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Optical Coherence Tomography Normative Peripapillary Retinal Nerve Fiber Layer and Macular Data in Children 0–5 Years of Age
Accepted Manuscript Optical Coherence Tomography normative peripapillary retinal nerve fiber layer and macular data in children ages 0-5 years Jill C. Rotruck, Robert J. House, Sharon F. Freedman, Michael P. Kelly, Laura B. Enyedi, S. Grace Prakalapakorn, Maria E. Lim, Mays A. El-Dairi PII:
S0002-9394(19)30302-2
DOI:
https://doi.org/10.1016/j.ajo.2019.06.025
Reference:
AJOPHT 11005
To appear in:
American Journal of Ophthalmology
Received Date: 17 March 2019 Revised Date:
18 June 2019
Accepted Date: 19 June 2019
Please cite this article as: Rotruck JC, House RJ, Freedman SF, Kelly MP, Enyedi LB, Prakalapakorn SG, Lim ME, El-Dairi MA, Optical Coherence Tomography normative peripapillary retinal nerve fiber layer and macular data in children ages 0-5 years, American Journal of Ophthalmology (2019), doi: https://doi.org/10.1016/j.ajo.2019.06.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Abstract
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Purpose: To determine reference values for the peripapillary retinal nerve fiber layer (pRNFL) and macula in children ages 0-5 years. Design: Prospective cross-sectional study Setting: Single large academic pediatric ophthalmology practice Study Population: Healthy, full-term children ages 0 to <6 years presenting for surgery under general anesthesia were prospectively recruited for participation. Excluded were children with systemic neurologic disease, optic nerve or retinal disease (even if unilateral), or any bilateral ocular disease process, and eyes with amblyopia, ocular disease, or spherical equivalent refractive error outside of -3.00 to +8.00 diopters. Observation Procedure: Following general anesthesia, OCT scans of the optic nerve and retina were acquired using an HRA+OCT Spectralis with Flex module (Heidelberg, Germany). Automated segmentation of the pRNFL and retinal layers was followed by manual correction. Results: Data was obtained from normal eyes of fifty-seven participants (mean age = 2.28 ± 1.50 years). Mean global pRNFL thickness was 107.6 ± 10.3 µm. Mean global pRNFL thickness was not dependent on age, but showed a negative relationship with axial length (p=0.01). The mean total macular volume was 8.56 ± 0.259 mm3 (n=38). No relationship was found between the total macular volume and age. The ganglion cell layer (GCL), ganglion cell complex (GCC), and inner nuclear layer (INL) volumes showed an inverse relationship with age while the photoreceptor layers showed a logarithmic increase with age. Conclusions: Global pRNFL thickness measurements remain stable over time. Macular volume and thickness values of segmented retinal layers reflect the development of the macula with age.
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Full title: Optical Coherence Tomography normative peripapillary retinal nerve fiber layer and macular data in children ages 0-5 years Short title: Optical Coherence Tomography normative data in children
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Jill C. Rotruck,1,2 Robert J. House,1 Sharon F. Freedman,1 Michael P. Kelly, 1 Laura B. Enyedi,1 S. Grace Prakalapakorn,1 Maria E. Lim,1,3 Mays A. El-Dairi1 1
Duke University Department of Ophthalmology, 2351 Erwin Road, Durham, NC 27705 Department of Ophthalmology and Visual Science, Yale School of Medicine, 40 Temple Street, New Haven, CT 06510 3 Dean McGee Eye Institute, University of Oklahoma School of Medicine, 608 Stanton L. Young Blvd, Oklahoma City, OK 73104
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Corresponding Author:
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Mays El-Dairi, MD Associate Professor Neuro-Ophthalmology Pediatric Ophthalmology and Strabismus Duke Eye Center 2351 Erwin Road Durham, NC 27705 Phone number: 919-681-9191 Fax number: 919-684-6096 email: [email protected]
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Participants and Methods
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Introduction Spectral domain optical coherence tomography (SD-OCT) is a non-invasive imaging technique which creates cross-sectional retinal images1,2 with an axial resolution of 5-7 µm.3 Automated segmentation software facilitates quantification of the peripapillary retinal nerve fiber layer (pRNFL) and individual macular layers. The utility of SD-OCT for diagnosing, monitoring, and managing adult optic nerve and retinal disease is well established. Progressive thinning of the pRNFL,4-6 macular RNFL (mRNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL)4,7 occur in glaucoma, and other optic neuropathies.8 Older children with glaucoma demonstrate RNFL and macular layer thinning.9-11 Both qualitative and quantitative macular data can show progressive damage in retinal diseases, e.g., retinal dystrophies, that affect children and adults.6,12-15 OCT has high specificity for identifying healthy eyes by comparing scan analyses to normative adult data,16 proprietary for each brand of OCT machine. Several groups have created normative OCT databases for children of various races from age 3 -17 years for Spectralis (Heidelberg Engineering, Inc., Heidelberg, Germany),17,18 Stratus (Carl Zeiss Meditec, Dublin, CA),19 and Cirrus (Carl Zeiss Meditec, Dublin, CA)20-23 commercial OCT units. The development of handheld OCT units allows for qualitative data in infants and young children24 and normative data for research purposes,25 but a commercially available unit with integrated software for quantitative analysis is lacking. The purpose of this study is to develop a reference database of pRNFL and macular values for children ages 0 to 5 years using a HRA+OCT Spectralis with Flex module and automated segmentation.
Participants
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This prospective cross-sectional study was approved by the Duke University Health System Institutional Review Board and was conducted in accordance with the US Health Insurance Portability and Accountability Act of 1996. All data was prospectively collected following parental consent.
Healthy, full-term (gestational age ≥37 weeks) children ages 0 to <6 years presenting to the Duke Eye Center for surgery under general anesthesia were prospectively recruited and consented for participation from January 2017 through March 2018. Excluded were children with systemic neurologic disease, optic nerve or retinal disease (even if unilateral), or any bilateral ocular disease process, and eyes with amblyopia, ocular disease, or spherical equivalent refractive error outside of -3.00 to +8.00 diopters.
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Data and Measurement Collection The following data was collected for each patient: gender, age, date of birth, gestational age, race, ethnicity, ocular and medical history. Refractive error for inclusion was determined based on most recent cycloplegic retinoscopy within 1 year of imaging or determined at the time of anesthesia. Intraocular pressure was obtained by Tono2
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pen (Reichert Technologies, Buffalo, NY) as soon after induction as safely possible. Axial length and anterior chamber depth were measured by immersion A-scan using an Ellex Eye Cubed ultrasound (Mawson Lakes, Australia) or the Sonomed Excalon Master-Vu USB A-Scan (New Hyde Park, NY).
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OCT Imaging and Analysis All OCT scans were performed using a portable HRA+OCT Spectralis with Flex module (investigational device). Participants were imaged supine under general anesthesia. The non-operative eye was imaged for monocular surgery. In cases of bilateral surgery where both eyes met inclusion criteria, the more-dilated eye was imaged. A 12° circle scan centered on the optic nerve was used to quantify the peripapillary retinal nerve fiber layer (pRNFL) (Figures 1a- 1b). A 61 raster 30° x 25° scan with cuts 116 µm apart (Figure 1c-1d) was centered on the macula and used for macular volume, thickness, and segmentation. All scans were reviewed by a single reader (JCR). When multiple scans were taken, the highest quality scan was chosen for inclusion. Scans subjectively determined to have >10 uncorrectable degrees of torsion were excluded from analyses evaluating quadrants. Macular scans with incomplete perifoveal data were excluded from total macular volume, individual quadrant analysis, and perifoveal analysis. Automated pRNFL and macular segmentation were performed using Heidelberg SD-OCT software. The segmentation results for the 12° circle scan and each cut of the 61 raster 30° x 25° scan were reviewed and manually corrected wit hin the Heidelberg SD-OCT HEYEX software. For macular scans, the 1, 3, 6 mm circle diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid26 was manually centered on the fovea. The 1, 3, and 6 mm diameter rings are referred to as the central fovea, parafovea, perifovea, respectively. During review of macular scans, the presence of vitreous opacities was noted as positive or negative.
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Data and Statistical Analysis Statistical analyses were performed using SPSS Statistical Software (IBM, Armonk, NY, USA), unless otherwise specified. Results for the Ganglion cell complex (GCC) were calculated by adding segmentation results for the retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer. Results for the photoreceptors layers (PRLs) were calculated by adding segmentation results for the outer plexiform layer, outer nuclear layer, and outer retina (external limiting membrane to Bruch membrane). Mean parafoveal and perifoveal values were calculated by adding values for the quadrants of the 3 mm and 6 mm diameter ring of the ETDRS grid, respectively, and dividing by 4. Mean, standard deviation, 5th percentile and 95th percentile values were calculated. Normality testing was performed using the Shaprio-Wilk test with a p value of 0.05. Multiple linear regression analysis included the following independent variables: age (all, <18 months, ≥18 months), axial length, gender, laterality, and race. Curve estimation for linear, logarithmic, exponential, and inverse models was performed to evaluate the best-fit relationship between age and retinal layers (all macular layers, GCC, inner nuclear layer (INL), and PRLs) by anatomical location based on the ETDRS grid (central foveal, parafoveal, and perifoveal thickness corresponding with the 1 mm, 3
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mm, and 6 mm diameter circles, respectively). Comparisons of global pRNFL thickness and central foveal thickness with outside studies17,18 were performed by one-way ANOVA using the already calculated mean and standard deviation17,18 in GraphPad Prism Software (La Jolla, CA, USA).
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Results From January 2017 through March 2018, 71 children met inclusion criteria for participation. In 3 cases, the parent/guardian declined and in 5 cases the surgeon declined due to scheduling issues. Written consent was obtained from the parent/guardian of 63 children. Of these, 1 case was cancelled, 2 were unusable for analysis due to poor image quality, and 3 were not imaged due to imager unavailability. Thus, the data of 57 participants was included in this study.
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Subject characteristics Mean participant age was 2.28 ± 1.50 years and was normally distributed. Twenty-nine of 57 participants (51%) were female. Racial background (parent/guardianreported) included 31 white, 7 black, 2 Asian, 8 mixed-race, and 9 unknown/not reported; 46 ethnic backgrounds were reported as non-Hispanic, 4 as Hispanic, and 7 unknown/not reported. Scheduled surgeries included: strabismus (24), anterior segment surgery of the contralateral eye (16), oculoplastic procedures (13, including chalazion drainage, nasolacrimal duct probing, dermoid excision, epiblepharon repair), minor surface procedure of contralateral eye (3), and examination under anesthesia following ruptured globe repair of contralateral eye (1). Of those with strabismus, 14 had amblyopia of the contralateral, non-imaged eye.
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Ocular characteristics Axial length, anterior chamber depth, central corneal thickness, and intraocular pressure were all normally distributed. Axial length averaged 21.05 ± 1.11 mm (n=52) and was positively correlated with age (r=0.669; p<0.001). Mean anterior chamber depth was 3.30 ± 0.37 mm (n=51). Mean central corneal thickness was 561.9 ± 28.1 µm (n=56). Intraocular pressure averaged 13.6 ± 3.32 mmHg. Peripapillary Retinal Nerve Fiber Layer Data from 56 participants was included in analysis of the pRNFL global thickness (Table 1). One subject did not have an adequate scan for analysis. An additional 4 participants were excluded from quadrant sub-analysis due to torsion of the image. Data for global thickness and all 4 quadrants was normally distributed. Mean pRNFL global thickness was 107.6 ± 10.3 µm; 5th percentile 90.9 µm, 95th percentile 129.2 µm. Multiple linear regression analysis showed no relationship between pRNFL global thickness and age, laterality, gender, or race. Axial length showed a significant negative relationship with pRNFL (p=0.01) (Figure 2).
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Macular Volume and Thickness Fifty-five participants were included in macular analyses. Two participants in this study did not have adequate macular scans for any analyses. One scan was inadequate for segmentation and was included only in analyses of all layers. Of the 55 scans 4
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included in macular analyses, 7 were torted by greater than 5 degrees and 17 lacked part of the perifoveal ring. These were excluded from certain analyses, as described in the methods section. During careful review of the OCT images, small, round, hyperreflective opacities were incidentally found in the vitreous in 53 of 57 patients (93%) (Figure 1d). Normative data for macular volume and thickness in children ages 0-5 years are detailed in Table 2. Total macular volume and mean values for location were each normally distributed. The mean total macular volume was 8.56 ± 0.259 mm3 (n=38). The mean parafoveal thickness (323.0 ± 12.84 µm, n=55) was greater than that of the perifoveal (299.8 ± 10.41 µm, n=38) and central foveal (233.7 ± 27.76 µm, n=55) thickness. The temporal quadrant showed the thinnest macular thickness in both the parafovea and perifovea. The nasal perifovea was observed to be thicker than other perifoveal quadrants. Relationships of macular segments and locations with age are depicted in Figure 3. No relationship was found between total macular volume and age. The mean thickness for all macular layers was found to increase logarithmically with age in the central fovea (r2=0.401; p<0.001), increase linearly with age in the parafovea (r2=0.338; p<0.001), and showed an inverse relationship with age in the perifovea (r2= 0.152; p=0.015). Following segmentation, the GCL, GCC and INL volumes were found to have an inverse relationship with age (r2=0.364; p<0.001, r2=0.401; p<0.001, r2= 0.443; p<0.001, respectively) while the PRLs were found to have a logarithmic increase with age (r2=0.408; p<0.001). No relationship was found between age and the central foveal thickness for the GCL, GCC or INL. The mean parafoveal and perifoveal thickness showed an inverse relationship with age for the GCL (r2=0.087; p=0.031 and r2=0.424; p<0.001), GCC (r2=0.161; p=0.003 and r2=0.379; p<0.001), and the INL (r2=0.429; p<0.001 and r2=0.408; p<0.001), respectively. The central foveal, parafoveal, and perifoveal thickness of the PRLs showed a logarithmic increase with age (r2=0.704; p<0.001, r2=0.614; p<0.001, r2=0.264; p=0.001). To better compare our results with those of prior work,27 results of segmentation analysis were divided into <18 months and ≥18 months of age. No relationship was found between age and the mean central foveal thickness for the GCL, GCC or INL in either group. In patients <18 months old, an inverse relationship was found between age and mean thickness of the parafovea and perifovea for the GCL (r2=0.489; p<0.001 and r2=0.685; p<0.001), GCC (r2=0.517; p<0.001 and r2=0.776; p<0.001), and INL (r2=0.708; p<0.001 and r2=0.514; p<0.001). In patients ≥18 months, no relationship was found between age and the mean thickness of the perifoveal GCL, parafoveal GCC, or the parafoveal or perifoveal INL. In this age group, the parafoveal GCL and GCC mean thicknesses showed a positive linear relationship with age (r2=0.428; p<0.001 and r2=0.315; p=0.001).
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Discussion This study establishes normative values for pRNFL and macular volume and thickness in children 0-5 years of age. When compared to normative data for older children (5-16 years of age) using a tabletop Spectralis OCT, there is no difference between the mean global pRNFL thickness for Turk et al17 (106.5 ± 9.41 µm), Yanni et 5
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al18 (107.6 ± 10.93 µm) and this study (107.6 ± 10.30 µm) (p=0.70). While several more pediatric OCT databases exist,19-23 results from different OCT manufacturers are highly correlated, but not interchangeable,28 so only results from Spectralis OCT units were used for comparison of the present study with other published databases. The pRNFL global thickness was not found to be dependent on age, laterality, gender, or race; however, the power of the study is limited by its size. pRNFL global thickness showed a weak negative correlation with axial length in multiple regression analysis. Prior studies in children have shown no relationship between global pRNFL thickness and axial length in some29-31 and a negative correlation in others.32,33 Aykut et al33 found this relationship disappeared when a correction was applied for the effect of ocular magnification as it relates to axial length. The thickness of the quadrants followed the “ISNT rule” of descending thickness in the order: inferior, superior, nasal, temporal.34 Prior histologic and OCT studies have shown development of the foveal pit by 25 weeks gestation with widening and shallowing of the pit over the first 15 months of life secondary to centrifugal migration of the GCL, IPL, and INL.35 Over the first 1-1.5 years of life, the cones become considerably more packed and the outer plexiform layer (OPL) consequently thickens.35,36 The foveal cones continue to pack over childhood, reaching >10 cell bodies in thickness in later childhood/ early teenage years.36 Four distinct outer retinal bands can be seen by 17 months.37 Our normative data did not find a relationship between age and central foveal GCL, GCC or INL thickness for all participants, or by subgroups < 18 months and ≥18 months. This varies from the exponential decrease in GCL and INL thickness over the first 18 months of life reported by Lee et al.27 This group reported an inverse relationship with age for the parafoveal and perifoveal mean GCL and INL thicknesses over the first 17 months, consistent with our findings. While Lee et al27 found a gradual increase of GCL and INL parafoveal and perifoveal mean thickness between 17 and 65.5 months, we found a relationship with age only for the parafoveal mean thickness of the GCL in this sub-group. Our sub-group analyses were of limited sample size and may have failed to detect an extant relationship. The PRLs showed a logarithmic increase for volume and central foveal, parafoveal, and perifoveal mean thicknesses, aligning with prior reports of increasing cone cell bodies over childhood.27,36 Lee et al27 similarly found a logarithmic increase for the foveal ONL, photoreceptor inner segments, and photoreceptor outer segments until 32.4, 26.9, and 45.3 months gestational age, respectively, but found a more gradual increase for the parafovea and perifovea. The total macular thickness is most impacted by the development of the photoreceptor layer, causing it to increase logarithmically. The linear increase in parafoveal macular thickness with age is secondary to the thickening of the photoreceptor layers, but is more tempered by the decreasing GCC and INL. The perifoveal mean thickness shows an overall decrease with age, owing to a less impressive rise in photoreceptor layer thickness over time with a nearly equivalent decrease in GCC and INL thickness. When compared to normative data for older children (5-16 years) using a Spectralis OCT, there is a difference between the average of the mean central thickness for Turk et al17 (258.6 ± 17.2 µm), Yanni et al18 (271.2 ± 18.2 µm), and this study (233.7 ± 27.8 µm) (p<0.0001) in younger children (0-5 years). The difference between means persists when using only data for patients from this study ages 2-5
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years, in order to remove the component of early logarithmic increase (245.0 ± 24.18 µm; p<0.0001). This is consistent with the continued increase in the photoreceptor layer over time, as described above. Using normative data for adults and older children to interpret macular segmentation data in young children may lead to false conclusions. Separate normative data for children ages 0-1 years and ages 2-5 years can be found in eTable1 and eTable 2, respectively.
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Limitations The results of this study must be taken in light of several limitations. The relatively small number of participants makes both the means and models subject to greater influence by outliers. It has been previously demonstrated that race impacts pRNFL and foveal measurements.19,38 The inclusion of small groups of patients from different racial backgrounds may fail to show the true mean for patients of any given race. The exclusion of patients with refractive error outside of -3.00 to +8.00 diopters may have impacted analysis of the effect of axial length on different parameters and limits the use of this normative data to eyes with low to moderate refractive error. The inclusion of patients undergoing ocular procedures may increase the likelihood that the eyes measured were not truly “normal”. Cases of developmental abnormality of one eye, such as persistent fetal vasculature or congenital cataract, may harbor subclinical changes in the other eye. Although in cases of amblyopia, the non-amblyopic eye was chosen, specific visual acuity criteria were not applied for this young group of participants and, though unlikely, the possibility of asymmetric but bilateral refractive amblyopia in some patients does exist. OCT and OCT angiography studies have shown small structural differences between amblyopic and non-amblyopic eyes of unclear clinical significance.39,40 Lastly, the ETDRS grid used for macular reference database numbers is not optimized for macular reference database values. We have chosen to use this grid because it is standardly available, increasing its clinical utility.
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Conclusion This study establishes normative data using Spectralis OCT for children ages 0-5 years. Global pRNFL thickness measurements do not differ from those of older children and do not show a clinically significant change with age or axial length. Mean macular thickness value for segmented retinal layers reflect the development of the macula with logarithmic increase of the PRL with age and an inverse of the GCC and INL with age. These changes are most pronounced over the first year and a half of life. Young children have different normative macular volume, and mean thickness values than older children and adults.
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Acknowledgments
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a. Funding/ Support: This research was generously supported by the Knights Templar Eye Foundation and Lions Eye Foundation. Thank you to Heidelberg Engineering Inc. for loaning the HRA+OCT Spectralis with Flex module for this study. b. Financial disclosures: c. Other acknowledgements: The authors would like to acknowledge Dr. David Wallace1 and Dr. Edward Buckley1 for their assistance with participant recruitment. 1 Duke University Department of Ophthalmology, 2351 Erwin Road, Durham, NC 27705
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17. Turk A, Ceylan OM, Arici C, et al. Evaluation of the nerve fiber layer and macula in the eyes of healthy children using spectral-domain optical coherence tomography. Am J Ophthalmol 2012; 153(3): 552-9.e1. 18. Yanni SE, Wang J, Cheng CS, et al. Normative reference ranges for the retinal nerve fiber layer, macula, and retinal layer thicknesses in children. Am J Ophthalmol 2013; 155(2): 354-60.e1. 19. El-Dairi MA, Asrani SG, Enyedi LB, Freedman SF. Optical coherence tomography in the eyes of normal children. Arch Ophthalmol (Chicago, Ill : 1960) 2009; 127(1): 50-8. 20. Barrio-Barrio J, Noval S, Galdos M, et al. Multicenter Spanish study of spectraldomain optical coherence tomography in normal children. Acta Ophthalmol 2013; 91(1): e56-63. 21. Guragac FB, Totan Y, Guler E, Tenlik A, Ertugrul IG. Normative Spectral Domain Optical Coherence Tomography Data in Healthy Turkish Children. Semin Ophthalmol 2017; 32(2): 216-22. 22. Nigam B, Garg P, Ahmad L, Mullick R. OCT Based Macular Thickness in a Normal Indian Pediatric Population. J Ophthalmic Vis Res 2018; 13(2): 144-8. 23. Queiros T, Freitas C, Guimaraes S. [Normative Database of Optical Coherence Tomography Parameters in Childhood]. Acta Med Port 2015; 28(2): 148-57. 24. Lee H, Proudlock FA, Gottlob I. Pediatric Optical Coherence Tomography in Clinical Practice-Recent Progress. Invest Ophthalmol Vis Sci 2016; 57(9): Oct69-79. 25. Rothman AL, Sevilla MB, Freedman SF, et al. Assessment of retinal nerve fiber layer thickness in healthy, full-term neonates. Am J Ophthalmol 2015; 159(4): 803-11. 26. Early Treatment Diabetic Retinopathy Study design and baseline patient characteristics. ETDRS report number 7. Ophthalmology 1991; 98(5 Suppl): 741-56. 27. Lee H, Purohit R, Patel A, et al. In Vivo Foveal Development Using Optical Coherence Tomography. Invest Ophthalmol Vis Sci 2015; 56(8): 4537-45. 28. Shin HJ, Cho BJ. Comparison of retinal nerve fiber layer thickness between Stratus and Spectralis OCT. Korean J Ophthalmol 2011; 25(3): 166-73. 29. Goh JP, Koh V, Chan YH, Ngo C. Macular Ganglion Cell and Retinal Nerve Fiber Layer Thickness in Children With Refractive Errors-An Optical Coherence Tomography Study. J Glaucoma 2017; 26(7): 619-25. 30. Prakalapakorn SG, Freedman SF, Lokhnygina Y, et al. Longitudinal reproducibility of optical coherence tomography measurements in children. J AAPOS 2012; 16(6): 523-8. 31. Al-Haddad C, Barikian A, Jaroudi M, Massoud V, Tamim H, Noureddin B. Spectral domain optical coherence tomography in children: normative data and biometric correlations. BMC Ophthalmol 2014; 14: 53. 32. Oner V, Ozgur G, Turkyilmaz K, Sekeryapan B, Durmus M. Effect of axial length on retinal nerve fiber layer thickness in children. Eur J Ophthalmol 2014; 24(2): 265-72. 33. Aykut V, Oner V, Tas M, Iscan Y, Agachan A. Influence of axial length on peripapillary retinal nerve fiber layer thickness in children: a study by RTVue spectraldomain optical coherence tomography. Curr Eye Res 2013; 38(12): 1241-7. 34. Alasil T, Wang K, Keane PA, et al. Analysis of normal retinal nerve fiber layer thickness by age, sex, and race using spectral domain optical coherence tomography. J Glaucoma 2013; 22(7): 532-41.
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35. Hendrickson A, Possin D, Vajzovic L, Toth CA. Histologic development of the human fovea from midgestation to maturity. Am J Ophthalmol 2012; 154(5): 767-78.e2. 36. Vajzovic L, Hendrickson AE, O'Connell RV, et al. Maturation of the human fovea: correlation of spectral-domain optical coherence tomography findings with histology. Am J Ophthalmol 2012; 154(5): 779-89.e2. 37. Dubis AM, Costakos DM, Subramaniam CD, et al. Evaluation of normal human foveal development using optical coherence tomography and histologic examination. Arch Ophthalmol (Chicago, Ill : 1960) 2012; 130(10): 1291-300. 38. Allingham MJ, Cabrera MT, O'Connell RV, et al. Racial variation in optic nerve head parameters quantified in healthy newborns by handheld spectral domain optical coherence tomography. J AAPOS 2013; 17(5): 501-6. 39. Kim YW, Kim SJ, Yu YS. Spectral-domain optical coherence tomography analysis in deprivational amblyopia: a pilot study with unilateral pediatric cataract patients. Graefes Arch Clin ExOphthalmol 2013; 251(12): 2811-9. 40. Lonngi M, Velez FG, Tsui I, et al. Spectral-Domain Optical Coherence Tomographic Angiography in Children With Amblyopia. JAMA Ophthalmol 2017; 135(10): 1086-91.
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Figure Legends
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Figure 1. Optic nerve and Macular segmentation by Spectralis Optical Coherence Tomography. a) Infrared image on the left showing a 12° circle scan and on the right segmentation of the retinal nerve fiber layer (RNFL). The thickness of the RNFL is measured from the Internal Limiting Membrane (ILM), in red, to the RNFL, in blue. b) Peripapillary retinal nerve fiber layer analysis report with thickness reports by location. On the left: G=Global; T=Temporal; TS=Temporal and Superior; NS= Nasal and Superior; N= Nasal; NI= Nasal and Inferior; TI= Temporal and Inferior. The TS and NS are averaged to give the results of the Superior quadrant; the TI and NI are averaged to give the results of the Inferior quadrant. On the right, the RNFL (black line) is traced against normal (green), borderline (yellow), and thin (red) RNFL values, based on normative data derived from subjects ages 18 years or older. c) An infrared image of the macula with a color overlay indicating macular thickness (blue=thinnest; red= thickest). The standard 1, 3, 6 mm circle diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid is centered on the fovea and demonstrates the anatomical locations analyzed for macular analysis. The 1 mm circle is referred to as the central fovea, the 3 mm circle as the parafovea, and the 6 mm circle as the perifovea. d) An optical coherence tomography slice through the fovea demonstrating macular segmentation. Yellow arrows indicating round, hyper-reflective areas in the vitreous seen in 93% of patients. (Internal limiting membrane= ILM, red; Retinal Nerve Fiber Layer= RNFL, blue; Ganglion Cell Layer=GCL, purple; Inner Plexiform Layer= IPL, periwinkle; Inner Nuclear Layer= INL, light orange; Outer Plexiform Layer= OPL, burnt sienna; External Limiting Membrane= ELM, pink; Photoreceptor 1= PR1, blue; Photoreceptor2= PR2, mint; Retinal Pigmented Epithelium=RPE, light blue; Bruch membrane= BM, red.) Figure 2. Peripapillary Retinal Nerve Fiber Layer (pRNFL) global thickness is plotted against age and axial length. Multiple linear regression analysis was performed with independent variables age (all, <18 months, ≥18 months), axial length, gender, laterality, and race. The analysis showed no relationship between pRNFL global thickness and age but finds a negative relationship between pRNFL global thickness and axial length (p=0.01). Figure 3. Segmented Retinal Layers Total Volume and Mean Thickness by Early Treatment Diabetic Retinopathy Study (ETDRS) Grid Location using Spectralis Optical Coherence Tomography (OCT) in Children Ages 0-5 Years. Scatter plots showing the relationship between age and macular location (by segment and anatomical location). Anatomical location based on the ETDRS grid (central foveal, parafoveal, and perifoveal thickness corresponding with the 1 mm, 3 mm, and 6 mm diameter circles, respectively). Results for the Ganglion cell complex were calculated
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by adding segmentation results for the retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer. Results for the photoreceptors layers (PRLs) were calculated by adding segmentation results for the outer plexiform layer, outer nuclear layer, and outer retina (External limiting membrane to the Bruch membrane). The equation of the model and coefficient of determination (r2) are included when a significant relationship was found. (n= number of participants included in the analysis)
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n
Mean
SD
95% CI
5th %
95 %
Global (μm) Nasal (μm) Superior (μm) Temporal (μm) Inferior (μm)
56 52 52 52 52
107.6 78.6 132.6 77.2 141.3
10.3 18.3 18.5 12.4 17.6
104.8- 110.3 73.5- 77.2 127.5- 137.8 73.8- 80.6 136.4- 146.2
90.9 53.7 102.7 57.7 118.0
129.2 124.5 167.7 99.5 181.4
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Abbreviations: n, number; SD, standard deviation; 95% CI, 95% confidence interval; 5%, 5th percentile; 95th %, 95th percentile
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Location Measured
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Table 2. Total Macular Volume and Mean Thickness Using Spectralis OCT in Children Ages 0-5 Years Mean
SD
SD
95% CI
5th %
95th %
38 55 48 48 48 44 48 42 48 40 55 38
8.56 233.7 325.1 318.9 330.0 301.2 313.9 287.4 326.1 295.0 323.0 299.8
0.259 27.76 14.47 11.94 12.02 11.46 12.24 11.30 11.79 10.77 12.84 10.41
0.259 27.76 14.47 11.94 12.02 11.46 12.24 11.30 11.79 10.77 12.84 10.41
8.48- 8.65 226.2- 241.2 320.9- 329.3 315.4- 322.4 326.5- 333.5 297.7- 304.7 310.3- 317.4 283.9- 290.9 322.7- 329.5 291.5- 298.4 319.5- 326.5 296.3- 303.2
8.19 182.2 300.5 302.4 312.5 284.8 294.7 268.6 307.4 278.1 306.0 282.7
9.19 280.4 353.7 347.2 357.2 327.0 338.1 312.3 349.6 315.6 349.7 325.6
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Total macular volume (mm ) Mean Central Thickness (μm) Mean Nasal Parafoveal Thickness (μm) Mean Nasal Perifoveal Thickness (μm) Mean Superior Parafoveal Thickness (μm) Mean Superior Perifoveal Thickness(μm) Mean Temporal Parafoveal Thickness (μm) Mean Temporal Perifoveal Thickness (μm) Mean Inferior Parafoveal Thickness (μm) Mean Inferior Perifoveal Thickness (μm) Mean Total Parafoveal Thickness (μm) Mean Total Perifoveal Thickness (μm)
n
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Location Measured
th
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Abbreviations: OCT, optical coherence tomography; n, number; SD, standard deviation; 95% CI, 95% confidence interval; 5%, 5 percentile; 95th %, 95th percentile. For macular analysis, the standard 1, 3, 6 mm circle diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid is centered on the fovea and the 1 mm circle is referred to as the central macula, the 3 mm circle as the parafovea, and the 6 mm circle as the perifovea.
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Thickness (µm) Age (years)
Thickness (µm)
Volume (mm3)
n= 55 Mean= 233.7 ± 27.76 y= 224.26 + 19.05*log(x) r2= 0.390; p<0.001
Age (years)
n= 54 Mean= 42.61 ± 10.147
n= 38 Mean= 300.0 ± 10.41 y= 296.51 + 3.55/x r2= 0.152; p=0.015
n= 54 Mean= 110.12 ± 7.60 y= 107.97 + 2.09/x r2= 0.161; p=0.003
n= 37 Mean= 103.59 ± 8.22 y= 99.54 + 4.37/x r2= 0.379; p<0.001
Thickness (µm)
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Volume (mm3)
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Age (years)
Age (years) n= 54 Mean= 15.31 ± 4.347
Age (years)
n= 37 Mean= 4.59 ± 0.19 y= 4.52 + 0.14 * log(x) r2= 0.408; p<0.001
n= 54 Mean= 41.29 ± 3.493 y= 39.68 + 1.57/x r2= 0.429; p<0.001
n= 37 Mean= 37.44 ± 2.777 y= 36.02 + 1.53/x r2= 0.408; p<0.001
Thickness (µm)
Volume (mm3)
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n= 37 Mean= 1.06 ± 0.75 y= 1.02 + 0.04/x r2= 0.433; p<0.001
PhotoPhotoreceptor Layers
n= 55 Mean= 323.0 ± 12.83 y= 4.94*x + 311.94 r2= 0.338; p<0.001
Age (years)
n= 37 Mean= 2.91 ± 0.190 y= 2.81 + 0.10/x r2= 0.401; p<0.001
Inner Nuclear Layer
Perifovea
Age (years)
n= 38 Mean= 8.56 ± 0.259
Ganglion Cell Complex
Parafovea
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Central Central Fovea
Volume (mm3)
Volume
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Age (years) n= 54 Mean= 176.30 ± 18.33 y= 168.15 + 16.78*log(x) r2= 0.704; p<0.001
n= 54 Mean= 171.86 ± 11.507 y= 167.09 + 9.84*log(x) r2= 0.614; p<0.001
n= 37 Mean= 159.07 ± 5.987 y= 157.24 + 3.60*log(x) r2= 0.264; p=0.001
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Highlights - Global pRNFL thickness and total macular volume do not significantly change with age. - Macular volume and thickness values for different macular layers and anatomical locations in the macula do vary with age. - Retinal growth and development should be considered when interpreting macular layer volume and thickness values in young children.
S0002-9394(19)30302-2
DOI:
https://doi.org/10.1016/j.ajo.2019.06.025
Reference:
AJOPHT 11005
To appear in:
American Journal of Ophthalmology
Received Date: 17 March 2019 Revised Date:
18 June 2019
Accepted Date: 19 June 2019
Please cite this article as: Rotruck JC, House RJ, Freedman SF, Kelly MP, Enyedi LB, Prakalapakorn SG, Lim ME, El-Dairi MA, Optical Coherence Tomography normative peripapillary retinal nerve fiber layer and macular data in children ages 0-5 years, American Journal of Ophthalmology (2019), doi: https://doi.org/10.1016/j.ajo.2019.06.025. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Abstract
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Purpose: To determine reference values for the peripapillary retinal nerve fiber layer (pRNFL) and macula in children ages 0-5 years. Design: Prospective cross-sectional study Setting: Single large academic pediatric ophthalmology practice Study Population: Healthy, full-term children ages 0 to <6 years presenting for surgery under general anesthesia were prospectively recruited for participation. Excluded were children with systemic neurologic disease, optic nerve or retinal disease (even if unilateral), or any bilateral ocular disease process, and eyes with amblyopia, ocular disease, or spherical equivalent refractive error outside of -3.00 to +8.00 diopters. Observation Procedure: Following general anesthesia, OCT scans of the optic nerve and retina were acquired using an HRA+OCT Spectralis with Flex module (Heidelberg, Germany). Automated segmentation of the pRNFL and retinal layers was followed by manual correction. Results: Data was obtained from normal eyes of fifty-seven participants (mean age = 2.28 ± 1.50 years). Mean global pRNFL thickness was 107.6 ± 10.3 µm. Mean global pRNFL thickness was not dependent on age, but showed a negative relationship with axial length (p=0.01). The mean total macular volume was 8.56 ± 0.259 mm3 (n=38). No relationship was found between the total macular volume and age. The ganglion cell layer (GCL), ganglion cell complex (GCC), and inner nuclear layer (INL) volumes showed an inverse relationship with age while the photoreceptor layers showed a logarithmic increase with age. Conclusions: Global pRNFL thickness measurements remain stable over time. Macular volume and thickness values of segmented retinal layers reflect the development of the macula with age.
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Full title: Optical Coherence Tomography normative peripapillary retinal nerve fiber layer and macular data in children ages 0-5 years Short title: Optical Coherence Tomography normative data in children
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Jill C. Rotruck,1,2 Robert J. House,1 Sharon F. Freedman,1 Michael P. Kelly, 1 Laura B. Enyedi,1 S. Grace Prakalapakorn,1 Maria E. Lim,1,3 Mays A. El-Dairi1 1
Duke University Department of Ophthalmology, 2351 Erwin Road, Durham, NC 27705 Department of Ophthalmology and Visual Science, Yale School of Medicine, 40 Temple Street, New Haven, CT 06510 3 Dean McGee Eye Institute, University of Oklahoma School of Medicine, 608 Stanton L. Young Blvd, Oklahoma City, OK 73104
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Corresponding Author:
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Mays El-Dairi, MD Associate Professor Neuro-Ophthalmology Pediatric Ophthalmology and Strabismus Duke Eye Center 2351 Erwin Road Durham, NC 27705 Phone number: 919-681-9191 Fax number: 919-684-6096 email: [email protected]
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Participants and Methods
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Introduction Spectral domain optical coherence tomography (SD-OCT) is a non-invasive imaging technique which creates cross-sectional retinal images1,2 with an axial resolution of 5-7 µm.3 Automated segmentation software facilitates quantification of the peripapillary retinal nerve fiber layer (pRNFL) and individual macular layers. The utility of SD-OCT for diagnosing, monitoring, and managing adult optic nerve and retinal disease is well established. Progressive thinning of the pRNFL,4-6 macular RNFL (mRNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL)4,7 occur in glaucoma, and other optic neuropathies.8 Older children with glaucoma demonstrate RNFL and macular layer thinning.9-11 Both qualitative and quantitative macular data can show progressive damage in retinal diseases, e.g., retinal dystrophies, that affect children and adults.6,12-15 OCT has high specificity for identifying healthy eyes by comparing scan analyses to normative adult data,16 proprietary for each brand of OCT machine. Several groups have created normative OCT databases for children of various races from age 3 -17 years for Spectralis (Heidelberg Engineering, Inc., Heidelberg, Germany),17,18 Stratus (Carl Zeiss Meditec, Dublin, CA),19 and Cirrus (Carl Zeiss Meditec, Dublin, CA)20-23 commercial OCT units. The development of handheld OCT units allows for qualitative data in infants and young children24 and normative data for research purposes,25 but a commercially available unit with integrated software for quantitative analysis is lacking. The purpose of this study is to develop a reference database of pRNFL and macular values for children ages 0 to 5 years using a HRA+OCT Spectralis with Flex module and automated segmentation.
Participants
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This prospective cross-sectional study was approved by the Duke University Health System Institutional Review Board and was conducted in accordance with the US Health Insurance Portability and Accountability Act of 1996. All data was prospectively collected following parental consent.
Healthy, full-term (gestational age ≥37 weeks) children ages 0 to <6 years presenting to the Duke Eye Center for surgery under general anesthesia were prospectively recruited and consented for participation from January 2017 through March 2018. Excluded were children with systemic neurologic disease, optic nerve or retinal disease (even if unilateral), or any bilateral ocular disease process, and eyes with amblyopia, ocular disease, or spherical equivalent refractive error outside of -3.00 to +8.00 diopters.
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Data and Measurement Collection The following data was collected for each patient: gender, age, date of birth, gestational age, race, ethnicity, ocular and medical history. Refractive error for inclusion was determined based on most recent cycloplegic retinoscopy within 1 year of imaging or determined at the time of anesthesia. Intraocular pressure was obtained by Tono2
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pen (Reichert Technologies, Buffalo, NY) as soon after induction as safely possible. Axial length and anterior chamber depth were measured by immersion A-scan using an Ellex Eye Cubed ultrasound (Mawson Lakes, Australia) or the Sonomed Excalon Master-Vu USB A-Scan (New Hyde Park, NY).
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OCT Imaging and Analysis All OCT scans were performed using a portable HRA+OCT Spectralis with Flex module (investigational device). Participants were imaged supine under general anesthesia. The non-operative eye was imaged for monocular surgery. In cases of bilateral surgery where both eyes met inclusion criteria, the more-dilated eye was imaged. A 12° circle scan centered on the optic nerve was used to quantify the peripapillary retinal nerve fiber layer (pRNFL) (Figures 1a- 1b). A 61 raster 30° x 25° scan with cuts 116 µm apart (Figure 1c-1d) was centered on the macula and used for macular volume, thickness, and segmentation. All scans were reviewed by a single reader (JCR). When multiple scans were taken, the highest quality scan was chosen for inclusion. Scans subjectively determined to have >10 uncorrectable degrees of torsion were excluded from analyses evaluating quadrants. Macular scans with incomplete perifoveal data were excluded from total macular volume, individual quadrant analysis, and perifoveal analysis. Automated pRNFL and macular segmentation were performed using Heidelberg SD-OCT software. The segmentation results for the 12° circle scan and each cut of the 61 raster 30° x 25° scan were reviewed and manually corrected wit hin the Heidelberg SD-OCT HEYEX software. For macular scans, the 1, 3, 6 mm circle diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid26 was manually centered on the fovea. The 1, 3, and 6 mm diameter rings are referred to as the central fovea, parafovea, perifovea, respectively. During review of macular scans, the presence of vitreous opacities was noted as positive or negative.
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Data and Statistical Analysis Statistical analyses were performed using SPSS Statistical Software (IBM, Armonk, NY, USA), unless otherwise specified. Results for the Ganglion cell complex (GCC) were calculated by adding segmentation results for the retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer. Results for the photoreceptors layers (PRLs) were calculated by adding segmentation results for the outer plexiform layer, outer nuclear layer, and outer retina (external limiting membrane to Bruch membrane). Mean parafoveal and perifoveal values were calculated by adding values for the quadrants of the 3 mm and 6 mm diameter ring of the ETDRS grid, respectively, and dividing by 4. Mean, standard deviation, 5th percentile and 95th percentile values were calculated. Normality testing was performed using the Shaprio-Wilk test with a p value of 0.05. Multiple linear regression analysis included the following independent variables: age (all, <18 months, ≥18 months), axial length, gender, laterality, and race. Curve estimation for linear, logarithmic, exponential, and inverse models was performed to evaluate the best-fit relationship between age and retinal layers (all macular layers, GCC, inner nuclear layer (INL), and PRLs) by anatomical location based on the ETDRS grid (central foveal, parafoveal, and perifoveal thickness corresponding with the 1 mm, 3
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mm, and 6 mm diameter circles, respectively). Comparisons of global pRNFL thickness and central foveal thickness with outside studies17,18 were performed by one-way ANOVA using the already calculated mean and standard deviation17,18 in GraphPad Prism Software (La Jolla, CA, USA).
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Results From January 2017 through March 2018, 71 children met inclusion criteria for participation. In 3 cases, the parent/guardian declined and in 5 cases the surgeon declined due to scheduling issues. Written consent was obtained from the parent/guardian of 63 children. Of these, 1 case was cancelled, 2 were unusable for analysis due to poor image quality, and 3 were not imaged due to imager unavailability. Thus, the data of 57 participants was included in this study.
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Subject characteristics Mean participant age was 2.28 ± 1.50 years and was normally distributed. Twenty-nine of 57 participants (51%) were female. Racial background (parent/guardianreported) included 31 white, 7 black, 2 Asian, 8 mixed-race, and 9 unknown/not reported; 46 ethnic backgrounds were reported as non-Hispanic, 4 as Hispanic, and 7 unknown/not reported. Scheduled surgeries included: strabismus (24), anterior segment surgery of the contralateral eye (16), oculoplastic procedures (13, including chalazion drainage, nasolacrimal duct probing, dermoid excision, epiblepharon repair), minor surface procedure of contralateral eye (3), and examination under anesthesia following ruptured globe repair of contralateral eye (1). Of those with strabismus, 14 had amblyopia of the contralateral, non-imaged eye.
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Ocular characteristics Axial length, anterior chamber depth, central corneal thickness, and intraocular pressure were all normally distributed. Axial length averaged 21.05 ± 1.11 mm (n=52) and was positively correlated with age (r=0.669; p<0.001). Mean anterior chamber depth was 3.30 ± 0.37 mm (n=51). Mean central corneal thickness was 561.9 ± 28.1 µm (n=56). Intraocular pressure averaged 13.6 ± 3.32 mmHg. Peripapillary Retinal Nerve Fiber Layer Data from 56 participants was included in analysis of the pRNFL global thickness (Table 1). One subject did not have an adequate scan for analysis. An additional 4 participants were excluded from quadrant sub-analysis due to torsion of the image. Data for global thickness and all 4 quadrants was normally distributed. Mean pRNFL global thickness was 107.6 ± 10.3 µm; 5th percentile 90.9 µm, 95th percentile 129.2 µm. Multiple linear regression analysis showed no relationship between pRNFL global thickness and age, laterality, gender, or race. Axial length showed a significant negative relationship with pRNFL (p=0.01) (Figure 2).
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Macular Volume and Thickness Fifty-five participants were included in macular analyses. Two participants in this study did not have adequate macular scans for any analyses. One scan was inadequate for segmentation and was included only in analyses of all layers. Of the 55 scans 4
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included in macular analyses, 7 were torted by greater than 5 degrees and 17 lacked part of the perifoveal ring. These were excluded from certain analyses, as described in the methods section. During careful review of the OCT images, small, round, hyperreflective opacities were incidentally found in the vitreous in 53 of 57 patients (93%) (Figure 1d). Normative data for macular volume and thickness in children ages 0-5 years are detailed in Table 2. Total macular volume and mean values for location were each normally distributed. The mean total macular volume was 8.56 ± 0.259 mm3 (n=38). The mean parafoveal thickness (323.0 ± 12.84 µm, n=55) was greater than that of the perifoveal (299.8 ± 10.41 µm, n=38) and central foveal (233.7 ± 27.76 µm, n=55) thickness. The temporal quadrant showed the thinnest macular thickness in both the parafovea and perifovea. The nasal perifovea was observed to be thicker than other perifoveal quadrants. Relationships of macular segments and locations with age are depicted in Figure 3. No relationship was found between total macular volume and age. The mean thickness for all macular layers was found to increase logarithmically with age in the central fovea (r2=0.401; p<0.001), increase linearly with age in the parafovea (r2=0.338; p<0.001), and showed an inverse relationship with age in the perifovea (r2= 0.152; p=0.015). Following segmentation, the GCL, GCC and INL volumes were found to have an inverse relationship with age (r2=0.364; p<0.001, r2=0.401; p<0.001, r2= 0.443; p<0.001, respectively) while the PRLs were found to have a logarithmic increase with age (r2=0.408; p<0.001). No relationship was found between age and the central foveal thickness for the GCL, GCC or INL. The mean parafoveal and perifoveal thickness showed an inverse relationship with age for the GCL (r2=0.087; p=0.031 and r2=0.424; p<0.001), GCC (r2=0.161; p=0.003 and r2=0.379; p<0.001), and the INL (r2=0.429; p<0.001 and r2=0.408; p<0.001), respectively. The central foveal, parafoveal, and perifoveal thickness of the PRLs showed a logarithmic increase with age (r2=0.704; p<0.001, r2=0.614; p<0.001, r2=0.264; p=0.001). To better compare our results with those of prior work,27 results of segmentation analysis were divided into <18 months and ≥18 months of age. No relationship was found between age and the mean central foveal thickness for the GCL, GCC or INL in either group. In patients <18 months old, an inverse relationship was found between age and mean thickness of the parafovea and perifovea for the GCL (r2=0.489; p<0.001 and r2=0.685; p<0.001), GCC (r2=0.517; p<0.001 and r2=0.776; p<0.001), and INL (r2=0.708; p<0.001 and r2=0.514; p<0.001). In patients ≥18 months, no relationship was found between age and the mean thickness of the perifoveal GCL, parafoveal GCC, or the parafoveal or perifoveal INL. In this age group, the parafoveal GCL and GCC mean thicknesses showed a positive linear relationship with age (r2=0.428; p<0.001 and r2=0.315; p=0.001).
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Discussion This study establishes normative values for pRNFL and macular volume and thickness in children 0-5 years of age. When compared to normative data for older children (5-16 years of age) using a tabletop Spectralis OCT, there is no difference between the mean global pRNFL thickness for Turk et al17 (106.5 ± 9.41 µm), Yanni et 5
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al18 (107.6 ± 10.93 µm) and this study (107.6 ± 10.30 µm) (p=0.70). While several more pediatric OCT databases exist,19-23 results from different OCT manufacturers are highly correlated, but not interchangeable,28 so only results from Spectralis OCT units were used for comparison of the present study with other published databases. The pRNFL global thickness was not found to be dependent on age, laterality, gender, or race; however, the power of the study is limited by its size. pRNFL global thickness showed a weak negative correlation with axial length in multiple regression analysis. Prior studies in children have shown no relationship between global pRNFL thickness and axial length in some29-31 and a negative correlation in others.32,33 Aykut et al33 found this relationship disappeared when a correction was applied for the effect of ocular magnification as it relates to axial length. The thickness of the quadrants followed the “ISNT rule” of descending thickness in the order: inferior, superior, nasal, temporal.34 Prior histologic and OCT studies have shown development of the foveal pit by 25 weeks gestation with widening and shallowing of the pit over the first 15 months of life secondary to centrifugal migration of the GCL, IPL, and INL.35 Over the first 1-1.5 years of life, the cones become considerably more packed and the outer plexiform layer (OPL) consequently thickens.35,36 The foveal cones continue to pack over childhood, reaching >10 cell bodies in thickness in later childhood/ early teenage years.36 Four distinct outer retinal bands can be seen by 17 months.37 Our normative data did not find a relationship between age and central foveal GCL, GCC or INL thickness for all participants, or by subgroups < 18 months and ≥18 months. This varies from the exponential decrease in GCL and INL thickness over the first 18 months of life reported by Lee et al.27 This group reported an inverse relationship with age for the parafoveal and perifoveal mean GCL and INL thicknesses over the first 17 months, consistent with our findings. While Lee et al27 found a gradual increase of GCL and INL parafoveal and perifoveal mean thickness between 17 and 65.5 months, we found a relationship with age only for the parafoveal mean thickness of the GCL in this sub-group. Our sub-group analyses were of limited sample size and may have failed to detect an extant relationship. The PRLs showed a logarithmic increase for volume and central foveal, parafoveal, and perifoveal mean thicknesses, aligning with prior reports of increasing cone cell bodies over childhood.27,36 Lee et al27 similarly found a logarithmic increase for the foveal ONL, photoreceptor inner segments, and photoreceptor outer segments until 32.4, 26.9, and 45.3 months gestational age, respectively, but found a more gradual increase for the parafovea and perifovea. The total macular thickness is most impacted by the development of the photoreceptor layer, causing it to increase logarithmically. The linear increase in parafoveal macular thickness with age is secondary to the thickening of the photoreceptor layers, but is more tempered by the decreasing GCC and INL. The perifoveal mean thickness shows an overall decrease with age, owing to a less impressive rise in photoreceptor layer thickness over time with a nearly equivalent decrease in GCC and INL thickness. When compared to normative data for older children (5-16 years) using a Spectralis OCT, there is a difference between the average of the mean central thickness for Turk et al17 (258.6 ± 17.2 µm), Yanni et al18 (271.2 ± 18.2 µm), and this study (233.7 ± 27.8 µm) (p<0.0001) in younger children (0-5 years). The difference between means persists when using only data for patients from this study ages 2-5
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years, in order to remove the component of early logarithmic increase (245.0 ± 24.18 µm; p<0.0001). This is consistent with the continued increase in the photoreceptor layer over time, as described above. Using normative data for adults and older children to interpret macular segmentation data in young children may lead to false conclusions. Separate normative data for children ages 0-1 years and ages 2-5 years can be found in eTable1 and eTable 2, respectively.
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Limitations The results of this study must be taken in light of several limitations. The relatively small number of participants makes both the means and models subject to greater influence by outliers. It has been previously demonstrated that race impacts pRNFL and foveal measurements.19,38 The inclusion of small groups of patients from different racial backgrounds may fail to show the true mean for patients of any given race. The exclusion of patients with refractive error outside of -3.00 to +8.00 diopters may have impacted analysis of the effect of axial length on different parameters and limits the use of this normative data to eyes with low to moderate refractive error. The inclusion of patients undergoing ocular procedures may increase the likelihood that the eyes measured were not truly “normal”. Cases of developmental abnormality of one eye, such as persistent fetal vasculature or congenital cataract, may harbor subclinical changes in the other eye. Although in cases of amblyopia, the non-amblyopic eye was chosen, specific visual acuity criteria were not applied for this young group of participants and, though unlikely, the possibility of asymmetric but bilateral refractive amblyopia in some patients does exist. OCT and OCT angiography studies have shown small structural differences between amblyopic and non-amblyopic eyes of unclear clinical significance.39,40 Lastly, the ETDRS grid used for macular reference database numbers is not optimized for macular reference database values. We have chosen to use this grid because it is standardly available, increasing its clinical utility.
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Conclusion This study establishes normative data using Spectralis OCT for children ages 0-5 years. Global pRNFL thickness measurements do not differ from those of older children and do not show a clinically significant change with age or axial length. Mean macular thickness value for segmented retinal layers reflect the development of the macula with logarithmic increase of the PRL with age and an inverse of the GCC and INL with age. These changes are most pronounced over the first year and a half of life. Young children have different normative macular volume, and mean thickness values than older children and adults.
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Acknowledgments
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a. Funding/ Support: This research was generously supported by the Knights Templar Eye Foundation and Lions Eye Foundation. Thank you to Heidelberg Engineering Inc. for loaning the HRA+OCT Spectralis with Flex module for this study. b. Financial disclosures: c. Other acknowledgements: The authors would like to acknowledge Dr. David Wallace1 and Dr. Edward Buckley1 for their assistance with participant recruitment. 1 Duke University Department of Ophthalmology, 2351 Erwin Road, Durham, NC 27705
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35. Hendrickson A, Possin D, Vajzovic L, Toth CA. Histologic development of the human fovea from midgestation to maturity. Am J Ophthalmol 2012; 154(5): 767-78.e2. 36. Vajzovic L, Hendrickson AE, O'Connell RV, et al. Maturation of the human fovea: correlation of spectral-domain optical coherence tomography findings with histology. Am J Ophthalmol 2012; 154(5): 779-89.e2. 37. Dubis AM, Costakos DM, Subramaniam CD, et al. Evaluation of normal human foveal development using optical coherence tomography and histologic examination. Arch Ophthalmol (Chicago, Ill : 1960) 2012; 130(10): 1291-300. 38. Allingham MJ, Cabrera MT, O'Connell RV, et al. Racial variation in optic nerve head parameters quantified in healthy newborns by handheld spectral domain optical coherence tomography. J AAPOS 2013; 17(5): 501-6. 39. Kim YW, Kim SJ, Yu YS. Spectral-domain optical coherence tomography analysis in deprivational amblyopia: a pilot study with unilateral pediatric cataract patients. Graefes Arch Clin ExOphthalmol 2013; 251(12): 2811-9. 40. Lonngi M, Velez FG, Tsui I, et al. Spectral-Domain Optical Coherence Tomographic Angiography in Children With Amblyopia. JAMA Ophthalmol 2017; 135(10): 1086-91.
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Figure Legends
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Figure 1. Optic nerve and Macular segmentation by Spectralis Optical Coherence Tomography. a) Infrared image on the left showing a 12° circle scan and on the right segmentation of the retinal nerve fiber layer (RNFL). The thickness of the RNFL is measured from the Internal Limiting Membrane (ILM), in red, to the RNFL, in blue. b) Peripapillary retinal nerve fiber layer analysis report with thickness reports by location. On the left: G=Global; T=Temporal; TS=Temporal and Superior; NS= Nasal and Superior; N= Nasal; NI= Nasal and Inferior; TI= Temporal and Inferior. The TS and NS are averaged to give the results of the Superior quadrant; the TI and NI are averaged to give the results of the Inferior quadrant. On the right, the RNFL (black line) is traced against normal (green), borderline (yellow), and thin (red) RNFL values, based on normative data derived from subjects ages 18 years or older. c) An infrared image of the macula with a color overlay indicating macular thickness (blue=thinnest; red= thickest). The standard 1, 3, 6 mm circle diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid is centered on the fovea and demonstrates the anatomical locations analyzed for macular analysis. The 1 mm circle is referred to as the central fovea, the 3 mm circle as the parafovea, and the 6 mm circle as the perifovea. d) An optical coherence tomography slice through the fovea demonstrating macular segmentation. Yellow arrows indicating round, hyper-reflective areas in the vitreous seen in 93% of patients. (Internal limiting membrane= ILM, red; Retinal Nerve Fiber Layer= RNFL, blue; Ganglion Cell Layer=GCL, purple; Inner Plexiform Layer= IPL, periwinkle; Inner Nuclear Layer= INL, light orange; Outer Plexiform Layer= OPL, burnt sienna; External Limiting Membrane= ELM, pink; Photoreceptor 1= PR1, blue; Photoreceptor2= PR2, mint; Retinal Pigmented Epithelium=RPE, light blue; Bruch membrane= BM, red.) Figure 2. Peripapillary Retinal Nerve Fiber Layer (pRNFL) global thickness is plotted against age and axial length. Multiple linear regression analysis was performed with independent variables age (all, <18 months, ≥18 months), axial length, gender, laterality, and race. The analysis showed no relationship between pRNFL global thickness and age but finds a negative relationship between pRNFL global thickness and axial length (p=0.01). Figure 3. Segmented Retinal Layers Total Volume and Mean Thickness by Early Treatment Diabetic Retinopathy Study (ETDRS) Grid Location using Spectralis Optical Coherence Tomography (OCT) in Children Ages 0-5 Years. Scatter plots showing the relationship between age and macular location (by segment and anatomical location). Anatomical location based on the ETDRS grid (central foveal, parafoveal, and perifoveal thickness corresponding with the 1 mm, 3 mm, and 6 mm diameter circles, respectively). Results for the Ganglion cell complex were calculated
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by adding segmentation results for the retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer. Results for the photoreceptors layers (PRLs) were calculated by adding segmentation results for the outer plexiform layer, outer nuclear layer, and outer retina (External limiting membrane to the Bruch membrane). The equation of the model and coefficient of determination (r2) are included when a significant relationship was found. (n= number of participants included in the analysis)
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n
Mean
SD
95% CI
5th %
95 %
Global (μm) Nasal (μm) Superior (μm) Temporal (μm) Inferior (μm)
56 52 52 52 52
107.6 78.6 132.6 77.2 141.3
10.3 18.3 18.5 12.4 17.6
104.8- 110.3 73.5- 77.2 127.5- 137.8 73.8- 80.6 136.4- 146.2
90.9 53.7 102.7 57.7 118.0
129.2 124.5 167.7 99.5 181.4
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Abbreviations: n, number; SD, standard deviation; 95% CI, 95% confidence interval; 5%, 5th percentile; 95th %, 95th percentile
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Table 2. Total Macular Volume and Mean Thickness Using Spectralis OCT in Children Ages 0-5 Years Mean
SD
SD
95% CI
5th %
95th %
38 55 48 48 48 44 48 42 48 40 55 38
8.56 233.7 325.1 318.9 330.0 301.2 313.9 287.4 326.1 295.0 323.0 299.8
0.259 27.76 14.47 11.94 12.02 11.46 12.24 11.30 11.79 10.77 12.84 10.41
0.259 27.76 14.47 11.94 12.02 11.46 12.24 11.30 11.79 10.77 12.84 10.41
8.48- 8.65 226.2- 241.2 320.9- 329.3 315.4- 322.4 326.5- 333.5 297.7- 304.7 310.3- 317.4 283.9- 290.9 322.7- 329.5 291.5- 298.4 319.5- 326.5 296.3- 303.2
8.19 182.2 300.5 302.4 312.5 284.8 294.7 268.6 307.4 278.1 306.0 282.7
9.19 280.4 353.7 347.2 357.2 327.0 338.1 312.3 349.6 315.6 349.7 325.6
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Total macular volume (mm ) Mean Central Thickness (μm) Mean Nasal Parafoveal Thickness (μm) Mean Nasal Perifoveal Thickness (μm) Mean Superior Parafoveal Thickness (μm) Mean Superior Perifoveal Thickness(μm) Mean Temporal Parafoveal Thickness (μm) Mean Temporal Perifoveal Thickness (μm) Mean Inferior Parafoveal Thickness (μm) Mean Inferior Perifoveal Thickness (μm) Mean Total Parafoveal Thickness (μm) Mean Total Perifoveal Thickness (μm)
n
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Location Measured
th
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Abbreviations: OCT, optical coherence tomography; n, number; SD, standard deviation; 95% CI, 95% confidence interval; 5%, 5 percentile; 95th %, 95th percentile. For macular analysis, the standard 1, 3, 6 mm circle diameter Early Treatment Diabetic Retinopathy Study (ETDRS) grid is centered on the fovea and the 1 mm circle is referred to as the central macula, the 3 mm circle as the parafovea, and the 6 mm circle as the perifovea.
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Thickness (µm) Age (years)
Thickness (µm)
Volume (mm3)
n= 55 Mean= 233.7 ± 27.76 y= 224.26 + 19.05*log(x) r2= 0.390; p<0.001
Age (years)
n= 54 Mean= 42.61 ± 10.147
n= 38 Mean= 300.0 ± 10.41 y= 296.51 + 3.55/x r2= 0.152; p=0.015
n= 54 Mean= 110.12 ± 7.60 y= 107.97 + 2.09/x r2= 0.161; p=0.003
n= 37 Mean= 103.59 ± 8.22 y= 99.54 + 4.37/x r2= 0.379; p<0.001
Thickness (µm)
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Age (years)
Age (years) n= 54 Mean= 15.31 ± 4.347
Age (years)
n= 37 Mean= 4.59 ± 0.19 y= 4.52 + 0.14 * log(x) r2= 0.408; p<0.001
n= 54 Mean= 41.29 ± 3.493 y= 39.68 + 1.57/x r2= 0.429; p<0.001
n= 37 Mean= 37.44 ± 2.777 y= 36.02 + 1.53/x r2= 0.408; p<0.001
Thickness (µm)
Volume (mm3)
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n= 37 Mean= 1.06 ± 0.75 y= 1.02 + 0.04/x r2= 0.433; p<0.001
PhotoPhotoreceptor Layers
n= 55 Mean= 323.0 ± 12.83 y= 4.94*x + 311.94 r2= 0.338; p<0.001
Age (years)
n= 37 Mean= 2.91 ± 0.190 y= 2.81 + 0.10/x r2= 0.401; p<0.001
Inner Nuclear Layer
Perifovea
Age (years)
n= 38 Mean= 8.56 ± 0.259
Ganglion Cell Complex
Parafovea
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Age (years) n= 54 Mean= 176.30 ± 18.33 y= 168.15 + 16.78*log(x) r2= 0.704; p<0.001
n= 54 Mean= 171.86 ± 11.507 y= 167.09 + 9.84*log(x) r2= 0.614; p<0.001
n= 37 Mean= 159.07 ± 5.987 y= 157.24 + 3.60*log(x) r2= 0.264; p=0.001
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Highlights - Global pRNFL thickness and total macular volume do not significantly change with age. - Macular volume and thickness values for different macular layers and anatomical locations in the macula do vary with age. - Retinal growth and development should be considered when interpreting macular layer volume and thickness values in young children.