Wen Jun Jiang

BRUCH MEMBRANE AND THE MECHANISM OF MYOPIZATION: A New Theory.

Background: The process of emmetropization is the adjustment of the length of the optical axis to the given optical properties of the cornea and lens after the end of the second year of life. Since its underlying mechanisms have not been fully explored yet, we reviewed findings available in the literature to discuss its potential etiology and the mechanism of myopization as an overshooting of emmetropization. Methods: Literature review. Results: The process of emmetropization occurs by axial elongation. Up to the end of the second year of life, the eye grows spherically by active increase in scleral volume. Axial elongation in the process of emmetropization is associated with thinning of the retina and reduced density of retinal pigment epithelium cells (RPE) in the retro-equatorial region, and with thinning more of the choroid than of the sclera, starting at the equator and being most marked at the posterior pole. In contrast, retinal thickness and RPE density in the macular region and thickness of Bruchs membrane (BM) in any region are independent of axial length. Conclusions: It led to the hypothesis that axial elongation occurs by production of BM in the retro-equatorial region leading to a decreased RPE density and retinal thinning in that region and a more tube-like than spherical enlargement of the globe, without compromise in the density of the macular RPE cells and in macular retinal thickness. The increased disc-fovea distance in axially myopic eyes is caused by the development and enlargement of parapapillary, BM free, gamma zone while the length of macular BM, and indirectly macular RPE cell density and macular retinal thickness, remain constant. The target tissue for medical modification of emmetropization/myopization may be the RPE, producing and elongating BM in the retro-equatorial region.

Intraocular Pressure and Associated Factors in Children: The Shandong Children Eye Study

PURPOSE We examined the distribution of intraocular pressure (IOP) and its associated factors in children. METHODS Using a random cluster sampling from kindergartens, primary schools, and junior and senior high schools from rural Guanxian County and the city of Weihai, the school-based cross-sectional Shandong Children Eye Study included children aged 4 to 18 years. All participants underwent an ocular examination, including ocular biometry, cycloplegic refractometry, and noncontact tonometry. RESULTS Mean IOP was 17.6 ± 2.7 mm Hg (range, 10-28 mm Hg). The IOP increased up to an age of 10 years and subsequently decreased with older age. In multivariate regression analysis, higher IOP was associated with female sex (P < 0.001; standardized correlation coefficient β, 0.06; regression coefficient β, 0.34; 95% confidence interval [CI], 0.18, 0.50), higher body mass index (P < 0.001; correlation coefficient β, 0.09; regression coefficient β, 0.07; 95% CI, 0.04,0.09), younger age (P < 0.001; correlation coefficient β, -0.15; regression coefficient β, -0.13; 95% CI, -0.17,-0.10), maternal myopia (P < 0.001; correlation coefficient β, 0.05; regression coefficient β, 0.34; 95% CI, 0.15,0.53), and more time spent indoors with reading/writing (P = 0.002; correlation coefficient β, 0.05; regression coefficient β, 0.07; 95% CI, 0.03,0.11), and with the ocular parameters of longer axial length (P < 0.001; correlation coefficient β, 0.14; regression coefficient β, 0.29; 95% CI, 0.21,0.37) and smaller corneal horizontal diameter (P < 0.001; correlation coefficient β, -0.06; regression coefficient β, -0.31; 95% CI, -0.46,-0.15). CONCLUSIONS In children aged 4 to 18 years, IOP showed an M-shaped association with age. Higher IOP was associated with the nonocular parameters of female sex (P < 0.001), higher body mass index (P < 0.001), younger age (P < 0.001), maternal myopia (P < 0.001), and more time spent indoors with reading/writing (P = 0.002), and with the ocular parameters of longer axial length (P < 0.001) and smaller corneal horizontal diameter (P < 0.001).

Macular Choroidal Thickness in Children: The Shandong Children Eye Study.

PURPOSE To examine the thickness of the macular choroid and its associations in school children aged 6 to 18 years. METHODS The school-based cross-sectional Shandong Children Eye Study included 6026 (94.7%) of 6364 eligible children fulfilling the inclusion criterion of an age from 4 to 18 years. Spectral-domain optical coherence tomography (SD-OCT) was performed for a subgroup of 972 school children aged 6+ years. All participants underwent ocular examinations, including measurement of visual acuity, cycloplegic refractometry, biometry, and SD-OCT (enhanced depth imaging mode) for measurement of choroidal thickness. RESULTS The study included 972 children (501 girls) with a mean age of 11.3 ± 3.3 years (range, 6-18 years) and mean axial length of 24.10 ± 1.56 mm (range, 16.57-28.82 mm). Mean choroidal thickness was thicker (P < 0.001) at 500 μm temporal to the foveola (290 ± 67 μm) than in the subfoveal region (283 ± 67 μm; range, 113-507 μm) and the region 500 μm superior to the fovea (283 ± 66 μm), where it was thicker (P < 0.001) than at 500 μm inferior of the foveola (281 ± 66 μm), and it was thinnest (P < 0.001) at 500 μm nasal of the foveola (268 ± 67 μm). In multivariate analysis, thicker SFCT was (overall correlation coefficient r: 0.51) associated with shorter axial length (P < 0.001; standardized correlation coefficient β: -0.48; B: -23.7; 95% confidence interval [CI]: -27.2 to -20.3), male sex (P = 0.006; β: -0.08; B: -10.7; 95% CI: -18.3 to -3.11), and younger age (P = 0.04; β: -0.07; B: -1.46; 95% CI: -2.85 to -0.07). CONCLUSIONS As in adults, thicker SFCT in children and teenagers was markedly associated with shorter axial length, and to a lesser degree with male sex and older age. As in adults, increasing axial myopia in teenagers is associated with choroidal thinning and development of a leptochoroid.

Education-Related Parameters in High Myopia: Adults versus School Children

Purpose Since high myopia in the younger generation may differ etiologically from high myopia in older generations, we examined whether education-related parameters differ between high myopia in today´s school children and high pathological myopia in today´s elderly generation. Methods The investigation included the adult populations of the population-based Beijing Eye Study (BES) (3468 adults;mean age:64.6±9.8years;range:50–93years) and Central India Eye and Medical Study (CIEMS) (4711 adults;age:49.±13.2years;range:30–100years), and the children and teenager populations of the Shandong Children Eye Study (SCES) (6026 children;age:9.7±3.3years;range:4–18years;cycloplegic refractometry), Gobi Desert Children Eye Study (1565;age:11.9±3.5years;range:6–21 years;cycloplegic refractometry), Beijing Pediatric Eye Study (681 children;age:7.7±1.6years;range:5–13 years;non-cycloplegic refractometry,calculation of axial length to corneal curvature radius ratio), Beijing Children Eye Study (15066 children;age:13.2±3.4years;range:7–18years;non-cycloplegic refractometry), Beijing High School Teenager Eye Study (4677 children;age:16.9±0.7years;range:16–18years;non-cycloplegic refractometry). Results In the BES and CIEMS, educational level did not differ significantly between, or was significantly lower in the highly myopic group (myopic refractive error ≥6 diopters) than in the non-highly myopic group. In all non-adult study populations, higher prevalence of high myopia was significantly associated with higher degree of education related parameters such as attendance of high-level schools, and more time spent for indoors near work versus time spent outdoors. Conclusions Comparing associations of old or genetic high myopia in adults with new or acquired high myopia in school children revealed that education-related parameters did not show a clear association with old or genetic high myopia, while in contrast, new high myopia showed strong associations with education. It confirms previous studies that the two forms of high myopia not only differed in age of onset, but also in associations with education as well. The data support the notion of two types of high myopia. Future studies may assess whether the risk of pathologic myopic maculopathy and high myopia associated open-angle glaucoma differs between both types of high myopia.

Amphiregulin Antibody and Reduction of Axial Elongation in Experimental Myopia

To examine the mechanism of ocular axial elongation in myopia, guinea pigs (age: 2–3 weeks) which either underwent unilateral or bilateral lens-induced myopization (group 1) or which were primarily myopic at baseline (group 2) received unilateral intraocular injections of amphiregulin antibody (doses: 5, 10, or 15 μg) three times in intervals of 9 days. A third group of emmetropic guinea pigs got intraocular unilateral injections of amphiregulin (doses: 0.25, 0.50 or 1.00 ng, respectively). In each group, the contralateral eyes received intraocular injections of Ringers solution. In intra-animal inter-eye comparison and intra-eye follow-up comparison in groups 1 and 2, the study eyes as compared to the contralateral eyes showed a dose-dependent reduction in axial elongation. In group 3, study eyes and control eyes did not differ significantly in axial elongation. Immunohistochemistry revealed amphiregulin labelling at the retinal pigment epithelium in eyes with lens-induced myopization and Ringers solution injection, but not in eyes with amphiregulin antibody injection. Intraocular injections of amphiregulin-antibody led to a reduction of lens-induced axial myopic elongation and of the physiological eye enlargement in young guinea pigs. In contrast, intraocularly injected amphiregulin in a dose of ≤ 1 ng did not show a significant effect. Amphiregulin may be one of several essential molecular factors for axial elongation.

Myopia in China: a population-based cross-sectional, histological, and experimental study

BACKGROUND The prevalence of myopia has markedly increased within the past three decades, in particular in China. Because of myopic retinopathy and myopia-associated glaucoma, myopia has become one of the leading blinding disorders. METHODS Conducting population-based studies and school-based investigations, we assessed prevalence and incidence of myopia and associated factors in children, university students, and adults in urban and rural regions of different Chinese provinces. We performed histomorphometric studies on human eyes, and examined whether the intraocular application of an antibody to amphiregulin was associated with a reduction of experimentally induced myopic axial elongation of eyes in guinea pigs. This study was approved by the ethics committee of the Shandong University of Traditional Chinese Medicine. FINDINGS In nine population-based studies with up to 560 000 child and adult participants, the prevalence of myopia was about 80% in 18-year-old school children and 17% in adults aged 40 years and older. These figures were significantly higher in urban regions than in rural regions (OR 1·63, 95% CI 1·51-1·75, p<0·0001). Myopic retinopathy and myopia-associated glaucoma were the most common causes for irreversible visual loss in adults. In children, the most common myopia-associated modifiable factor was less time spent outdoors/more time spent indoors with studying. Histological studies revealed that the density of retinal pigment epithelium cells and retinal thickness decreased with longer axial length in the retinal midperiphery, while retinal cell density and thickness in the macula were statistically independent (p>0·40) of axial length, as was Bruchs membrane thickness. Intraocular application of amphiregulin antibody reduced axial elongation in guinea pigs in a dosage-dependent manner (p=0·002; regression coefficient -0·58, 95% CI of difference 0·20 to 0·63). INTERPRETATION These findings suggest that the increase in prevalence of myopia in the young Chinese generation is associated with lifestyle factors. The histological findings indicated that myopic axial elongation was associated with formation of Bruchs membrane in the midperiphery. Since the retinal pigment epithelium has receptors for amphiregulin, a member of the epithelial growth factor family, this hypothesis fits with the finding that amphiregulin antibody was associated with a dosage-dependent reduction in axial elongation. Further studies are warranted on the medical reduction of axial myopisation by amphiregulin antibody. FUNDING None.

Prevalence and Associations of Anisometropia in Children.

PURPOSE To describe prevalence and associations of anisometropia in children. METHODS The cross-sectional school-based study included children aged 4 to 18 years. RESULTS The study included 6025 (94.7%) of 6364 eligible children. Mean refractive anisometropia was 0.37 ± 0.57 diopters (median: 0.25 diopters; range: 0-7.88 diopters; prevalence [≥1 diopter]: 7.0% ± 0.3%). In multivariate analysis (regression coefficient r: 0.66), higher refractive anisometropia was associated with older age (P < 0.001; β: 0.07; B: 0.01; 95% CI: 0.01-0.02), higher maternal education level (P < 0.001; β: 0.04; B: 0.02; 95% CI: 0.01-0.03), more total time spent indoors reading or writing (P = 0.001; β: 0.04; B: 0.01; 95% CI: 0.01-0.02), larger intereye difference in axial length (P < 0.001; β: 0.57; B: 1.20; 95% CI: 1.15-1.24), shorter mean axial length of both eyes (P = 0.03; β: -0.03; B: -0.02; 95% CI: -0.03 to -0.001), larger intereye difference in best corrected visual acuity (BCVA) (P < 0.001; β: 0.14; B: 1.83; 95% CI: 1.54-2.12), and lower stereoacuity (P < 0.001; β: 0.08; B: 0.31; 95% CI: 0.22-0.39). Refractive anisometropia showed a U-shaped correlation with refractive error. Higher anisomyopia was associated (r: 0.57) with older age (P = 0.001; β: 0.05; B: 0.006; 95% CI: 0.002-0.009), higher level of paternal education (P = 0.001; β: 0.01; B: 0.01; 95% CI: 0.01-0.02), more total time spent indoors reading or writing (P = 0.01; β: 0.03; B: 0.01; 95% CI: 0.00-0.01), larger intereye difference in axial length (P < 0.001; β: 0.22; B: 0.26; 95% CI: 0.23-0.29), greater myopic refractive error (P < 0.001; β: -0.46; B: -0.07; 95% CI: -0.08 to -0.07), and lower corneal astigmatism (P < 0.001; β: -0.10; B: -0.06; 95% CI: -0.08 to -0.05). In the same multivariate model, hyperopic anisometropia was not significantly associated with time spent indoors with reading (P = 0.18). Cylindrical anisometropia (mean: 0.30 ± 0.32 diopters; prevalence [≥1 diopter]: 3.7% ± 0.2%) increased with higher refractive anisometropia (P < 0.001; β: 0.16; B: 0.09; 95% CI: 0.08-0.11), greater myopic refractive error (P < 0.001; β: -0.06; B: -0.01; 95% CI: -0.01 to -0.01), higher corneal astigmatism (P < 0.001; β: -0.22; B: -0.15; 95% CI: -0.17 to -0.13), and lower mean BCVA (P < 0.001; β: 0.11; B: 0.90; 95% CI: 0.68-1.17). CONCLUSIONS In 4- to 18-year-old children, refractive anisometropia and anisomyopia increased with systemic parameters such as age, parental education level, and lifestyle of the children, for example, more time spent indoors reading or writing. In contrast, hyperopic anisometropia and cylindrical anisometropia were not related with lifestyle parameters.

Corneal Curvature Radius and Associated Factors in Chinese Children: The Shandong Children Eye Study

Purpose To investigate the distribution of the (CCR) and its associated factors in children. Methods Using a random cluster sampling method, the school-based, cross-sectional Shandong Children Eye Study included children aged 4 to 18 years from the rural county of Guanxian and the city of Weihai in the province of Shandong in East China. CCR was measured by ocular biometry. Results CCR measurements were available for 5913 (92.9%) out of 6364 eligible children. Mean age was 10.0±3.3 years, and mean CCR was 7.84±0.27 mm (range: 6.98 to 9.35 mm). In multivariate linear regression analysis, longer CCR (i.e. flatter cornea) was significantly associated with the systemic parameters of male sex (P<0001;standardized regression coefficient beta: -0.08;regression coefficient B:-0.04; 95% Confidence Interval (CI):-0.05,-0.03), younger age (P<0.001;beta:-0.37;B:-0.03;95%CI:-0.04,-0.03), taller body height (P = 0.002;beta:0.06;B:0.001;95%CI:0.000,0.001), lower level of education of the father (P = 0.001;beta:-0.04;B:-0.01;95%CI:-0.02,-0.01) and maternal myopia (P<0.001;beta:-0.07;B:-0.04;95%CI:-0.06,-0.03), and with the ocular parameters of longer ocular axial length (P<0.001;beta:0.59;B:0.13;95%CI:0.12,0.14), larger horizontal corneal diameter (P<0.001;beta:0.19;B:0.13;95%CI:0.11,0.14), and smaller amount of cylindrical refractive error (P = 0.001;beta:-0.09;B:-0.05;95%CI:-0.06,-0.04). Conclusions Longer CCR (i.e., flatter corneas) (mean:7.84±0.27mm) was correlated with male sex, younger age, taller body height, lower paternal educational level, maternal myopia, longer axial length, larger corneas (i.e., longer horizontal corneal diameter), and smaller amount of cylindrical refractive error. These findings may be of interest for elucidation of the process of emmetropization and myopization and for corneal refractive surgery.

Corneal diameter and associated parameters in Chinese children: the Shandong children eye study

To assess the corneal diameter and its associations in children.

Lens thickness and associated factors in Chinese children: The Shandong Children Eye Study

3730 DNA analyser (Applied Biosystems, Foster City, CA,USA).Datawere collected and analysed using DNAMAN Windows 5.2.2.0 software (Lynnon, San Ramon, CA, USA) and Chromas DNA sequencing software (Technelysium, South Brisbane, QLD, Australia). Genetic analysis of exon 3 of the TTR gene revealed that the patients were heterozygous for a single nucleotide substitution (3930 G>C) (Fig. 1B). This substitution resulted in an amino acid change from glycine (GGC) to arginine (CGC) at codon 83. However, there was no similar change among the normal controls. Mutations in the TTR gene are the most common causes of hereditary amyloidosis. Among more than 100 amyloid-genic TTR gene mutations, 99% are concentrated at exons 2, 3 and 4. ATTR Val30Met is the most common mutation worldwide, with substantial foci in Portugal, Sweden and Japan. Other common mutations are Val28Met, Leu58His, Leu58Arg, Lys78Phe, Ile84Ser, Tyr114His, Trp4 1Leu, Tyr69His, Asp18Glu, Val30Gly, Gly67Glu, Gly83Arg, Arg54Gly, Lys 35Thr and Leu55Arg. In the mainland Chinese population, Zhang reported three families with a total of 26 subjects who had the G83R mutation (Zhang et al. 2013). Liu reported 12 affected individuals heterozygous for the missense Gly83Arg mutation in TTR from a five-generation Chinese family (Liu et al. 2014). Our patient was heterozygous for the novel Gly83Arg TTR mutation. So far, however, no related research has been reported regarding this rare mutant form of the TTR gene except in the Chinese Han population. We speculate that the Gly83Arg heterozygous mutation is a novel and characteristic variant of the TTR gene in the Chinese Han family. The study was supported by the National Natural Science Foundation ofChina (81360150) and the Science and Technology Foundation of Guizhou Province, China (No. 2014-7007).