Cynthia A. Toth

Importance: If noninvasive optical coherence tomography (OCT) retinal imaging could predict 2-year neurodevelopment of very preterm (VPT; P < .001) and cognitive scores (mean score change per 10-µm increase in RNFL thickness, 3.71 [95% CI, 0.73-6.69]; P = .02) and lower M-CHAT-R autism risk scores (mean score change per 10-µm increase in RNFL thickness, −0.64 [95% CI, −1.19 to −0.09]; P = .03) and Child Behavior Checklist internalizing problems scores (mean score change per 10-µm increase in RNFL thickness, −2.25 [95% CI, −4.41 to −0.09]; P = .04). Greater choroidal thickness was associated with higher motor scores (mean score change per 100-µm increase in choroidal thickness, 4.84 [95% CI, 0.45-9.23]; P = .03). When considered in addition to infant factors, RNFL thickness improved prediction of the BSID-III motor score ( R ² increased from 0.36 to 0.53; difference, 0.17 [95% CI, 0.04-0.26]) and cognitive score ( R ² increased from 0.29 to 0.35; difference, 0.06 [95% CI, 0.00-0.16]); choroidal thickness improved predictions less than RNFL thickness and did not add to the improved predictions with RNFL thickness. Conclusions and Relevance: In this cohort study, RNFL thickness in VPT infants at 36 weeks’ PMA predicted motor and cognitive neurodevelopmental outcomes at age 2 years. These findings, if confirmed independently, could help guide management of VPT infants through age 2 years.

Background: Scattering of the sclera limits optical coherence tomography (OCT) imaging of deeper targets including lesions, malignancies, and other surgical targets. While existing applications of fluorescein dye are currently focused on fluorescence properties for tissue labeling, the absorption characteristics of the dye also hold potential for scleral tissue clearing. Methods: Fluorescein is investigated here to gauge the potential impact of its optical clearing on intrasurgical OCT guidance. Fluorescein was applied topically to ex vivo porcine and human eye models. OCT imaging was conducted over time to assess the increases in imaging depth due to fluorescein clearing. High-speed microscope-integrated OCT was used during pilot trabeculectomy surgery on cleared eye models to assess clearing applications in a surgical context. Results: The OCT depth of imaging increased with fluorescein concentration and application time. The effect saturates at a near-20% concentration with 50 min of application time, with a maximum signal increase of +15 dB. Reversal of the effect was observed following 10 min of rinsing. Conclusions: High-concentration fluorescein dye has novel applications as an optical clearing agent, increasing the OCT imaging depth through highly scattering biological tissue. These properties can be leveraged for improved image guidance in surgical contexts.

To evaluate macular optical coherence tomography (OCT) features at term-equivalent age in preterm and term infants, and to test the hypothesis that both preterm birth and retinopathy of prematurity (ROP) are associated with differences in OCT measures and features at term-equivalent age, with the choroid potentially influencing the outer retina. This study analyzed data for 162 preterm and 78 term infants from prospective, handheld OCT imaging studies, with images of both eyes at 37 to 42 weeks postmenstrual age (PMA). Quantitative and qualitative features, from reading center grading, were compared between preterm and term infants, with subgroup comparison between stage <2 vs. more severe ROP. Multivariate analyses explored the associations of OCT features with variables including gestational age (GA), ROP, and choroidal thickness, adjusting for PMA at imaging and intereye correlation using generalized estimating equations. Compared to term infants, preterm infants had a greater total and inner retinal thickness at the fovea (232.4 [mean] ± 126.9 [SD] vs. 108.0 ± 35.3 µm and 47.3 ± 20.7 vs. 25.0 ± 14.8 µm, respectively; both P < 0.001), and thinner choroid (267.2 ± 90.3 vs. 350.2 ± 161.4 µm; P < 0.001). Rates of intraretinal fluid were higher (63.8 vs. 6.6%; P < 0.001) in preterm infants, whereas subretinal fluid was only present (7.0%) in term infants. Despite similar outer retinal thickness, the ellipsoid zone was more frequently observed at the foveal center in term infants (35.2%) than preterm infants (8.5%; P < 0.001). Multivariate analyses identified significant associations between higher GA and reduced foveal inner and outer retinal thicknesses. More severe ROP and decreased choroidal thickness were associated with increased foveal inner retinal thickness (both P < 0.01), but not with outer retinal thickness. By term-equivalent age, foveal inner retinal immaturity and photoreceptor under-development is evident in preterm versus term-born retinas. A thinner choroid is associated with thicker inner retina.

Pigment epithelial detachment (PED) is well-documented in adult retinal diseases but is rarely reported in neonates. This case describes a preterm infant, born at 31 weeks, who developed PED with thickened choroid at term-equivalent age, detected using handheld OCT. The PED emerged at 39 weeks postmenstrual age, coinciding with inhaled steroid treatment for respiratory distress, and resolved by 41 weeks after steroid discontinuation without structural damage. The temporal relationship suggests an association between steroid use and PED with choroidal changes. This case highlights the value of OCT in detecting retinal and choroidal abnormalities in preterm infants and underscores the potential impact of systemic conditions and medications on the choroid.

Retinal diseases such as age-related macular degeneration, diabetic retinopathy, and uveitic macular edema are leading causes of visual impairment.^{1 – 3} Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents and/or steroids have been effective in controlling vascular leakage and often restoring visual acuity but require repeated injections. Novel treatments such as intravitreal reservoirs or subretinal injections of gene therapies can be effective over a longer period but may cause glaucoma and cataract (in the case of steroids) or incur the cost and complexity of delivery in a microsurgical setting (in the case of subretinal gene therapy).⁴ This has led to the development of ocular therapeutics that can be delivered by transscleral injection into the suprachoroidal space in an office-based procedure.⁵ Triamcinolone suspension via suprachoroidal injection was approved in 2021 by the U.S. Food and Drug Administration for the treatment of uveitic macular edema, and clinical trials are underway using this delivery route for other posterior segment diseases. A limitation of this procedure is that clinicians are unable to obtain real-time feedback on the location and spread of the delivered product; rather, heat map imaging is used to estimate this.⁵

Significance Imaging deep structures with optical coherence tomography (OCT) is difficult in highly scattering biological tissue, such as the sclera. There is a need to visualize the suprachoroidal space and choroid through the sclera to study suprachoroidal drug delivery. Aim We aim to develop optical methods to image through the highly scattering sclera with a custom-built OCT system to visualize the suprachoroidal space and drug delivery within. Approach We developed a custom handheld OCT scanner to image the anterior segment and suprachoroidal space in ex vivo eye models. Tartrazine (Yellow 5) solution, which has been shown to optically clear biological tissue in the visible regime, was tested as a clearing agent to optimize near infrared OCT imaging through the sclera. Results Tartrazine dramatically increased OCT signal return from the deeper sclera and choroid and thus enabled visualization of the suprachoroidal drug delivery after transscleral injection. Conclusions We demonstrated successful optical clearing of the thick, porcine sclera with a compact handheld OCT system to image the suprachoroidal space. We believe there is broader potential to use optical clearing with handheld OCT for a variety of previously inaccessible, highly scattering tissue samples.

The increasing survival of preterm infants has led to the importance of improving long-term outcomes associated with preterm birth. Antenatal and perinatal insults not only impact mortality, but also long-term disability. While in the intensive care nursery, preterm infants are also exposed to various stressors that lead to long-term cognitive deficits. It is therefore critical to identify early, low-stress, non-invasive biomarkers for preterm infant health. Optical coherence tomography (OCT) is a powerful imaging modality that has recently been adapted to the infant population and provides noninvasive, high-resolution, cross-sectional imaging of the infant eye at the bedside with low stress relative to conventional examination. In this review we delve into discussing the associations between preterm systemic health factors and OCT-based retinal findings and their potential contribution to the development of non-invasive biomarkers for infant health and for retinopathy of prematurity (ROP).

Purpose: To evaluate the association of fundus pigmentation with the visibility of retinal versus choroidal layers on optical coherence tomography (OCT) in preterm infants. Methods: For infants enrolled in BabySTEPS, ophthalmologists recorded fundus pigmentation (blond, medium, or dark) at the first retinopathy of prematurity (ROP) examination. Bedside OCT imaging was performed at each examination, and a masked grader evaluated all OCT scans from both eyes of each infant for visibility (yes/no) of all retinal layers and of the chorio–scleral junction (CSJ). Multivariable logistic regression was used to assess associations between fundus pigmentation and visibility of all retinal layers and CSJ, controlling for potential confounders (i.e., birth weight, gestational age, sex, OCT system, pupil size, and postmenstrual age at imaging). Results: Among 114 infants (mean birth weight, 943 grams; mean gestational age, 27.6 weeks), 43 infants (38%) had blond, 56 infants (49%) had medium, and 15 infants (13%) had dark fundus pigmentation. Of 1042 scans, all retinal layers were visible in 977 (94%) and CSJ in 895 (86%). Pigmentation was not associated with retinal layer visibility (P = 0.49), but medium and dark pigmentation were associated with decreased CSJ visibility (medium: odds ratio [OR] = 0.34, P = 0.001; dark: OR = 0.24, P = 0.009). For infants with dark pigmentation, retinal layer visibility increased (OR = 1.87 per week; P ≤ 0.001) and CSJ visibility decreased (OR = 0.78 per week; P = 0.01) with increasing age. Conclusions: Although fundus pigmentation was not associated with the visibility of all retinal layers on OCT, darker pigmentation decreased CSJ visibility, and this effect increased with age. Translational Relevance: The ability of bedside OCT to capture retinal layer microanatomy in preterm infants, regardless of fundus pigmentation, may represent an advantage over fundus photography for ROP telemedicine.