Abstract
Purpose:
Age-related changes in glaucoma endophenotypes have been described thoroughly, yet, there are limited data on the normal age-related changes in young adults. This study profiles the 8-year longitudinal change in peripapillary retinal nerve fiber layer (pRNFL), intraocular pressure (IOP), and central corneal thickness (CCT) in young adults.
Methods:
A community-based cohort of young adults from the Raine Study underwent eye examinations that included optical coherence tomography of the optic disc, tonometry, and pachymetry when they were 20 and 28 years old. The main outcome measures were the changes in pRNFL thickness, IOP, and CCT over 8 years, adjusted for sex, ethnicity, and other potential confounders.
Results:
A total of 693, 712, and 680 participants were included in the pRNFL, IOP, and CCT analyses, respectively. Over the 8 years, the global pRNFL reduced from a mean of 100.6 ± 9.3 to 97.9 ± 9.4 µm, at an average rate of 0.27 µm/year (95% confidence interval [CI], 0.24–0.30). Sectoral pRNFL similarly thinned by 0.06 to 0.38 µm/year, but this thinning was not statistically significant at the superotemporal and inferonasal sectors. IOP decreased and CCT increased between 20 and 28 years old, at an average rate of 0.18 mm Hg/year (95% CI, 0.15–0.20) and 0.18 µm/year (95% CI, 0.10–0.27), respectively.
Conclusions:
During the third decade of life, there is a decrease in pRNFL thickness and IOP in healthy adults.
Translational Relevance:
The current study findings will enable clinicians to differentiate potential pathological change from normal age-related variations in these measures.
As the human eye ages, several well-documented physiological changes occur. Thickening and hardening of the crystalline lens, loss of retinal ganglion cells (RGCs), and decreases in the number and density of retinal photoreceptors are only a few examples of a myriad of age-related changes that the human eye undergoes.
1 An acceleration in any of these changes may lead to pathology or early onset of disease. For example, although there is a normal age-related loss of RGCs that may not or only minimally impact visual function, an excessive loss of the RGC axons can result from diseases such as glaucoma.
2,3 According to the World Glaucoma Association,
4 glaucoma is a chronic, progressive, degenerative disorder of the optic nerve that produces visual field damage. Given the progressive nature of the disease and the normal age-related reduction in RGC count, early diagnosis of glaucoma is challenging. Delay in glaucoma diagnosis was identified by Grant and Burke in 1984
5 as one of three major reasons that people go blind from the disease, and remains a major issue today.
6
Another important glaucoma phenotype is the intraocular pressure (IOP). Although not a defining feature, raised IOP remains an important and the only modifiable risk factor for glaucoma. However, the age-related variation in IOP remains unclear, with a lack of consensus on whether it tends to increase or decrease with age.
7–15
To recognize an abnormally fast rate of change in phenotypic measures of glaucoma, one must first understand the normal rate of age-related change. However, there is limited data on the normative age-related change in IOP or measures of the integrity of the RGC, such as peripapillary retinal nerve fiber layer (pRNFL) thickness, in young adults with healthy eyes. This is particularly important given the increased reliance on commercial optical coherence tomography (OCT) for assessing RGC integrity. OCT devices usually have their own normative databases constructed from data obtained from a few hundred European eyes with a wide age range. For example, Heidelberg Engineering based their reference database on the scans of 330 healthy European individuals ranging from 20 to 90 years of age.
16 However, their reference population is limited by the small sample spanning a wide age range.
Even though glaucoma tends to affect older adults, glaucoma can occur at any age and we should consider the possibility that subtle subclinical changes, which only later become visually significant, may occur earlier in life. Moreover, the detection of glaucoma in young adults is critical as a younger age of disease onset results in a longer duration of morbidity, loss of productivity in this working-age group, and more time for the disease to progress. Thus, documenting the normal age-related rate of change in ocular parameters in this age group is critical in differentiating the normal or expected changes from the pathological or prepathological ones. To address this goal, we aim to profile the 8-year longitudinal change in pRNFL thickness and IOP in a community-based cohort of young healthy adults. As a supplementary aim, we additionally explored the longitudinal change in CCT that, although not generally considered a phenotypic measure of glaucoma, affects the evaluation of IOP.
The Gen2 20-year visit took place in 2010–2012 and included a comprehensive baseline eye examination at the Lions Eye Institute in Western Australia. Participants then returned for a follow-up eye examination in 2018–2020 as part of the Gen2 28-year visit (although the period of the 28-year follow-up was cut short by the coronavirus disease 2019 pandemic, thus reducing the number of participants). The protocols for both eye examinations have been described in detail previously.
17,18 The eye examinations at both visits included ocular biometry (IOLMaster V.5; Carl Zeiss Meditec AG, Jena, Germany), and Spectral domain (SD) OCT imaging (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany). The SD-OCT was performed after instillation of 1 drop of tropicamide 1% in both eyes to achieve mydriasis, improving imaging quality. before imaging, the central corneal radius was entered into the OCT to account for corneal curvature-related magnification effects. The scan centered and focused on the optic disc. One-hundred frames of a circular B-scan made up of 768 A-scans centered on the optic disc were taken to obtain the pRNFL thickness. Given that the scan diameter was fixed at 12° regardless of scan focus and eye size, the actual scan diameter varied from 3.1–4.3 mm, as estimated by the OCT based on the scan focus and included as a covariable in the models with pRNFL thickness as the outcome measure. Scans with signal-to-noise quality less than 20 were discarded from the analysis.
19 The 28-year scans were acquired with the 20-year (baseline) scans set as the reference.
Tonometry was conducted using a rebound tonometer (ICare TA01i, ICare Finland Oy, Vantaa, Finland). Central corneal thickness (CCT) was measured using Scheimpflug imaging (Pentacam, Oculus Optikgerate GmbH, Wetzlar, Germany). All tests and imaging were conducted without contact lens wear. The same protocol and device models for SD-OCT imaging, and IOP and CCT measurements were used at both visits. Self-administered questionnaires collected information on contact lens wear and previous laser refractive corneal surgery.
Analyses were conducted on R version 3.6.2 (The R Foundation for Statistical Computing Platform), and the level of significance was set at P < 0.05. Continuous measurements were described in terms of mean and standard deviation or median and interquartile range (IQR) as appropriate. Linear mixed-effect models were used to explore the longitudinal change with age, as it allowed for data from both eyes at all visits to be included in the analysis with a random intercept and slope for participants entered into the models to account for the repeated measure (2 eyes and 2 time points). The suitability of linear mixed-effect models was further confirmed after checking for the normality of the residuals of the models. The main explanatory factor is age, with sex, ethnicity, and current axial length included in the models as co-variates. The pRNFL analysis additionally controlled for Bruch's membrane opening area diameter, scan diameter (in millimeters), and baseline IOP. The longitudinal IOP analysis additionally controlled for CCT, the time of measurement, body mass index, resting heart rate, and systolic blood pressure. The CCT longitudinal analysis also corrected for contact lens wear and excluded participants who had undergone laser refractive surgery or other corneal surgery. The interaction effect of age with each of these factors were explored in the models to identify the factors that affected the longitudinal rate of these phenotypic changes.
The authors thank the Raine Study and Lions Eye Institute team for study coordination and data collection, as well as the NHMRC and the Raine Medical Research Foundation for their long-term contribution to funding the Raine Study over the last 30 years.
The core management of the Raine Study is funded by The University of Western Australia, Curtin University, Telethon Kids Institute, Women and Infants Research Foundation, Edith Cowan University, Murdoch University, The University of Notre Dame Australia, and the Raine Medical Research Foundation. The eye data collection of the Raine Study Gen2 20- and 28-year follow-ups were funded by the National Health and Medical Research Council (NHMRC; grants 1021105, 1126494, and 1121979), the Ophthalmic Research Institute of Australia, Alcon Research Institute, Lions Eye Institute, the Australian Foundation for the Prevention of Blindness, and the Heart Foundation (Grant no. 102170). This work was additionally funded by a NHMRC Program Grant. Dr Mackey is supported by a NHMRC Practitioner Fellowship and Dr Hewitt is supported by a NHMRC Investigator Grant. The sponsor or funding organization had no role in the design or conduct of this research.
Disclosure: S.S.-Y. Lee, None; G. Lingham, (E) Ocumetra Ltd, Ireland; A.W. Hewitt, None; D.A. Mackey, (C) Novartis