Ocular Axial Growth Research Articles

Axial Growth Driven by Physical Development and Myopia among Children: A Two Year Cohort Study.

Background: The physical process of axial length growth among children and its role in the occurrence of myopia remain insufficiently explored. In this study, we investigate the patterns of ocular axial growth among persistent myopia (PM) and persistent non-myopia (PNM) children aged 3 to 15 years. Methods: A group of 6353 children aged 3 to 15 years, selected from rural schools in China, were followed up annually for 2 years. Biometric measurements including axial length (AL) and spherical equivalent refraction (SER) were obtained. Body height was recorded. Children were divided into two groups: PM group defined as SER of −0.50 D or less; PNM group defined as −0.50 D < SER < +3.0 D during follow-up. Results: Annual AL growth was fairly consistent for PNM eyes of children aged 3 to 11 years and then reduced significantly (independent t test, p < 0.001) for children aged 12 years and older. This pattern of AL changes was similar for PM children, although the AL growth was greater among them. Among children aged 6 and older, body height change was concomitant to AL growth (p < 0.01) and SER myopic shift (p < 0.001) until reaching 12 years old (p = 0.308 and p = 0.679, respectively). Conclusions: Stature growth and AL growth are both remarkable and consistent and concomitant but start to attenuate when the children reach 10 to 12 years old among emmetropic children. This observation suggests that AL growth is driven by physical development until 12 years old, whereas its excessive growth is dominated by myopia development.

Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation.

Precise regulation of ocular size is a critical determinant of normal visual acuity. Although it is generally accepted that ocular growth relies on a cascade of signaling events transmitted from the retina to the sclera, the factors and mechanism(s) involved are poorly understood. Recent studies have highlighted the importance of the retinal secreted serine protease PRSS56 and transmembrane glycoprotein MFRP, a factor predominantly expressed in the retinal pigment epithelium (RPE), in ocular size determination. Mutations in PRSS56 and MFRP constitute a major cause of nanophthalmos, a condition characterized by severe reduction in ocular axial length/extreme hyperopia. Interestingly, common variants of these genes have been implicated in myopia, a condition associated with ocular elongation. Consistent with these findings, mice with loss of function mutation in PRSS56 or MFRP exhibit a reduction in ocular axial length. However, the molecular network and cellular processes involved in PRSS56- and MFRP-mediated ocular axial growth remain elusive. Here, we show that Adamts19 expression is significantly upregulated in the retina of mice lacking either Prss56 or Mfrp. Importantly, using genetic mouse models, we demonstrate that while ADAMTS19 is not required for ocular growth during normal development, its inactivation exacerbates ocular axial length reduction in Prss56 and Mfrp mutant mice. These results suggest that the upregulation of retinal Adamts19 is part of an adaptive molecular response to counteract impaired ocular growth. Using a complementary genetic approach, we show that loss of PRSS56 or MFRP function prevents excessive ocular axial growth in a mouse model of early-onset myopia caused by a null mutation in Irbp, thus, demonstrating that PRSS56 and MFRP are also required for pathological ocular elongation. Collectively, our findings provide new insights into the molecular network involved in ocular axial growth and support a role for molecular crosstalk between the retina and RPE involved in refractive development.

Emmetropia Is Maintained Despite Continued Eye Growth From 16 to 18 Years of Age

To examine, in Norwegian adolescents, to what degree emmetropia and low hyperopia were maintained from 16 to 18 years of age, and if this was the case, whether it was associated with continued coordinated ocular growth. Cycloplegic autorefraction and ocular biometry, including crystalline lens thickness, were measured in 93 Norwegian adolescents (mean age: 16.7 ± 0.3 years; 63.4% females) and repeated after 2 years. Crystalline lens power was determined by ray tracing over a 1-mm pupil, based on the Gullstrand-Emsley model. Serum vitamin D3 concentration was measured at follow-up. Emmetropia and low hyperopia (-0.50 diopters [D] < spherical equivalent refractive error [SER] < +2.00 D) were present in 91.4% at baseline and 89.2% at follow-up. The emmetropes and low hyperopes who maintained their refractive error exhibited continued ocular axial growth (+0.059 ± 0.070 mm) together with a decrease in crystalline lens power (-0.064 ± 0.291 D) and a deepening of the anterior chamber (+0.028 ± 0.040 mm). Thinning of the crystalline lens was found in 24%. Overall, the negative change in SER was larger in those with the most negative SER at baseline (R2 = 0.178, P < 0.001), and was associated with increases in vitreous chamber depth and in crystalline lens power (R2 = 0.752, P < 0.001), when adjusted for sex. There was no difference in vitamin D3 level between those who exhibited negative versus positive changes in refractive error. The results show that emmetropic and low hyperopic eyes were still growing in late adolescence, with refractive errors being maintained through a coordinated decrease in crystalline lens power.

Müller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error

A mismatch between optical power and ocular axial length results in refractive errors. Uncorrected refractive errors constitute the most common cause of vision loss and second leading cause of blindness worldwide. Although the retina is known to play a critical role in regulating ocular growth and refractive development, the precise factors and mechanisms involved are poorly defined. We have previously identified a role for the secreted serine protease PRSS56 in ocular size determination and PRSS56 variants have been implicated in the etiology of both hyperopia and myopia, highlighting its importance in refractive development. Here, we use a combination of genetic mouse models to demonstrate that Prss56 mutations leading to reduced ocular size and hyperopia act via a loss of function mechanism. Using a conditional gene targeting strategy, we show that PRSS56 derived from Müller glia contributes to ocular growth, implicating a new retinal cell type in ocular size determination. Importantly, we demonstrate that persistent activity of PRSS56 is required during distinct developmental stages spanning the pre- and post-eye opening periods to ensure optimal ocular growth. Thus, our mouse data provide evidence for the existence of a molecule contributing to both the prenatal and postnatal stages of human ocular growth. Finally, we demonstrate that genetic inactivation of Prss56 rescues axial elongation in a mouse model of myopia caused by a null mutation in Egr1. Overall, our findings identify PRSS56 as a potential therapeutic target for modulating ocular growth aimed at preventing or slowing down myopia, which is reaching epidemic proportions.

Abstracts from the 15th International Myopia Conference

Table of contentsO1 Changes in peripheral refraction associated with decreased ocular axial growth rate in marmosetsAlexandra Benavente-Perez, Ann Nour, Tobin Ansel, Kathleen Abarr, Luying Yan, Keisha Roden, David TroiloO2 PPARα activation suppresses myopia development by increasing scleral collagen synthesis--a new drug target to suppress myopia developmentChanyi Lu, Miaozhen Pan, Min Zheng, Jia Qu, Xiangtian ZhouO3 Evidence and possibilities for local ocular growth regulating signal pathwaysChristine F WildsoetO4 Myopia researches at Eye Hospital of Wenzhou Medical UniversityFan Lu, Xiangtian Zhou, Jie Chen, Jinhua Bao, Liang Hu, Qinmei Wang, Zibing Jin, Jia QuO5 Color, temporal contrast and myopiaFrances Rucker, Stephanie Britton, Stephan Hanowsky, Molly SpatcherO6 The impact of atropine usage on visual function and reading performance in myopic school children in TaiwanHui-Ying Kuo, Ching-Hsiu Ke, I-Hsin Kuo, Chien-Chun Peng, Han-Yin SunO7 Increased time outdoors prevents the onset of myopia: evidence from randomised clinical trialsIan G MorganO8 Environmental risk factors and gene-environment interactions for myopia in the ALSPAC cohortJeremy A. Guggenheim, Rupal L. Shah, Cathy WilliamsO9 Retinal metabolic profiling identifies declines in FP receptor-linked signaling as contributors to form-deprived myopic development in guinea pigsJinglei Yang, Peter S. Reinach, Sen Zhang, Miaozhen Pan, Wenfeng Sun, Bo Liu, Xiangtian ZhouO10 The study of peripheral refraction in moderate and high myopes after one month of wearing orthokeratology lensJun Jiang, Haoran Wu, Fan LuO11 Axial length of school children around the earth’s equatorial area and factors affecting the axial lengthKazuo Tsubota, Hiroko Ozawa, Hidemasa Torii, Shigemasa Takamizawa, Toshihide Kurihara, Kazuno NegishiO12 Processing of defocus in the chicken retina by retinal ganglion cellsKlaus Graef, Daniel Rathbun, Frank SchaeffelO13 Blue SAD light protects against form deprivation myopia in chickens, by local signaling within the retinaLadan Ghodsi, William K. StellO14 Contributions of ON and OFF pathways to emmetropization and form deprivation myopia in miceMachelle T. Pardue, Ranjay Chakraborty, Han na Park, Curran S. Sidhu, P. Michael IuvoneO15 Response of the human choroid to defocusMichael J CollinsO16 What can RNA sequencing tell us about myopic sclera?Nethrajeith Srinvasalu, Sally A McFadden, Paul N BairdO17 Overview of dopamine, retinal function, and myopiaP. Michael IuvoneO18 The eye as a "robust" optical system and myopiaPablo ArtalO19 Effect of discontinuation of orthokeratology lens wear on axial elongation in childrenPauline Cho, SW CheungO20 Myopia prevention in TaiwanPei-Chang WuO21 Alternatives to ultraviolet light and riboflavin for in vivo crosslinking of scleral collagenQuan V. Hoang, Sally A. McFaddenO22 Absence of intrinsically photosensitive retinal ganglion cells (ipRGC) alters normal refractive development in miceRanjay Chakraborty, Duk C. Lee, Erica G. Landis, Michael A. Bergen, Curran Sidhu, Samer Hattar, P. Michael Iuvone, Richard A. Stone, Machelle T. PardueO23 Scleral micro-RNAs in myopia development and their potential as therapeutic targetsRavi MetlapallyO24 Effects of the long-wavelength filtered continuous spectrum on emmetropization in juvenile guinea pigsRuiqin Li, Qinglin Xu, Hong Zhon, Chenglin Pan, Weizhon Lan, Xiaoning Li, Ling Chen, Zhikuan YangO25 Ocular and environmental factors associated with eye growth in childhoodScott A. ReadO26 Overview- prevention and prediction of myopia and pathologic myopiaSeang-Mei SawO27 New insights into the roles of retinal dopamine in form-deprivation myopia and refractive development in C57BL/6 miceShi-Jun Weng, Xiao-Hua Wu, Kang-Wei Qian, Yun-Yun Li, Guo-Zhong Xu, Furong Huang, Xiangtian Zhou, Jia Qu, Xiong-Li Yang, Yong-Mei ZhongO28 The effects of the adenosine antagonist, 7-methylxanthine, on refractive development in rhesus monkeysEarl L Smith III, Baskar Arumugam, Li-Fang Hung, Lisa A. Ostrin, Klaus Trier, Monica Jong, Brien A. HoldenO29 Application of SWATH™ based next generation proteomics (NGP) in studying eye growth: opportunities and challengesThomas Chuen Lam, Bing Zuo, Samantha Shan, Sally A. McFadden, Dennis Yan-yin Tse, Jingfang Bian, King-Kit Li, Quan Liu, Chi-ho ToO30 How could emmetropization make use of longitudinal chromatic aberration?Timothy J. Gawne, John T. Siegwart Jr., Alexander H. Ward, Thomas T. NortonO31 Balance effect of dopamine D1 and D2 receptor subtype activation on refraction developmentXiangtian ZhouO32 BMP gene expression changes in chick rpe in response to visual manipulationsYan Zhang, Yue Liu, Carol Ho, Eileen Phan, Abraham Hang, Emily Eng, Christine Wildsoet

Ocular axial growth in pseudophakic eyes of patients operated for monocular infantile cataract: a comparison of operated and fellow eyes measured at surgery and 5 or more years later

To report the change in axial length (AL) over time and to compare the percentage of AL growth of pseudophakic eyes operated on for monocular cataract to that of the unoperated fellow eyes. The medical records of children operated on by a single surgeon for monocular congenital cataract before 7months of age were retrospectively reviewed. Inclusion criteria were corneal diameter of ≥9mm and availability of AL data for >5years' follow-up after cataract surgery and >1year after IOL implantation (in case of secondary IOL). Cataract with persistent fetal vasculature causing stretching of the ciliary processes, diagnosis of glaucoma or glaucoma suspect, and eyes with aphakia were excluded. Globe AL was measured by immersion ultrasound at surgery and 5 or more years later. A total of 24 children were identified. Average age at cataract surgery was 2.6±2.1months. Age at last follow-up was 8.4±2.8years and duration of follow-up was 8.2±2.8years. 13 eyes received a primary IOL and 11 eyes received a secondary IOL. AL was significantly different between operative and fellow eyes, preoperatively (18.1mm vs 18.7mm, P=0.004), and at the final follow-up (22.2mm vs 23.0mm, P=0.03). Differences in AL growth of operated and fellow eyes were not significant (4.1mm vs 4.4mm, P=0.4). Similarly, percentage of AL growth of operated and fellow eyes was also not significantly different (23% vs 23.6%, P=0.7). Eyes operated for monocular cataract have similar axial growth to that of fellow unoperated eyes, despite having a shorter AL at the time of surgery.

Ocular axial growth in pseudophakic eyes of patients operated for monocular infantile cataract: a comparison of operated and fellow eyes measured at surgery and 5 or more years later

Ocular axial growth in pseudophakic eyes of patients operated for monocular infantile cataract: a comparison of operated and fellow eyes measured at surgery and 5 or more years later

Role of the dopaminergic system in the development of myopia in children and adolescents.

This review summarizes the experimental evidence that supports the role of dopamine in the regulation of ocular axial growth. The most important functions attributed to dopamine are light adaptation and regulation of the retinal circadian rhythm. An increase of the retinal levels of dopamine activates D1 and D2 dopaminergic receptors present throughout the retina, generating a signal that inhibits axial growth once the eye has reached emmetropization. Researchers induced form-deprivation myopia in animal models in order to assess the different changes of ocular axial growth. Other studies have shown that phenylethylamine is an endogenous precursor-neurotransmitter capable of modulating the activity of dopamine. Considering the role of the dopaminergic system in the development of myopia (in children and adolescents) and the fact that phenylethylamine improves the consequences of a dopamine deficit, it would be interesting to study the effect of phenylethylamine on the regulation of axial growth, which represents the genesis of myopia.

Identification of Apolipoprotein A-I as a “STOP” Signal for Myopia

Good visual acuity requires that the axial length of the ocular globe is matched to the refractive power of the cornea and lens to focus the images of distant objects onto the retina. During the growth of the juvenile eye, this is achieved through the emmetropization process that adjusts the ocular axial length to compensate for the refractive changes that occur in the anterior segment. A failure of the emmetropization process can result in either excessive or insufficient axial growth, leading to myopia or hyperopia, respectively. Emmetropization is mainly regulated by the retina, which generates two opposite signals: "GO/GROW" signals to increase axial growth and "STOP" signals to block it. The presence of GO/GROW and STOP signals was investigated by a proteomics analysis of the retinas from chicken with experimental myopia and hyperopia. Of 18 differentially expressed proteins that were identified, five displayed an expression profile corresponding to GO/GROW signals, and two corresponded to STOP signals. Western blotting confirmed that apolipoprotein A-I (apoA-I) has the characteristics of a STOP signal both in the retina as well as in the fibrous sclera. In accordance with this, intraocular application of the peroxisome proliferator-activated receptor alpha agonist GW7647 resulted in up-regulation of apoA-I levels and in a significant reduction of experimental myopia. In conclusion, using a comprehensive functional proteomics analysis of chicken ocular growth models we identified targets for ocular growth control. The correlation of elevated apoA-I levels with reduced ocular axial growth points toward a functional relationship with the observed morphological changes of the eye.

Longitudinal changes of optical aberrations in normal and form-deprived myopic chick eyes

We performed measurements of refraction (with retinoscopy), axial length (with ultrasound biometry) and ocular aberrations (with a custom-built Hartmann–Shack aberrometer) on seven awake White-Leghorn chicks occluded monolaterally with diffusers for two weeks. Treatment started on the first day after hatching (day 0) and measurements were conducted on several days between day 0 and 13. Non-occluded eyes experienced normal emmetropization (decreasing hyperopia at 0.2 ± 0.09 D/day and increasing axial length at 0.05 ± 0.03 mm/day), while occluded eyes developed axial myopia (1.50 ± 0.2 D/day and 0.12 ± 0.02 mm/day). Interocular differences in refraction and axial length by day 13 were on average 17.43 D and 0.86 mm, respectively. Monochromatic high order aberrations decreased with age in both eyes. Average RMS (for 1.5 mm pupil diameter) decreased from 0.11 ± 0.03 at day 0 to 0.06 ± 0.03 μm (day 13) in occluded eyes, and from 0.12 ± 0.05 to 0.03 ± 0.01 μm in non-occluded eyes. MTF-based optical quality metrics also show an improvement with age. However, while this improvement occurs in both eyes, after day 8 myopic eyes tend to show significantly higher amounts of aberrations (and consequently worse best-corrected optical quality) than normal eyes. The degradation imposed by aberrations is small compared to that imposed by defocus and the diffuser. These results suggest a decrease of aberrations during development which does not seem to be visually guided. Myopic eyes showed slightly worse optical quality than normal eyes, suggesting that the geometrical changes resulting from excessive ocular axial growth also affect the optical quality of the ocular components.