961 g (SD = 269, range: 490-1580). In the final predictive model, longer AL was associated with earlier GA, higher birthweight, later PMA, non-White race, and thicker subfoveal choroid (all p values ≤ 0.01). AL increased linearly up to 42 weeks PMA. There was no difference in AL growth rate by GA, sex, race, multiparity, maximum ROP severity, central foveal thickness, or subfoveal choroidal thickness (all p values > 0.05); but AL growth rate was slower in infants with lower birthweight (p = 0.01). CONCLUSIONS: Among preterm infants, those with earlier GA, higher birthweight, later PMA, non-White race, and thicker subfoveal choroid had the longest AL. AL increased linearly up to 42 weeks PMA and lower birthweight was associated with slower AL growth. These findings may improve the accuracy of measurements taken on preterm infants using imaging techniques affected by AL (e.g., measuring lateral dimensions on OCT). TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT02887157 , date of registration: August 25, 2016.

Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results.

OBJECTIVE: To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment. DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial. INTERVENTIONS: At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment. MAIN OUTCOME MEASURES: Mean change in visual acuity. RESULTS: Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF). CONCLUSIONS: Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

MicroRNA-129-5p is regulated by choline availability and controls EGF receptor synthesis and neurogenesis in the cerebral cortex.

Choline availability modulates neurogenesis and cerebral cortex development through the regulation of neural progenitor cell (NPC) proliferative and differentiation capacity. In this study, we demonstrated that cortical NPC self-renewal is controlled by choline via the expression of a microRNA (miR-129-5p), whose role in the developing brain has not been examined, and which, in turn, inhibits synthesis of the epidermal growth factor receptor (EGFR) protein. Specifically, we found that low choline (LC) availability led to the upregulation of miR-129-5p expression in cortical NPCs in vitro and in vivo, causing the downregulation of EGFR and thereby disrupting NPC self-renewal and cortical neurogenesis. Furthermore, in response to LC availability, methylation potential (the S-adenosylmethionine: S-adenosylhomocysteine ratio) in the developing brain was reduced. Restoring methylation potential in LC cortical NPCs led to the re-establishment of normal miR-129-5p expression. We concluded that inhibiting miR-129-5p function and restoring EGFR protein levels in vivo is sufficient to reverse LC-induced defects in cortical NPC self-renewal. For the first time, to our knowledge, we have identified the molecular links that explain how a change in the availability of the diet metabolite choline impacts the essential cellular processes underlying brain development.-Trujillo-Gonzalez, I., Wang, Y., Friday, W. B., Vickers, K. C., Toth, C. L., Molina-Torres, L., Surzenko, N., Zeisel, S. H. MicroRNA-129-5p is regulated by choline availability and controls EGF receptor synthesis and neurogenesis in the cerebral cortex.

Appearance of pediatric choroidal neovascular membranes on optical coherence tomography angiography.

PURPOSE: Compared with fluorescein angiography (FA), the gold standard for diagnosing choroidal neovascularization (CNV) activity, optical coherence tomography angiography (OCTA) is non-invasive without risks associated with fluorescein dye use, and may be especially advantageous in the diagnosis and monitoring of children with CNV. METHODS: Eight eyes from eight patients aged 12 months to 18 years were imaged with the investigational Spectralis OCTA (version 6.9, Heidelberg Engineering, Heidelberg, Germany) and the RTVue XR Avanti (Optovue Inc., Fremont, CA, USA). Two patients were imaged during examination under anesthesia while six patients were imaged in the clinic. Demographic information, ocular characteristics, treatment history, and imaging studies (color photos, fluorescein angiography, OCT) were collected and reviewed. RESULTS: Three eyes had active CNV while five had quiescent CNV at the time of imaging. CNV was idiopathic or secondary to trauma, retinal vascular dysgenesis versus retinopathy of prematurity, pigmentary retinopathy, Best vitelliform macular dystrophy, panuveitis, morning glory disc anomaly, and optic disc drusen. OCTA of two active CNV demonstrated presence of a main trunk with multiple fine capillaries, vessel loops, and anastomoses. OCTA was repeated after treatment for two CNV and demonstrated a decrease in size with loss of fine capillaries, vessel loops, and anastomoses. For the third active CNV, OCTA verified flow in the CNV complex despite the uncertainty of FA hyperfluorescence in the setting of grossly abnormal retinal vasculature. The five quiescent CNV all lacked fine capillaries, vessel loops, and anastomoses on OCTA. CONCLUSION: OCTA demonstrates morphological differences between active and quiescent pediatric CNV.

Subclinical Retinal versus Brain Findings in Infants with Hypoxic Ischemic Encephalopathy.

PURPOSE: To detect retinal features and abnormalities on optical coherence tomography (OCT) without pupil dilation and relate these to brain injury in infants with a clinical diagnosis of hypoxic ischemic encephalopathy (HIE). METHODS: Under an institutional review board-approved protocol, we imaged eight infants without pharmacologic mydriasis, using handheld, non-contact spectral-domain (Leica Microsystems, IL) or investigational swept-source OCT at the bedside in an intensive care nursery, after birth (depending on primary clinical care team permission based on health status) and weekly until discharge. The newborn infant with HIE is neurologically unstable; therefore, pharmacologic mydriasis and stimulation with visible light for retinal examination are usually avoided. We analyzed images for retinal pathologies, central foveal thickness, and retinal nerve fiber layer (RNFL) thickness at the papillomacular bundle and compared them to historical controls and published normative data, HIE clinical assessment, and abnormalities on brain magnetic resonance imaging (MRI). RESULTS: On OCT, three of eight infants had bilateral multiple small macular and perimacular cystoid spaces; two of these three infants also had pronounced retinal ganglion cell layer thinning and severe brain injury on MRI and the third had bilateral paracentral acute middle maculopathy and mild brain injury on MRI. Other findings in HIE infant eyes included abnormally thin fovea and thin RNFL and markers of retinal immaturity such as the absence of sub-foveal photoreceptor development and sub-foveal fluid. CONCLUSIONS: Bedside handheld OCT imaging within the first 2 weeks of life revealed retinal injury in infants with HIE-related brain injury. Future studies may determine the relationship between acute/subacute retinal abnormalities and brain injury severity and neurodevelopmental outcomes in HIE.

HANDHELD SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY FINDINGS OF X-LINKED RETINOSCHISIS IN EARLY CHILDHOOD.

BACKGROUND/PURPOSE: Using handheld spectral domain optical coherence tomography (SDOCT) imaging to investigate in vivo microanatomic retinal changes and their progression over time in young children with juvenile X-linked retinoschisis (XLRS). METHODS: This retrospective analysis was of handheld SD OCT images obtained under a prospective research protocol in children who had established XLRS diagnosis based on genetic testing or clinical history. Three OCT graders performed standardized qualitative and quantitative assessment of retinal volume scans, which were divided into foveal, parafoveal, and extrafoveal regions. Visual acuity data were obtained when possible. RESULTS: Spectral domain OCT images were available of both eyes in 8 pediatric patients with ages 7 months to 10 years. The schisis cavities involved inner nuclear layer in over 90% (15/16) of eyes in all 3 regions. Retinal nerve fiber and ganglion cell layer involvement was present only in the extrafoveal region in 63% (10/16) eyes and outer nuclear and plexiform layer in few others. In 7 children followed over 2 months to 15 months, the location of schisis remained consistent. Central foveal thickness decreased from the baseline to final available visit in 4/6 eyes. Ellipsoid zone disruption seemed to accompany lower visual acuity in 1/4 eyes. CONCLUSION: Early in life, the SD OCT findings in XLRS demonstrate differences in schisis location in fovea-parafoveal versus extrafoveal region, possible association between poor visual acuity and degree of ellipsoid zone disruption and decrease in central foveal thickness over time in this group. Furthermore, they illustrates that the pattern of XLRS in adults is already present in very young children, and unlike in older children and adults, those presenting with earlier disease may have a more aggressive course. Further studies in this early age group may provide more insights into treatment and prevention of progressive visual impairment in children with XLRS.

Macular Morphology and Visual Acuity in Year Five of the Comparison of Age-related Macular Degeneration Treatments Trials.

PURPOSE: To evaluate associations of morphologic features with 5-year visual acuity (VA) in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). DESIGN: Cohort study within a randomized clinical trial. PARTICIPANTS: Participants in CATT. METHODS: Eyes with age-related macular degeneration-associated choroidal neovascularization (CNV) and VA between 20/25 and 20/320 were eligible. Treatment was assigned randomly to ranibizumab or bevacizumab and to 3 dosing regimens for 2 years and was at the ophthalmologists' discretion thereafter. MAIN OUTCOME MEASURES: Visual acuity, thickness and morphologic features on OCT, and lesion size and foveal composition on fundus photography (FP) and fluorescein angiography (FA). RESULTS: Visual acuity and image gradings were available for 523 of 914 participants (57%) alive at 5 years. At 5 years, 60% of eyes had intraretinal fluid (IRF), 38% had subretinal fluid (SRF), 36% had subretinal pigment epithelium (RPE) fluid, and 66% had subretinal hyper-reflective material (SHRM). Mean (standard deviation) foveal center thickness was 148 µm (99) for retina, 5 µm (21) for SRF, 125 µm (107) for subretinal tissue complex, 11 µm (33) for SHRM, and 103 µm (95) for RPE + RPE elevation. The SHRM, thinner retina, greater CNV lesion area, and foveal center pathology (all P < 0.001) and IRF (P < 0.05) were independently associated with worse VA. Adjusted mean VA letters were 62 for no pathology in the foveal center; 61 for CNV, fluid, or hemorrhage; 65 for non-geographic atrophy (GA); 64 for nonfibrotic scar; 53 for GA; and 56 for fibrotic scar. Incidence or worsening of 8 pathologic features (foveal GA, foveal scar, foveal CNV, SHRM, foveal IRF, retinal thinning, CNV lesion area, and GA area) between years 2 and 5 was independently associated with greater loss of VA from years 2 to 5 and VA loss from baseline to year 5. CONCLUSIONS: Associations between VA and morphologic features previously identified through year 1 were maintained or strengthened at year 5. New foveal scar, CNV, intraretinal fluid, SHRM and retinal thinning, development or worsening of foveal GA, and increased lesion size are important contributors to the VA decline from years 2 to 5. A significant need to develop therapies to address these adverse pathologic features remains.

Five-Year Follow-up of Nonfibrotic Scars in the Comparison of Age-Related Macular Degeneration Treatments Trials.

PURPOSE: To describe changes in visual acuity (VA) and macular morphologic features at 5 years in eyes with nonfibrotic scar (NFS) identified at 1 year in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). DESIGN: Prospective cohort study within a randomized clinical trial. PARTICIPANTS: Participants in CATT. METHODS: Participants assigned to ranibizumab or bevacizumab and to 1 of 3 dosing regimens were released from the clinical trial protocol after 2 years and recalled at 5 years. Nonfibrotic scar was identified on color images at year 1 as flat, small, well-circumscribed areas of pigmentation with varying degrees of central hypopigmentation without exposure of underlying choroidal vessels at the site of baseline choroidal neovascularization. Follow-up images were assessed for changes in and around NFS. MAIN OUTCOME MEASURES: Pigmentation changes, VA, development of fibrotic scar (FS), nongeographic atrophy (NGA), geographic atrophy (GA), retinal fluid on OCT, and fluorescein leakage. RESULTS: Among 474 eyes with images obtained at 1, 2, and 5 years, 39 (8.2%) showed NFS at 1 year with a mean VA of 80 letters (Snellen equivalent, 20/25). Among these eyes, FS developed in 5% at 2 years and 28% at 5 years. Nongeographic atrophy was observed in 34%, 47%, and 65% of eyes at 1, 2, and 5 years, respectively. Geographic atrophy developed in 5% of eyes at 2 years and 21% at 5 years. Among eyes with NFS, FS, or no scar at 1 year, mean VA at 5 years was 73 letters (20/32), 48 letters (20/100), and 62 letters (20/63), respectively. At 5 years, NFS eyes demonstrated less GA, less intraretinal fluid, more subretinal fluid, and less subretinal pigment epithelium fluid (all P < 0.01). Among NFS eyes, mean thickness of the retina, subretinal tissue complex, and total retina did not change across years 1 to 5 (P > 0.50). The proportion of eyes with fluid on OCT also did not change (P = 0.36). Subretinal hyperreflective material disappeared by 5 years in 40% of eyes with NFS. CONCLUSIONS: These results indicate that, on average, eyes with NFS after anti-VEGF treatment have good VA not only at 1 and 2 years, but also through 5 years.

Assessment of Macular Microvasculature in Healthy Eyes of Infants and Children Using OCT Angiography.

PURPOSE: To assess macular vasculature in healthy infants and children using OCT angiography (OCTA). DESIGN: Prospective cross-sectional study. PARTICIPANTS: One hundred thirty-five normal maculae of 89 healthy infants and children (mean age, 8.5±5.3 years; range, 9 weeks-17 years) treated at the Duke University Eye Center. METHODS: We imaged 135 maculae of 89 pediatric patients using the standard Spectralis tabletop and investigational Spectralis with Flex module devices, both equipped with investigational OCTA software (Heidelberg Engineering, Heidelberg, Germany). OCT angiography images of the superficial vascular complex (SVC) and deep vascular complex (DVC) were analyzed for foveal avascular zone (FAZ) area and superficial and deep vessel density. We assessed effects of age, gender, race, axial length (AL), and central subfield thickness on FAZ and vessel density. Patients with both eyes imaged were assessed for agreement between the FAZ and vessel densities of the left and right eyes. MAIN OUTCOME MEASURES: The FAZ area, as well as vessel area density (VAD) and vessel length density (VLD) in the SVC and DVC. RESULTS: The FAZ varied significantly with race; white patients showed a significantly smaller FAZ than black patients (mean difference, 0.11 mm2; P = 0.004). The FAZ did not vary with age, gender, or AL (P > 0.05). In the SVC, VAD and VLD varied significantly with age (P < 0.001) and AL (R2 = 0.46; P < 0.001) but not gender (P > 0.05). The SVC VLD was significantly different between races and ethnicities (P = 0.037), but VAD was not (P < 0.05). In the DVC, VAD and VLD also varied significantly with age (P < 0.001) and AL (R2 = 0.46; P < 0.001) but not gender or race (P > 0.05). There was excellent agreement between the right and left eyes for FAZ (intraclass correlation [ICC], 0.97), SVC VLD (ICC, 1.00), and DVC VLD (ICC, 1.00). CONCLUSIONS: Quantitative studies of pediatric perifoveal vasculature should consider age, race, and AL. In eyes with unilateral disease, the perifoveal vasculature in the unaffected eye may be used as a control comparison because there is excellent agreement between eyes.

Three-dimensional pattern of extraretinal neovascular development in retinopathy of prematurity.

BACKGROUND: The application of three-dimensional (3D) visualization techniques to evaluate the earliest visible onset of abnormal retinal vascular development in preterm infants with retinopathy of prematurity (ROP), using bedside non-contact optical coherence tomography (OCT) imaging to characterize morphology and sequential structural changes of abnormal extraretinal neovascularization. METHODS: Thirty-one preterm infants undergoing routine ROP screening with written informed consent for research imaging were enrolled in this prospective observational study. We imaged the macula and temporal periphery of preterm infants using a handheld OCT system (Envisu 2300 or handheld swept-source research system). The scans obtained were segmented and, using enhanced ray casting, were converted to 3D volumes to which color filter was applied. RESULTS: Using colorized 3D visualization, we defined extraretinal neovascular structures as buds, bridging networks, and placoid lesions. We could longitudinally follow progression and regression of extraretinal neovascularization in stage 3 ROP after treatment in one infant over 12 weeks and document the appearance of early buds, and formation of florid neovascularization. From stages 2 to 3 ROP, we observed progression from sessile buds to a complex plaque that corresponded to stage 3 ROP on clinical examination. We demonstrated regression of neovascular complexes to small pre-retinal tufts after treatment with anti-VEGF. CONCLUSIONS: The extension of OCT processing to include surface flattening and colorization that further improved structural analysis rendered better understanding of extraretinal tissue. Our ability to image similar areas in the same infant over multiple visits enabled us to study the evolution of these structural components and follow pathological vascular events longitudinally in development and regression after treatment. These methods can be applied to further study which are likely contribute to our understanding of the pathophysiology of neovascularization in ROP.

LONGITUDINAL CHANGES IN THE OPTIC NERVE HEAD AND RETINA OVER TIME IN VERY YOUNG CHILDREN WITH FAMILIAL EXUDATIVE VITREORETINOPATHY.

PURPOSE: To explore vitreoretinal pathologies and their longitudinal changes visible on handheld optical coherence tomography (OCT) of young children with familial exudative vitreoretinopathy. METHODS: The authors retrospectively analyzed handheld OCT images for vitreoretinal interface and retinal abnormalities and optic nerve head (ONH) elevation. RESULTS: From 26 eyes of 16 children (mean age 32 months) with familial exudative vitreoretinopathy, 10 had ONH dragging on photographs, and in these, handheld OCT revealed temporal and anterior retinal displacement, prominent vitreopapillary adhesion or traction, and retinal nerve fiber layer thickening at ONH margins with adjacent retinal elevation. Despite a nearly normal photographic appearance, handheld OCT revealed ONH elevation with vitreopapillary traction (6/16 eyes), ONH edema (1/16 eye), and retinal vascular protrusion (5/16 eyes). Handheld OCT-visualized vitreous abnormalities (18/26 eyes) were more prevalent at higher stages of disease. Handheld OCT-visualized elevation of ONH and the retina worsened over time in nine eyes and improved in 5/6 eyes after vitrectomy. CONCLUSION: Handheld OCT can detect early ONH, retinal, and vitreous changes in eyes with familial exudative vitreoretinopathy. Contraction of strongly adherent vitreous in young patients with familial exudative vitreoretinopathy appears to cause characteristic ONH dragging and tractional complications without partial posterior vitreous detachment. Vitreopapillary dragging may be visible only on OCT and may progress in the absence of obvious retinal change on conventional examination.

Demonstration of anatomical development of the human macula within the first 5 years of life using handheld OCT.

PURPOSE: To demonstrate the anatomical development of the human macula using handheld spectral domain optical coherence tomography (SD-OCT) during the first 5 years of life. METHODS: This study is a cross-sectional, observational case series. Thirty-five normal eyes of 35 full-term/late preterm infants and children under 5 years of age were included. Handheld SD-OCT was used to image the macula of each eye. The data were analyzed using the Duke OCT Retinal Analysis Program v17 software. Retinal thickness maps were generated for the total retinal thickness (TRT), the inner retinal layers thickness (IRL), and the photoreceptor layer thickness (PRL). Based on the early treatment diabetic retinopathy study macular map, average thickness measurements were taken at 4 circles centered on the fovea (diameter): the foveal center (0.5 mm), sector 1 (S1) (1 mm), sector 2 (S2) (3 mm), sector 3 (S3) (6 mm). RESULTS: The median age at participation was 24 months (range 5-52 months). The TRT increased throughout the first 5 years of life, and this increase was statistically significant at the foveal center and S1 (p = 0.01, p = 0.016, respectively). The IRL did not show any significant change in thickness from birth and throughout the first 5 years of life. The PRL thickness showed thickening in the first 24 months of age at the foveal center and S1 which was statistically significant at S1 (p = 0.066, p = 0.016, respectively). Interestingly, this PRL thickness increase plateaus beyond 24 months of age. The photoreceptors inner segment/outer segment (IS/OS) band was identified as a distinct layer in all our subjects. CONCLUSION: Our findings conform with the literature that the anatomical development of the macular IRL completes before 5 months of age and hence before the PRL. We also identify 24 months of age as an important developmental milestone for photoreceptors development in the human macula.

Development and Course of Scars in the Comparison of Age-Related Macular Degeneration Treatments Trials.

PURPOSE: To describe risk factors for scar formation and changes to fibrotic scar through 5 years in the Comparison of Age-related Macular Degeneration Treatments Trials (CATT). DESIGN: Multicenter, prospective cohort study. PARTICIPANTS: A total of 1061 subjects in CATT. METHODS: Color photographic and fluorescein angiographic images from baseline and 1, 2, and 5 years were evaluated. Incidence of scar formation was estimated with Kaplan-Meier curves. Risk factors were assessed with Cox regression models. MAIN OUTCOME MEASURES: Scar formation, fibrotic scar area, and macular atrophy associated with fibrotic scar ("atrophy"). RESULTS: Cumulative proportion of eyes with scar was 32%, 46%, and 56% at years 1, 2, and 5, respectively. Baseline factors associated with increased risk (adjusted hazards ratio [aHR] and 95% confidence interval [CI]) were classic choroidal neovascularization (CNV) (aHR, 4.49; 95% CI, 3.34-6.04) versus occult, hemorrhage >1 disc area (DA) (aHR, 2.28; 95% CI, 1.49-3.47) versus no hemorrhage, retinal thickness >212 µm (aHR, 2.58; 95% CI, 1.69-3.94) versus <120 µm, subretinal tissue complex thickness >275 µm (aHR, 2.64; 95% CI, 1.81-3.84) versus ≤75 µm, subretinal fluid thickness >25 µm (aHR, 1.31; 95% CI, 0.97-1.75) versus no fluid, visual acuity (VA) in fellow eye 20/20 (aHR, 1.72; 95% CI, 1.25-2.36) versus 20/50 or worse, retinal pigment epithelium elevation absence (aHR, 1.71; 95% CI, 1.21-2.41), and subretinal hyperreflective material (aHR, 1.72; 95% CI, 1.25-2.36). Among 68 eyes that developed fibrotic scar at year 1, VA decreased by a mean of additional 13 letters between years 1 and 5. Mean scar area was 1.2, 1.2, and 1.9 DA at 1, 2, and 5 years, respectively. Atrophy was present in 18%, 24%, and 54% of these eyes at years 1, 2, and 5, respectively; the mean areas were 1.6, 2.0, and 3.1 DA, respectively. Atrophy replaced fibrotic scar in 8 eyes at year 5. There was no significant correlation between scar growth and atrophy growth. The rate of growth for both was similar between the clinical trial and observation periods. CONCLUSIONS: Several morphologic features, including classic CNV and large hemorrhage, are associated with scar formation. Rate of new scar formation declined after 2 years. Most fibrotic scars and accompanying macular atrophy expanded over time, reducing VA.

HANDHELD SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING THROUGH THE UNDILATED PUPIL IN INFANTS BORN PRETERM OR WITH HYPOXIC INJURY OR HYDROCEPHALUS.

PURPOSE: The authors investigated feasibility of undilated handheld spectral domain optical coherence tomography (SDOCT) retinal imaging in preterm infants and children with neurologic abnormalities. METHODS: Under an institutional review board-approved protocol, the authors attempted handheld SDOCT imaging of the retina, choroid, and optic nerve in infants and young children without pupil dilation. Scans were analyzed for quality and successful capture of foveal, optic nerve, and retinal structural parameters and abnormalities. RESULTS: The authors obtained images through an undilated pupil of 11 infants/children over 28 eye imaging sessions, 27 at the bedside without sedation, and one under anesthesia. Infants had retinopathy of prematurity (n = 8), hypoxic ischemic encephalopathy (n = 2), or obstructive hydrocephalus (n = 1 child). Pupil sizes ranged from 1.0 mm to 3.5 mm. The authors captured fovea and optic nerve scans in 25/28 eye imaging sessions, with scans of adequate quality to discern prespecified foveal and optic nerve morphology, and of the 25 sessions, the choroidal-scleral junction was visible in all but 6 sessions. CONCLUSION: Undilated, handheld SDOCT imaging is a potential alternative method to evaluate the retina and optic nerve in patients with relative contraindication to pharmacological pupil dilation. This approach will enable the study of the eye-brain connection and ocular manifestations of neurologic diseases.

VISUALIZATION FROM INTRAOPERATIVE SWEPT-SOURCE MICROSCOPE-INTEGRATED OPTICAL COHERENCE TOMOGRAPHY IN VITRECTOMY FOR COMPLICATIONS OF PROLIFERATIVE DIABETIC RETINOPATHY.

PURPOSE: To evaluate the use of live volumetric (4D) intraoperative swept-source microscope-integrated optical coherence tomography in vitrectomy for proliferative diabetic retinopathy complications. METHODS: In this prospective study, we analyzed a subgroup of patients with proliferative diabetic retinopathy complications who required vitrectomy and who were imaged by the research swept-source microscope-integrated optical coherence tomography system. In near real time, images were displayed in stereo heads-up display facilitating intraoperative surgeon feedback. Postoperative review included scoring image quality, identifying different diabetic retinopathy-associated pathologies and reviewing the intraoperatively documented surgeon feedback. RESULTS: Twenty eyes were included. Indications for vitrectomy were tractional retinal detachment (16 eyes), combined tractional-rhegmatogenous retinal detachment (2 eyes), and vitreous hemorrhage (2 eyes). Useful, good-quality 2D (B-scans) and 4D images were obtained in 16/20 eyes (80%). In these eyes, multiple diabetic retinopathy complications could be imaged. Swept-source microscope-integrated optical coherence tomography provided surgical guidance, e.g., in identifying dissection planes under fibrovascular membranes, and in determining residual membranes and traction that would benefit from additional peeling. In 4/20 eyes (20%), acceptable images were captured, but they were not useful due to high tractional retinal detachment elevation which was challenging for imaging. CONCLUSION: Swept-source microscope-integrated optical coherence tomography can provide important guidance during surgery for proliferative diabetic retinopathy complications through intraoperative identification of different complications and facilitation of intraoperative decision making.