Subclinical Macular Findings in Infants Screened for Retinopathy of Prematurity with Spectral-Domain Optical Coherence Tomography

doi:10.1016/j.ophtha.2013.01.028

Ophthalmology

Volume 120, Issue 8, August 2013, Pages 1665-1671

https://doi.org/10.1016/j.ophtha.2013.01.028 Get rights and content

Objective

To evaluate subclinical macular findings in premature patients at risk of retinopathy of prematurity (ROP) with the use of handheld spectral-domain optical coherence tomography (SD-OCT).

Design

Prospective, observational case series.

Participants

Forty-nine prematurely born neonates.

Methods

Forty-nine infants were imaged using a handheld SD-OCT. Images were acquired in nonsedated infants in the neonatal intensive care unit (NICU). Some patients were followed and reimaged over the course of several weeks. A total of 300 total images were acquired and evaluated for cystoid macular edema (CME) and persistence of inner retinal layers.

Main Outcome Measures

In vivo determination of foveal retinal lamination, image analysis, and clinical observation.

Results

A total of 241 (80%) of the images from 46 patients were usable (defined as having scans passing through the fovea with clearly identifiable retinal layers). Persistence of 1 or more inner retinal layers was seen in 43 of the patients with usable images (93%). Of the patients with at least 1 persistent layer, 17, 4, 8, 12, and 1, had a maximum ROP stage of 0, 1, 2, 3, and 4A, respectively. Cystoid macular edema was seen in 25 of the 46 patients (54%) during 1 or more imaging sessions. Cystoid macular edema was present in 9, 1, 5, 9, and 1 patient with maximum ROP stage of 0, 1, 2, 3, and 4A, respectively.

Conclusions

Our data suggest there is persistence of inner retinal layers in premature infants regardless of maximal ROP stage. Subclinical CME is seen in premature infants; however, CME does not appear to be correlated with ROP stage. This suggests that there may be other causes for the CME seen in this patient population. Hand-held SD-OCT imaging is a viable technique for evaluating subclinical macular findings in premature infants, although larger datasets are needed from multiple centers to further evaluate the generalizability of these findings.

Financial Disclosure(s)

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Section snippets

Materials and Methods

This study was approved by the institutional review boards at the Medical College of Wisconsin and Children's Hospital of Wisconsin, conformed to the requirements of the US Health Insurance Portability and Privacy Act, and followed the tenets of the Declaration of Helsinki. Informed consent was obtained from the parent or legal guardian of all patients. Forty-nine patients in the neonatal intensive care unit (NICU) at Children's Hospital of Wisconsin were enrolled. Children's Hospital of

Results

There were 241 (80%) usable scans obtained from 46 of the 49 patients. Images were evaluated for the presence of inner retinal layers at the foveal center. Subject-specific data for residual inner retinal layers are shown in Table 1 (available at http://aaojournal.org). Only 3 patients showed complete foveal excavation with no residual inner retinal layers present. Persistence of 1 or more retinal layers was present in 43 patients (93%), examples of this are shown in Figure 2. In 3 patients the

Discussion

Foveal development involves the centrifugal displacement of inner retinal cells and centripetal displacement of photoreceptors.¹⁷ Previous studies have shown that there is persistence of inner retinal layers in children and adults with a history of ROP.5, 6 In these patients, the presence of inner retinal layers does not appear to affect visual acuity.⁵ Studies, including ours, have also shown a persistence of inner retinal layers in infants undergoing screening for acute ROP.¹⁰ Our data add

References (24)

M.M. Joshi et al.
Optical coherence tomography findings in stage 4A retinopathy of prematurity: a theory for visual variability
Ophthalmology
(2006)
R.S. Maldonado et al.
Dynamics of human foveal development after premature birth
Ophthalmology
(2011)
S.H. Chavala et al.
Insights into advanced retinopathy of prematurity using handheld spectral domain optical coherence tomography imaging
Ophthalmology
(2009)
R.S. Maldonado et al.
Reversible retinal edema in an infant with neonatal hemochromatosis and liver failure
J AAPOS
(2011)
J.M. Provis et al.
Ontogeny of the primate fovea: a central issue in retinal development
Prog Neurobiol
(1998)
D.L. Epstein et al.
Bevacizumab for macular edema in central retinal vein occlusion: a prospective, randomized, double-masked clinical study
Ophthalmology
(2012)
Visual acuity at 10 years in Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study eyes: effect of retinal residua of retinopathy of prematurity
Arch Ophthalmol
(2006)
H. Akerblom et al.
Central macular thickness is correlated with gestational age at birth in prematurely born children
Br J Ophthalmol
(2011)
M. Ecsedy et al.
A comparison of macular structure imaged by optical coherence tomography in preterm and full-term children
Invest Ophthalmol Vis Sci
(2007)
F.M. Recchia et al.
Foveal dysplasia evident by optical coherence tomography in patients with a history of retinopathy of prematurity
Retina
(2007)

D.X. Hammer et al.

Foveal fine structure in retinopathy of prematurity: an adaptive optics Fourier domain optical coherence tomography study

Invest Ophthalmol Vis Sci

(2008)

R.S. Maldonado et al.

Spectral-domain optical coherence tomographic assessment of severity of cystoid macular edema in retinopathy of prematurity

Arch Ophthalmol

(2012)

Cited by (76)

Longitudinal Choroidal Development in Preterm Infants
2024, Ophthalmology Science
To characterize changes in subfoveal choroidal thickness in preterm infants from 30 to 60 weeks' postmenstrual age (PMA).
The prospective, observational Study of Eye Imaging in Preterm infantS (BabySTEPS) enrolled infants eligible for retinopathy of prematurity screening per the American Association of Pediatrics guidelines.
Infants imaged with an investigational, handheld OCT at ≥ 4 distinct imaging sessions between 30 to 60 weeks' PMA as part of BabySTEPS.
Average choroidal thickness across the central subfoveal 1 mm in each eye at each time point was measured using custom segmentation software, and errors were manually corrected by a trained grader. We prospectively collected birth history data. A segmented mixed model was used to analyze the change in choroidal thickness as a function of PMA, birth weight, and gestational age (GA).
Characterization of normative subfoveal choroidal thickness values and choroidal growth rate between 30 to 60 weeks' PMA.
We included 592 imaging sessions of 79 preterm infants (152 eyes). Mean (± standard deviation) GA was 27.5 ± 2.5 weeks. Mean choroidal thickness was 141.4 ± 34.5 μm at 30 weeks, 272.2 ± 83.9 μm at 38 weeks, and 306.2 ± 77.4 μm between 56 and 60 weeks. Between 30 and 60 weeks' PMA, choroidal growth followed a biphasic model, with a linear growth rate of 14.8 μm per week (95% confidence interval [CI], 13.6–16.0) from 30 until 38.4 weeks, then cessation of growth, with a growth rate of 0.3 μm per week (95% CI, −1.1 to 1.6) from 38.4 to 60 weeks. Infants with extremely low birth weight (ELBW; < 1000 g) and extremely preterm (GA < 28 weeks) infants had significantly slower initial growth rates compared with very low and low birth weight and very preterm and preterm infants (ELBW 13.0 vs. 21.0 μm per week; P < 0.0001 and extremely preterm 13.2 vs. 18.0 μm per week; P = 0.003).
Preterm infant choroidal thickness experiences rapid linear growth from 30 to 38 weeks' PMA, at which time growth nearly stops. These foundational measurements and identification of the impact of extremes of low birth weight and prematurity on choroidal development will be essential as researchers begin to understand the role of choroidal development in ocular and retinal health in human infants.
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Identification of novel biomarkers for retinopathy of prematurity in preterm infants by use of innovative technologies and artificial intelligence
2023, Progress in Retinal and Eye Research
Retinopathy of prematurity (ROP) is a leading cause of preventable vision loss in preterm infants. While appropriate screening is crucial for early identification and treatment of ROP, current screening guidelines remain limited by inter-examiner variability in screening modalities, absence of local protocol for ROP screening in some settings, a paucity of resources and an increased survival of younger and smaller infants. This review summarizes the advancements and challenges of current innovative technologies, artificial intelligence (AI), and predictive biomarkers for the diagnosis and management of ROP. We provide a contemporary overview of AI-based models for detection of ROP, its severity, progression, and response to treatment. To address the transition from experimental settings to real-world clinical practice, challenges to the clinical implementation of AI for ROP are reviewed and potential solutions are proposed. The use of optical coherence tomography (OCT) and OCT angiography (OCTA) technology is also explored, providing evaluation of subclinical ROP characteristics that are often imperceptible on fundus examination. Furthermore, we explore several potential biomarkers to reduce the need for invasive procedures, to enhance diagnostic accuracy and treatment efficacy. Finally, we emphasize the need of a symbiotic integration of biologic and imaging biomarkers and AI in ROP screening, where the robustness of biomarkers in early disease detection is complemented by the predictive precision of AI algorithms.
Insights into the developing fovea revealed by imaging
2022, Progress in Retinal and Eye Research
Citation Excerpt :
As most studies perform OCT imaging at the time of ROP screening, and ROP screening frequency is determined by the ROP severity, there is thus far no study with consistent and frequent OCT scans captured every 1–2 weeks to determine the exact onset and duration of macular edema. Based on the best available information, macular edema occurs as early as 31 weeks PMA (Dubis et al., 2013; Gursoy et al., 2016; Lee et al., 2011; Maldonado et al., 2011b, 2012; Vinekar et al., 2011; Vogel et al., 2018) and is transient and self-resolving with a resolution between 40 and 65 weeks PMA in preterm infants (Maldonado et al., 2011b). Early-onset edema (occurring at or before 33 weeks PMA) had a more severe morphology, with foveal bulging and elongated cystoid spaces compared to late-onset edema (occurring at or after 36 weeks PMA), which presented with small cystoid spaces in the parafovea (Mangalesh et al., 2020).
Early development of the fovea has been documented by histological studies over the past few decades. However, structural distortion due to sample processing and the paucity of high-quality post-mortem tissue has limited the effectiveness of this approach. With the continuous progress in high-resolution non-invasive imaging technology, most notably optical coherence tomography (OCT) and OCT angiography (OCT-A), in vivo visualization of the developing retina has become possible. Combining the information from histologic studies with this novel imaging information has provided a more complete and accurate picture of retinal development, and in particular the developing fovea.
Advances in neonatal care have increased the survival rate of extremely premature infants. However, with enhanced survival there has been an attendant increase in retinal developmental complications. Several key abnormalities, including a thickening of the inner retina at the foveal center, a shallower foveal pit, a smaller foveal avascular zone, and delayed development of the photoreceptors have been described in preterm infants when compared to full-term infants. Notably these abnormalities, which are consistent with a partial arrest of foveal development, appear to persist into later childhood and adulthood in these eyes of individuals born prematurely. Understanding normal foveal development is vital to interpreting these pathologic findings associated with prematurity.
In this review, we first discuss the various advanced imaging technologies that have been adapted for imaging the infant eye. We then review the key events and steps in the development of the normal structure of the fovea and contrast structural features in normal and preterm retina from infancy to childhood. Finally, we discuss the development of the perifoveal retinal microvasculature and highlight future opportunities to expand our understanding of the developing fovea.
Analysis of optical coherence tomography angiographic findings of prematurely born children and its relationship with macular edema of prematurity
2022, Journal of AAPOS
Citation Excerpt :
To our knowledge, this is the first study to evaluate the FAZ area and foveal VD in preterm children with and without a history of CME. Macular edema in premature infants has been reported in various ethnic groups and has been shown to resolve spontaneously.2-5 Vinekar and colleagues3 showed that visual acuity is worse in eyes with macular edema compared to controls through the first year of life and that these eyes had higher hyperopic refraction.
To compare foveal avascular zone (FAZ) area, foveal vascular density (VD), and foveal thickness in pre- and full-term children and to evaluate their relationship with cystoid macular edema (CME) in the prematurity period using spectral domain optical coherence tomography angiography (SD-OCTA).
OCTA imaging was performed at 4-6 years of age in 90 eyes of 45 prematurely born children and 50 eyes of 25 term children. Subjects were divided into three groups: prematurely born with CME (group 1); prematurely born without CME (group 2); healthy, term children (group 3). Imaging results in the three groups were compared.
FAZ area was significantly larger in group 3 than in groups 1 and 2 (P < 0.001 [ANOVA]). FAZ area was found to be correlated with birth weight (r = 0.511; P < 0.001) and gestational age (r = 0.532; P < 0.001). No significant relationship was found between history of CME and FAZ area.
In our study cohort, FAZ area was smaller in prematurely born children and was correlated with older gestational age and higher birth weight. CME in the neonatal period did not seem to affect retinal microvascular development in premature infants.
Dome-shaped macula in premature infants visualized by handheld spectral-domain optical coherence tomography
2021, Journal of AAPOS
To describe dome-shaped macula and associated clinical findings in premature infants.
This prospective, observational cohort study included a consecutive sample of premature infants screened for retinopathy of prematurity (ROP) with 9-month follow-up. Handheld spectral domain optical coherence tomography (SD-OCT) was performed at the time of ROP screening. Images were assessed for dome-shaped macula, cystoid macular edema, epiretinal membrane, vitreous bands, and punctate hyperreflective vitreous opacities. Dome height measurements were performed in a subset of images. Teller visual acuity and cycloplegic refraction were performed at an adjusted age of 8-10 months.
Of 37 infants (74 eyes; 49% male; mean gestational age 27.8 ± 3.2 weeks; mean birth weight 949 ± 284 g), 24/37 (65%) demonstrated dome-shaped macula in at least one eye (13 both eyes, 5 right eye only, and 6 left eye only). Of the 74 eyes, 26 (35%) could be reliably measured, with a mean dome height of 139.0 ± 72.3 μm (range, 54–369 μm). Presence of dome-shaped macula was associated with a diagnosis of ROP (P = 0.02; OR, 3.03; 95% CI, 1.18-7.82) and pre-plus or plus disease (P = 0.02; OR, 4.20; 95% CI, 1.05-16.78). Infants with dome-shaped macula had lower birth weight compared with those without (877 vs 1081 g; P = 0.04). No associations with other demographics, OCT findings, and 9-month refractive outcomes were found.
Dome-shaped macula was frequently identified by handheld SD-OCT in premature infants, especially those with lower birth weight and severe ROP. The long-term clinical significance of this finding is unknown.
Macular OCT Characteristics at 36 Weeks’ Postmenstrual Age in Infants Examined for Retinopathy of Prematurity
2021, Ophthalmology Retina
Citation Excerpt :
Also in this cohort, our data indicated that macular edema was present and mostly bilateral in at least 60% of infants. The prevalence of macular edema in our current study was similar to that of previous reports from the United States8,12 but was higher than those reported in India10 and Turkey11 (Table 6). We found lower rates of bilateral edema,8,10,11 but all eyes with unilateral edema showed mild severity; the asymmetry of edema in these few cases may be the result of the presence of microcysts in the other eye that may not have reached the level for a grade of mild edema.
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).
Prospective, observational study.
Preterm infants eligible for ROP screening with parental consent for research and a 36 ± 1 weeks’ postmenstrual age (PMA) visit.
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.
Macular OCT features and layer thicknesses, gender, race or ethnicity, gestational age, birth weight, ROP stage, and plus disease.
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.
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.

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: Manuscript no. 2012-1543.

: Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

: Supported by National Institutes of Health Grants P30EY001931, T32EY014537, and R01EY017607; The E. Matilda Ziegler Foundation for the Blind; RD and Linda Peters Foundation; and an unrestricted departmental grant from Research to Prevent Blindness. Part of this investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant C06 RR016511 from the National Center for Research Resources, National Institutes of Health. PG is supported by a research award from the VitreoRetinal Surgery Foundation.

: Both Adam M. Dubis, PhD and C. Devika Subramaniam, MD contributed equally to the work presented and should be regarded as equivalent authors.

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Original articleSubclinical Macular Findings in Infants Screened for Retinopathy of Prematurity with Spectral-Domain Optical Coherence Tomography

Objective

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Materials and Methods

Results

Discussion

Ophthalmology

Ophthalmology

Ophthalmology

J AAPOS

Prog Neurobiol

Ophthalmology

Visual acuity at 10 years in Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) study eyes: effect of retinal residua of retinopathy of prematurity

Arch Ophthalmol

Central macular thickness is correlated with gestational age at birth in prematurely born children

Br J Ophthalmol

A comparison of macular structure imaged by optical coherence tomography in preterm and full-term children

Invest Ophthalmol Vis Sci

Foveal dysplasia evident by optical coherence tomography in patients with a history of retinopathy of prematurity

Retina

Foveal fine structure in retinopathy of prematurity: an adaptive optics Fourier domain optical coherence tomography study

Invest Ophthalmol Vis Sci

Spectral-domain optical coherence tomographic assessment of severity of cystoid macular edema in retinopathy of prematurity

Arch Ophthalmol

Original article
Subclinical Macular Findings in Infants Screened for Retinopathy of Prematurity with Spectral-Domain Optical Coherence Tomography