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.

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.

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.

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.

ASSESSMENT OF THE RETINAL STRUCTURE IN CHILDREN WITH INCONTINENTIA PIGMENTI.

PURPOSE: This report aims at expanding the current knowledge of retinal microanatomy in children with incontinentia pigmenti using hand-held spectral domain optical coherence tomography (SDOCT). METHODS: We reviewed OCT scans from 7 children (4 weeks-13 years) obtained either in the clinic or during an examination under anesthesia. The scans were analyzed for anatomical changes in the outer and inner retina, by certified graders. Medical records were assessed for systemic findings. RESULTS: We observed abnormal retinal findings unilaterally in three children. We found inner and outer retinal thinning temporally in two participants. This thinning was present prior to and persisted after treatment. One child showed a distorted foveal contour and significant retinal thickening secondary to dense epiretinal membrane and vitreomacular traction. All other children had normal retinae. CONCLUSION: Hand-held SDOCT imaging of the retina has brought to light additional retinal structural defects that were not previously reported or visualized via routine clinical ophthalmic examination including retinal photography. Despite a normal foveal structure and visual acuity, we identified inner and outer retinal thinning on SDOCT which may benefit from future functional assessment such as visual field testing.

Poorer neurodevelopmental outcomes associated with cystoid macular edema identified in preterm infants in the intensive care nursery.

PURPOSE: To evaluate the association between cystoid macular edema (CME) observed in very preterm infants and developmental outcomes at 18 to 24 months corrected age. DESIGN: Cohort study. PARTICIPANTS: Infants born at or less than 1500 g or at or less than 30 weeks postmenstrual age who underwent screening for retinopathy of prematurity (ROP) in an intensive care nursery. METHODS: Bedside handheld spectral-domain optical coherence tomography (SD OCT; Envisu, Bioptigen, Inc, Research Triangle Park, NC) imaging was obtained from preterm infants who were being screened for ROP and graded for presence of CME, central foveal thickness (CFT), inner nuclear layer thickness, and foveal-to-parafoveal thickness ratio. At 18 to 24 months corrected age, the children were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition. MAIN OUTCOME MEASURES: Scores on the Bayley cognitive, language, and motor subscales. RESULTS: Among 77 children with SD OCT imaging, 53 were evaluated with the Bayley Scales. Compared with children who did not have CME as infants (n=22), the mean score for children who had CME (n=31) was 7.3 points (95% confidence interval [CI], -15.5 to 0.9; P=0.08) lower on the cognitive subscale, 14.1 points (95% CI, -22.7 to -5.5; P=0.002) lower for the language subscale, and 11.5 points (95% CI, -21.6 to -1.3; P=0.03) lower for the motor subscale. Differences were maintained after adjusting for gestational age and birth weight. Severity of CME, as assessed by foveal-to-parafoveal thickness ratio, within the CME group correlated with poorer cognitive (R2=0.16, P=0.03) and motor (R2=0.15, P=0.03) development. CONCLUSIONS: Cystoid macular edema observed on SD OCT in very preterm infants screened for ROP is associated with poorer language and motor skills at 18 to 24 months corrected age. Evaluation of the retina with SD-OCT may serve as an indicator of neurodevelopmental health for very preterm infants in the intensive care nursery.

FUNCTIONAL OUTCOMES OF YOUNG INFANTS WITH AND WITHOUT MACULAR EDEMA.

PURPOSE: The authors relate posterior segment microanatomy from perinatal spectral domain optical coherence tomography to visual acuity, brain abnormalities, and neurodevelopment. METHODS: Thirteen infants (11 preterm and 2 term birth), imaged in the nursery with portable spectral domain optical coherence tomography, had visual acuity and sensorimotor testing at age 9 months to 15 months (grating acuity) or 4 years to 5 years (optotype), and medical records reviewed for brain magnetic resonance imaging reports and Bayley scales testing at age 18 months to 24 months. RESULTS: Eight children with age-appropriate macular microanatomy without edema on perinatal spectral domain optical coherence tomography had optimal (≥ 20/40) or within normal limits (grating acuity) visual acuity. Five children with perinatal macular edema had suboptimal visual acuity (in 9/10 eyes) and sensorimotor deficits, magnetic resonance imaging abnormalities, or poor neurodevelopment. Macular edema persisted in 1 infant through 9-month corrected age. CONCLUSION: Maturation of the visual system and evolution of retinal anomalies can be monitored with posterior segment spectral domain optical coherence tomography. Retinal microanatomy observed in infancy might relate to subsequent vision and other central nervous system events, but additional studies are needed to determine the range of normal microanatomy in infants and how this relates to vision and neurodevelopment.

INTRAOPERATIVE SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IMAGING AFTER INTERNAL LIMITING MEMBRANE PEELING IN IDIOPATHIC EPIRETINAL MEMBRANE WITH CONNECTING STRANDS.

PURPOSE: To report the intraoperative optical coherence tomography findings in idiopathic epiretinal membrane (ERM) with connecting strands and to describe the postoperative outcomes. METHODS: A retrospective, case series study within a prospective observational intraoperative optical coherence tomography imaging study was performed. Epiretinal membranes with connecting strands were characterized on preoperative spectral domain optical coherence tomography images and assessed against corresponding intraoperative (after internal limiting membrane [ILM] peeling) and postoperative spectral domain optical coherence tomography images. RESULTS: Eleven locations of the connecting strands in 7 eyes were studied. The connecting strands had visible connections from the inner retinal surface to the ERM in all locations, and the reflectivity was moderate in 8 locations and high in 3 locations. After ERM and ILM peeling, disconnected strands were identified in all of the intraoperative optical coherence tomography images. The reflectivity of the remaining intraoperative strands was higher than that of the preoperative lesions and appeared as "finger-like" and branching projections. The remaining disconnected lesions were contiguous with the inner retinal layers. Postoperatively, the intraoperative lesions disappeared completely in all locations, and recurrent formation of ERM was not identified in any eyes. CONCLUSION: In ERM eyes with connecting strands, intraoperative spectral domain optical coherence tomography imaging showed moderately to highly reflective sub-ILM finger-like lesions that persist immediately after membrane and ILM peeling. Postoperatively, the hyperreflective lesions disappeared spontaneously without localized nerve fiber layer loss. The sub-ILM connecting strands may represent glial retinal attachments.

Three-dimensional assessment of vascular and perivascular characteristics in subjects with retinopathy of prematurity.

PURPOSE: To study vascular features detected with spectral domain optical coherence tomography (SD-OCT) in subjects undergoing retinopathy of prematurity (ROP) screening. DESIGN: Cross-sectional study. PARTICIPANTS AND CONTROLS: Fifty-seven premature neonates, 10 with plus disease in at least 1 eye and 47 without plus disease. METHODS: Bedside noncontact SD-OCT imaging was performed after obtaining parental consent on 97 consecutive infants between January 2009 and September 2012. Fifty-seven subjects (31-49 weeks' post-menstrual age) who had an SD-OCT scan in at least 1 eye showing the edge of the optic nerve and at least 1 major retinal vascular arcade were included. One eye per subject was randomly selected for analysis. Two masked graders evaluated scans for (1) retinal vessel elevation, (2) scalloped retinal layers, (3) hyporeflective vessels, and (4) retinal spaces. To coalesce the weight of these features, a Vascular Abnormality Score by OCT (VASO) was created. For quantitative assessment of vessel elevation, retinal surface maps were created. MAIN OUTCOME MEASURES: Prevalence of SD-OCT vascular abnormalities, the VASO, intergrader agreement, and presence of elevation on surface maps. RESULTS: From among 67 SD-OCT characteristics that were recorded, the most common characteristics found were vessel elevation (44%), hyporeflective vessels (40%), scalloped layers (22%), and retinal spaces (11%). Features significantly associated with plus disease were vessel elevation (P = 0.01), hyporeflective vessels (P = 0.04), and scalloped retinal layers (P = 0.006). Intragrader agreement was between 74% and 90% for all features. The VASO was significantly higher in subjects with plus disease (P = 0.0013). On 3-dimensional SD-OCT volumes, eyes with plus disease had greater retinal surface elevation that more often matched en face retinal vascular patterns. CONCLUSIONS: We present a novel 3-dimensional analysis of vascular and perivascular abnormalities identified in SD-OCT images of eyes with ROP. The SD-OCT characteristics that are more common in eyes with plus disease provide the first in vivo demonstration of the effects of vascular dilation and tortuosity on perivascular tissue. The VASO and surface maps also delineate the severity of vascular pathology in plus disease. Further studies evaluating these findings in eyes with pre-plus versus normal posterior pole vessels may determine the usefulness of SD-OCT in the early detection of vascular abnormalities in ROP.

A pilot optical coherence tomography angiography classification of retinal neovascularization in retinopathy of prematurity.

Extraretinal neovascularization is a hallmark of treatment-requiring retinopathy of prematurity (ROP). Optical coherence tomography angiography (OCTA) offers vascular flow and depth information not available from indirect ophthalmoscopy and structural OCT, but OCTA is only commercially available as a tabletop device. In this study, we used an investigational handheld OCTA device to study the vascular flow in and around retinal neovascularization in seven preterm infants with treatment-requiring ROP and contrasted them to images of vascular flow in six infants of similar age without neovascular ROP. We showed stages of retinal neovascularization visible in preterm infants from 32 to 47 weeks postmenstrual age: Intraretinal neovascularization did not break through the internal limiting membrane; Subclinical neovascular buds arose from retinal vasculature with active flow through the internal limiting membrane; Flat neovascularization in aggressive ROP assumed a low-lying configuration compared to elevated extraretinal neovascular plaques; Regressed neovascularization following treatment exhibited decreased vascular flow within the preretinal tissue, but flow persisted in segments of retinal vessels elevated from their original intraretinal location. These findings enable a pilot classification of retinal neovascularization in eyes with ROP using OCTA, and may be helpful in detailed monitoring of disease progression, treatment response and predicting reactivation.

Biphasic change in retinal nerve fibre layer thickness from 30 to 60 weeks postmenstrual age in preterm infants.

BACKGROUND/AIMS: The optic nerve development during the critical postnatal weeks of preterm infants is unclear. We aimed to investigate the change of retinal nerve fibre layer (RNFL) in preterm infants. METHODS: We used an investigational handheld optical coherence tomography (OCT) system to serially image awake preterm infants between 30 and 60 weeks postmenstrual age (PMA) at the bedside. We assessed RNFL thickness in the papillomacular bundle and nasal macular ganglion cell layer+inner plexiform layer (GCL+IPL) thickness. We applied a segmented mixed model to analyse the change in the thickness of RNFL and GCL+IPL as a function of PMA. RESULTS: From 631 OCT imaging sessions of 101 infants (201 eyes), RNFL thickness followed a biphasic model between 30 and 60 weeks, with an estimated transition at 37.8 weeks PMA (95% CI: 37.0 to 38.6). RNFL thickness increased at 1.8 µm/week (95% CI: 1.6 to 2.1) before 37.8 weeks and decreased at -0.3 µm/week (95% CI: -0.5 to -0.2) afterwards. GCL+IPL thickness followed a similar biphasic model, in which the thickness increased at 2.9 µm/week (95% CI: 2.5 to 3.2) before 39.5 weeks PMA (95% CI: 38.8 to 40.1) and then decreased at -0.8 µm/week (95% CI: -0.9 to -0.6). CONCLUSION: We demonstrate the feasibility of monitoring RNFL and GCL+IPL thickness from OCT during the postnatal weeks of preterm infants. Thicknesses follow a biphasic model with a transition age at 37.8 and 39.5 weeks PMA, respectively. These findings may shed light on optic nerve development in preterm infants and assist future study designs.

Associations between systemic health and retinal nerve fibre layer thickness in preterm infants at 36 weeks postmenstrual age.

BACKGROUND/AIMS: Neonatal insults from systemic diseases have been implicated in the pathway of impaired neurodevelopment in preterm infants. We aimed to investigate the associations between systemic health factors and retinal nerve fibre layer (RNFL) thickness in preterm infants. METHODS: We prospectively enrolled infants and imaged both eyes at 36±1 weeks postmenstrual age (PMA) using a hand-held optical coherence tomography system at the bedside in the Duke intensive care nurseries. We evaluated associations between RNFL thickness and 29 systemic health factors using univariable and multivariable regression models. RESULTS: 83 infants with RNFL thickness measures were included in this study. Based on the multivariable model, RNFL thickness was positively associated with infant weight at imaging and was negatively associated with sepsis/necrotising enterocolitis (NEC). RNFL thickness was 10.4 µm (95% CI -15.9 to -4.9) lower in infants with than without sepsis/NEC in the univariable analysis (p<0.001). This difference remained statistically significant after adjustment for confounding variables in various combinations (birth weight, birthweight percentile, gestational age, infant weight at imaging and growth velocity). A 250 g increase in infant weight at imaging was associated with a 3.1 µm (95% CI 2.1 to 4.2) increase in RNFL thickness in the univariable analysis (p<0.001). CONCLUSIONS: Low infant weight and sepsis/NEC were independently associated with thinner RNFL in preterm infants at 36 weeks PMA. To our knowledge, this study is the first to suggest that sepsis/NEC may affect retinal neurodevelopment. Future longitudinal studies are needed to investigate this relationship further.

Integrated Visualization Highlighting Retinal Changes in Retinopathy of Prematurity From 3-Dimensional Optical Coherence Tomography Data.

Importance: Early diagnosis of plus disease is critical in the management of retinopathy of prematurity (ROP). However, there is substantial interexpert disagreement in the diagnosis of plus disease based on vascular changes alone. Information derived from optical coherence tomography (OCT) may help characterize the severity of vascular and structural abnormalities in ROP. Objective: To describe integrated visualization of 3-dimensional (3-D) data from investigational swept-source OCT optimized to delineate retinal vascular and microanatomical features in eyes with and without ROP. Design, Setting, and Participants: This cross-sectional, observational report of OCT was captured in the prospective Study of Eye Imaging in Preterm Infants (BabySTEPS) designed in July 2016 at the Duke Health Intensive Care Nursery. Between December 2018 and August 2019, 2 preterm infants born at 24 and 30 weeks' gestation were enrolled, underwent ROP screening, and were imaged at those screening visits. Data at 36 weeks' postmenstrual age were analyzed via this visualization developed between September 2020 and May 2021. Main Outcomes and Measures: Superimposed en face retinal vascular shadow view (RVSV) montages and thickness maps were used along with OCT B-scans to evaluate retinal vasculature and cross-section in eyes with and without ROP. Results: In the right eyes of 2 infants, 3-D data were integrated and visualized from investigational bedside OCT imaging at the posterior pole. In the infant who developed type 1 ROP, RVSV-OCT confirmed presence of dilated and tortuous posterior pole vessels, shunting, and incomplete perifoveal vascular development, resulting in a temporal notch of avascular retina in zone 1. The thickness map revealed irregular pockets of thickening and thinning, and integrated visualization outlined the demarcation between thicker vascularized retina and thinner avascular fovea and presence of extraretinal neovascularization overlying elevated vessels in the superior arcades. In the infant without ROP (stage 0), RVSV-OCT revealed no abnormal vascular findings at the posterior pole. The integrated visualization showed a dome-shaped retinal thickening at the fovea, which was confirmed as macular edema. Conclusions and Relevance: In 2 preterm infants in BabySTEPS, 3-D visualization of OCT findings during the ongoing ROP disease process demonstrated supplemental information about the retinal vasculature and microanatomy that can be useful to clinicians. These additional details provided by OCT could be integrated into future ROP screening methods with artificial intelligence-based analytics.

Preterm Infant Stress During Handheld Optical Coherence Tomography vs Binocular Indirect Ophthalmoscopy Examination for Retinopathy of Prematurity.

IMPORTANCE: Binocular indirect ophthalmoscopy (BIO) examination for retinopathy of prematurity (ROP) is a well-known cause of repeated preterm infant stress. OBJECTIVE: To compare stress during investigational optical coherence tomography (OCT) imaging to that during BIO for ROP. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study examined infants at the bedside in the intensive care nursery. Consecutive preterm infants enrolled in Study of Eye Imaging in Preterm Infants (BabySTEPS) who had any research OCT imaging as part of the study. Patients were recruited from June to November 2019, and analysis began April 2020. MAIN OUTCOMES AND MEASURES: Infant stress was measured using modified components of a neonatal pain assessment tool before (baseline) and during OCT imaging and BIO examination of each eye. RESULTS: For 71 eye examinations of 16 infants (mean [SD] gestational age, 27 [3] weeks; birth weight, 869 [277] g), change from baseline to each eye examination was lower during OCT imaging than during BIO and the difference between OCT imaging and BIO at each eye examination was significant for the following: infant cry score (first eye examination: mean [SD], 0.03 [0.3] vs 1.68 [1.2]; -1.65 [95% CI, -1.91 to -1.39]; second eye examination: mean [SD], 0.1 [0.3] vs 1.97 [1.2]; -1.87 [95% CI, -2.19 to -1.54]), facial expression (first eye: 3 [4%] vs 59 [83%]; -79% [95% CI, -87% to -72%]; second eye: 4 [6%] vs 61 [88%]; -83% [95% CI, -89% to -76%]), and heart rate (first eye: mean [SD], -7 [16] vs 13 [18]; -20 [95% CI, -26 to -14]); second eye: mean [SD], -3 [18] vs 20 [20] beats per minute; -23 [95% CI, -29 to -18]) (P < .001 for all). Change in respiratory rate and oxygen saturation did not differ between OCT imaging and BIO. CONCLUSIONS AND RELEVANCE: While the role of OCT alone or in combination with BIO is currently unknown for ROP, these findings suggest that investigational OCT imaging of ROP is less stressful than BIO examination by a trained ophthalmologist.

Macular OCT Characteristics at 36 Weeks' Postmenstrual Age in Infants Examined for Retinopathy of Prematurity.

PURPOSE: To report our ability to capture,-grade reliably, and analyze bedside macular OCT images from preterm infants and relate OCT findings to biological factors and retinopathy of prematurity (ROP) status at a single time window in the Study of Eye Imaging in Preterm Infants (BabySTEPS). DESIGN: Prospective, observational study. PARTICIPANTS: Preterm infants eligible for ROP screening with parental consent for research and a 36 ± 1 weeks' postmenstrual age (PMA) visit. METHODS: We imaged both eyes of preterm infants with an investigational noncontact, handheld swept-source (SS) OCT at the time of clinical ROP examinations. Macular OCT features and layer thicknesses for untreated eyes of infants at 36 ± 1 weeks' PMA were compared with demographic data and clinical ROP examination performed by experts. Statistical analyses accounted for the use of both eyes of infants. MAIN OUTCOME MEASURES: Macular OCT features and layer thicknesses, gender, race or ethnicity, gestational age, birth weight, ROP stage, and plus disease. RESULTS: We captured macular OCT from 169 eyes (1 eye excluded because of prior ROP treatment) at 36 ± 1 weeks' PMA. The quality of OCT volumes was excellent in 33 eyes (19%), acceptable in 112 eyes (67%), poor in 24 eyes (14%), and unusable in 0 eyes (0%). Macular edema was present in 60% of eyes and was bilateral in 82% of infants with edema. At the fovea, retinal and inner nuclear layer thickness increased with edema severity: 183 ± 36 µm and 51 ± 27 µm in mild (16% of eyes), 308 ± 57 µm and 163 ± 53 µm in moderate (25%), and 460 ± 76 µm and 280 ± 83 µm in severe edema (12%), respectively. With an increase in ROP stage from 0 to 2, the mean ± standard deviation retinal thickness at the fovea increased from 227± 124 µm to 297 ± 99 µm (P < 0.001). The choroid was thinner, 155 ± 72 µm, with preplus or plus disease versus without, 236 ± 79 µm (P = 0.04), whereas retinal thickness did not vary. CONCLUSIONS: We demonstrated the reliability of methods and the prevalence of OCT findings in preterm infants enrolled in BabySTEPS at a single time point of 36 ± 1 weeks' PMA. Variations in layer thicknesses in infants at this time point may reflect abnormalities resulting from delay in foveal development that may be impacted by macular edema, ROP, or both.

Depth-Resolved Visualization of Perifoveal Retinal Vasculature in Preterm Infants Using Handheld Optical Coherence Tomography Angiography.

Purpose: To establish methods to visualize depth-resolved perifoveal retinal vasculature in preterm infants using handheld optical coherence tomography angiography (OCT-A). Methods: In this exploratory study, eyes of preterm infants were imaged using an investigational noncontact, handheld swept-source OCT-A device as part of the prospective BabySTEPS infant retinal imaging study. We selected high-quality OCT-A volumes at two developmental stages for analysis. Customized MATLAB scripts were used to segment retinal layers, test offset parameters, and generate depth-resolved OCT-A slabs. The superficial (SCP), intermediate (ICP), and deep (DCP) capillary plexuses were visualized and qualitatively assessed by three image graders. Results: Six eyes from six preterm infants were included in this analysis. A three-layered perifoveal retinal vasculature was successfully visualized in all three eyes (three infants) in the 40 weeks postmenstrual age (PMA) group (one of three eyes with treated type 1 retinopathy of prematurity [ROP]). No obvious ICP or DCP was found in good-quality scans of the three eyes (three infants) in the 35 weeks PMA group (three of three eyes developed type 1 ROP). Conclusions: Custom segmentation parameters are useful to visualize perifoveal retinal vasculature in preterm infants. At term age, a three-layered capillary structure is visible in most eyes, while prior to detectable flow within the ICP and DCP, the perifoveal vasculature may be better visualized in two layers. Translational Relevance: Development of segmentation parameters for depth-resolved OCT-A of perifoveal retinal vasculature in preterm infants facilitates the study of human retinal vascular development and vascular pathologies of ROP.

Morphological characteristics of early- versus late-onset macular edema in preterm infants.

Macular images of infants with early-onset edema (occurring at or before 33 weeks' postmenstrual age [PMA]) and infants with late-onset edema (at or after 36 weeks' PMA) were compared. At first appearance, early-onset edema has a more severe morphology, with foveal bulging and elongated cystoid spaces than late-onset edema, which presents as small cystoid spaces outside the foveal center. Morphological variations may be an indicator of the underlying cause of edema in preterm infants. The presence of mostly parafoveal small cystoid spaces in the late-onset edema group may be suggestive of an association with neurological injury.

Repeatability and Reproducibility of Axial and Lateral Measurements on Handheld Optical Coherence Tomography Systems Compared with Tabletop System.

Purpose: To compare the repeatability and reproducibility of axial and lateral retinal measurements using handheld optical coherence tomography (OCT) systems and a tabletop OCT system. Methods: Graders measured central foveal thickness (CFT), optic nerve-to-fovea distance (OFD), and retinal nerve fiber layer (RNFL) thickness on OCT scans of the right eye of 10 healthy adults. Three OCT systems were used: handheld Leica Envisu, investigational handheld swept-source OCT (UC3), and Heidelberg Spectralis tabletop system. All eyes were imaged five times with each OCT system by each of two imagers. A components of variance analysis provided estimates of repeatability (variation due to random error) and reproducibility (variation due to imager, grader, and random error) expressed as standard deviation and (coefficient of variation %). Results: Repeatability of CFT (µm) for Envisu, UC3, and Spectralis was 5.9 (2.6%), 6.9 (2.9%), and 4.7 (2.1%), and the reproducibility was 6.1 (2.7%), 7.3 (3.1%), and 4.7 (2.1%), respectively. The repeatability of OFD (mm) was 0.13 (2.9%), 0.10 (2.3%), and 0.07 (1.6%), and the reproducibility was 0.13 (3.0%), 0.10 (2.3%), and 0.07 (1.6%,) respectively. The repeatability for RNFL thickness (µm) for Envisu, UC3, and Spectralis was 4.3 (7.8%), 2.7 (5.4%), and 2.9 (4.9%), and the reproducibility was 4.5 (8.3%), 2.9 (5.8%), and 2.9 (4.9%), respectively. Conclusions: All three OCT systems had good repeatability and reproducibility with coefficients of variation of less than 3.5% for CFT and OFD measurements, and less than 8.5% for RNFL thickness. Translational Relevance: Our findings inform the repeatability and reproducibility of retinal axial and lateral measurements on handheld OCT and are useful for both clinical research and patient care.

Understanding the variability of handheld spectral-domain optical coherence tomography measurements in supine infants.

PURPOSE: Central foveal thickness (CFT) measurements from optical coherence tomography (OCT) scans provide a precise measure of severity of pathologic changes in the fovea, progress of disease and response to treatment. Although these measures are additionally valuable to assess foveal development in infants, their reproducibility is not known. The goal of this retrospective study is to evaluate the variation and reproducibility of CFT measurements using handheld spectral-domain OCT (hh-SDOCT) in supine infants compared to conventional adult tabletop imaging. METHODS: Imaging sessions with multiple macular, volume scans in one eye were selected for analysis from two participant groups: Group 1, 25 imaging sessions from 21 preterm infants without macular edema imaged supine in the nursery using hh-SDOCT (Leica/Bioptigen Envisu C2300, RTP, NC); Group 2, 25 imaging sessions from 25 adults imaged using tabletop Bioptigen SDOCT. For each imaging session, three macular OCT volumes with acceptable image quality were selected for analysis. CFTs were measured using a customized script for automatic segmentation. An expert grader and a typical grader corrected the segmentation lines for the central foveal frame. Coefficient of variations (CV) and intraclass correlation coefficients (ICC) were calculated for graders and systems and compared to the previous literature on OCT reproducibility. RESULTS: CFT measurements were repeatable and reproducible for both handheld and tabletop SDOCT systems. For handheld, grader ICC (CI) and mean CV were 0.94 (0.90-0.97) and 3.8 (typical) and 0.98 (0.96-0.99) and 2.9 (expert), and for tabletop were 0.91(0.83-0.96) and 2.1 (typical) and 0.92 (0.86-0.96) and 1.9 (expert). Intergrader reproducibility of handheld and tabletop SDOCT systems were ICC(CI) 0.97 (0.95-0.98) and 0.93 (0.89-0.96) respectively, and both are comparable to previously reported reproducibility of tabletop systems. CONCLUSION: Handheld SDOCT is a reproducible instrument to measure foveal thicknesses in supine infants. It can be used in clinical research to evaluate foveal changes during retinal development and pathological conditions.