Myopia: Risk Factors, Disease Mechanisms, Diagnostic Modalities, and Therapeutic Options

Lead Guest Editor: Malgorzata Mrugacz Guest Editors: Marzena Gajęcka, Ewa Mrukwa‑Kominek, and Katarzyna J. Witkowska Myopia: Risk Factors, Disease Mechanisms, Diagnostic Modalities, and Therapeutic Options Journal of Ophthalmology

This is a special issue published in “Journal of Ophthalmology.” All articles are open access articles distributed under the Creative Com- mons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Editorial Board

Steven F. Abcouwer, USA J. M. Gonzalez-Méijome, Portugal Neville Osborne, UK Monica L. Acosta, New Zealand Jakob Grauslund, Denmark Ji-jing Pang, USA Luca Agnifili, Italy Ian Grierson, UK Mohit Parekh, Italy Hamid Ahmadieh, Iran Vlassis Grigoropoulos, Greece Enrico Peiretti, Italy Hee B. Ahn, Republic of Korea Shigeru Honda, Japan Grazia Pertile, Italy Usha P. Andley, USA Pierluigi Iacono, Italy David P. Piñero, Spain Siamak Ansari-Shahrezaei, Austria Takeshi Iwase, Japan Jesús Pintor, Spain Taras Ardan, Czech Republic Vishal Jhanji, Hong Kong Antonio Queiros, Portugal Francisco Arnalich-Montiel, Spain Nathan M. Kerr, New Zealand Miguel Rechichi, Italy Takayuki Baba, Japan Naoshi Kondo, Japan Anthony G. Robson, UK Stefano Baiocchi, Italy Ozlem G. Koz, Turkey Mario R. Romano, Italy Paul Baird, Australia Hiroshi Kunikata, Japan Marta Sacchetti, Italy Angelo Balestrazzi, Italy Toshihide Kurihara, Japan Wataru Saito, Japan Antonio Benito, Spain Sentaro Kusuhara, Japan Juan A. Sanchis-Gimeno, Spain Mehmet Borazan, Turkey George Kymionis, Greece Dirk Sandner, Germany Florence Cabot, USA Achim Langenbucher, Germany Ana Raquel Santiago, Portugal Carlo Cagini, Italy Van C. Lansingh, Mexico Patrik Schatz, Sweden Francis Carbonaro, Malta Paolo Lanzetta, Italy Kin Sheng Lim, UK Gonzalo Carracedo, Spain Theodore Leng, USA Wisam A. Shihadeh, USA Arturo Carta, Italy Hong LIANG, France Bartosz Sikorski, Poland Alejandro Cerviño, Spain Marco Lombardo, Italy ASugar,USA Chi-Chao Chan, USA Antonio Longo, Italy Shivalingappa K. Swamynathan, USA Lingyun Cheng, USA Norberto López-Gil, Spain Nóra Szentmáry, Hungary Chung-Jung Chiu, USA Tamer A. Macky, Egypt Masaru Takeuchi, Japan Colin Clement, Australia Mauricio Maia, Brazil Suphi Taneri, Germany Inés Contreras, Spain Edward Manche, USA Christoph Tappeiner, Switzerland Miguel Cordero-Coma, Spain Flavio Mantelli, USA Stephen Charn Beng Teoh, Singapore Ciro Costagliola, Italy Leonardo Mastropasqua, Italy Panagiotis Theodossiadis, Greece Roberto dell’Omo, Italy Cosimo Mazzotta, Italy Biju B. Thomas, USA Vasilios F. Diakonis, USA Enrique Mencía-Gutiérrez, Spain Oren Tomkins-Netzer, UK Priyanka P. Doctor, India Marcel Menke, Switzerland Lisa Toto, Italy Beth Edmunds, USA CarstenH.Meyer,Switzerland Maurizio Uva, Italy Manuel S. Falcão, Portugal Elad Moisseiev, Israel Manuel Vidal-Sanz, Spain Bao Jian Fan, USA Mário Monteiro, Brazil Paolo Vinciguerra, Italy Michel E. Farah, Brazil Paolo Mora, Italy Gianmarco Vizzeri, USA Paulo Fernandes, Portugal Lawrence S. Morse, USA Suichien Wong, UK Giulio Ferrari, Italy Majid M. Moshirfar, USA Victoria W Y Wong, Hong Kong Michele Figus, Italy Marco Mura, USA Tsutomu Yasukawa, Japan Paolo Fogagnolo, Italy Jean-Claude Mwanza, USA Hyeong Gon Yu, Republic of Korea Joel Gambrelle, France Ramon Naranjo-Tackman, Mexico Vicente Zanon-Moreno, Spain M.-A. Gamulescu, Germany Anna Nowinska, Poland Tomasz Zarnowski, Poland Santiago García-Lázaro, Spain Carlo Nucci, Italy María J. González-García, Spain Naoki Okumura, Japan Contents

Myopia: Risk Factors, Disease Mechanisms, Diagnostic Modalities, and Therapeutic Options Malgorzata Mrugacz , Marzena Gajecka, Ewa Mrukwa-Kominek, and Katarzyna J. Witkowska Editorial (2 pages), Article ID 7942379, Volume 2018 (2018)

Internal Astigmatism and Its Role in the Growth of Axial Length in School-Age Children Liangcheng Wu , Chenghai Weng ,FeiXia , Xiaoying Wang ,andXingtaoZhou Research Article (5 pages), Article ID 1686045, Volume 2018 (2018)

Myopia Progression Risk: Seasonal and Lifestyle Variations in Axial Length Growth in Czech Children Stepan Rusnak , Vaclav Salcman, Lenka Hecova, and Zdenek Kasl Research Article (5 pages), Article ID 5076454, Volume 2018 (2018)

Effect of Altered Retinal Cones/Opsins on Refractive Development under Monochromatic Lights in Guinea Pigs Leilei Zou, Xiaoyu Zhu, Rui Liu, Fei Ma, Manrong Yu, Hong Liu , and Jinhui Dai Research Article (9 pages), Article ID 9197631, Volume 2018 (2018)

Choroidal and Retinal Thickness of Highly Myopic Eyes with Early Stage of Myopic Chorioretinopathy: Tessellation Yanping Zhou, Minlu Song, Minwen Zhou, Yiming Liu, Fenghua Wang ,andXiaodongSun Research Article (9 pages), Article ID 2181602, Volume 2018 (2018)

Early Intervention and Nonpharmacological Therapy of Myopia in Young Adults Katarzyna Zorena , Aleksandra Gładysiak, and Daniel Ślęzak´ Review Article (11 pages), Article ID 4680603, Volume 2018 (2018)

The Comparison of Regional RNFL and Fundus Vasculature by OCTA in Chinese Myopia Population Yuanjun Li , Hamza Miara ,PingboOuyang ,andBingJiang Research Article (10 pages), Article ID 3490962, Volume 2018 (2018)

Long-Term Natural Outcomes of Simple Hemorrhage Associated with Lacquer Crack in High Myopia: A Risk Factor for Myopic CNV? Bing Liu , Xiongze Zhang, Lan Mi, Ling Chen, and Feng Wen Research Article (7 pages), Article ID 3150923, Volume 2018 (2018)

Modern Diagnostic Techniques for the Assessment of Ocular Blood Flow in Myopia: Current State of Knowledge Ewa Grudzińska and Monika Modrzejewska Review Article (8 pages), Article ID 4694789, Volume 2018 (2018)

Prevalence and Related Factors for Myopia in School-Aged Children in Qingdao Jin Tao Sun ,MengAn ,XiaoBoYan,GuoHuaLi ,andDaBoWang Research Article (6 pages), Article ID 9781987, Volume 2018 (2018)

The Influence of Environmental Factors on the Prevalence of Myopia in Poland Maciej Czepita, Damian Czepita, and Wojciech Lubiński Research Article (5 pages), Article ID 5983406, Volume 2017 (2018) Hindawi Journal of Ophthalmology Volume 2018, Article ID 7942379, 2 pages https://doi.org/10.1155/2018/7942379

Editorial Myopia: Risk Factors, Disease Mechanisms, Diagnostic Modalities, and Therapeutic Options

Malgorzata Mrugacz ,1 Marzena Gajecka,2 Ewa Mrukwa-Kominek,3 and Katarzyna J. Witkowska 4

1Medical University of Bialystok, 15-089 Białystok, Poland 2Poznan University of Medical Sciences, 61-701 Poznan´, Poland 3Medical University of Silesia, 40-055 Katowice, Poland 4Medical University of Vienna, 1090 Wien, Austria

Correspondence should be addressed to Malgorzata Mrugacz; [email protected]

Received 17 April 2018; Accepted 18 April 2018; Published 26 June 2018

Copyright © 2018 Malgorzata Mrugacz et al. "is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Myopia is a global problem, being particularly prevalent in education, and urbanization. "e interactions between genes the urban areas of East and Southeast Asia. "e distribution and environmental factors may be significant in determining of myopia according to the World Health Organization is individual risks of high myopia and may help explain the not equal in different countries and the age groups. In pathogenetic mechanisms of myopia in human population. children, the prevalence of myopia is 11.7% and ranged from In the past years, various techniques had been used to 4.9% in Southeast Asia to 18.2% in the Western Pacific study ocular blood in myopia, such as fluorescein angiog- Region. In adults, the prevalence of myopia is 26.5% and raphy (FA), indocyanine green angiography (ICGA), color ranged from 16.2% in the Americas to 32.9% in Southeast Doppler imaging (CDI), optical coherence tomography Asia. "e results of metaregression showed that the prev- (OCT), and optical coherence tomography angiography alence of myopia increased from 10.4% (1993) to 34.2% (OCTA). "ese tools provide a noninvasive and quantitative (2016) [1]. In 2050, a total of 4758 million people worldwide approach for monitoring choroidal and retinal changes in (49.8% of the world’s population) are expected to be myopic, pathologic myopia. Especially, OCTA is an imaging tech- and 938 million people (9.8% of the world’s population) are nique that enables high-speed, high-resolution, and depth- expected to suffer from high myopia. In addition to the resolved imaging of the retinal and choroidal vasculatures in economic and social burdens, associated ocular complica- myopia-related complications diagnosis such as chorior- tions may lead to visual impairment [2]. Myopia has a di- etinal atrophy and choroidal neovascularization (CNV). verse etiology, with both environmental and genetic factors Most nearsighted patients observe marked improvement believed to be involved in the myopia’s development and with treatment including corrective lenses, corneal refractive progression. Genetic linkage studies have mapped the dozen therapy, and refractive surgery. Early treatment of myopia loci, while association studies have found more than 70 can prevent social and academic difficulties that can ac- different genes. Many of these genes are involved in com- company poor vision. mon biological pathways known to mediate extracellular "e first paper of this special issue addresses the axial matrix composition and regulate connective tissue remod- length growth depending on the season and the type of elling. Other associated genomic regions suggest novel behavior and demonstrates the impact of regular sporting mechanisms in the etiology of high myopia, such as activities and day light exposure as preventative factors mitochondrial-mediated cell death and photoreceptor- against the eyeball growth. "e second paper presents the mediated visual signal transmission. "e environmental study on altered retinal cones/opsins induced by mono- factors implicated in myopia include near work, light ex- chromatic lights that might be involved in the refractive posure, lack of physical activity, diet, a higher level of development in guinea pigs. "e third paper is on the 2 Journal of Ophthalmology choroidal thickness (CT) and retinal thickness (RT) in highly myopic tessellated eyes and the role of early quantitative assessment of choroidal thickness and qualitative examination of choroid morphology in predicting myopic maculopathy. "e fourth paper of this special issue presents nonpharmacological therapeutic possibilities of refraction defect prevention in young adults, with special regard to myofascial therapy, osteopathy, and massage of acupuncture points surrounding the eye. "e fifth paper describes the correlations between peripapillary vessel density, retinal nerve fibre layer (RNFL) thickness, and axial length (AL) with optical coherence tomography angiography (OCTA) in myopia. "e sixth paper addresses the relationship between simple hemorrhage (SH) associated with lacquer crack (LC) and myopic choroidal neovascularization (CNV) in high myopia. "e seventh paper proposes the newly developed diagnostic techniques for the assessment of ocular blood flow in myopics. "e two subsequent papers present the prevalence and related factors for myopia in school-aged children. Intensive near work (writing, reading, and working on a computer) leads to a higher prevalence of myopia, watching television does not influence the prevalence of myopia, and being outdoors decreases the prevalence of myopia.

Malgorzata Mrugacz Marzena Gajecka Ewa Mrukwa-Kominek Katarzyna J. Witkowska References [1] H. Hashemi, A. Fotouhi, A. Yekta, R. Pakzad, H. Ostadimoghaddam, and M. Khabazkhoob, “Global and regional estimates of prevalence of refractive errors: systematic review and meta-analysis,” Journal of Current Ophthalmology, vol. 30, no. 1, pp. 3–22, 2018. [2] E. Dolgin, “"e myopia boom,” Nature, vol. 519, no. 7543, pp. 276–278, 2015. Hindawi Journal of Ophthalmology Volume 2018, Article ID 1686045, 5 pages https://doi.org/10.1155/2018/1686045

Research Article Internal Astigmatism and Its Role in the Growth of Axial Length in School-Age Children

1 1 1 1,2 Liangcheng Wu , Chenghai Weng , Fei Xia , Xiaoying Wang , 2 and Xingtao Zhou

1Department of Ophthalmology, Jing’an District Centre Hospital of Shanghai, Fudan University, Shanghai, China 2Department of Ophthalmology and Vision Science, Eye and ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China

Correspondence should be addressed to Xingtao Zhou; [email protected]

Received 10 September 2017; Revised 12 December 2017; Accepted 24 December 2017; Published 18 April 2018

Academic Editor: Ewa Mrukwa-Kominek

Copyright © 2018 Liangcheng Wu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Objectives. To explore the role of internal astigmatism (IA) in the growth of axial length (AL) in school-age children. Methods. Total astigmatism (TA), corneal astigmatism (CA), and AL of all children in Jing’an District 2nd Centre Primary School in Shanghai were measured. In IA, the difference between TA and CA was also calculated using vector analysis. The association of axial length with IA, genders, and age was analyzed using linear regression. The difference of IA between both eyes was also calculated. The AL between both eyes was compared using paired samples t-test when DIA = 0 D, <0.5 D, and ≥0.5 D. Results. Six hundred and twelve cases (98.23%) in 623 children aged 7–12 yrs older entered into the study. Genders, age, and IA all affected AL. This could be represented by a linear regression line in the form AL = 21.46 − 0.43 ∗ gender + 0.22 ∗ age + 0.46 ∗ IA (male = 1, female = 2; t =701, P <001 for sex; t =116, P <001 for age; and t =66, P <001 for IA; R2 =016). The AL in the eye with larger IA was also longer when DIA was larger than 0.5 D (t =265, P <001). Conclusions. IA was observed to be associated with AL and might be a risk factor of the onset and progress of myopia in school-age children.

1. Introduction total astigmatism (TA) consists of CA and internal astigmatism (IA). TA and CA can be independently measured. The Myopia is becoming a common public health problem diﬀerence between the two, internal astigmatism (IA), is worldwide especially in eastern Asian countries [1]. The thought to arise from the internal optics of the eye, including myopia-related complications are major causes of visual asymmetries related to the crystalline lens [8]. We speculate impairments and blindness [1–3]. To explore the mecha- that IA may play a more important role in the progress or nism and risk factors of myopia is always the hot focus creation of myopia. In the present study, we examined TA, of myopia study. It is well known but still under debate that CA, and axial length (AL) for all children in Jing’an District astigmatism takes an important role in the creation and 2nd Centre Primary School in Shanghai, and the purpose progress of myopia in the growth and development stage of was to explore the role of IA in the growth of eye axial length. humans and some animals. Many studies supported that astigmatism was a risk factor for myopia progress or cre- 2. Methods ation [4–6]. But not all studies have shown an association between the presence of astigmatism and the progression The study was based on a school survey and was approved by of myopic refractive errors. Czepita and Filipiak reported the Jing’an District Hospital Ethics Committee and con- that a negative correlation was found between cornea astig- ducted in accordance with the principles of the Declaration matism (CA) and myopia progress, and a positive correlation of Helsinki. The study was a part of routine school refraction was observed between TA and myopia [7]. Astigmatism or screening program and was performed in Jing’an District 2nd 2 Journal of Ophthalmology

Centre Primary School. Jing’an District 2nd Central Primary 140 School was a school with 5 grades, 20 classes, and 623 chil- 120 dren including 335 male and 288 females in 2016. All chil- 100 dren were asked to test for uncorrected visual acuity, 80 60

presenting visual acuity, refraction, and axial length. The eye- Number 40 ball axial length was measured by a commercial instrument 20 (IOLMaster; Carl Zeiss Meditec AG, Jena, Germany). Noncy- 0 cloplegic autorefraction was performed using an Auto Ref- 789101112 Keratometer (HRK-7000A; HUVITZ Co. Ltd., Korea). In Age (yrs) fully automated mode, the Auto Ref-Keratometer performed Female at least five autorefractions in each eye and gave a standard- Male ized value as its output. TA, CA, and IA were expressed in negative correcting Figure 1: The distribution of gender at various age in 623 children. cylinder form and were described at the corneal vertex surface. So the vertex distance was set as zero during autorefrac- sphere and TA, CA, and AL along with DIA were showed tor examination and TA was given in the autorefractor in Table 1. output. CA axis was set along the Kmin meridian. We calculated CA based on the autokeratometry reading using a cor- 3.1. Association of AL with IA, Age, and Gender. The AL of neal refractive index of 1.3375. This takes into account the boys was 23.46 ± 0.92 mm, and that of girls was 23.01 negative refractive power of the posterior corneal surface ± 0.99 mm. The AL of boys was longer significantly than that − t =657 P <0001 [8]. CA was calculated as Kmin Kmax, where Kmin represents of girls (independent-samples t-test: , ). the meridian with the least refractive power and Kmax the There was a linear relationship between AL and age in both meridian with the greatest refractive power. IA was calcu- genders (linear regression analysis: t =1056, P <0001 in lated as the vector difference between TA and CA and was male; t =914, P <0001 in female; Figure 2). detailed described in other studies [8, 9]. The IA was 0.61 ± 0.46(−D) in boys and 0.66 ± 0.41(−D) The difference of IA between both eyes (DIA) was also in girls; there was no significant difference between genders calculated; these children were divided into 3 groups (independent-samples t-test: t =188, P >005). IA main- according to the DIA including DIA = 0 D, DIA <0.5 D, tained stable with age in both genders (linear regression anal- and DIA ≥ 0.5 D. ysis: t =056, P >005 in male; t =0053, P >005 in female). But a linear relationship was found between AL and IA (linear regression analysis: t =627, P <0001 in male; t =368, 2.1. Statistical Analysis. Statistical analysis was performed P <0001 in female; Figure 2). using SPSS software version 13 (SPSS Inc., Chicago, IL). IA Linear regression analysis showed that genders, age, and and DIA were expressed as absolute value (positive value) IA all affected AL. This could be represented by a linear in statistical process. The age, AL, and IA in between both regression line in the form AL = 21.46 − 0.43 ∗ gender + 0.22 genders were compared using independent-samples t-test. ∗ age + 0.46 ∗ IA (male = 1, female = 2; t =701, P <001 for Paired-samples t-test was used to compare AL between both t =116 P <001 t =66 P <001 < ≥ sex; , for age; and , for IA; eyes when DIA = 0 D, DIA 0.5 D, and DIA 0.5 D. Linear R2 =016 regression was used to analyze relationship between AL and ). age, relationship between IA and age, relationship between 3.2. Association of AL with DIA. The DIA was AL and IA, and relationship between AL and some factors −0.38 ± 0.42(D) in male and −0.33 ± 0.33(D) in female; the including age and genders along with IA. The sex ratio difference was not significant between genders (indepen- between boys and girls in various ages was compared using dent-samples t-test: t =162, P >005) and also did not vary a chi-square test. P <005 was considered as statistically with age (one-way ANOVA: F =066, P >005 in male; F significant. =018, P >005 in female), but when DIA was larger than 0.5 D, the axial length with larger IA was also longer 3. Results (pared-samples t-test: t =265, P <001) and was showed in Table 2. Six hundred and twelve cases (98.23%) in 623 children aged 7–12 yrs older were enrolled into the study, including 330 4. Discussion boys and 282 girls. Four children were excluded from the study because of being absent from school and 7 because of Cycloplegic refraction was a need in school-age children due obtaining unreliable data. The distribution of age in both to high accommodation. However, cycloplegic refraction was genders was showed in Figure 1; the average age between difficult to perform in school. AL is the primary determinant genders was not significantly different (independent-samples of nonsyndromic myopia. It is a parameter representing the t-test: 9.51 ± 1.59 yrs for boys versus 9.41 ± 1.56 yrs for girls, combination of anterior chamber depth, lens thickness, and t =079, and P >005), and there was no significant differ- vitreous chamber depth of the eye. The AL elongation in chil- ence in sex ratio between boys and girls in all ages (chi-square dren can be related to the normal growth of the eyeball and, test: χ2 =681, P >005). The refractive errors including thus, affect the refractive status of the eye. Considering the ora fOphthalmology of Journal

Table 1: Axial length, IA, and DIA in school children in Jing’an District 2nd Primary School 2016.

Axial length (mm) Sphere (−D) TA (−D) CA (−D) IA (−D) DIA (−D) Age (yrs) Male Female Male Female Male Female Male Female Male Female Male Female 7 22.93 ± 0.56 22.56 ± 0.58 0.16 ± 0.36 0.29 ± 1.13 0.91 ± 0.93 0.6 ± 0.44 0.92 ± 0.89 0.6 ± 0.52 0.60 ± 0.37 0.61 ± 0.36 0.34 ± 0.24 0.31 ± 0.30 8 23.15 ± 0.72 22.60 ± 0.78 0.31 ± 0.77 0.41 ± 0.97 0.89 ± 0.75 0.85 ± 0.56 0.84 ± 0.70 0.85 ± 0.62 0.63 ± 0.57 0.64 ± 0.37 0.43 ± 0.62 0.35 ± 0.30 9 23.41 ± 0.84 22.94 ± 0.93 0.37 ± 0.65 0.64 ± 1.29 0.79 ± 0.62 0.84 ± 0.75 0.83 ± 0.67 0.84 ± 0.74 0.58 ± 0.37 0.72 ± 0.42 0.36 ± 0.26 0.35 ± 0.34 10 23.37 ± 0.77 23.08 ± 0.93 0.51 ± 0.97 0.78 ± 1.30 0.85 ± 0.63 0.76 ± 0.58 0.88 ± 0.65 0.75 ± 0.60 0.63 ± 0.45 0.61 ± 0.43 0.41 ± 0.40 0.31 ± 0.39 11 23.71 ± 1.02 23.26 ± 1.19 0.97 ± 1.31 1.11 ± 1.40 0.89 ± 0.72 1.04 ± 0.85 0.88 ± 0.74 1.02 ± 0.83 0.57 ± 0.42 0.69 ± 0.48 0.31 ± 0.36 0.32 ± 0.39 12 24.16 ± 1.06 23.78 ± 1.06 1.22 ± 1.37 1.67 ± 1.65 1.05 ± 0.79 0.90 ± 0.49 1.10 ± 0.84 0.84 ± 0.51 0.68 ± 0.49 0.71 ± 0.35 0.40 ± 0.40 0.32 ± 0.34 Average 23.45 ± 0.92 23.01 ± 0.99 0.58 ± 1.04 0.76 ± 1.34 0.89 ± 0.73 0.83 ± 0.64 0.90 ± 0.74 0.82 ± 0.66 0.61 ± 0.46 0.66 ± 0.41 0.38 ± 0.42 0.33 ± 0.33 TA: total astigmatism; CA: corneal astigmatism; IA: internal astigmatism; DIA: difference of internal astigmatism between both eyes. The axial length of boys was longer significantly than that of girls (t =814, P <0001). A linear relationship between axial length and age was found in both genders (t =1056, P <0001 in male; t =914, P <0001 in female). And there was no significant difference in IA and DIA between genders (t =188, P >005 for IA; t =163, P >005). IA and DIA did not grow significantly with age in both genders (t =056, P >005 in male, and t =0053, P >005 in female, resp.). 3 4 Journal of Ophthalmology

IA and age 1.5 Axial length and age 30 y = 0.247x + 21.13 P < 0.05 y = 0.243x + 20.71 P < 0.05 1.0 25 IA (D) IA 0.5 20 R2 = 0.17 R2 = 0.14 Axial length (mm) Axial length 15 0.0 6 8 10 12 14 6 8 10 12 14 Age (yrs) Age (yrs) Male Male Female Female

DIA and age Axial length and IA 1.5 y = 0.47x + 23.14 P < 0.05 30 y = 0.50x + 22.67 P < 0.05 1.0 − D) 20 R2 = 0.056 0.5 R2

= 0.024 ( DIA 10 0.0 8 101214 Axial length (mm) Axial length 0 −0.5 0246 Age (yrs) IA (D) Male Male Female Female

Figure 2: The relationship between axial length and age as well as the relationship between internal astigmatism age.

Table 2: The axial length in diﬀerent DIA.

Group Cases Axial length in the eye with less IA (mm) Axial length in the eye with larger IA (mm) t P DIA = 0 D 128 23.27 ± 0.99 (right eye) 23.29 ± 0.96 (left eye) 0.89 >0.05 0 < DIA< 0.5 D 292 23.22 ± 0.92 23.24 ± 0.95 0.44 >0.05 DIA ≥ 0.5 D 192 23.17 ± 0.95 23.28 ± 0.97 2.65 <0.05 DIA: difference of internal astigmatism between both eyes; IA: internal astigmatism. contribution of AL, lens power, and corneal power together growth [12]. They pointed out that axial eye growth might using multiple linear regression analyses, AL can explain up alter anterior ocular structures through stretching and the to 96% of the variation of refraction in populations [10]. fact that changes in axial length correlated significantly with The AL is a valid parameter for monitoring myopic progres- changes in corneal power or lens power during early infancy. sion [10, 11]. In our study, the AL was used to evaluate the Although these results seem to be contradictory, we still refractive status and the growth of the eyeball in school-age speculate that IA was a stimulus factor of AL growth children. rather than the outcome of AL elongation. Firstly, IA Our study showed that genders, age, and IA all affected was independent from age, which meant that AL growth the AL. A linear relationship was found between AL and with age did not increase IA. Secondly, the AL growth IA. In fact, many factors including age, genders, outdoor mainly led to increase of CA [12]. Thirdly, the conclusion activities, ethics, refraction correction pattern, and so on all from the animal experiment was based on eyeball abnor- affect the AL growth. In order to exclude these disturbing fac- mal growth [12], and in the present study, most patients tors, we compared the AL difference between both eyes when were less than 26 mm. DIA = 0 D, 0–0.5 D, and ≥0.5 D. The eye with larger IA had Blurred image focusing on the retina was considered the also a longer AL (P <005) when the DIA was more than mechanism of myopia occurrence or progress. Deprivation 0.5 D, which suggested that IA might be a stimulus factor of of a focused retinal image can cause high myopia in primates myopia progress or occurrence. and chicks, and peripheral retinal hyperopic defocus impos- One study showed that it was possible that astigmatism ing peripheral hyperopic defocus produces axial myopia was a passive byproduct of abnormal posterior axial eye [13, 14]. Even with spectacle corrections, IA can create a Journal of Ophthalmology 5 blurred retinal image especially in the peripheral retina American children,” Optometry & Vision Science, vol. 90, because there is an axial distance between the corrected spec- no. 11, pp. 1267–1273, 2013. tacle and the intraocular lens (the internal astigmatism loca- [6] F. Rezvan, A. Yekta, H. Hashemi et al., “The association tion). The study confirmed the linear relationship between between astigmatism and spherical refractive error in a clinical AL growth and IA. It is this line of reasoning, along with population,” Iranian Journal of Ophthalmology, vol. 23, no. 4, reports of an association between astigmatism and the onset pp. 37–42, 2011. of myopia in animal experiment [4]. [7] D. Czepita and D. Filipiak, “Role of astigmatism in the creation We acknowledge certain limitations in our study. Firstly, of myopia,” Klinika Oczna, vol. 105, no. 6, pp. 385-386, 2003. the present study had a cross-sectional design based on a sin- [8] Y. C. Liu, P. Chou, R. Wojciechowski et al., “Power vector gle elementary school. The conclusion should be applied with analysis of refractive, corneal, and internal astigmatism in an caution and need to be further studied in the future. Sec- elderly Chinese population: the Shihpai Eye Study,” Investiga- ondly, AL was used as the only parameter for monitoring tive Ophthalmology & Visual Science, vol. 52, no. 13, pp. 9651– myopia progress in the study. In fact, other ocular structures 9657, 2011. such as the cornea, aqueous humor, lens, and the vitreous [9] S. Marasini, “Pattern of astigmatism in a clinical setting in humor also contribute to the refractive status of a given Maldives,” Journal of Optometry, vol. 9, no. 1, pp. 47–53, 2015. human eye. The ratio between the AL and corneal radius [10] W. Meng, J. Butterworth, F. Malecaze, and P. Calvas, “Axial may be a better indicator of myopia [15]. Thirdly, our study length of myopia: a review of current research,” Ophthalmolo- does not analyze the relationship between AL and TA (CA) gica, vol. 225, no. 3, pp. 127–134, 2011. and the relationship between high myopia and high astigma- [11] S. W. Cheung and P. Cho, “Validity of axial length measure- tism. Finally, in the corneal refractive astigmatism calculated ments for monitoring myopic progression in orthokeratol- from autoref, the results were rather coarse; it is better to use ogy,” Investigative Ophthalmology & Visual Science, vol. 54, – some advanced machine to measure corneal astigmatism, no. 3, pp. 1613 1615, 2013. such as IOL master [16]. [12] C. Kee and L. Deng, “Astigmatism associated with experimen- ” In conclusion, IA was observed to be associated with axial tally induced myopia or hyperopia in chickens, Investigative – length and might be a risk factor of the onset and progress of Ophthalmology & Visual Science, vol. 49, no. 3, pp. 858 867, myopia in school-age children. 2008. [13] J. Yang, P. S. Reinach, S. Zhang et al., “Changes in retinal metabolic profiles associated with form deprivation myopia devel- Conflicts of Interest opment in guinea pigs,” Scientific Reports, vol. 7, no. 1, article No author has conflicts of interest to report. 2777, 2017. [14] A. Benaventepérez, A. Nour, and D. Troilo, “Axial eye growth and refractive error development can be modified by exposing Acknowledgments the peripheral retina to relative myopic or hyperopic defocus,” This work was supported by the Clinical Multicenter Coop- Investigative Ophthalmology & Visual Science, vol. 55, no. 10, pp. 6765–6773, 2014. eration Project of Shanghai Science and Technology Com- “ mission (no.: 17411950200 and no.: 17411950208), the Eye [15] X. He, H. Zou, L. Lu et al., Axial length/corneal radius ratio: Disease Prevention Personnel Training Plan of Shanghai, association with refractive state and role on myopia detection combined with visual acuity in Chinese schoolchildren,” PLoS China (no.:15GWZK0601-QJGG02), the Shanghai Shenkang One, vol. 10, no. 2, article e0111766, 2015. Hospital Development Center (Grant no. SHDC12016207), and the Health and Family Planning Committee of Pudong [16] M. Shajari, C. Cremonese, K. Petermann, P. Singh, M. Müller, and T. Kohnen, “Comparison of axial length, corneal curva- New District of Shanghai (Grant no. PW2014D-1). ture, and anterior chamber depth measurements of 2 recently introduced devices to a known biometer,” American Journal References of Ophthalmology, vol. 178, pp. 58–64, 2017.

[1] P. C. Wu, H. M. Huang, H. J. Yu, P. C. Fang, and C. T. Chen, “Epidemiology of myopia,” Asia-Paciﬁc Journal of Ophthal- mology, vol. 5, no. 6, pp. 386–393, 2016. [2] F. Xia, L. Wu, C. Weng, and X. Zhou, “Causes and three-year incidence of irreversible visual impairment in Jing-an District, Shanghai, China from 2010–2015,” BMC Ophthalmology, vol. 17, no. 1, p. 216, 2017. [3] L. C. Wu, X. H. Sun, X. T. Zhou, and C. H. Wen, “Unrecog- nized and unregistered blindness in people 70 or older in Jin- g’an District, Shanghai, China,” International Journal of Ophthalmology, vol. 6, no. 3, pp. 321–326, 2013. [4] C. CHG and C. S. Kee, “Eﬀects of optically imposed astigmatism on early eye growth in chicks,” PLoS One, vol. 10, no. 2, article e0117729, 2015. [5] J. D. Twelker, J. M. Miller, D. L. Sherrill, and E. M. Harvey, “Astigmatism and myopia in Tohono O’odham Native Hindawi Journal of Ophthalmology Volume 2018, Article ID 5076454, 5 pages https://doi.org/10.1155/2018/5076454

Research Article Myopia Progression Risk: Seasonal and Lifestyle Variations in Axial Length Growth in Czech Children

1 2 1 1 Stepan Rusnak , Vaclav Salcman, Lenka Hecova, and Zdenek Kasl

1Department of Ophthalmology, University Hospital in Pilsen, Alej Svobody 80, 304 60 Pilsen, Czech Republic 2Faculty of Education, University of West Bohemia, Veleslavínova 42, 306 14 Pilsen, Czech Republic

Correspondence should be addressed to Stepan Rusnak; [email protected]

Received 24 October 2017; Accepted 6 February 2018; Published 6 March 2018

Academic Editor: Marzena Gajecka

Copyright © 2018 Stepan Rusnak et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The growth in the prevalence of myopia leads to the growth of socioeconomic stress in society. It is important to detect any potential risk factors leading to myopia onset and progression. Among the potential risk factors, the lack of natural daylight exposure and the lack of the physical activity together with excess of near-work activities in children are the most prevalent. In the study, the axial length growth depending on the season and the type of behaviour was measured. The assessment was performed in 12-year-old children, 398 eyes of whom were included and measured during the winter and summer period. The children were categorized by the amount of time spent on near-work, physical, and outdoor activity. Results. Statistically significantly higher (p <00001) axial length growth was observed during the winter period. Statistically significantly (p <00001) more frequently, the eyeball growth has been proved during the winter season. According to the way of spending leisure time, no statistically significant difference was reported within the individual subgroups in the development of the eyeball length during the observed period. However, statistically significant differences were ascertained in the eyeball initial length within various groups. Conclusion. The lack of daylight exposure may lead to myopia progression.

1. Introduction It is very important to look for the reasons for the growth of myopia prevalence in the population and to find ways to The prevalence of myopia is growing worldwide, and myopia reduce the occurrence of myopia and its progression due to is becoming a major epidemiological problem. In 2000, the increase of myopia occurrence in society, as well as the according to the latest studies, 1406 million people (i.e., potential severe health and social consequences. According 22.9% of the world’s population) suffered from myopia, and to the outcomes of the studies carried out in recent years, life- 163 million people (i.e., 2.7% of the world’s population) style can influence the onset and progression of myopia. suffered from high myopia. In 2050, a total of 4758 million Physical activity and stays in daylight have a possible protec- people worldwide (49.8% of the world’s population) are tive effect [6–8], while near work is a risk factor [9, 10]. expected to be myopic, and 938 million people (9.8% of the As previously mentioned, the prevalence of myopia is world’s population) are expected to suffer from high myopia dependent upon a number of factors. Therefore, we decided [1]. The prevalence of this refractive error varies according to to map this situation in the Central European population of age, ethnicity, and geographical locality [2]. children in the age range of 11 to 17 years. Biometric exami- High myopia is associated with comorbidities that nations of both eyes and examinations of central visual acuity increase the risk of severe and irreversible loss of vision, such of both eyes are performed at regular, six-month intervals. At as dense cataract, retinal detachment, subretinal neovas- the same time, questionnaire surveys are carried out, oriented cularization, and glaucoma [3–5]. Growth in the preva- towards the method of spending leisure time. We concen- lence of myopia leads to the growth of socioeconomic stress trate primarily on the development of the axial length of in society. the eyeball at particular periods of time and on the presence 2 Journal of Ophthalmology of any risk, or protective factors affecting the growth of the the Wilcoxon paired test and Friedman ANOVA analysis. axial length of the eyeball. Our research is conducted in The differences in categorical variables between the studied cooperation with specialists involved in physical education groups were tested using the chi-square test and Fisher exact and prevention, who evaluate the ascertained data on a con- test. With the aid of odds ratio expression, specificity, and tinual basis and prepare preventive programs for preschool- sensitivity, we searched for an optimal cut-off value of vari- aged children. ous factors in relation to the eye length growth. The repeated ANOVA test was used to evaluate the development of the eye 2. Materials and Methods length in relation to various factors, such as the amount of time spent reading, on the computer, outdoors, or on sports. 2.1. Methodology. A prospective single-centre study was initi- The relationships between the studied parameters were ated in the spring of 2016 (April‐May). The children enrolled described using the Spearman correlation coefficient and in this study are examined at six-month intervals. For the expressed using the linear regression (least-square method). purposes of this paper, we used the data from 3 initial exam- The statistical significance was determined at the bound- inations (time 1—spring 2016, time 2—autumn 2016, and ary of alpha = 5% (0.05). time 3—spring 2017), and according to the plan, the study will not be finished earlier than in the spring of 2019. 2.3. Patient Group. The study involves 264 children, junior The examination starts with the determination of the students of grammar schools in the city of Pilsen—a best-uncorrected central visual acuity of both eyes. The visual homogenous group from one geographical location (Pilsen), acuity is measured with ETDRS logMAR charts, at a distance Caucasian race, and exposed to a similar level of environ- of 4 metres; the room lighting intensity is between 50–100 mental pollutants, with similar diet habits. On account of foot-candles of light. During the examination, the school- lack of data (absence of children at the time of any examina- child is sitting and is without correction (that means without tion, failure to complete examination due to photophobia, spectacles or contact lenses), and the other eye is covered etc.), 66 children were removed from our statistics. with an eye patch or pad. At the time of initiation of the study, our research sample Subsequently, the ocular biometry is measured using the consisted of 396 eyes of 198 children in the age range of 11 to optical biometry technique. In our case, the ocular biometry 13 years (median of 12 years). The research sample consisted consists of determining the axial length (ALX, measured in of 43.4% boys and 56.6% girls. millimetres, the final value is an average of 3 measurements) The research sample was divided into various subgroups, and anterior chamber depth (ACD, measured in millimetres, according to the method of spending leisure time. 9.6% of the final value is an average of 5 measurements) of both eyes. children spend time outdoors less than 1 hour, 55% spend The measurements are provided in a noncontact way with 1 to 2 hours, and 35.4% spend more than 2 hours. 7.1% of IOL Master equipment from Zeiss. children are not involved in any sporting activities, 47% Afterwards, the questionnaire survey is done. spend 3 hours a day or less on sporting activities, and 46% The eye history of children is checked on a regular do sports more than 3 hours a day. 53% of the research sam- basis—primarily the previous history of eye surgeries, wear- ple spent less than 3 hours a day with near work and 47% ing of spectacles for vision correction, and its possible spent 3 hours and more. 60.6% of children spend less than changes. In addition, the questionnaire focuses on the 3 hours a day on the computer and 39.4% spend 3 hours method of spending leisure time after classes and necessary and more. home study and homework. The goal is to determine how many hours a day children spend outdoors during daylight, the amount of time spent on sports, and the amount of time 3. Results and Discussion spent on near work (reading, work on a mobile phone or tablet) and on the computer. 3.1. Results. In the statistical evaluation of the project pilot part, we focused on the development of the eye length in 2.2. Statistical Methods. The statistical analysis was carried two periods between time 1 and time 2 (i.e., between spring out using the SAS Institute Inc., Cary, NC, USA, and and autumn 2016—summer season) and time 2 and time 3 SW Statistics programs (StatSoft Inc., Tulsa, OK, USA). (i.e., between autumn 2016 and spring 2017—winter season). The basic statistical data, such as mean values, standard The median length of the eyeball was 23.34 mm at time 1 deviation, variance, median, minimum, and maximum (range of 21.15 to 23.73 mm, 75th percentile, 23.85 mm), values, were calculated for the measured parameters in the 23.37 mm at time 2 (range of 21.15 to 26.02 mm, 75th percen- whole research sample, as well as in individual groups and tile, 23.83), and 23.43 mm at time 3 (range of 21.11 to subgroups. Frequencies were tested for categorical variables. 26.25 mm, 75th percentile, 23.91 mm). Statistically signifi- Selected statistical figures were also graphically processed to cantly higher (p <00001) axial length growth during the so-called box and whisker plot diagrams, histograms, and winter period was observed (Figure 1). pie charts. Statistically significantly (p <00001) more frequently, To compare the differences in the distribution of individ- the eyeball growth during the winter season has been proved. ual parameters between various groups, we used a nonpara- In 77.02% of eyes, the axial length growth during the winter metric analysis of variance (Wilcoxon two-tailed test). The season was observed, contrary to 22.47% during the summer development of the eye length over time was tested using season (Figure 2). Journal of Ophthalmology 3

Parametric repeated ANOVA most cited [11]. The results of our research demonstrate that Vertical bars denote 0.95 confidence intervals 24.0 the eyeballs of our probands grew more during the winter ﬀ 23.9 season. The seasonal e ect on the progression of the eyeball ﬁ 23.8 length in myopia in Chinese children is con rmed, for exam- 23.7 ple, by Donovan et al. [12], and the similar conclusions were 23.6 found by Fulk et al. [7] in North American school children. 23.5 Similarly, as the authors of the said papers, we assume that 23.4 the main reason of this state is a generally lower exposure

ALX 23.3 to natural daylight and less amount of time spent outdoors 23.2 in the winter season. 23.1 In the Czech Republic, summer holidays last 2 months 23.0 (July and August), while winter holidays last only 2 weeks 22.9 (1 week in December and 1 week between February and 22.8 mid-April). The Czech Republic is between 48 and 51 Time = 1 Time = 2Time = 3 degrees of north latitude. At 50 degrees of north latitude, Figure the daylight lasts 13 hours and 30 minutes up to 16 hours 1 and 15 minutes in the period of July and August, and, for example, the daylight lasts only 8 hours and 5 minutes up to 8 hours and 15 minutes during the Christmas holiday According to the method of spending leisure time, no season in December [13]. That means that during several statistically significant difference was reported within the weeks of winter season, school children are not exposed individual subgroups in the development of eyeball length to daylight on working days. during the observed period, but statistically significant differ- Our paper also points out that a different growth of the ences were ascertained (using the parametric repeated eyeball length, in dependence of the method of spending ANOVA analysis) in the eyeball initial length (time 1) within leisure time, occurs in children before the start of study various groups. at grammar schools, that is, before 11 to 13 years of age. A statistically significant difference (p =00002) was Within the framework of preventive programs, it will be nec- demonstrated in the eyeball length at time 1 in children doing essary to focus on preschool-age children and juniors at near-work activities for almost 3 hours a day or more primary schools. (23.57 mm median) than children who were involved in this Sporting activities, as a preventive factor against excessive type of work for less than 3 hours a day (23.29 mm median) eyeball growth, have been proven to be effective if these activ- (Figure 3). A not statistically significantly (p =018) higher ities are performed for 3 hours a day, or more. By contrast, eyeball length at time 1 was found in the group working on near work and computer work could be a risk factor for the computer for 3 hours per day and more (23.49 mm increased eyeball growth if children spend 3 hours a day or median) versus the group involved in this type of activity less more with these activities (outside the framework of school than 3 hours (23.31 mm median) (Figure 4). The eyeball teaching and school duties). Contrary to our assumptions length at time 1 was statistically significantly (p =0002) and the results of other work [6], our study did not show lower in the group of children involved in sporting activities any protective effect of staying outdoors. As a possible cause for 3 hours and more (23.21 mm median), children involved of this discrepancy, we consider the fact that the length of in sporting activities less than 3 hours, respectively, children stay outdoors in general was ascertained regardless of the not involved in any sporting activities where the median of carried-out activities; therefore, the total length of outdoor the initial eyeball length was 23.56 mm, respectively, stay also counts the time the children spend on near work 23.51 mm (Figure 5). The highest eyeball length at time 1 (e.g., reading, working on a tablet/mobile phone, etc.). (23.53 mm median) was in the group of eyes of probands Our study also showed that no statistically significant spending their time outdoors for 2 hours and more; the low- difference occurred within 1 year in the growth of the eye- est eyeball length was in the group of probands spending ball length in comparison to individual groups with differ- their time outdoors for 1 hour a day or less (23.29 mm ent risk, or protective factors. We can assume therefore median); and in the group spending their time outdoors for that the influence of these factors is long lasting and cumu- 1-2 hours a day, the median eyeball length was 23.34 mm lates over time. In the next phase of our study, we will (Figure 6). The differences in between these groups were sta- therefore focus on determining the minimum time of influ- tistically significant (p =0002). ence of these factors that is necessary to capture the statis- Age and gender did not have a statistically significant tically significant changes in the growth of the axial eyeball effect on the eyeball length at any of the tested times. length. Katuzny and Koszewska-Kolodziejczak [14] point out to the fact that the proportional eye growth is devel- 4. Discussion oped in myopic eyes until the age of 14, and the growth in the axial length is significantly accelerated after this Myopia is known to be influenced by both genetic and envi- age. The study will continue at least until spring 2019, ronmental factors. The educational level, near-work over- and we consider it extending to spring 2023 (i.e., until the load, daylight exposure, and physical activity are among the time when the probands will achieve the age of 18 to 20) 4 Journal of Ophthalmology

Bar plot Variable: axial length growth per period

Nubmer of eyes of Nubmer Axial length growth per period: 305 eyes/77.02% Winter > summer

Winter = summer 2 eyes/0.51%

Winter < summer 89 eyes/22.47%

Figure 2

Parametric repeated ANOVA Parametric repeated ANOVA Vertical bars denote 0.95 confidence intervals Vertical bars denote 0.95 confdence intervals 24.0 24.0 23.9 23.9 23.8 23.8 23.7 23.7 23.6 23.6 23.5 23.5 23.4 23.4 ALX 23.3 ALX 23.3 23.2 23.2 23.1 23.1 23.0 23.0 22.9 22.9 22.8 22.8 Time = 1 Time = 2 Time = 3 Time = 1 Time = 2Time = 3

Near work less than 3 hours PC less than 3 hours Near work more than 3 hours PC more than 3 hours

Figure 3 Figure 4 in order to capture the period when stopping or accelerat- differences in eyeball length are statistically significant, ing the eyeball growth occurs. depending on the daily regimens of the children. Our study demonstrates the impact of regular sporting activities as a 5. Conclusions preventative factor against the eyeball growth; therefore, active and regular sporting activities should be included in Children and adult myopia is a considerable worldwide prob- preschool and school education, and children should be lem with the prevalence of myopia increasing over recent motivated to regularly perform these activities also after clas- decades, and expressive growth could also be expected in ses. Our paper also points to a negative influence of near the future. Discovering the causes of the development and work and a possible negative influence of work on the com- progression of myopia in the children population and puter for 3 hours a day, or more. The use of state-of-the-art designing preventive programs should belong among the pri- technology and means such as tablets, computers, and so orities of ophthalmologists and paediatricians. on is a frequent teaching trend already as early as in pre- The preschool age, or the start of school attendance, school education. Due to the significant burden of children should be critical for the initiation of preventative programs. with these devices after school too, regular use of these tech- Already, at the time of entering grammar schools, the nologies should be carefully considered in classrooms, and Journal of Ophthalmology 5

Parametric repeated ANOVA Disclosure Vertical bars denote 0.95 confidence intervals 24.0 23.9 The authors alone are responsible for the content and writing 23.8 of the paper. 23.7 23.6 23.5 Conflicts of Interest 23.4 ﬂ ALX 23.3 The authors report no con icts of interest. 23.2 23.1 23.0 References 22.9 “ 22.8 [1] B. A. Holden, T. R. Fricke, D. A. Wilson et al., Global Time = 1Time = 2Time = 3 prevalence of myopia and high myopia and temporal trends from 2000 through 2050,” Ophthalmology, vol. 123, no. 5, No sport activities – Sport less than 3 hours pp. 1036 1042, 2016. Sport more than 3 hours [2] P. J. Foster and Y. Jiang, “Epidemiology of myopia,” Eye, vol. 28, no. 2, pp. 202–208, 2014. Figure 5 [3] M. R. Praveen, A. R. Vasavada, U. D. Jani, R. H. Trivedi, and P. K. Choudhary, “Prevalence of cataract type in relation to axial length in subjects with high myopia and emmetropia in Parametric repeated ANOVA an Indian population,” American Journal of Ophthalmology, Vertical bars denote 0.95 confdence intervals – 24.0 vol. 145, no. 1, pp. 176 181.e1, 2008. 23.9 [4] Beijing Rhegmatogenous Retinal Detachment Study Group, 23.8 “Incidence and epidemiological characteristics of rhegmato- 23.7 genous retinal detachment in Beijing, China,” Ophthalmology, 23.6 vol. 110, no. 12, pp. 2413–2417, 2003. 23.5 [5] P. Mitchell, F. Hourihan, J. Sandbach, and J. J. Wang, “The 23.4

ALX relationship between glaucoma and myopia: the Blue Moun- 23.3 ” – 23.2 tains Eye Study, Ophthalmology, vol. 106, no. 10, pp. 2010 23.1 2015, 1999. 23.0 [6] D. Cui, K. Trier, and S. Munk Ribel-Madsen, “Eﬀect of day 22.9 length on eye growth, myopia progression, and change of 22.8 ” Time = 1Time = 2 Time = 3 corneal power in myopic children, Ophthalmology, vol. 120, no. 5, pp. 1074–1079, 2013. Outside less than 1 hour [7] G. W. Fulk, L. A. Cyert, and D. A. Parker, “Seasonal variation Outside 1-2 hours in myopia progression and ocular elongation,” Optometry and Outside more than 1 hour Vision Science, vol. 79, no. 1, pp. 46–51, 2002. [8] A. Russo, F. Semeraro, M. R. Romano, R. Mastropasqua, Figure 6 R. Dell’Omo, and C. Costagliola, “Myopia onset and progression: can it be prevented?,” International Ophthalmology, children and their parents should be thoroughly instructed vol. 34, no. 3, pp. 693–705, 2014. about the negative impacts of their overuse in near work [9] L. Muhamedagic, B. Muhamedagic, E. A. Halilovic, J. A. “ and computer work on the development of eyeball length Halimic, A. Stankovic, and B. Muracevic, Relation between ” and the possible progression of myopia. near work and myopia progression in student population, Materia Socio Medica, vol. 26, no. 2, pp. 100–103, 2014. To determine the critical age where the negative or pro- “ tective impact of the individual factors under consideration [10] L. J. Wu, Y. X. Wang, Q. S. You et al., Risk factors of myopic shift among primary school children in Beijing, China: a pro- begins to manifest, further work needs to be carried out. spective study,” International Journal of Medical Sciences, vol. 12, no. 8, pp. 633–638, 2015. [11] E. Goldschmidt and N. Jacobsen, “Genetic and environmental Ethical Approval eﬀects on myopia development and progression,” Eye, vol. 28, no. 2, pp. 126–133, 2014. The conduct of this study and the collection of the data “ ’ [12] L. Donovan, P. Sankaridurg, A. Ho et al., Myopia progression within it were approved by the hospital s Institutional Review in Chinese children is slower in summer than in winter,” Optom- Board. etry and Vision Science, vol. 89, no. 8, pp. 1196–1202, 2012. [13] https://www.timeanddate.com/sun/czech-republic/plzen?month= 10&year=2017. Consent [14] B. J. Katuzny and A. Koszewska-Kolodziejczak, “Changes of axial dimensions of the eye during growth in emmetropia, Informed consent to participate in this study was obtained myopia and hyperopia,” Klinika Oczna, vol. 107, no. 4-6, from the patients. pp. 292–296, 2005. Hindawi Journal of Ophthalmology Volume 2018, Article ID 9197631, 9 pages https://doi.org/10.1155/2018/9197631

Research Article Effect of Altered Retinal Cones/Opsins on Refractive Development under Monochromatic Lights in Guinea Pigs

1,2,3 1,2,3 1,2,3 4 1,2,3 1,2,3 Leilei Zou, Xiaoyu Zhu, Rui Liu, Fei Ma, Manrong Yu, Hong Liu , 1,2,3 and Jinhui Dai

1Department of Ophthalmology, Eye and ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, China 2Key Laboratory of Myopia, Ministry of Health, 83 Fenyang Road, Shanghai 200031, China 3Shanghai Key Laboratory of Visual Impairment and Restoration, Eye and ENT Hospital, Fudan University, 83 Fenyang Road, Shanghai 200031, China 4Department of Ophthalmology, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing 210018, China

Correspondence should be addressed to Jinhui Dai; [email protected]

Received 5 October 2017; Revised 19 December 2017; Accepted 17 January 2018; Published 20 February 2018

Academic Editor: Katarzyna J. Witkowska

Copyright © 2018 Leilei Zou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To analyze the changes of refraction and metabolism of the retinal cones under monochromatic lights in guinea pigs. Methods. Sixty guinea pigs were randomly divided into a short-wavelength light (SL) group, a middle-wavelength light (ML) group, and a white light (WL) group. Refraction and axial length were measured before and after 10-week illumination. The densities of S-cones and M-cones were determined by retinal cone immunocytochemistry, and the expressions of S-opsins and M-opsins were determined by real-time PCR and Western blot. Results. After 10-week illumination, the guinea pigs developed relative hyperopia in the SL group and relative myopia in the ML group. Compared with the WL group, the density of S-cones and S-opsins increased while M-cones and M-opsins decreased in the SL group (all, p <005); conversely, the density of S-cones and S-opsins decreased while M-cones and M-opsins increased in the ML group (all, p <005). Increased S-cones/opsins and decreased M-cones/opsins were induced by short-wavelength lights. Decreased S-cones/opsins and increased M-cones/opsins were induced by middle-wavelength lights. Conclusions. Altered retinal cones/opsins induced by monochromatic lights might be involved in the refractive development in guinea pigs.

1. Introduction wearing which affects the light sense also results in myopia [6–8]. Therefore, color sense, as another important charac- Myopia is the most common ocular disorder that causes teristic of vision in mammals, may also be involved in emme- visual dysfunction such as premature cataracts, glaucoma, tropization. A survey of epidemiology showed that the retinal detachment, and macular degeneration. The prev- prevalence of myopia is significantly lower in the students alence of myopia is increasing, while there has not been with color vision deficiencies than in those with normal color a breakthrough in the prevention and treatment of myo- vision [9]. The authors speculated that this phenomenon pia because the underlying mechanisms have not fully might be linked to reduced functionality of the L/M chro- been understood. matic mechanism. Kröger and Wagner [10] found that naso- Previous studies have suggested that emmetropization temporal diameters of fish, the blue acara, were enlarged depends on visual information [1, 2]. When form deprivation when they were raised in lights of longer wavelength. When is employed to reduced contrast and spatial frequency con- chickens were raised in blue or red light for two days, the tent of animals, myopia is induced [3–5]. Negative lens chickens in red light became 1.69 D more myopic during 2 Journal of Ophthalmology the subsequent rearing period compared with chickens raised in compliance with the ARVO Statement for the Use of in blue light [11]. All these studies suggest that emmetropiza- Animals in Ophthalmic and Vision Research. tion can be affected when the chromatic cues are modified, Sixty pigmented guinea pigs (2 weeks old) from the Ani- though the mechanism is still unclear. mal Experiments Laboratory (Fudan University, Shanghai, There are two kinds of photoreceptors in the retina: rods China) were randomly assigned to three groups. In the and cones. The latter mediate color vision [12]. Furthermore, SL group (n =20), the guinea pigs were raised under in foveate animals, high spatial resolution is mediated by 430 nm short-wavelength lights for 10 weeks. In the ML cone vision. Mice had grating acuity when lacking only func- group (n =20), the guinea pigs were raised under 530 nm tional rods but had no detectable grating acuity when lacking middle-wavelength lights. In the WL group (n =20), the both rods and cones [13]. Two or more types of cones with guinea pigs were reared in normal lights without any spectrally different visual pigments (opsin binds to 11-cis intervention. Three types of LED light tubes were used: retinal) are required to generate color discrimination. In short-wavelength light (blue light, peak value of 430 nm, the outer segment (OS), visual pigments absorb different half-bandwidth of 10 nm), middle-wavelength light (green wavelengths of light. In retina of primates, there are three light, peak value of 530 nm, half-bandwidth of 10 nm), and types of functional cones, which contain long-wavelength-, normal light (white light, broadband, color temperature of medium-wavelength-, or short-wavelength-specific opsin in 5000 K). The photon flux density of each treatment was OS [14, 15]. However, other mammals such as guinea pigs selected to produce equal quantal numbers for each group − − − − have only two types of cones that respond maximally to and was set at 3 × 10 4 μmol·cm 2·s 1 (about 1770 mW·m 2 − − two different wavelengths: S-cones respond to 430 nm for blue light, 700 mW·m 2 for green light, and 740 mW·m 2 short-wavelength light while M-cones respond to 530 nm for white light). Specially designed rearing cages of the middle-wavelength light [16]. In these mammals, cones have three groups were mutually independent, and different a characteristic distribution in retina. It has been established wavelength lights did not interfere with each other. Details that in guinea pigs, the ventral retina expresses mostly M- on the cage and light settings were described previously in cones while the dorsal retina expresses mostly S-cones. Materials and Methods [21]. All the animals were raised The expression of opsin in cones in retina is not constant. under a 12/12 h light/dark cycle. Long-term changes in the spectral composition of light, as typical for the transition from dusk to dawn, or changes in 2.2. Refraction Assessment. Refraction, corneal curvature the spectral transmittance of water at different depths, can (CC), anterior chamber depth (ACD), lens thickness (LT), alter the expression of levels of opsins and cones [17]. Previ- and axial length (AL) were measured at the onset of the ous studies showed that the expression of M-cones and experiment and 10 weeks later in the guinea pigs. Data of opsins in guinea pigs increased in 530 nm wavelength light both eyes were enrolled. Refraction was measured with reti- [18]. This observation shows that color processing in the ret- noscopy in a dark room. One hour before which, a drop of ina displays developmental plasticity. It is also expected that 1% cyclopentolate hydrochloride (Alcon, Belgium) was topi- the density of cones changes with axial length and refractive cally administered to achieve cycloplegia. Measures were per- state [19]. In guinea pigs with form deprivation or negative formed by an experienced investigator who was blinded to lens-induced myopia, the expressions of S-opsin mRNA the group assignment. The results of refractive states were increased. Retinal cones serve as detector for form depriva- recorded as the mean refractions in the horizontal and verti- tion and defocus [20]. Therefore, changes in the expression cal meridians. The corneal radius of curvature was measured of the cone opsins may play a role in the development of by keratometry (Topcon OM-4, Japan). The animals were experimental myopia. anesthetized with a topical application of 4% oxybuprocaine The study done by Hu et al. [18, 20] indicated that the hydrochloride, and then the ACD, LT, and AL were mea- number and distribution of M-cones changes with mono- sured by A-scan ultrasonography (11 MHz; Optikon HiScan chromatic light. In our research, we further investigated the A/B). More details for the specific instruments and methods relationship between changes of cone densities and refractive for these biometric measurements were described in our development in monochromatic light. The aim of the present other published article [22]. study is to determine how long-term monochromatic environments affect the expression of cones and opsins and 2.3. Immunohistofluorescence. After 10-week raising, the whether the changes of refraction are related to the metabo- guinea pigs were executed by cervical vertebra dislocation lism of the cones in retina under these environments in at 8 o’clock. Ten animals were randomly selected from each guinea pigs. Our research may enhance the understanding group. The retinas that marked at the 12 o’clock position of mechanism between color sense and myopia and may by a notch were dissected in ice-cold PBS and immersed in bring forward a novel way to prevent myopia. 4% paraformaldehyde for 20 min. The left and right retinas were rinsed in PBS for three times and were prepared for immunocytochemistry of S-cones and M-cones, respectively. 2. Materials and Methods The left retinas were then exposed to polyclonal antibodies specific to the S-opsin (rabbit anti-S-opsin; Chemicon, 2.1. Animal Model. All research procedures were approved USA) at a 1 : 200 dilution. The retinas were then incubated by the Institutional Animal Care and Ethics Committee at with the primary antibodies overnight, rinsed for 5 times, ° the Eye and ENT Hospital of Fudan University and were and then incubated for 1 h in a dark chamber at 37 C with Journal of Ophthalmology 3 secondary antibodies (goat anti-rabbit IgG conjugated 1 : 1000 dilution (Jackson ImmunoResearch, Pennsylvania, FITC; Molecular Probes, USA) at a 1 : 100 dilution, rinsed USA). After washing, the membranes were stained with an for 5 times. The right retinas were exposed to primary ECL kit (Thermo Fisher Scientific, USA). Images were cap- polyclonal antibodies specific to the M-opsin (rabbit anti- tured with a Fujifilm LA-S3000 imaging system and analyzed M-opsin; Chemicon, USA) at a 1 : 200 dilution and a with MultiGauge software (Fujifilm, Japan). The band of secondary antibody (goat anti-rabbit IgG conjugated rho- each protein was normalized by β-tubulin (Kang Chen, damine; Molecular Probes, USA) at a 1 : 100 dilution at China) as an internal control. the same procedure. A scanning laser confocal microscope was used to photo- 2.6. Statistical Analysis. Statistical analysis was performed graph S-cones (green florescence) in the left eyes and M- using SPSS 15.0 statistical software (IBM, Chicago, IL). All ± cones (red florescence) in the right eyes. The dorsal retina values are shown as the mean standard deviation (SD). A measured 4 × 2 mm. It was measured from 2 mm vertically one-way ANOVA was used for comparisons of the three above the optic disc, and laterally, it was measured 2 mm groups. All pairwise comparisons were adjusted for multiple ff away from the optic disc on both sides. The ventral retina comparisons using the Bonferroni approach. A di erence at p <005 fi was similarly measured, but this was done on the opposite was considered statistically signi cant. side (vertically below the optic disc). To examine the topo- graphic distribution of the fluorescent cones, the numbers 3. Results of fluorescent cones were counted in contiguous sampling 3.1. Biometric Changes in the Guinea Pig Eyes Induced by windows (240 × 132 μm window) from one side to the other Monochromatic Lights. There were no significant differences side. The cone density data were analyzed with Image-Pro in refraction, CC, ACD, LT, or AL among the three groups of Plus v5.1 software. guinea pigs at the beginning of the experiments. After ten weeks, the mean sphere refraction in the SL group was signif- 2.4. Real-Time PCR. Total RNA was isolated from the left eye icantly more hyperopic than that in the WL group (1.95 D; of ten animals using the phenol-chloroform extraction +4.30 ± 0.88 D versus +2.53 ± 0.86 D; n =20, p <001), while method of Chomczynski and Sacchi [23]. The following refraction in the ML group was more myopic than that in primers obtained from Hu et al. [18] were used: β-actin, for- ± ± ′ ′ ′ the WL group eyes (0.75 D; +2.00 1.06 D versus +2.53 ward 5 -GACGAAGCCCAGAGCAAA-3 , reverse 5 -CCAG 0.86 D; n =20, p <001). The AL of the SL group was shorter ′ ′ AGGCATACAGGGACAG-3 ; S-cone, forward 5 -GAGT relative to that in the WL group by 0.26 mm (8.17 ± 0.11 mm ATTTCGCCTGGTTCCTT-3′, reverse 5′-CCTTCTGGGTT versus 8.40 ± 0.20 mm; n =20, p <001), while ML eyes were GTAGCTGATT-3′; M-cone, forward 5′-TCATCGCATCC longer relative to the WL eyes by 0.12 mm (8.56 ± 0.20 mm ± n =20 p <001 ATCTTTACCA-3′, reverse 5′-AGCACGAAGTAGCCGT versus 8.40 0.20 mm; , ). Other parameters, fi ff AGACC-3′. PCR conditions were performed as follows: such as CC, AC, and LT, showed no signi cant di erences ° 3 min preincubation at 95 C followed by 40 cycles of 30 s at among the three groups (Figure 1). ° ° ° 95 C, annealing at 58 C for 30 s, and extension at 72 C for fi 3.2. Densities of Retinal Cones Were Changed in 30 s. PCR products were veri ed by melting curve analysis, Monochromatic Lights. Because the dorsal retina was agarose gel electrophoresis, and DNA sequencing. All exper- reported to be dominated by M-cones, whereas the ventral iments were performed at least three times. Expression of the retina was dominated by S-cones, we studied the abundancy target mRNAs was normalized to β-actin levels, and the −ΔΔCT and opsin expression of the two types of cones in the dorsal 2 (cycle threshold) method was used to calculate rela- and ventral retinas. After 10 weeks, retinal cone immunocy- tive expression levels. The results of real-time PCR were tochemistry indicated that, compared with the WL group, reported as the fold changes in gene expression levels and the S-cone density increased and the M-cone density checked by analyzing melting curves. decreased in the dorsal and ventral retinas of the SL group (all, p <005) and the density of S-cone decreased and the 2.5. Western Blot. Total protein was extracted from frozen density of M-cone increased in the dorsal and ventral retinas retinas of the right eye of ten animals with ice-cold extrac- of the ML group (all, p <005) (Figures 2 and 3 and Table 1). tion buffer as well as protease inhibitors. After calculating the protein concentrations, samples (30 μg) were electro- 3.3. S- and M-Opsins Were Changed at mRNA and Protein phoresed and subjected to Western blotting using S-cone Expression Levels (Fold Changes). Real-time PCR showed and M-cone antibodies. The membranes were incubated that, after 10 weeks, relative S-opsin mRNA levels in the overnight with primary antibodies at a 1 : 100 dilution retinas of the SL, ML, and WL groups were 1.53 ± 0.23, (rabbit anti-guinea pig S-cone; Abcam, Cambridge, UK) 0.90 ± 0.15, and 1.24 ± 0.22, respectively; relative M-opsin and a 1 : 500 dilution (chicken anti-guinea pig M-cone; mRNA levels in the retinas of the SL, ML, and WL groups ° Millipore, Massachusetts, USA) at 4 C in blocking solution. were 1.12 ± 0.11, 1.94 ± 0.2, and 1.42 ± 0.2, respectively. The membranes were then washed three times with TBST Compared with the WL group, the expression of S-opsin and incubated with secondary antibodies for another 1 h at was increased (p <005), while M-opsin expression was room temperature. Goat anti-rabbit IgG-HRP was for S- decreased (p <005) in the SL group, and the expression cone at a 1 : 3000 dilution (Abmart, Shanghai, China), and of S-opsin was decreased (p <005), while M-opsin expres- rabbit anti-chicken IgY (IgG) (H + L) was for M-cone at a sion was increased (p <005) in the ML group (Figure 4). 4 Journal of Ophthalmology

10 6 9 # ⁎ ⁎ 8 5

4 6

# 5 3

Length (mm) 4 Diopter (D) Diopter

2 3

2 1 1

0 0 0‑week 10‑week CC ACD LT AL

SL group SL group

ML group ML group

WL group WL group (a) (b)

Figure 1: Biometric changes before and after intervention. Mean biometric results from guinea pigs reared under the three different lighting conditions (SL: short-wavelength light; ML: middle-wavelength light; WL: white light). (a) Diopters and (b) biometric results in 0-week and 10-week in the three groups. AL: axial length. ∗ means significant differences between the SL and WL groups. # means significant differences between the ML and WL groups.

SL group ML group WL group

50 휇m 50 휇m 50 휇m

Figure 2: S-cones changed in diﬀerent areas in the three groups. Top: dorsal retina; bottom: ventral retina. SL: short-wavelength light; ML: middle-wavelength light; WL: white light. Scale bar = 50 μm. Journal of Ophthalmology 5

SL group ML group WL group

50 휇m 50 휇m 50 휇m

Figure 3: M-cones changed in diﬀerent areas in the three groups. Top: dorsal retina; bottom: ventral retina. SL: short-wavelength light; ML: middle-wavelength light; WL: white light. Scale bar = 50 μm.

Table 1: The densities of S-cones and M-cones in the diﬀerent groups (mean ± SD, mm2).

SL group ML group WL group Cell Area Mean ± SD p Mean ± SD p Mean ± SD Dorsal 1476 ± 317.5 0.014 592 ± 105.8 0.018 887.7 ± 90.2 S-cone Ventral 17844 ± 518.7 0.026 11766 ± 108.3 0.029 15621 ± 185.6 Dorsal 12646 ± 554.7 0.041 18115 ± 761.4 0.020 16492 ± 835.3 M-cone Ventral 4646 ± 737.2 0.022 8494 ± 817.6 0.011 5992 ± 635.9 “p” represents the signiﬁcance of the diﬀerences between the eyes from the SL and WL groups or the ML and WL groups. SL: short-wavelength light; ML: middle-wavelength light; WL: white light.

Western blot analysis also showed that changes in the [21, 22, 27]. In this study, we selected guinea pigs aged 2 levels of S-opsins and M-opsins in the retina differed weeks, raised them under 430 nm or 530 nm monochromatic according to illumination at different wavelengths of light. lights for 10 weeks, and examined the longitudinal changes in After 10 weeks, relative S-opsin protein levels in the retinas of refraction and eye growth at the end the 10th week. The eyes the SL, ML, and WL groups were 1.34 ± 0.36, 0.70 ± 0.18, and from the WL group displayed a decrease in hyperopic error 1.00 ± 0.29, respectively; relative M-opsin protein levels in the from approximately 4.03 D to 2.53 D, accompanied by an retinas of the SL, ML, and WL groups were 0.34 ± 0.41, 1.17 ± elongation of the axial length from 7.57 mm to 8.40 mm. 0.31, and 0.76 ± 0.15, respectively. Compared with the WL Compared to the WL group, the eyes in the SL group demon- group, the expression of S-opsin was increased (p <005), strated more hyperopia by 1.95 D and a shorter axial length while M-opsin expression was decreased (p <005) in the by 0.26 mm. Meanwhile, the eyes in the ML group showed SL group, and the expression of S-opsin was decreased (p < a further reduction of hyperopic refractive error (0.75 D) 0 05), while M-opsin expression was increased (p <005)in and greater axial length (0.12 mm). For all these three groups, the ML group (Figure 5). corneal curvature showed a similar trend of change during the experiment, regardless of wavelength of lights they were 4. Discussion exposed to. The same were true of anterior chamber and lens thickness. This result is consistent with the results in fish [28] Chromatic cues may normally contribute to the regulation of and chicks [11]. refractive development [24–26]. Our previous study also Studies of refractive development under monochromatic indicated that ocular refraction and axial length of the eyes lights vary in different animals such as monkeys [29], tree of animals adjusted refractive states according to the wave- shrews [30], chicks [11], and guinea pigs [31]. Recent inves- length of light. Compared to animals exposed to white lights, tigation in tree shrews reported that chronic exposure to animals in mid-wavelength light become more myopic and long-wavelength lights (628 ± 10 nm) produced hyperopic animals in short-wavelength light become more hyperopic shifts, but in guinea pigs in our study (530 ± 10 nm), the 6 Journal of Ophthalmology

2.5 the reason for abnormal refractive development under monochromatic environment. In our previous research [22], the diﬀerence of the 2 refraction between the animals raised under 530 nm wavelength lights for 12 weeks and counterparts under 430 nm 1.5 wavelength lights was 4.5 D, while LCA between these two lights was only 1.5 D. In our study, after 10 weeks under 1 monochromatic lights, refractive changes were also larger than those required to compensate for LCA. The magnitudes of refractive changes did not agree well with prediction by the

Relative mRNA expression mRNA Relative 0.5 LCA in the guinea pigs’ eyes. Therefore, factors other than chromatic defocus must be involved to explain the overcom- 0 pensated refraction induced by monochromatic lights. S-opsin M-opsin As photoreceptor cells for bright light and color vision, retinal cones may be related to ocular growth [15, 34]. SL group Short-wavelength sensitive (S) cones (maximum absorbance, ML group 430 nm) dominate in the ventral parts of the retina in guinea pigs while middle-wavelength sensitive (M) cones (maxi- WL group mum absorbance, 530 nm) in the dorsal regions [35, 36]. Figure The transitional zone between these two retinal areas is pop- 4: S- and M-opsin mRNA expressions in the retinas of guinea ulated by coexpressing cones that express both S-cone and pigs irradiated by short-wavelength light, middle-wavelength light, or white light (represented as a bar graph). Expressions of S- M-cone photopigments [35]. In our study, we used blue opsins in the retinas of guinea pigs in the SL group were lights and green lights with peak sensitivities at 430 nm and significantly higher than those in the ML group (p <005) while 530 nm, respectively [36]. Lights at short wavelength and expressions of M-opsins in the retinas of guinea pigs in the middle wavelength will mainly be absorbed by the S-cones SL group were significantly lower than those in the ML group in the ventral part and M-cones in the dorsal part of the ret- (p <005). SL: short-wavelength light; ML: middle-wavelength ina, respectively. Thus, it was convenient to compare the light; WL: white light. ∗ means significant differences between the changes of cones and opsins in the ventral and dorsal parts SL and WL groups. # means significant differences between the under different lighting conditions in this study and further ML and WL groups. investigate the relationships of cones and refractions in the eyes of guinea pig. refractions changed in the opposite direction. Even for the The results of this study and the previous studies indi- same animal exposed in long-wavelength light, experimen- cate that refractive error changes are larger than those tal results of refractive state can be surprisingly opposite required to compensate for LCA. We speculate that this in different researches. The results of Smith et al. [32] also may be related to the changes in retinal cones and opsins. differ significantly from the findings of Liu et al. [29] in Lighting environments have influence on number and distri- rhesus monkeys under long-wavelength lights. Why do bution of cones, and such influence is associated with the patterns of results obtained in these studies differ? changes in expression of opsins [18]. For example, winter There are substantial methodological differences between flounders have only one cone pigment, but during metamor- the studies, such as age of the subjects, sources of lights phosis to benthic, they express three other cones [37]. Man- (LED versus long-wavelength pass filter), and luminance tis shrimps are sensitive to the wavelengths of lights in the levels. These differing results demonstrate clearly that we environment because these shrimps adjust the properties of do not yet understand all relevant parameters that deter- their cone filters [38]. Our study also indicated that, com- mine the effects of light of different spectral composition pared with the WL group, the S-cone density increased on refractive development. and the M-cone density decreased in the dorsal and ventral The mechanism for how monochromatic light controls retinas of the SL group, while the reverse was true of the eye growth is not well understood. Previous studies found ML group. Results of the study done by Hu et al. indicated that refractive development depends on the wavelength of that coexpressing cones (cones that express both S-cone the illuminating lights. Natural light, as a mixture of different and M-cone photopigments) in the transitional zone of the monochromatic lights with different wavelengths, may con- guinea pig retina could regulate the number of S-cones and tribute to a backward displacement of the retina toward the M-cones in the retina [18]. Thus, cones expressed in the eye’s image plane, causing longitudinal chromatic aberration transitional zone are probably related to or identical in ori- (LCA) [33]. LCA is a wavelength-dependent refractive error gin with S-cones and M-cones and can lead to plasticity in that influences the emmetropization of the eyes. For an different monochromatic environments. emmetropic human eye looking at a distant object, the focal Although in both our study and the research done by Hu image for each wavelength is usually formed at different loca- et al., M-cones displayed changes with monochromatic tions, with short wavelengths focused in front of the retina, lights, S-cones showed no change in number and distribu- long wavelengths behind the retina, and middle wavelengths tion. In our study, the density of S-cones changed under dif- at the retina [9]. Therefore, LCA was initially considered as ferent monochromatic lights, whereas in the study by Hu Journal of Ophthalmology 7

S‑opsin M‑opsin

훽‑Tublin 훽‑Tublin

1.8 ⁎

1.6 #

1.4

1.2

1 # ⁎ 0.8

0.6

Relative protein expression 0.4

0.2

0 S‑opsin M‑opsin

SL group

ML group

WL group

Figure 5: S- and M-opsin protein expressions in the retinas of guinea pigs illuminated by short-wavelength light, middle-wavelength light, or white light (represented as a bar graph). Expressions of S-opsins in the retinas of guinea pigs in the SL group were significantly higher than those in the ML group (p <005) while expressions of M-opsins in the retinas of guinea pigs in the SL group were significantly lower than those in the ML group (p <005). SL: short-wavelength light; ML: middle-wavelength light; WL: white light. ∗ means significant differences between the SL and WL groups. # means significant differences between the ML and WL groups. et al., S-cones were not affected in monochromatic lights wavelength sensitive cones respond to the myopic defocus [18]. The different response of S-cones may be explained by and the longer-wavelength sensitive cones respond to the different short-wavelength lights used and duration of light- hyperopic defocus [33]; for another, the changes in cones ing in these two studies. Hu et al. [18, 20] used violet light and opsins under monochromatic lights may activate relative whose peak value was at 400 nm, whereas blue light at signaling pathways by local regulation. Under monochro- 430 nm was chosen in our study. Besides, the modeling time matic lights, the metabolites of opsins, such as retinoic acid in this research was 2 weeks longer than Hu’s research, which and other factors in the retinoic acid cycle, may induce the may also cause the different results. retina to secrete a signal that modulates the related factors. As the key components of cones, opsins were studied as These factors in turn modulate eye growth, thereby overcom- well to see if there were any changes in expression with spec- pensating for defocusing of the LCA. tral environment. We compared expressions of S-opsins and The limitation of this paper is that the causal relationship M-opsins on the levels of mRNA and protein and found the between the change of cone expression and refractive devel- changes in cones match those in opsins. The increase in S- opment remains unclear. The alteration in cone opsin cone and M-cone densities led to an increase in S-opsin expression might be associated with the circumstantial and M-opsin expressions and vice versa. change of the monochromatic lights. Hopefully, future prog- In our study, opsin expression went up when the pre- ress could be made by pharmacologically changing S and M ferred wavelength was predominant but the biological sense cone opsin expressions in eyes of guinea pigs. In such an is still unknown. We hypothesize that change of visual by interference model under monochromatic lights, refractive monochromatic light is to provide cues for eye growth. The development can be further investigated. visual may trigger the changes in cone density and opsin In summary, retinal cones and opsins changed under expression that finally affect eye growth. For one thing, reti- monochromatic lights and might play a very important role nal cones may affect ocular growth of guinea pigs by in ocular growth. Further research is needed to study the responding to different defocusing signals under monochro- function of metabolic products of retinal cones and investi- matic light. Former studies have hinted that the short- gate the roles of cones and opsins in eye growth. 8 Journal of Ophthalmology

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Research Article Choroidal and Retinal Thickness of Highly Myopic Eyes with Early Stage of Myopic Chorioretinopathy: Tessellation

1 1 1 1 1,2 Yanping Zhou, Minlu Song, Minwen Zhou, Yiming Liu, Fenghua Wang , 1,2,3 and Xiaodong Sun

1Department of Ophthalmology, Shanghai General Hospital (Shanghai First People’s Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China 2Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China 3Shanghai Key Laboratory of Fundus Diseases, Shanghai, China

Correspondence should be addressed to Fenghua Wang; [email protected]

Received 30 October 2017; Revised 3 January 2018; Accepted 18 January 2018; Published 11 February 2018

Academic Editor: Katarzyna J. Witkowska

Copyright © 2018 Yanping Zhou et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To investigate the choroidal thickness (CT) and retinal thickness (RT) in highly myopic tessellated eyes. Methods. In this study, 115 highly myopic eyes were recruited and divided as tessellated fundus (n =93) and normal fundus (n =22). RT and CT were quantified using optical coherence tomography with enhanced depth imaging (EDI-OCT). Correlation between subfoveal CT (SFCT) and tessellation was analyzed using logistic regression models. Results. Tessellated fundus eyes had thinner CT than did normal fundus eyes, while RT was not statistically different across groups. The tessellated eyes had a thinner choroid than did the control eyes at all measured macular locations (all P <005). After adjustment for AL, age, and gender, the SFCT was significantly associated with tessellation. The odds ratio (OR) and 95% confidence interval (CI) was 0.975 (0.960–0.990, P =0001, binary logistics regression) and 0.991 (0.984–0.999, P =0022, Cox regression). The area under the curve (AUC) of SFCT was the greatest for detecting tessellation (AUC = 0.824, P <0001). For sensitivity and specificity analyses, SFCT had the highest diagnostic value (sensitivity = 81.8%, specificity = 74.2%). Conclusions. Highly myopic eyes with tessellation have thinner CT than do normal highly myopic eyes. CT may serve as an early pathologic predictor of high myopia.

1. Introduction earliest pathologic chorioretinal change of pathologic myopic eyes [8], similar to the Avila classification [9]. One of the High myopia is a common global public health problem. Its most common longitudinal progression patterns observed prevalence varies from 2.4% in the USA [1], 4.2% in Taiwan in a long-term study of myopia (mean follow-up time of [2], and 8.2% in Japan [3]. Worldwide, the prevalence of 12.7 years) [10] was for tessellated fundus to develop lacquer adult myopic chorioretinopathy ranges from 1.2 to 3.1% cracks and diffuse atrophy. Wang et al. [11] reported a [2, 4–6]. Further, the prevalence of myopia is particularly choroid thinning in eyes with lacquer crack. The choroid, as high as 95.5% in a population of Chinese university given its special position between sclera and retina and its students [7]. Given such high prevalence of myopia and role of offering nutrient and oxygen for outer retina [12], is myopic chorioretinopathy, the earlier-stage characteristics potentially important in the process of myopic chorioreti- of pathologic myopia is warranted. nopathy. However, it is unknown how choroidal thinning Recently, Ohno-Matsui et al. [8] have summarized the is associated with the initial stages (C1: tessellation) of pathologic myopic macular chorioretinopathy and graded pathologic myopia. them from grade C0 to C5 to describe the increasing severity. To characterize the choroid and to evaluate early tessella- fi Tessellated fundus is classi ed into category 1 (C1) and is the tion changes in myopic chorioretinopathy, we quantitatively 2 Journal of Ophthalmology assess the retinal thickness and choroidal thickness using to the RPE to the inner surface of the sclera (Figure 1) [11]; EDI-OCT in highly myopic eyes with normal visual acuity. (2) central retinal thickness was measured from the inner limiting membrane to the outer border of the RPE; (3) CT 2. Materials and Methods measurements were made at an interval of 0.5 mm from central fovea to superior, inferior, temporal, and nasal sides 2.1. Design and Patients. A cross-sectional study was per- (S, I, T, and N); (4) central subfield thickness was the mean formed to observe choroid and retina features of highly thickness of the central 1 mm subfield according to the Early myopic subjects diagnosed as tessellation fundus with Treatment of Diabetic Retinopathy Study Grid, which was normal visual acuity using EDI-OCT. This study was automatically measured by the built-in software with manual approved by the Ethical Review Committee of the Shanghai correction of segmentation or foveal location permitted; General Hospital affiliated with Shanghai Jiao Tong (5) macular choroidal thickness is referred to as the average University and was in accordance with the Declaration of of choroidal thickness in different locations. Each mea- Helsinki. All subjects signed an informed consent form after surement was independently performed by two observers an explanation of the purpose and procedures of the OCT (Yanping Zhou and Yiming Liu) for repeated-measures examination. analysis of variance. Major study ocular eligibility criteria include the following: (1) phakic eyes with best-corrected visual acuity 2.4. Diagnosis of Tessellation. Two of our authors (Minlu (BCVA) ≥ 20/20 and refractive error worse than −6 diopter Song and Minwen Zhou), masked from patients’ basic (D); (2) adults (older than 18 years); and (3) no myopic information and OCT scanning, graded the color fundus retinal degenerative lesion (C0) or only tessellated fundus photographs independently into normal fundus (C0) and fi fi (C1) related to myopia [8]. Tessellated fundus is de ned as tessellated fundus (C1) based on the classi cation reported the condition in which the choroidal vessels can be seen by Ohno-Matsui et al. [8]. Divergences were finally approved through the retina owing to reduced pigmentation or hypo- by another senior retinal specialist (Xiaodong Sun). plasia of the retinal pigment epithelium (RPE) [13]. Patients with history of hypertension or diabetes, con- 2.5. Statistical Analysis. All of the data were analyzed by a founding ocular disease, additional eye operations, includ- statistical software program (SPSS 18.0; SPSS, Inc., Chicago, ing vitreoretinal or cataract surgery or refractive surgeries, IL), and results presented are the mean ± standard devia- and other myopic complications (including lacquer cracks, tion (SD). The Kolmogorov-Smirnov test was used to posterior staphyloma, choroidal atrophy, choroidal neovas- decide normal distributions. Independent t-test was per- cularization, subretinal hemorrhage, macular traction, formed to test the between-group comparisons. One-way macular hole, retinal detachment, and retinoschisis) were ANOVA was applied to compare mean thickness in dif- excluded. ferent locations. Then, multiple linear regression analysis using stepwise selection method was used to see the asso- 2.2. Eye Examinations. The following were performed before ciation factors with SFCT. We also used logistic regres- the OCT scanning: (1) evaluation of refractive error without sion models to determine the risk factors of tessellation. pupil dilation by optometry (AR-310A, NIDEK, Japan); Further, age- and gender-matched subgroup analysis was (2) axial length measurement by IOLMaster (Carl Zeiss performed to determine the risk factors of tessellation Meditec AG, Germany); (3) intraocular pressure measure- using Cox regression. What is more, receiver operating ment by noncontact tonometer (TX-20, Canon, Japan); characteristic (ROC) curves were generated, and the area (4) color fundus photography (retinal camera CR-DGi, under the curve (AUC) was applied to assess the property Canon, Japan); (5) ultrasonography of the eye ball to exclude of biometric parameters in perceiving highly myopic tes- posterior staphyloma (B-scan CineScan, Quantel Medical, sellation. P <005 was considered statistically significant France); and (6) careful examination of the peripheral retina in all tests. by a senior retinal specialist (Fenghua Wang) using an indirect ophthalmoscope to exclude peripheral degeneration, 3. Results retinal tear, or retinal detachment. 3.1. Basic Information. There were 67 Chinese subjects from 2.3. EDI-OCT Scanning and Measurements. Choroidal thick- Shanghai included for our study, both eyes of the patients ness was measured using the built-in EDI Mode of the Cirrus were examined, and we excluded 19 eyes with the following High-Definition SD-OCT (model 4000, software version 5.2; conditions: 6 eyes cannot gain enough signal strength of Carl Zeiss Meditec, Dublin, CA) with the instrument close 5 lines in the HD-Scan, 3 eyes had lacquer cracks, and enough to the eye to obtain an inverted image. A 5-line 10 eyes had BCVA less than 20/20. 93 eyes were graded (6 mm) high-resolution raster scan was taken of each eye in as C1 (group C1: tessellated fundus), and 22 eyes were graded two directions (horizontal and vertical) by an experienced as C0 (group C0: normal fundus). Therefore, data from 93 operator. Also, a macular cube scanning of 512 ∗ 128 was eyes with tessellation and 22 eyes nontessellation with high- operated for an exclusion of other maculopathies in the quality OCT images were available and were included in posterior pole. Measurements from the scans were taken as the statistical analysis. Table 1 presents the basic features of follows: (1) choroidal thickness (CT) was measured from the two groups. There were significant differences between the outer portion of the hyperreflective line corresponding the two groups for axial length and spherical equivalent Journal of Ophthalmology 3

Figure 1: Examples of photographs of the posterior pole and spectral domain optical coherence tomography (SD-OCT) in highly myopic eyes. Fundus photograph (top left) and EDI-OCTs in the horizontal direction (bottom) and in the vertical direction (right). This is a tessellated fundus of a 21-year-old female with refractive error equal to −8.75 diopter and 27.24 mm elongation of the eye ball. Both horizontal (bottom) and vertical scans (right) across the fovea of this tessellated myopic eye. The yellow cross in the fundus photograph shows the scan protocol of high-resolution scan with enhanced depth imaging. The white and black dotted lines refer to the ETDRS auxiliary lines. The white concentric circles have diameters of 1.0 mm (inner), 3.00 mm (middle), and 5.0 mm (outer). Although the scan length was set to 6 mm, the actual measurements were stopped in loci of 5.0 mm because of a little missing image. The yellow double- headed arrows in OCT scans demonstrate the measured loci of the 500 μm intervals.

Table 1: Basic biometrics of tessellation eyes and normal fundus eyes.

Tessellated fundus eyes Normal fundus eyes P value No. of eyes 93 22 — Age, year 34.3 ± 10.5 37.2 ± 9.9 0.239 IOP at imaging, mmHg 15.81 ± 2.26 16.01 ± 2.59 0.724 ∗ Axial length, mm 27.04 ± 0.71 26.12 ± 0.74 <0.001 ∗ Spherical equivalent, diopter −8.813 ± 1.647 −7.882 ± 1.017 0.025 ∗ Subfoveal choroidal thickness, μm 165.9 ± 52.4 223.6 ± 39.3 <0.001 ∗ Macular choroidal thickness, μm 169.4 ± 45.1 224.3 ± 29.1 <0.001 Foveal retinal thickness, μm 191.2 ± 15.0 192.9 ± 14.7 0.626 Central subfield thickness, μm 249.2 ± 18.9 245.0 ± 21.0 0.360 Data are demonstrated as mean ± SD. IOP: intraocular pressure. ∗P value < 0.05. refraction (SER) (P <005). As expected, the highly myo- 3.2. Choroidal Thickness in Different Locations. The mean pic eyes with tessellation had longer axial length and subfoveal choroidal thickness (SFCT) was 165.9 μm (SD, worse refractive errors. There was no significant difference ±52.4) in the tessellation eyes and 223.6 μm (SD, ±39.3) in in mean age and intraocular pressure (IOP) between the the normal fundus eyes (P <0001). Relatedly, the macular two groups. choroidal thickness (MCT) was 169.4 μm (SD, ±45.1) in the 4 Journal of Ophthalmology

300 300

250 250 휇 m) 휇 m)

200 200

150 150

100 100 Mean choroidal thickness ( thickness choroidal Mean ( thickness choroidal Mean

50 50 F F T 2.5 T 2.0 T 1.5 T 1.0 T 0.5 T 2.5 T 2.0 T 1.5 T 1.0 T 0.5 N 0.5 N 1.0 N 1.5 N 2.0 N 2.5 N 0.5 N 1.0 N 1.5 N 2.0 N 2.5

Choroidal thickness in horizontal direction (C1) Choroidal thickness in horizontal direction (C0) (a) (b) Figure 2: Mean choroidal thickness of group C1 and group C0 in the horizontal direction. Group C1 is referred to as the highly myopic eyes with only tessellated fundus in the posterior pole, while group C0 is referred to as the normal highly myopic eyes. Both groups have a tendency for choroid thinning from the temporal side to the nasal side. Eyes with tessellation fundus have much thinner choroid in each locus in the horizontal direction.

300 300

250 250 휇 m) 휇 m)

200 200

150 150

100 100 Mean choroidal thickness ( thickness choroidal Mean ( thickness choroidal Mean

50 50 F F I 2.5 I 2.0 I 1.5 I 1.0 I 0.5 I 2.5 I 2.0 I 1.5 I 1.0 I 0.5 S 0.5 S 1.0 S 1.5 S 2.0 S 2.5 S 0.5 S 1.0 S 1.5 S 2.0

Choroidal thickness in horizontal direction (C1) Choroidal thickness in horizontal direction (C0) (a) (b) Figure 3: Mean choroidal thickness of group C1 and group C0 in the vertical direction. Choroidal thickness of normal highly myopic eyes in the vertical direction is thicker than that of highly myopic eyes with only tessellation fundus. Choroid becomes thicker from central to the surrounding of group C1. And the central subfoveal choroidal thickness of group C1 is the thinnest in the vertical direction. However, choroidal thickness in group C0 was much lesser than that in group C1. The central subfoveal choroidal thickness thins the most between the two groups. tessellation eyes and 224.3 μm (SD, ±29.1) in the normal 191.2 μm (SD, ±15.0) in the tessellation eyes and 192.9 μm fundus eyes (P <0001). Choroidal thickness (CT) decreased (SD, ±14.7) in the normal fundus eyes (P =0626). Also, horizontally from temporal to nasal positions as showed in their macular retinal thickness was not statistically signifi- Figure 2. And the CT in the vertical direction is shown in cant, with P value = 0.360 (P >005). We conclude that Figure 3. Table 2 demonstrates the mean CT of these two the retina thickness was similar between the two groups. groups at different loci in the horizontal direction. And Table 3 demonstrates the corresponding data in the vertical fi 3.4. Stepwise Multiple Linear Regression Analysis. As choroi- direction. The choroidal thickness was signi cantly thinner dal thickness was significantly different between the two in the tessellated fundus than in the normal fundus of highly P <005 groups as mentioned before, we speculated that it may be a myopic eyes in all locations (all ). risk factor of tessellation. Therefore, we performed stepwise analysis to find out factors associated with the SFCT. Age, 3.3. Retinal Thickness. The retinal thickness was also com- gender, axial length, and the tessellation diagnosis were pared between the two groups. The foveal thickness was included in this model. Table 4 exhibits the results of Journal of Ophthalmology 5

Table 2: Mean choroidal thickness in the horizontal direction. Table 4: Stepwise multiple linear regression model of subfoveal choroidal thickness. Tessellated Normal Location fundus eyes fundus eyes P value Beta (mm from fovea) Factors P value Mean ± SD, μm Mean ± SD, μm (95%, confidence interval) Temporal (2.5) 197.6 ± 50.3 266.3 ± 35.9 <0.001 Normal fundus 54.61 (29.55, 79.67) <0.001 Temporal (2.0) 192.4 ± 51.3 261.1 ± 30.4 <0.001 (versus tessellation fundus) − − − Temporal (1.5) 193.1 ± 50.1 255.4 ± 35.3 <0.001 Axial length (mm) 14.31 ( 27.06, 1.56) 0.028 − − − Temporal (1.0) 186.5 ± 53.8 245.3 ± 37.2 <0.001 Age (year) 1.60 ( 2.50, 0.71) 0.001 Temporal (0.5) 178.4 ± 53.0 231.2 ± 44.0 <0.001 Gender (male versus female) 29.39 (8.98, 49.80) 0.005 Fovea (0) 167.3 ± 53.6 223.2 ± 39.3 <0.001 Nasal (0.5) 153.3 ± 50.0 210.4 ± 40.3 <0.001 Nasal (1.0) 139.2 ± 47.9 192.7 ± 43.0 <0.001 Table 5: Stepwise multiple linear regression analysis of the Nasal (1.5) 119.2 ± 43.9 174.1 ± 40.4 <0.001 choroidal thickness in various loci (adjusted for axial length, age, and gender). Nasal (2.0) 99.8 ± 40.2 151.0 ± 36.0 <0.001 Nasal (2.5) 82.4 ± 35.8 125.7 ± 32.3 <0.001 95% confidence Mean difference interval Loci between C and P value 1 Lower Upper C groups (μm) 0 limit limit Table 3: Mean choroidal thickness in the vertical direction. SFCT −54.61 −79.67 −29.55 <0.001 Tessellated Normal Temporal (2.5) −68.71 −91.21 −46.20 <0.001 Location fundus eyes fundus eyes P value Temporal (2.0) −68.70 −91.31 −46.10 <0.001 (mm from fovea) Mean Mean − − − < CT ± SD, μm CT ± SD, μm Temporal (1.5) 62.30 84.92 39.68 0.001 Temporal (1.0) −58.80 −82.79 −34.81 <0.001 Inferior (2.5) 180.3 ± 54.1 221.6 ± 37.7 0.001 Temporal (0.5) −52.82 −77.00 −28.65 <0.001 Inferior (2.0) 180.8 ± 51.6 226.1 ± 40.2 <0.001 Nasal (0.5) −57.13 −79.85 −34.42 <0.001 Inferior (1.5) 176.1 ± 50.1 225.9 ± 38.2 <0.001 Nasal (1.0) −53.50 −75.60 −31.40 <0.001 Inferior (1.0) 170.9 ± 50.5 225.4 ± 36.6 <0.001 Nasal (1.5) −54.87 −74.74 −35.00 <0.001 Inferior (0.5) 169.7 ± 51.0 231.7 ± 36.0 <0.001 Nasal (2.0) −51.27 −69.81 −32.728 <0.001 Fovea (0) 164.5 ± 52.0 224.1 ± 39.8 <0.001 Nasal (2.5) −43.29 −59.83 −26.74 <0.001 Superior (0.5) 175.2 ± 51.8 232.2 ± 41.5 <0.001 Inferior (2.5) −41.33 −65.51 −17.14 <0.001 Superior (1.0) 182.4 ± 54.8 238.0 ± 40.3 <0.001 Inferior (2.0) −45.35 −68.70 −22.00 <0.001 Superior (1.5) 196.9 ± 55.9 257.8 ± 32.9 <0.001 Inferior (1.5) −49.80 −72.55 −27.05 <0.001 Superior (2.0) 206.2 ± 54.5 256.9 ± 43.1 <0.001 Inferior (1.0) −54.52 −76.75 −32.30 <0.001 Superior (2.5) 213.7 ± 56.5 257.9 ± 43.7 0.001 Inferior (0.5) −61.96 −84.76 −39.17 <0.001 Superior (0.5) −57.01 −80.51 −33.50 <0.001 Superior (1.0) −55.64 −80.24 −31.04 <0.001 fi multiple regression analysis. The tessellation classi cation Superior (1.5) −60.85 −85.46 −36.24 <0.001 P <0001 was associated with SFCT ( ) after adjusting for the Superior (2.0) −50.72 −75.40 −26.04 <0.001 axial length, age, and gender by multiple linear regression Superior (2.5) −44.20 −69.74 −18.66 0.001 analysis. We now calculated that between tessellation and nontessellation eyes; the latter had a thicker SFCT averaged SFCT: subfoveal choroidal thickness; C0: normal fundus; C1: tessellated as 54.61 μm than had tessellation eyes (P <0001). Likewise, fundus. this model was also used for other locations. Table 5 shows ff and SFCT for highly myopic tessellation still remained the detailed data in various locations. The di erences in all fi locations remained statistically significant (P <005). statistically signi cant. 3.6. Age- and Gender-Matched Subgroup Analysis. In the 3.5. Risk Factors Causing Tessellation. Further, we made present study, we performed 2 : 1 age- and gender-matched binary logistic regression models to determine the risk fac- case-control subgroup analysis to evaluate the potential risk tors of highly myopic tessellation. After screening for age, factors associated with myopic tessellation. Age was matched gender, axial length, refractive error, SFCT, and foveal retinal as ±3 years. Table 7 demonstrates the basic information of thickness for tessellation, there was a statistically significant each subgroup. Additionally, conditional logistic regression association between increased axial length and decreased model (Cox regression) was performed. After adjusting for SFCT as listed in Table 6. After the multivariate logistic the age, gender, axial length, refractive error, SFCT, and regression, the multivariate-adjusted ORs of axial length foveal retinal thickness, there was a significant association 6 Journal of Ophthalmology

Table 6: Risk factors associated with highly myopic tessellation.

Factors Unadjusted OR (95%, CI) P value Adjusted OR (95%, CI) P value Axial length 7.597 (2.547, 22.549) <0.001 5.622 (1.769, 17.872) 0.003 SFCT 0.979 (0.966, 0.991) 0.001 0.975 (0.960, 0.990) 0.001 SFCT: subfoveal choroidal thickness; OR: odds ratio; CI: conﬁdence interval.

Table 7: Basic biometrics of age- and gender-matched subgroups.

Tessellated fundus eyes Normal fundus eyes P value No. of eyes 44 22 — Mean age, year 37.3 ± 10.5 37.2 ± 9.9 0.953 IOP at imaging, mmHg 15.76 ± 2.40 16.01 ± 2.59 0.705 ∗ Axial length, mm 27.11 ± 0.78 26.12 ± 0.74 <0.001 ∗ Spherical equivalent, diopter −9.242 ± 1.585 −7.882 ± 1.017 0.001 ∗ Subfoveal choroidal thickness, μm 150.96 ± 49.9 223.6 ± 39.3 <0.001 ∗ Macular choroidal thickness, μm 158.92 ± 44.1 224.3 ± 29.1 <0.001 Foveal retinal thickness, μm 190.7 ± 14.6 192.9 ± 14.7 0.849 Central subﬁeld thickness, μm 246.4 ± 18.4 245.0 ± 21.0 0.787 Data are demonstrated as mean ± SD. IOP: intraocular pressure. ∗P value < 0.05.

– between increased axial length (OR 2.001, 95% CI 1.042 Table 8: AUC, sensitivity, and specificity of various biometric 3.843, P =0037) and decreased SFCT (OR 0.991, 95% CI parameters in detecting highly myopic tessellation. 0.984–0.999, P =0022). Sensitivity Specificity Factor AUC (95%, CI) P value 3.7. AUC Analysis of Ocular Parameters for Detecting (%) (%) Tessellation in Highly Myopic Eyes. The AUC, sensitivity, SFCT 0.824 (0.747, 0.901) <0.001 81.8 74.2 fi and speci city of ocular parameter were analyzed to diagnose AL 0.820 (0.716, 0.924) <0.001 78.5 77.3 highly myopic tessellation. Table 8 summarizes these results. RE 0.639 (0.529, 0.749) 0.043 81.8 50.5 The largest AUC was referred to SFCT (AUC = 0.824), and the AUC of axial length (AUC = 0.820) was rank only sec- FRT 0.528 (0.390, 0.666) 0.688 77.4 36.4 ond to SFCT, followed by refractive error (AUC = 0.639). AUC: area under the curve; CI: confidence interval; SFCT: subfoveal However, it was noted that foveal retinal thickness was choroidal thickness; AL: axial length; RE: refractive error; FRT: foveal not statistically significant for diagnosing highly myopic retinal thickness. tessellation (AUC = 0.528, P =0688). For the sensitivity and specificity analyses, SFCT had the highest diagnostic length, more myopia, and thinner choroid but no significant value (sensitivity = 81.8%, specificity = 74.2%). difference in retinal thickness. Previous EDI-OCT-based studies have associated choroidal thickness changes in 4. Discussion pathologic myopic eyes with lacquer cracks [11] and choroidal neovascularization [17, 18]. Also, Wang et al. [19] Previous data have shown the ocular predictors for high compared choroidal thickness in pathologic myopic eyes in myopia including a worsening of refractive error, an exten- early classification of dry-type myopic maculopathy which sion of axial length, and thinning of retina and choroid were with a tessellated fundus and with diffuse chorioretinal [14, 15]. Besides, female gender, older age, ethnicity of atrophy. Better BCVA, less myopia, shorter axial length, and developing countries, and less outdoor exercise lifestyle are less staphyloma were found in tessellation eyes than in the demographic risk factors [16]. A previous study also diffuse chorioretinal atrophic eyes. Relatedly, our study spe- showed that the thinning choroid was the main ocular cifically focused on these young subjects who had only predictor for lacquer cracks [11]. The present study examines tessellation fundus in the posterior pole (which is graded as the choroidal features and retinal thickness of high myopia C1, the earliest fundus changes of pathologic myopia), allow- in early stage: tessellation. And it was suspected that the ing us to quantify choroidal thickness changes and to infer thinning of choroid is the risk factor of great concern potential early pathologic prognostic indicators. Foveal reti- for tessellation. nal thickness of C0 group and C1 group had no statistically As present in Table 1, compared with the normal highly significant changes. Even foveal retinal thickness remained fi myopic eyes (C0 group), pathologic myopic eyes with a in the normal range despite a signi cant decrease in SFCT fi tessellated fundus (C1 group) had signi cantly longer axial in C1 group compared with C0 group [20, 21], suggesting that Journal of Ophthalmology 7 choroidal thinning may occur before retinal thinning in the found that the decreased choroidal thickness was indepen- early stage of high myopia and that accelerated choroidal dently associated with myopic tessellation after adjusting thinning may result in a series lesions of maculopathy. Thus, for AL, age, gender, and RE, which indicated choroid thin- knowing about the role of choroid may gain a better under- ning may be relatively the most important factor for standing of the start of pathologic myopia. tessellation. Until now, no one can figure out the AL elon- In addition to central subfoveal choroidal thickness, we gation and choroid thinning, the two factors which take also measured horizontal and vertical variations in CTs in place earlier and had more powerful influence in the for- the macula. It was observed that the choroid gradually mation of tessellation. However, our study proved that became thinner from the temporal to nasal side, similar to choroid thinning played a more important role in tessella- what was observed in several other studies of horizontal tion. The thinning of choroidal thickness does not certainly variation in CT of highly myopic eyes [18, 19, 22, 23]. Both present the occurrence of tessellation. It is only one stage of C1 group and C0 group had this tendency. Comparing tessellation formation. choroidal thickness at each corresponding locations of C1 Even though there were lots of studies on highly myopic fi group with C0 group, we found that it was signi cantly choroidal thickness, there were no such quantitative analyses thinner in eyes with tessellation changes. However, previous of choroidal thickness being associated with tessellation. In studies of normal eyes indicate that the choroid is thickest at this study, both multivariate logistic regression and age- the fovea in the horizontal direction [20, 21]. Ohsugi et al. and gender-matched Cox regression demonstrated that the compared the CT of otherwise normal highly myopic eyes thinner SFCT and longer axial length had significant associ- and normal eyes using three-dimensional tomography and ation with tessellation. So increased SFCT seemed to be a found that the choroid in all regions of myopic eyes is thinner protective factor for tessellation; in turn, the decreased SFCT than in normal eyes and only the outer nasal choroid was may be one risk factor for tessellation. Statistically, these find- significantly thinner than the central subfoveal choroid ings were significant; longer axial length and thinner SFCT [24]. The blood supply for the choroid originates from the eyes had greater risks for forming tessellation. These two posterior ciliary arteries in the macula and then travels to parameters could be the main parameters for the diagnosis the so-called watershed zones of the choroid periphery, of tessellation. which may be the reason for the reduction in CT towards Last but not least, the area under the curve (AUC) the outer nasal regions [25]. This may also explain why the predicted that pathologic myopic tessellation–associated pathologic myopia-associated depigmentation known as choroid degeneration in the posterior pole of the eye myopic conus first occurs on the temporal side of the occurred before retina degeneration. We made AUC analysis optic disc. to assess SFCT, AL, RE, and FRT in detecting highly myopic On the vertical direction, we found that the choroid was tessellation. The main AUC of SFCT was the highest, which thinnest at the central subfovea in tessellation eyes while was 0.824, 95% CI (0,747, 0.901), followed by axial length there was no significant difference between central subfoveal and then refractive error, which were statistically significant choroidal thickness and inferior choroidal thickness in for detecting highly myopic tessellation. However, the AUC normal highly myopic eyes. However, Ding et al. [26] found of foveal retinal thickness was not statistically significant, that the choroid was the thickest underneath the fovea in which was 0.528, 95% CI (0.390, 0.666). What is more, SFCT Chinese normal eyes. Those variations might change with and axial length had relatively great sensitivity (81.8% of the process of myopia. Elongation of axial length may explain SFCT) and specificity (77.3% of axial length), which means the phenomenon of greater choroidal thinning in the central SFCT, as one of the most important parameter, may play a fovea versus thinning found in the regions inferior and great role in detecting highly myopic tessellation. superior to the central fovea. Axial length is referred as to Nevertheless, this study has some limitations. Firstly, the distance between cornea and central fovea. Whether there was lack of prospective observations. Secondly, as all choroidal thinning leads to globe elongation or the inverse of the measurements were performed manually, the determi- remains unknown. Visual signal stimulation in fovea may nation of the sclera border was somewhat subjective. Thirdly, be another risk factor influencing the decrease of central sub- Tan et al. [28] had reported that choroidal thickness was foveal choroidal thickness. A brief but infrequent period of significantly different diurnally in normal healthy subjects. hyperopic defocus from negative lenses showed choroidal We did not scan the subjects’ choroid at the same time, but thinning without axial elongation in experimental chick eyes all of the OCT scanning was taken near noontime. Lastly, [27]. Since no experimental research could take place in there may be some residual error by not taking into account human eyes without invasion, longitudinal observation of axial length to correct for ocular magnification in this paper tessellation is needed. [29]. Also, as only tessellated pathologic myopic eyes are As it is known that C1 group eyes had decreased choroi- usually less myopic and have shorter axial length than does dal thickness in comparison with C0 group eyes, multiple severe chorioretinal atrophy, the refractive error and axial regression analysis revealed that the SFCT of C1 group eyes length are narrowly distributed in our study. Thus, correla- μ fi ff was 54.61 m on average thinner than that of C0 group eyes. tion of their choroidal thickness has no signi cant di erence, After adjusting of axial length, gender, age, and refractive which differs from other previous studies. Ikuno et al. [30] error by multivariate linear regression analysis, the mean and Ohno-Matsui et al. [31] have demonstrated that patho- fi ’ SFCT of C1 group eyes still remained statistically signi cantly logic degeneration starts at the choriocapillaris layer, Bruch s thinner than that of the C0 group eyes. Furthermore, we also membrane, and RPE layer. Myopia-related stretching of axial 8 Journal of Ophthalmology length and the ischemia and hypoxias resulting from hypo- population: the Hisayama Study,” Ophthalmology, vol. 119, perfusion may cause tearing of Bruch’s membrane and alter no. 9, pp. 1760–1765, 2012. the structure of RPE cells [32]. However, it remains unclear [7] J. Sun, J. Zhou, P. Zhao et al., “High prevalence of myopia and how choroidal thinning is associated with the beginning of high myopia in 5060 Chinese university students in Shanghai,” this chorioretinal degeneration. Further prospective studies Investigative Ophthalmology & Visual Science, vol. 53, no. 12, are needed to characterize longitudinal changes in the cho- pp. 7504–7509, 2012. roid, RPE layer, and outer retina in highly myopic eyes. Such [8] K. Ohno-Matsui, R. Kawasaki, J. B. Jonas et al., “International a follow-up study would focus on the role of choroidal photographic classification and grading system for myopic ” changes in the progression of pathologic myopia. maculopathy, American Journal of Ophthalmology, vol. 159, – In conclusion, choroid thins in highly myopic tessellated no. 5, pp. 877 83.e7, 2015, e877. eyes than in normal highly myopic eyes while retina does not, [9] M. P. Avila, J. J. Weiter, A. E. Jalkh, C. L. Trempe, R. C. Pruett, and C. L. Schepens, “Natural history of choroidal neovascu- suggesting an important role of the choroid in the early stage ” of myopic chorioretinopathy. Early quantitative assessment larization in degenerative myopia, Ophthalmology, vol. 91, no. 12, pp. 1573–1581, 1984. of choroidal thickness and qualitative examination of cho- “ roid morphology can be predictive of myopic maculopathy. [10] K. Hayashi, K. Ohno-Matsui, N. Shimada et al., Long-term pattern of progression of myopic maculopathy: a natural history study,” Ophthalmology, vol. 117, no. 8, pp. 1595– Conflicts of Interest 1611.e4, 2010. “ fl [11] N. K. Wang, C. C. Lai, C. L. Chou et al., Choroidal thickness The authors declare that there are no con icts of interest and biometric markers for the screening of lacquer cracks in regarding the publication of this paper. patients with high myopia,” PLoS One, vol. 8, no. 1, article e53660, 2013. Acknowledgments [12] J. Kur, E. A. Newman, and T. Chan-Ling, “Cellular and physiological mechanisms underlying blood flow regula- This work was supported by the National Nature Science tion in the retina and choroid in health and disease,” Foundation of China (81730026 and 81470640), Transla- Progress in Retinal and Eye Research, vol. 31, no. 5, pp. 377– tional Medicine Innovation Fund of Shanghai Jiao Tong Uni- 406, 2012. versity School of Medicine (15ZH4005), Shanghai Municipal [13] R. 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[22] I. Flores-Moreno, F. Lugo, J. S. Duker, and J. M. Ruiz-Moreno, “The relationship between axial length and choroidal thickness in eyes with high myopia,” American Journal of Ophthal- mology, vol. 155, no. 2, pp. 314–319.e1, 2013. [23] M. Ho, D. T. L. Liu, V. C. K. Chan, and D. S. C. Lam, “Choroi- dal thickness measurement in myopic eyes by enhanced depth optical coherence tomography,” Ophthalmology, vol. 120, no. 9, pp. 1909–1914, 2013. [24] H. Ohsugi, Y. Ikuno, K. Oshima, and H. Tabuchi, “3-D choroidal thickness maps from EDI-OCT in highly myopic eyes,” Optometry and Vision Science, vol. 90, no. 6, pp. 599– 606, 2013. [25] S. S. Hayreh, “In vivo choroidal circulation and its watershed zones,” Eye, vol. 4, no. 2, pp. 273–289, 1990. [26] X. Ding, J. Li, J. Zeng et al., “Choroidal thickness in healthy Chinese subjects,” Investigative Ophthalmology & Visual Sci- ence, vol. 52, no. 13, pp. 9555–9560, 2011. [27] J. Winawer and J. Wallman, “Temporal constraints on lens compensation in chicks,” Vision Research, vol. 42, no. 24, pp. 2651–2668, 2002. [28] C. S. Tan, Y. Ouyang, H. Ruiz, and S. V. R. Sadda, “Diurnal variation of choroidal thickness in normal, healthy subjects measured by spectral domain optical coherence tomography,” Investigative Ophthalmology & Visual Science, vol. 53, no. 1, pp. 261–266, 2012. [29] T. Higashide, S. Ohkubo, M. Hangai et al., “Influence of clinical factors and magnification correction on normal thickness profiles of macular retinal layers using optical coherence tomography,” PLoS One, vol. 11, no. 1, article e0147782, 2016. [30] Y. Ikuno, K. Sayanagi, K. Soga et al., “Lacquer crack formation and choroidal neovascularization in pathologic myopia,” Retina, vol. 28, no. 8, pp. 1124–1131, 2008. [31] K. Ohno-Matsui, T. Yoshida, S. Futagami et al., “Patchy atrophy and lacquer cracks predispose to the development of choroidal neovascularisation in pathological myopia,” British Journal of Ophthalmology, vol. 87, no. 5, pp. 570–573, 2003. [32] K. Neelam, C. M. G. Cheung, K. Ohno-Matsui, T. Y. Y. Lai, and T. Y. Wong, “Choroidal neovascularization in pathological myopia,” Progress in Retinal and Eye Research, vol. 31, no. 5, pp. 495–525, 2012. Hindawi Journal of Ophthalmology Volume 2018, Article ID 4680603, 11 pages https://doi.org/10.1155/2018/4680603

Review Article Early Intervention and Nonpharmacological Therapy of Myopia in Young Adults

1 2 3 Katarzyna Zorena , Aleksandra Gładysiak, and Daniel Ślęzak

1Department of Immunobiology and Environment Microbiology, Medical University of Gdańsk, Gdańsk, Poland 2Students’ Scientiﬁc Group Department of Immunobiology and Environment Microbiology, Medical University of Gdańsk, Gdańsk, Poland 3Emergency Medicine Workshop, Department of Emergency Medicine, Medical University of Gdańsk, Gdańsk, Poland

Correspondence should be addressed to Katarzyna Zorena; [email protected]

Received 14 October 2017; Accepted 13 December 2017; Published 8 February 2018

Academic Editor: Malgorzata Mrugacz

Copyright © 2018 Katarzyna Zorena et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Myopia is a condition of the eye where parallel rays focus in front of, instead of on, the retina, which results in excessive refractive power of the cornea or the lens or eyeball elongation. Studies carried out in recent years show that the etiology of myopia is complex with genetic and environmental factors playing a role. Refraction defects decrease the quality of vision, while progressing myopia can lead to partial loss of vision, which can be particularly dramatic in young adults. Therefore, it is so crucial to take appropriate actions aimed at preventing myopia progression. This is a review of nonpharmacological therapeutic possibilities of refraction defect prevention in young adults, with special regard to myofascial therapy, osteopathy, and massage of acupuncture points surrounding the eye.

1. Introduction Myopia is divided into three levels: low (≤−3.0 D), medium (between −3.0 D and −6.0 D), and high (over Myopia, being defined as more than or equal to −0.50 diopter −6.0 D). Approximately one-fifth of people with myopia (D), is one of the most commonly occurring defects of refrac- developed high myopia (≥−6 D), which can result in loss of tion. The prevalence of myopia varies in different parts of the vision due to retinal detachment, neovascularization, world, with the fastest growing tendency in the countries of cataract, glaucoma, or macular atrophy. High axial myopia East Asia, especially in Singapore and China [1]. In studies is caused by a too long eyeball and progresses with its elonga- carried out with a participation of 12-year-olds, myopia was tion and stretching in the posterior pole of the sclera, observed in as much as 62% of children examined in choroid, and retina [6, 7]. Recent studies showed that in Singapore and 49.7% in China, compared to 20.0% in the 2000, the number of people that developed myopia USA or 11.9% in Australia [2, 3]. Studies conducted in amounted to 1406 million while in 2010, it grew to 1950 mil- Poland on a large number children aged 6–18 years showed lion. It is predicted that by 2050, this number will have that among 11-year-old children, the prevalence of myopia increased to 4758 million [3]. Moreover, in the same manu- amounts to 12.17% [4]. Moreover, it was observed that there script, the authors pointed out that myopia is a condition is a relation between reading and writing from a short dis- occurring in people aged 10–39 years. However, the authors tance and the development of myopia. Computer work leads suggest that by 2050, myopia will be developing in patients to it as well while watching TV was not found to cause the aged 10–79 years (Figure 1) [3]. development of myopia. The authors also observed that The etiology of myopia is complex with genetic and envi- outdoor activity leads to lower prevalence of myopia in chil- ronmental factors playing a role, for example, education and dren and adolescents in the Polish population [5]. urbanization, lifestyle, vitamin D, and electronic devices 2 Journal of Ophthalmology

500 70%

60% 400 50%

300 40%

200 30%

20% (%) Prevalence Number (millions) Number 100 10%

0 0% 0-4 5-9 100+ 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90-94 95-99 Age group (years)

Number of myopes (2000) Prevalence of myopia (2000) Number of myopes (2050) Prevalence of myopia (2050)

Figure 1: Graph showing the likelihood of developing myopia in people aged between 10 and 79 years [3]. including smartphones [8–13]. Furthermore, the authors be associated with low-to-moderate amounts of myopia in point out that myopia varies among different ethnic groups; white subjects [13]. Biological activity of vitamin D is also that is, it is more common among children born in East Asia manifested in genome activity (together with nuclear recep- than those born in European ethnic groups [9]. Studies indi- tors, vitamin D connects with the vitamin D receptor cated that myopia occurs in 33–60% of children, whose par- (VDR) and then creates a heterodimer with the retinoid X ents also developed myopia. If only one parent presents with receptor (RXR) of transcription factor properties. Therefore, myopia, the defect occurs in 23–40% of children. In the case there are studies available, indicating that the physiological of children whose parents do not have myopia, the occur- role of active metabolites of cholecalciferol (D3) is also rence amounts to 6–15% [8]. manifested in the effect on the expression of genes that can affect myopia [13–16]. 2. Risk Factors for Myopia in Young Adults 2.2. Vitamin D Level versus Myopia. Studies carried out to 2.1. Genetic Factors versus the Risk of Myopia Development. It this date showed that low level of vitamin D3 observed is believed that inheritance of the refraction defect is multi- among various populations can be associated with the factorial and of polygenic nature. There is extensive research increasing prevalence of myopia [17, 18]. Yazar et al. sug- conducted, aimed at identifying the locus in the human gested that lower vitamin D3 level is one of the factors that genome that is responsible for myopia and at assessing the mediate in the prevalence of myopia between various ethnic effect of the genome on the phenotype presentation, that is, groups [17]. In many populations, the main source of vita- the status of the refraction defect. So far, there have been min D3 is the endogenous synthesis triggered by the expo- approximately 30 loci identified that are associated with sure of the skin to sunlight. Hypovitaminosis D is common myopia, among which at least 13 are associated with high among many populations, and its level is constantly decreas- myopia [6, 10, 11]. The list of genes potentially meaningful ing. This probably results from behavioral changes which for the development of both the hereditary and the sporadic lead to the limited exposure to sunlight. Fast growth in the form of high myopia, located in the identified loci, is long prevalence of myopia in East Asian populations results from and goes beyond the scope of this article. The list includes limitations in the amount of time people spend outside in the candidate genes such as TGIF (MYP2), LUM (MYP3), open air. Within the last 10 years, many observational studies COL1A1 (MYP5), IGF-1, PAX6 and SOX2, BICC1, and confirmed the hypothesis that longer time spent in the open RASGRF1. However, in subsequent years, there were contra- air protects one against myopia [5, 18–21]. It has been shown dictory study results published, which did not fully confirm that increased UVB exposure in children and adolescents is the effect of the above-mentioned genes in the development associated with regression of myopia, especially during the of myopia [11–13]. A recent study indicated that genetic puberty period [20]. Pan et al. analyzed studies published in variants in BICC1 and RASGRF1 are closely associated with Great Britain, which pertained to the relation between the high myopia, which appears to be a potential candidate for time spent outdoors, the level of vitamin D, and myopia. high myopia in a Chinese Han population [11]. Meta- They concluded that the time spent outdoors decreases the analysis showed a relation between gene PAX6 rs644242 risk of myopia development, which was well established in and high myopia in the Asian population [12]. Interestingly, numerous observational studies. They identified 5 studies it has been shown that polymorphisms within vitamin D showing the relation between vitamin D level in blood and receptor (VDR) at 12q13.11 and GC at 4q12-13 appear to the risk of myopia and 2 studies investigating changes in Journal of Ophthalmology 3 vitamin D receptor as a potential risk factor for the develop- distance from the lenses, close to the eyes. People using ment of myopia. Most of the proof was obtained from large- a HMD suffer from visual discomfort (headaches, blurred scale studies. Proof confirming that vitamin D plays any role vision) and eye strain. Han et al. carried out a subjective in the development of myopia was too indefinite, and the and objective analysis of the visual discomfort and eye mechanisms behind it were vague. Currently, it is still unclear strain caused by the use of HMD and smartphones [28]. whether vitamin D level triggers the onset and promoted the The experiment showed that the use of both HMD and progression of myopia. According to Pan et al., the level of smartphones may cause myopia, even though the users vitamin D can be used only as a marker of exposure to the were not able to see the loss of the quality of vision. This external environment, which is an actual protective factor mild change is temporary, and it subsides within a few against myopia [21]. minutes. Results show that during the use of HMD, the user presents with visual discomfort and eye strain, while 2.3. Lifestyle and Myopia in Young Adults. As early as in the during the use of smartphones, the intensity of symptoms 80s, near work was already considered a key risk factor for was statistically insignificant. HMD did not cause any developing myopia. In subsequent years, the authors ana- significant eye strain, but it did cause eye dryness, which lyzed the effect of the number of near work hours on the can lead to an eye infection [28]. Since introduction of occurrence of myopia in children. They observed that myo- smartphones into the market in 1997, the number of pia was statistically more common in children spending patients with progressive myopia has increased by 35%. more than 0.8 hour in front of a computer screen and reading Smartphones are currently omnipresent, and they accom- and/or writing for over 2 hours a day [22]. In a 4-year-long pany both children and adults in their everyday life. The study, Guo et al. found a relation between shorter time spent mean time of daily smartphone use is constantly growing, outside, elongation of time spent in closed spaces when learn- and between 2011 and 2013, it almost doubled from 98 ing, and axial elongation of the eyeball, resulting in the minutes to 195 minutes [29]. National studies conducted progression of myopia. The above-mentioned studies also in 2013 in the USA showed that 39% of the Americans confirmed the effect of other factors such as the child’s sex, use their cell phones in the bedroom one hour before they place of residence, and the level of parents’ education. The go to sleep, while among adolescents, this proportion was authors concluded that exposure to daylight prevents axial twice as high [30]. Smartphones are frequently equipped elongation of the eyeball [22]. Another study, conducted on with light-emitting diodes (LEDs), which suppress the a group of 514 children, confirmed that myopia in parents production of melatonin, cause mood changes, affect cog- and less time spent on physical activity are significant risk nitive function, and contribute to fatigue. An average factors for the development of myopia in children [23]. smartphone or tablet user holds the device approx. 30 cm According to the authors, devoting additional 10 hours per from his/her face, some even only 18 cm away from their week to reading increases the risk of myopia progression by face, compared to 40 cm when reading a newspaper. It is −0.08 diopters [24]. Studies carried out in Poland showed a estimated that within the next 10 years, the problem of double increase in the occurrence of myopia among students myopia will increase by 50% [31]. at medical universities compared to people of the same age but not studying. It is believed that approx. 13% of medical 2.5. Relation between High Level of Intelligence and Myopia. university students have high risk of developing myopia dur- Colom et al. defined intelligence as a general, mental abil- ing their studies, while those who already developed this con- ity to reason, solve problems, and learn [32]. The relation dition have high risk of progression [25]. The most recent between myopia and high intelligence level was investi- study shows the low occurrence of myopia among farmers, gated by many scientists [9]. The first study carried out which confirms the positive effect of spending time in the in 1995 showed a strong positive correlation between open air on the prevention of myopia. Studies also indicate myopia and high intelligence [33]. A study carried out in that the incidence of myopia is similar in children whose par- Singapore assessed the relation between myopia and the ents were farmers and those whose parent were not farmers. IQ in a group of 1204 Chinese children aged 10–12 years Thus, it can be concluded that the distribution of genes in three Chinese schools. The analysis involved several responsible for myopia is similar in both groups. Very low parameters including the age, sex, type of school, family incidence of myopia among farmers results from the fact that history of myopia, father’s level of education, the number they have no risk factors. Also, it can be concluded that in the of books read per week, and IQ. The investigators case of no environmental risk factors, myopia will not observed that children with higher IQ develop higher develop, even with genetic load [26]. myopia. What is more, the authors emphasized that the refraction defect cannot only result from the number of 2.4. The Effect of Electronic Devices on Myopia. Recent studies books read per week, and the IQ can be an independent have shown that looking at and reading text in a small font on risk factor for myopia [34]. In addition, other studies have a smartphone lead to eye strain, blurred vision, dizziness, and shown that children who read a lot get higher scores in IQ eye dryness. Blurred vision and tension of neck muscles can tests and are more prone to myopia, because they tend to cause headaches [27–31]. Moreover, in recent years, the do more near work. On the other hand, the researchers technology of head-mounted displays (HMD) was devel- revealed a statistically significant correlation between the oped, which allows the users to experience virtual reality occurrence of myopia in children and higher education (VR) [27, 28]. The HMD holds the phone at a certain of their parents [35, 36]. 4 Journal of Ophthalmology

3. Early Intervention and Nonpharmacological overnight wear can potentially cause infectious keratitis. Therapy of Myopia The previously obtained clinical data indicated that most microbiological infections associated with the use of the 3.1. Glasses and Contact Lenses in the Progression of Myopia. ortho-k lens resulted in a corneal scar and almost 10% In order to eliminate myopia or hinder its progression, sev- eyes required surgical treatment [47]. eral therapeutic methods have been tested, with a relatively poor effect though. These included contact lenses, bifocal 3.2. Use of “Chinese Eye Exercises” in the Treatment of and multifocal spectacle lenses, and pinhole glasses. It was Myopia in Children. In 1963, the Chinese government observed that progressive spectacle lenses do hinder the approved Chinese eye exercises in order to prevent myopia progression of myopia with statistical significance, though and protect the eyesight in children. The exercises have this effect is marginal [37, 38]. Another type of glasses recom- become a common and everyday habit of children in primary mended in myopia is the nonlensed, pinhole glasses invented and secondary schools. Chinese eye exercises are a type of thousands of years ago in India [39]. In the last 10 years, massage of acupuncture points surrounding the eye, and they billboards have been informing us that the use of nonlensed come from traditional Chinese medicine [48]. There are 16 glasses helps in exercising the oculomotor muscles and their acupuncture points located symmetrically within the human relaxation. However, there is no sufficient proof to confirm face. The BL-2 point is located at the medial end of the brows; the effect of continuous wearing of glasses on the permanent BL-1 is located at the medial angle of the eye; ST-2 is located correction of ametropia (abnormal ratio of accommodation in the line of the pupil, at the level of the nostrils; EX-HN5 is abilities and the eyeball length) and presbyopia [40]. The located on the forehead; and TE-23, EX-HN4, GB-1, and study enrolled 48 people aged 20–50, wearing nonlensed ST-1 are located around the eye sockets (Figure 2) [49]. glasses 7 days a week, and it was observed that the visual acu- Points BL-2, BL-1, and ST2 must be pressed for 1 minute, ity at a short distance was improved, but the patients also while the other ones for 30 seconds [49]. presented with decreased sensitivity in the field of vision test According to the most recent reports, there is no relation and contrast sensitivity testing [40]. Soft contact lenses do between the Chinese eye exercises and common occurrence not guarantee control of myopia progression either. Hard of myopia as indicated in some studies aimed at evaluating lenses, compared to soft ones, allow for a decrease in progres- the effectiveness of Chinese eye exercises on delayed accom- sion by 0.63 D, but they have been reported to cause tempo- modation in children [49–51]. A significant improvement in rary morphological corneal lesions [41]. accommodation delay (−0.10 D) directly after the exercises Retrospective studies and case studies carried out so far was observed in 54% of children. In 46% of children from have indicated that modern orthokeratology methods allow the study group, there was no improvement observed in us to hinder the progression of myopia in children [42–45]. accommodation delay, which may have been caused by One of the therapeutic methods to treat low and medium genetic or psychological factors, sensitivity of the acupunc- myopia in children and adolescents is the contact lenses of ture points, or the severity of the defect [49]. One hundred properly selected shape worn nightly. It is the so-called ninety patients participated in this study. The mean age was ortho-correction, which is based on reshaping (flattening) 12.62 ± 0.56. Sixty-three patients performed 5-minute the anterior surface of the cornea with rigid permeable con- exercises every day, before going to school. Therapy of the tact lenses. Flattening of the surface of the cornea sustains BL-2 and ST-1 points can trigger tear secretion, increase for the entire day after removal of the therapeutic lenses. the level of lactoferrin, and affect the intraocular pressure. Ortho-correction can be applied in myopia between 1 D Lactoferrin is an important element of the immune system, and 5 D [44]. The study showed that orthokeratology was a which is probably associated with its affinity for iron. By therapeutic alternative which allows for effective limitation picking up and bonding iron in the body, it prevents bacteria of the progression of myopia, compared to correction with from having access to the ion necessary for their develop- glasses, in a group of girls with a slower pace of progression ment and growth [52]. Chinese eye exercises can increase before the beginning of the study. Moreover, they presented the flow of blood to the eyeball and improve the response with a lower level of myopia at the beginning of the study, of the parasympathetic nervous system of the ciliary muscle deeper anterior chamber of the eye, higher optical power of by stimulation of the area of the eye or the visual cortex, the cornea, more elongated shape of the cornea, and larger and by that, it affects the process of accommodation as indi- diameter of the iris and pupil, and their parents presented cated in the first study assessing the long-term use of Chinese with a lower level of myopia [42, 44]. It was observed that eye exercise in children [52, 53]. The studies were conducted orthokeratology slows down the progression of myopia by in 201 primary school students aged 12.7 ± 0.5. The students 30–50%, which translates to 0.5 D per year, compared to cor- performed 5-minute-long exercises at least once a day for 2 rection with glasses and soft contact lenses [42]. However, years. In a group of those who systematically and correctly during a 7-year-long observation, the authors found no sta- performed the exercises (15% of all participants), after 2 tistically significant differences in respect of the change of years, the scientists observed slightly slower myopia progres- the length of the eyeball between the group of subjects treated sion (0.15 D) than that in the participants who did not with orthokeratology and the control group [46]. Moreover, perform the exercises correctly. The limiting factor in the the safety profile of orthokeratology is a matter of concern. study was the fact that approximately 90% of the children Compressive forces of the reverse geometry rigid lenses were not able to perform the exercises in accordance with can disturb the corneal epithelium, and a too long the standard procedures. It is problematic to locate the points Journal of Ophthalmology 5

Location of SCEE Location of SPEE properly and apply appropriate pressure force [54]. Other studies also showed the positive eﬀect of eye exercises of acupoints on the myopia in children. A study by Lin et al. indicated that 10-minute eye exercises performed daily have a less protective eﬀect in children aged 4–17 years living in rural areas [55].

3.3. Use of Vision Training in Patients with Myopia. The use of visual training with a simultaneous use of soft lenses in subjects with myopia is another nonpharmacological therapy of myopia in young adults. The training is to improve the (a) accuracy and dynamics of accommodation in young adults with myopia. An interesting visual training was carried out by Allen et al. [56]. The study enrolled 94 people with myopia. The study group used contact lenses with spherical aberration (SA) and performed visual training, while the control group used contact lenses without SA and did not perform any training. The patients performed 18-minute-long exercises with the use of a flipper for 6 weeks. The training comprised 82 exercises with a flipper +2.00 D/−2.00 D, at a distance of 40 cm. After 3 months, their accommodation improved significantly. Accommodation response to near (b) objects was improved by SA lenses, and the index of active accommodation was improved as a result of the visual training. The study confirmed that the treatment of the accommodation function is effective. Both the near and distant viewing functions were significantly improved after the training, compared to baseline [56].

3.4. Use of the Myofascial Therapy in the Treatment of Myopia. Disturbances in vision lead to increased tension within the trapezius and the sternocleidomastoid muscle, which can lead to cranial tension. Patients commonly com- (c) pensate vision problems by bending forward or turning their head to the sides. Overuse of the oculomotor muscles can cause headaches and neck pain. Those with myopia commonly present with protractive positioning of the head and cervical segment of the vertebral column, which leads to increased tonus of the thoracic muscles, the descending fibres of the trapezius, the levator scapulae, and the sternocleidomastoid muscle and decreased tonus of the deep muscles that stabilize the cervical segment of the vertebral column, the rhomboid muscles, and the serratus anterior (d) [57]. The suboccipital muscles are responsible for the stabilization of the upper cervical segment of the vertebral column and the normal movement of the cranium relative to the atlas and the atlas relative to the odontoid vertebra. One of the suboccipital muscles, the lesser posterior straight muscle of the head, has a proprioceptive function ensuring proper deep sensibility in the area of the head and neck. Atrophy of this muscle can result in decreased postural balance of the head and the neck [58]. Head protraction can be associated with (e) upper crossed syndrome, in which deep cervical flexors are Figure “ weakened and the suboccipital muscles are shortened. The 2: Location of the acupuncture points used in the Chinese upper cervical segment becomes extended, and there is eye exercise” technique [49]. Acupoint code (name in Chinese)—BL-2: cuanzhu; BL-1: jingming; ST-2: sibai; EX-HN5: compensation which is to lift the eyeballs. Long-lasting short- taiyang; TE-23: sizhukong; EX-HN4: yuyao; GB-1: tongziliao; ening of the suboccipital muscles can result in ischemia and ST-1: chengqi [49]. cause complaints including headaches and dizziness, tinni- tus, and nuchal rigidity [59]. Moving the head forward results 6 Journal of Ophthalmology in mechanical offload of the neck. Due to lack of muscular balance resulting from overloading, some muscles become weak. The technique of relaxation of the suboccipital muscles is based on putting pressure in the ventral direction in the suboccipital area while the patient’s head is resting on the therapist’s hands, as presented in Figure 3 [60]. The pressure should be even and constant for 5 minutes. The use of this technique is to improve the mobility of the cervical spine and restore proper positioning of the head [60]. Proper selection of corrective glasses is of key significance for maintaining proper tension balance within the head and neck. The use of contact lenses with a too short focal length Figure 3: The technique relaxing the suboccipital muscles [60]. leads to habitual lowering of the head when reading or per- forming near work. Placing the glasses too high or too low on the nose can result in head bending to the front or back. Moreover, studies indicated that the Tenon’s fascia and This mechanism can activate trigger points in the suboccipi- the muscles of the eye constitute a functional whole; there- tal muscles and the semispinalis muscle of the head and neck. fore, it is not possible to separate the muscular activity from According to Jack Holladay, most corrective glasses are too fascial activity. There is a close relation between each muscle strong and lead to chronic tension within the eyes and head and its fascial sheath. The fascia holds the muscles together [57]. The myofascial trigger point (MTP) is a hypersensitive and strengthens their activity. Each of them needs some pre- area in skeletal muscles and has a form of a taut band or a liminary tension of the Tenon’s fascia and the tendon of the nodule. The area is painful on compression and stretching. eye. Any tension in the myofascial system that affects the It can cause characteristic signs such as pain, hypersensitivity orbit is picked up by the periorbita, which is connected with to touch, disturbed motor activity, and autonomic symptoms the Tenon’s fascia with the epicranial fascia. Constant, exces- [61]. Cachinero-Torre et al. found a relation between hyper- sive tension coming from the limbs can be transferred in the sensitivity of the supraorbital nerve and the presence of an proximal direction as far as to the head, along the connection active trigger point in the lateral rectus of the eye in persons of the trunk with the platysma muscle and neck extensors with tension-type headaches [62]. According to the Interna- [69–71]. An interesting study was conducted by Ohno- tional Headache Society, tension-type headaches (TTH) are Matsui et al. who made an attempt to investigate the struc- the most common type of initial headaches in all age groups tural features of the posterior part of the episclera and the [63]. Despite the high number of studies conducted in recent Tenon’s fascia in patients with high myopia [70]. The study years, the etiological mechanism of TTH has not yet been involved 278 eyes of 175 patients aged 60.9 ± 11.4 years with fully established. It is presupposed that disturbances in the a refraction defect of >−8 D or an axial length of ≥26.5 mm. trochlear region, central sensitivity of the trigeminal nerve, The posterior parts of the episclera and the Tenon’s fascia and muscular pain are the main factors associated with were examined with optical coherence tomography. Analysis TTH [64]. Moreover, the oculomotor system is closely with the use of OCT allowed for a visualization of the poste- related to the above-mentioned factors and the signs of rior part of the sclera and the episclera, and in some cases also TTH in the following ways: Firstly, disturbances in the troch- of the Tenon’s fascia (Figure 5) [70]. It was observed that eyes lear region cause orbital pain that can stimulate oculomotor with a detectable episclera had significantly longer axial muscles and disturb their dynamics [65]. Secondly, the ocu- length and thinner central retinal thickness than eyes without lomotor muscles are innervated by the supraorbital branch it. Moreover, the fibres seemed to be more loosely arranged of the trigeminal nerve. Consequently, disturbed function and more split up in the Tenon’s capsule [70]. of the lateral rectus muscle can trigger the signs of TTH The diameter was measured along the axis perpendicular [66]. Thirdly, “visual effort,” that is, excessive load of the to the curvature of the pigmented epithelium of the retina. visual system in inappropriate conditions (e.g., looking at a The red arrow indicates the sclera. The blue arrow indicates computer screen in a dark room and from an insufficient dis- the episclera. The yellow arrow indicates the Tenon’s fascia tance), was described as the cause of disturbed mobility of the [70]. The fascia is characterized by a multilayer structure of eyeball and the cause of TTH [67]. The fascia of the head and the collagen fibres, which results in more complicated mech- neck has a very important proprioceptive function in the anisms than those involving tendons. Such orientation of the human body. It frequently is a source of tension pain of fibres ensures high resistance in case of multidirectional the head, neck, and temporomandibular joint and a source stretching forces [69, 72]. Experimental studies showed that of disturbed vision. The Tenon’s fascia is a deep fascia of the resistance of a deep fascia that is 1 cm wide exceeds the eye. According to Kakizaki et al., it can be divided into 390 N. Moreover, this resistance seems to be associated with three parts: anterior, central, and posterior. The central the muscular mass and maximum muscle power. This allows part makes a fascial sheath for four recti of the eye and us to presuppose that the deep fascia works like a tendon, two oblique muscles and a separate sheath for the elevat- transferring force from one segment to another [73]. ing muscle of the upper eyelid. The posterior part, on Trindade et al. showed that the deep temporal fascia plays a the other hand, fuses with the sheath of the optic nerve fundamental role in the transfer of tension and stretching (Figure 4) [68]. forces generated by temporal muscles on the masticatory Journal of Ophthalmology 7

Smooth muscle Conjunctiva Tarsus Tarsus bres Conjunctiva Lacrimal sac Trochlea Sclera Sclera Anterior Anterior Tenon’s capsule Tenon’s capsule Smooth muscle Posterior bres Tenon’s capsule Orbital fat Posterior Orbital fat Optic nerve Tenon’s capsule

(a) (b)

Tarsus Tarsus Smooth muscle bres Conjunctiva Conjunctiva

Sclera Sclera Anterior Tenon’s capsule Anterior Lacrimal Smooth Tenon’s capsule gland muscle bres Posterior Inferior oblique muscle Tenon’s capsule Orbital fat Posterior Optic nerve Tenon’s capsule Orbital fat

Smooth muscle fibres Tarsus Superior Sclera oblique muscle Conjunctiva tendon Anterior Orbital Tenon’s capsule fat

Posterior Superior Tenon’s capsule oblique muscle

(e)

Figure 4: The structure of the Tenon’s capsule: (a) superomedial projection; (b) inferomedial projection; (c) superolateral projection; (d) inferolateral projection [68]. system [74]. The deep fascia of the neck consists of three lam- segment of the vertebral column. Due to the continuity along inae, and each of them is attached to the muscles below. It is the superﬁcial fascia and the tendinous galea, tension can be not possible to separate the function of the deep fascia from transferred from the trunk to the eyeball. There is a similar the function of the extensors of the head and the cervical continuity along the superﬁcial fascia of the chest and the 8 Journal of Ophthalmology

Intrascleral blood vessel

Figure 5: The method used to measure the diameter of the episclera, sclera, and Tenon’s fascia [70].

platysma, which is connected with the superficial muscular Myopia is usually treated with glasses, contact lenses, or sur- aponeurotic system (SMAS) comprising the mimical muscles gical procedures. However, this kind of therapy is aimed at of the face [69, 72, 73]. limiting the defect, not preventing it. Within the last decade, researchers published the results of their studies of vision 3.5. Use of Osteopathy in the Treatment of Myopia. Osteo- training, myofascial therapy, and osteopathy in the treatment pathic medicine is a noninvasive, alternative form of man- of myopia. They have suggested probable mechanisms of fi ual therapy, classi ed as a supplementary manipulative brain-eye paths and made another step on the way to under- – technique [75 77]. According to Sandhouse et al., osteo- standing and knowing how to prevent refraction defects in pathic manipulative treatment decreases intraocular pres- young adults. Without doubt, there is a need for further ff fi sure and a ects the eld of vision and positioning of the research in order to identify the most effective therapy of eyeballs. Osteopathic techniques applied to cranial areas refraction defects. can have a positive effect on the visual function in young adults with myopia [76]. The authors carried out the analysis on a group of 29 young adults with myopia, aged Abbreviations 24.38 ± 3.03. Within the study, 15 patients were subject D: Diopter to one session of osteopathic manipulative treatment BL-1: Jingming (OMT). After this treatment, the researchers observed BL-2: Cuanzhu improvement in visual acuity from distance and an increase EX-HN4: Yuyao in the size of the pupil [76]. There are two potential mecha- EX-HN5: Taiyang nisms to explain the improvement in visual acuity. Firstly, GB-1: Tongziliao oculomotor muscles are connected with the eyeball, the orbit, HMD: Head-mounted display and the adjoining muscles that are directly or indirectly con- MTP: Myofascial trigger point nected with the sphenoid bone. If bones that are connected OCT: Optical coherence tomography with the oculomotor muscles change their position (by OMT: Osteopathic manipulative treatment cranial manipulations), the eye changes its shape and conse- SA: Spherical aberration quently its axial length. Secondly, parasympathetic innerva- SMAS: Superficial muscular aponeurotic system tion of the eyes is provided by the oculomotor nerve and ST-1: Chengqi the ocular branch of the trigeminal nerve, which run through ST-2: Sibai the fissure of the sphenoid bone. Manipulations of the sphe- TE-23: Sizhukong noid bone release the bones or fascial restrictions, which can TTH: Tension-type headaches. restore normal functioning of the autonomic system by decreasing the afferent activity of the oculomotor nerve and the trigeminal nerve [76, 77]. Conflicts of Interest fl 4. Conclusions The authors declare that they have no con ict of interests. Myopia is currently perceived as a civilization-related dis- Acknowledgments ease, and sight defects in children have their onset at a youn- ger age. There is no satisfactory effective method of The study was financed by the Medical University of Gdańsk, prevention of refraction defects in children and adolescents. Gdańsk, Poland (Grant ST-02-0108). Journal of Ophthalmology 9

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Research Article The Comparison of Regional RNFL and Fundus Vasculature by OCTA in Chinese Myopia Population

1,2 1 1 1 Yuanjun Li , Hamza Miara , Pingbo Ouyang , and Bing Jiang

1Department of Ophthalmology, Hunan Clinical Research Center of Ophthalmic Disease, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China 2Department of Ophthalmology, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, The Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China

Correspondence should be addressed to Bing Jiang; [email protected]

Received 24 September 2017; Revised 3 December 2017; Accepted 18 December 2017; Published 31 January 2018

Academic Editor: Katarzyna J. Witkowska

Copyright © 2018 Yuanjun Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To determine the correlations between peripapillary vessel density, retinal nerve ﬁbre layer (RNFL) thickness, and myopic indices at retina quadrants with optical coherence tomography angiography (OCTA) in Chinese. Methods. Fifty-six subjects with a mean spherical equivalent (MSE) of −3.63 ± 0.29 D were included. Peripapillary RNFL thickness and retinal vessel density in four sectors (superior, nasal, inferior, and temporal quadrants) were determined by OCTA, and correlations of the main outcomes were analyzed. Results. Negative correlations were found between the peripapillary RNFL thickness and axial length (AL) at superior (r = −0 335, P =0001) and inferior (r = −0 551, P <0001) quadrants. There was a signiﬁcant positive correlation with spherical equivalent (SE) at the corresponding quadrants as well as at the nasal quadrant (r =0339, P =0001; r =0379, P <0001;and r =0209, P =0039, resp.). Peripapillary retinal vessel density was also negatively correlated with AL at the nasal quadrant (r = −0 392, P <0001), and only at the nasal quadrant, there was a positive correlation between the peripapillary vessel density and SE (r =0319, P =0001). Conclusions. The degree of myopia and elongation of AL were negatively correlated with peripapillary RNFL thickness at superior and inferior quadrants and with peripapillary retinal vessel density at the nasal quadrant.

1. Introduction illustrated a reduced retinal capillary microvasculature and increased flow deficit in choriocapillaris in the eyes with Worldwide, myopia is among the most common ocular greater myopia [5]. Besides the reported decreased peripapil- disorder with high prevalence in Asian population [1]. As lary retinal perfusion in the highly and pathological myopic a major cause of low vision and legal blindness, myopia in a eyes as compared to the emmetropic eyes, it was found that greater stage may lead to macular complications, including the retinal vasculature was positively correlated with RNFL posterior staphyloma, retinoschisis, lacquer crack forma- thickness in myopic subjects [1, 7]. tion, chorioretinal atrophy, and myopic choroidal neovas- However, it remains unknown whether there are signifi- cularization [2]. cant sectional correlations between regional RNFL thickness, Optical coherence tomography angiography (OCTA) is a retinal vessel distribution, and eye structural parameters, novel noninvasive technology that provides fast, depth- since the previous OCTA studies about myopia only assessed resolved visualization of the retinal and choroidal microvas- the association between vascular and RNFL structure in an culature [3–6]. Previously, an increasing number of OCTA overall way. Because different eye diseases such as myopia studies have focused on pathological eye changes in myopia, and glaucoma often originate and exaggerate regionally with including the association between retinal vasculature, retinal different patterns [8], it is worthwhile to explore and test the nerve fibre layer (RNFL), and eye structural parameters. By RNFL and retinal vasculature from locational perspectives. quantitatively assessing the microvasculature of the retina Furthermore, there are sparse researches about the specific and choriocapillaris in the myopic eyes, OCTA studies have regional correlations between RNFL, vasculature, and 2 Journal of Ophthalmology myopic parameters though the course of myopia develop- S S ment. Bearing this in mind, we aimed to investigate the global 315o 45o 315o 45o and regional correlations between RNFL thickness, vessel density, and eye structural parameters via OCTA assessment, TNTN in various stages of myopia. 225o 135o 225o 135o 2. Methods I I (a) (b) 2.1. Participants. This cross-sectional, observational study was conducted in the Department of Ophthalmology, the Figure 1: Peripapillary RNFL thickness and vessel density at Second Xiangya Hospital, Central South University. The quadrants were identified by OCTA. The boundaries of study population consisted of healthy and myopia subjects segmentation are indicated by the red lines ((a) peripapillary RNFL thickness) or blue lines ((b) peripapillary vessel density). recruited from October 2016 to January 2017. This study ° was conducted in accordance with the tenets of the Declara- Peripapillary quadrants are identified as 6.0 mm radial scans 90 apart, around the central point of the optic disc. S, superior, radial tion of Helsinki (1964) and fully approved by the ethics com- ° ° ° ° scan from 315 to 45 ; N, nasal, from 45 to 135 ; I, inferior, from mittee of the Second Xiangya Hospital, Central South ° ° ° ° University. Informed consent as to the scientific objectives 135 to 225 ; T, temporal, from 225 to 315 . and process of the study was obtained from each subject. (36 mm2) area OCTA acquisition centered on the optic disc was performed, to record the overall and regional retinal 2.2. Inclusion and Exclusion Criteria. Inclusion criteria were RNFL thickness and vessel density. Three-dimensional (3D) age of 18 years or more and presence of myopia in the studied OCTA scans were acquired by using two repeated B-scans eyes, as assessed by the refraction error and axial length. For at 304 raster positions, with each B-scan consisting of 304 each participant, one or both eyes meeting the criteria were A-scans. With a B-scan frame rate of 210 frames per second, included in the study. Participants had no known eye dis- each OCTA volume scan can be acquired in approximately eases as determined by full ophthalmic examinations. 3 s. Two volumetric raster scans, including one horizontal The studied eyes were assigned to one of the four groups priority (x-fast) and one vertical priority (y-fast), were according to refraction: emmetropia (EM; mean spherical obtained consecutively. The volumetric scans were processed equivalent (MSE) 0.50 D to −0.50 D), mild myopia (MIM; by the split-spectrum amplitude-decorrelation angiography MSE −0.75 D to −2.75 D), moderate myopia (MOM; MSE (SSADA) algorithm. All scans were reviewed by an examiner −3.00 D to −5.75 D), and high myopia (HM; MSE ≤−6.00 D). to ensure correct imaging and sufficient scan quality. Signal Exclusion criteria were any history of prior vitreous or strength index (SSI) <45 and severe artifacts (double vessel retinal surgery or evidence of retinal diseases (other than pattern, loss of fixation, motion artifacts, and/or segmenta- myopic degeneration, such as age-related macular degeneration error resulting in poor outlining of vascular networks) tion, macular hole, and foveal hypoplasia) affecting the in scans were the OCTA exclusion criteria. All of this pro- retinal or choroidal vasculature by history or examination, cessing can be achieved using the contained software presence of media opacities preventing reliable retinal thick- (Optovue Inc., software V.2014.2.0.65). ness which prevents good visualization of the retinal struc- Peripapillary retinal vessel density was imaged by OCTA ture, having systemic diseases such as glaucoma or diabetes with lateral fixation position of the subjects and quantified mellitus which might affect the ocular circulation, and with the Angio Retina program. Measurements were auto- medication usage within 2 weeks of measurements. matically performed at four peripapillary quadrants: superior 2.3. Data Collection and Examinations. All participants in the (S), inferior (I), nasal (N), and temporal (T) (Figure 1). study underwent comprehensive ophthalmologic examination including spherical equivalent (SE) refraction measure- 2.5. Statistical Analysis. Raw data results were processed by ment with an autorefractometer (KR-8800, Topcon, Tokyo, statistical analysis software (IBM SPSS version 22.0 for Mac, Japan), slit-lamp biomicroscopy, and fundus examination. SPSS Inc., Chicago, IL, USA). The Spearman rank correlation An IOL Master (Carl Zeiss Inc., Jena, Germany) keratometer analysis was performed to determine the relationships was used for measuring anterior chamber depth, K values, between the overall and regional RNFL thickness, vessel den- and axis length. OCTA (Optovue RTVue XR Avanti, Opto- sity, and myopia-related eye structural parameters. Qualitative vue Inc., Fremont, California, USA) was used for retinal variables are presented as numbers and percentages. Quantita- nerve fibre layer (RNFL) and vascularization assessment. tive variables are presented as means and standard deviations. Demographic data (age, gender), general medical history, Nonparametric ANOVA comparing the 4 tested eye groups and ophthalmologic history were also collected. used the nonparametric Kruskal-Wallis test. Qualitative variable (gender) was compared by the Fisher exact test. 2.4. Optical Coherence Tomography Angiography. OCTA P <005 was considered statistically significant. images were acquired with AngioVue (Optovue RTVue XR Avanti, Optovue Inc., Fremont, CA, USA) using automated 3. Results segmentation algorithms. The system has an A-scan rate of 70 kHz scans per second, with a light source centered on 3.1. Demographics. A total of 56 healthy subjects (98 eyes) 840 nm and a bandwidth of 45 nm. A 6 mm × 6mm were included in this cross-sectional OCTA study. Journal of Ophthalmology 3

Table 1: Demographic and ocular characteristics of participants between the refractive groups.

Measurements EM (n =17) MIM (n =27) MOM (n =33)HM(n =21) P value Gender (male : female) 8 : 9 9 : 18 16 : 17 9 : 12 0.671 Laterality (OD : OS) 9 : 8 11 : 16 18 : 15 10 : 11 0.565 Age (years) 23.9 ± 2.7 25.0 ± 3.3 22.6 ± 2.1 23.5 ± 4.9 0.113 MSE (dioptres) 0.2853 ± 0.65 −1.7893 ± 0.74 −4.6379 ± 0.81 −7.5976 ± 1.57 <0.001 Axial length (mm) 23.2 ± 0.57 24.2 ± 0.92 25.2 ± 0.84 26.5 ± 0.68 <0.001 RNFL thickness (μm) Average 109.8 ± 5.2 110.3 ± 6.2 105.5 ± 6.3 101.0 ± 8.9 <0.001 S 137.5 ± 10.7 140.0 ± 11.2 131.9 ± 13.9 124.2 ± 14.8 0.002 N 81.4 ± 5.8 83.2 ± 8.7 79.4 ± 14.0 76.0 ± 16.5 0.211 I 139.4 ± 10.4 140.3 ± 14.1 132.1 ± 11.3 123.1 ± 14.9 <0.001 T 80.4 ± 7.1 77.7 ± 12.0 79.1 ± 11.3 78.3 ± 16.2 0.919 Vessel density (%) Average 59.9 ± 3.5 61.3 ± 2.7 59.9 ± 3.9 58.7 ± 3.6 0.023 S 59.7 ± 6.2 62.8 ± 3.7 62.4 ± 3.9 59.7 ± 6.3 0.028 N 57.8 ± 3.8 57.7 ± 3.7 55.7 ± 4.4 53.9 ± 4.1 0.016 I 60.9 ± 3.1 63.0 ± 3.0 61.5 ± 5.4 61.8 ± 3.7 0.206 T 58.5 ± 4.9 61.7 ± 4.0 60.0 ± 5.2 59.3 ± 3.0 0.015 Numbers appear as mean ± SD. I: inferior quadrant; MSE: mean spherical equivalent; N: nasal quadrant; RNFL: retinal nerve fibre layer; S: superior quadrant; T: temporal quadrant. P values significant at 5% level, Kruskal-Wallis test. Significant values are in italic type.

Table Demographic characteristics and eye structural measure- 2: Correlation between overall and regional peripapillary RNFL thickness and myopic measurements. ments are shown in Table 1. Of the examined eyes, 17 eyes in the subjects had emmetropia. Twenty-seven eyes had mild AL SE myopia, 33 had moderate myopia, and 21 had high myopia. Average −0.450 (<0.001) 0.379 (<0.001) There were 42 eyes from men and 56 eyes from women; there − were 48 right eyes (OD) and 50 left eyes (OS). The mean age S 0.335 (0.001) 0.339 (0.001) − of all subjects was 24.5 ± 5.1 years. Between the studied N 0.145 (0.154) 0.209 (0.039) groups, statistically significant differences were found in I −0.551 (<0.001) 0.379 (<0.001) terms of MSE (P <0001), axial length (AL) (P <0001), aver- T −0.007 (0.942) −0.026 (0.798) P <0001 age peripapillary RNFL thickness ( ), and peripapil- Numbers appear as correlation coefficient (P value). Significant values are lary vessel density (P =0023). Otherwise, there were no in italic type. Comparison of correlation coefficients by the Spearman significant differences in age, laterality, or gender between rank correlation. AL: axial length; I: inferior quadrant; N: nasal quadrant; the four groups (all P >005). S: superior quadrant; SE: spherical equivalent; T: temporal quadrant. Generally, significant differences among the four groups were found at the superior and inferior quadrants of the RNFL emmetropia and the myopic groups at the superior quadrant thickness in the peripapillary area according to our OCTA (P =0028), the nasal quadrant (P =0016), and the temporal results. At the inferior quadrant, the peripapillary RNFL (P =0015) quadrant. The inferior quadrant was the only one thickness decreased as the myopia grew. The measurement where peripapillary vessel density did not differ significantly was 139.4 ± 10.4 μm, 140.3 ± 14.1 μm, 132.1 ± 11.3 μm, and between the four MSE groups. 123.1 ± 14.9 μm, in the emmetropia, mild myopia, moderate myopia, and high myopia groups, respectively (P <0001). 3.2. Correlation between Regional Peripapillary RNFL Similarly, at the superior quadrant, the greater myopic Thickness and Myopia. The results of the Spearman correla- eyes had thinner RNFL thickness of 137.5 ± 10.7 μm, tion analysis of the RNFL thickness at quadrants, AL, and 140.0 ± 11.2 μm, 131.9 ± 13.9 μm, and 124.2 ± 14.8 μm, in SE are shown in Table 2. Generally, there were significantly the emmetropia, mild myopia, moderate myopia, and high negative correlations between peripapillary RNFL thickness myopia groups, respectively (P =0002), although the supe- and AL as shown in the table (r = −0 450, P <0001; rior RNFL in mild myopia was slightly thicker than that in Table 2 and Figure 2). Among the quadrants, there were emmetropia. However, no statistically significant change significant negative correlations at superior and inferior was found in the nasal or temporal RNFL thickness (P = regions (r = −0 335, P =0001 and r = −0 551, P <0001, 0 211 and P =0919, resp.) among the four groups. resp.; Table 2 and Figure 2). At the nasal and temporal Overall, the highly myopic eyes had a lower peripapillary quadrants, however, no statistical significant association vessel density, as shown in Table 1. There were significant was found between the peripapillary RNFL measurements differences in the peripapillary vessel density between the and AL (r = −0 145, P =0154 and r = −0 007, P =0942, 4 Journal of Ophthalmology

r = −0.335 r = −0.145 P = 0.001 140 P = 0.154

160 120 휇 m) 휇 m) 140 100

80 120 RNFL ( Nasal Superior RNFL ( Superior

60 100

22.00 24.00 26.00 28.00 22.00 24.00 26.00 28.00 Axial length (mm) Axial length (mm) EM MOM EM MOM MIM HM MIM HM

r = −0.551 r = −0.007 180 P < 0.001 110 P = 0.942

100 160 휇 m) 휇 m) 90 140 80 120 Inferior RNFL ( Inferior

Temporal RNFL ( Temporal 70

100 60

22.00 24.00 26.00 28.00 22.00 24.00 26.00 28.00 Axial length (mm) Axial length (mm) EM MOM EM MOM MIM HM MIM HM

Figure 2: Scatterplots illustrating the linear (black line) associations between axial length (mm) and OCTA peripapillary quadrant (superior, nasal, inferior, and temporal) RNFL thickness (μm) measurement of the studied eyes. r, correlation coeﬃcient from the Spearman rank correlation analysis; EM, emmetropia, MSE 0.50 D to −0.50 D; MIM, mild myopia, MSE −0.75 D to −2.75 D; MOM, moderate myopia, MSE −3.00 D to −5.75 D; HM, high myopia, MSE ≤−6.00 D. resp.; Table 2 and Figure 2). As expected, there was a signif- correlations between peripapillary vessel density and AL icant positive correlation with SE at the corresponding quad- (r = −0 234, P =0020; Table 3). However, as for the four rants as well as at the nasal quadrant (r =0339, P =0001; quadrants, only at the nasal quadrant, there was a statistically r =0379, P <0001; and r =0209, P =0039, resp.; Table 2 inverse correlation between peripapillary vessel density and and Figure 3), which agreed with the trend between peripa- AL (r = −0 392, P <0001; Table 3 and Figure 4). At the supe- pillary RNFL thickness and AL. At the temporal quadrant, rior, inferior, and temporal quadrants, peripapillary vessel the peripapillary RNFL thickness did not correlate with the density did not correlate with AL (r = −0 121, P =0236; SE (r = −0 026, P =0798; Table 2 and Figure 3). Collectively, r = −0 053, P =0607; and r = −0 117, P =0252, resp.; these results indicate that peripapillary RNFL thickness thins Table 3 and Figure 4). Unlike the peripapillary RNFL thick- as the myopia degree increases, especially at the superior and ness, no statistical correlation was found between the average inferior quadrants of the retina. peripapillary vessel density and SE (r =0152, P =0135; Table 3). As for the four regions, similarly only at the nasal 3.3. Correlation between Regional Peripapillary Vessel Density quadrant, there was a positive correlation between the and Myopia. Generally, there were signiﬁcantly negative peripapillary vessel density and SE (r =0319, P =0001; Journal of Ophthalmology 5

r = 0.339 r = 0.209 P = 0.001 140 P = 0.039

160 120 휇 m) 휇 m) 140 100

80 120 RNFL ( Nasal Superior RNFL ( Superior

60 100

−12.00 −8.00 −4.00 0.00 −12.00 −8.00 −4.00 0.00 Spherical equivalent (D) Spherical equivalent (D) EM MOM EM MOM MIM HM MIM HM

r = 0.379 r = −0.026 180 P < 0.001 110 P = 0.798

100 160 휇 m) 휇 m) 90 140 80 120 Inferior RNFL ( Inferior

Temporal RNFL ( Temporal 70

100 60

−12.00 −8.00 −4.00 0.00 −12.00 −8.00 −4.00 0.00 Spherical equivalent (D) Spherical equivalent (D) EM MOM EM MOM MIM HM MIM HM

Figure 3: Scatterplots illustrating the linear (black line) associations between spherical equivalent (D) and optical coherence tomography angiography (OCTA) peripapillary quadrant (superior, nasal, inferior, and temporal) RNFL thickness (μm) measurement of the studied eyes. r, correlation coeﬃcient from the Spearman rank correlation analysis; EM, emmetropia, MSE 0.50 D to −0.50 D; MIM, mild myopia, MSE −0.75 D to −2.75 D; MOM, moderate myopia, MSE −3.00 D to −5.75 D; HM, high myopia, MSE ≤−6.00 D.

Table 3: Correlation between overall and regional peripapillary Table 3 and Figure 5). The correlation efficiency was not vessel density and myopic measurements. statistically significant at the superior, inferior, and temporal quadrants (r =0054, P =0600; r = −0 047, P =0646; and AL SE r =0093, P =0360, resp.; Table 3 and Figure 5). Overall, Average −0.234 (0.020) 0.152 (0.135) these results suggest that the peripapillary vessel density S −0.121 (0.236) 0.054 (0.600) reduces mainly at the nasal quadrant as the myopia N −0.053 (0.607) −0.047 (0.646) increases, indicating a graphical pattern different from that I −0.392 (<0.001) 0.319 (0.001) of peripapillary RNFL thickness. T −0.117 (0.252) 0.093 (0.360) Numbers appear as correlation coefficient (P value). Significant values are 4. Discussion in italic type. Comparison of correlation coefficients by the Spearman rank correlation. AL: axial length; I: inferior quadrant; N: nasal quadrant; In the present study, the graphical relationship between peri- S: superior quadrant; SE: spherical equivalent; T: temporal quadrant. papillary RNFL and vasculatures with the stages of myopia has been quantified with the OCTA technique. It was shown 6 Journal of Ophthalmology

r = −0.121 r = −0.392 P = 0.236 65.00 P < 0.001

70.00

60.00

55.00

50.00 Nasal vessel den (%) Nasal Superior vessel den (%) Superior 50.00

40.00

22.00 24.00 26.00 28.00 22.00 24.00 26.00 28.00 Axial length (mm) Axial length (mm) EM MOM EM MOM MIM HM MIM HM

r = −0.053 r = −0.117 70.00 P = 0.607 70.00 P = 0.252

60.00 60.00

Inferior vessel den (%) vessel Inferior 50.00 50.00 Temporal vessel den (%) Temporal

22.00 24.00 26.00 28.00 22.00 24.00 26.00 28.00 Axial length (mm) Axial length (mm) EM MOM EM MOM MIM HM MIM HM

Figure 4: Scatterplots illustrating the linear (black line) associations between axial length (mm) and optical coherence tomography angiography (OCTA) peripapillary quadrant (superior, nasal, inferior, and temporal) vessel density (%) measurement of the studied eyes. r, correlation coefficient from the Spearman rank correlation analysis; EM, emmetropia, MSE 0.50 D to −0.50 D; MIM, mild myopia, MSE −0.75 D to −2.75 D; MOM, moderate myopia, MSE −3.00 D to −5.75 D; HM, high myopia, MSE ≤−6.00 D. that as myopia increases, the reduction of peripapillary RNFL their results suggest thicker RNFL measurements at the thickness mainly occurred at the superior and inferior quad- 8, 9, and 10 o’clock sectors in moderate and high myopia rants of the retina. Characterization of RNFL thickness in the as compared with the mild myopia (P =0001, 0.003, and myopic eyes with OCT-based techniques has been described <0.001, resp.) [11]. With OCT (version 3, Stratus OCT, Carl in the literature (Table 4). Our results are in agreement with Zeiss Medites Inc.), Leung et al. studied 115 healthy control those of the previous OCT studies that reported a signifi- and 115 myopic eyes (MSE −7.31 ± 3.04 D) and showed that cantly lower RNFL thickness in high myopia at 12, 1, and 7 there were significant negative correlations between RNFL o’clock regions (12 o’clock sectors) or superior/inferior areas thickness and AL and negative SE [9]. Using OCTA (quadrant sectorial division), as compared to the mild to (RTVue-XR OCT, Optovue Inc., software V.2014.2.0.65), moderate myopia [9, 10]. Recently, using Cirrus HD-OCT Wang et al. also showed that highly myopic eyes had longer (software version 6.0) and three-dimensional analysis, Seo AL and thinner RNFL thickness [1]. Although there were et al. reported that RNFL thickness of the 1, 2, 5, 6, and 12 studies using OCT to quantify the RNFL with different o’clock sectors was significantly thinner in moderate to high methods of retinal division, results from the present study myopia than in mild myopia (P <0001) [11]. Interestingly, first made use of the OCTA technique to describe the Journal of Ophthalmology 7

r = 0.054 r = 0.319 P = 0.600 65.00 P = 0.001

70.00

60.00

55.00

50.00 Nasal vessel den (%) Nasal Superior vessel den (%) Superior 50.00

40.00

−12.00 −8.00 −4.00 0.00 −12.00 −8.00 −4.00 0.00 Spherical equivalent (D) Spherical equivalent (D) EM MOM EM MOM MIM HM MIM HM

r = −0.047 r = 0.093 70.00 P = 0.646 70.00 P = 0.360

60.00 60.00

Inferior vessel den (%) vessel Inferior 50.00 50.00 Temporal vessel den (%) Temporal

−12.00 −8.00 −4.00 0.00 −12.00 −8.00 −4.00 0.00 Spherical equivalent (D) Spherical equivalent (D) EM MOM EM MOM MIM HM MIM HM

Figure 5: Scatterplots illustrating the linear (black line) associations between spherical equivalent (D) and optical coherence tomography angiography (OCTA) peripapillary quadrant (superior, nasal, inferior, and temporal) vessel density (%) measurement of the studied eyes. r, correlation coefficient from the Spearman rank correlation analysis; EM, emmetropia, MSE 0.50 D to −0.50 D; MIM, mild myopia, MSE −0.75 D to −2.75 D; MOM, moderate myopia, MSE −3.00 D to −5.75 D; HM, high myopia, MSE ≤−6.00 D. graphical details and correlations of regional peripapillary lower peripapillary retinal perfusion measurement, includ- RNFL thickness and AL at different myopia degrees. It ing retinal flow index and vessel density, with respect to may indicate that the OCTA could be used as an effective emmetropic eyes in Chinese population [1]. In another and efficient way to study the RNFL structure and vascular study with the OCTA technique, the same research team network in the myopic eyes, which is a promising alternative demonstrated a significantly reduced peripapillary RNFL of the OCT. flow index, retinal flow index, and retinal vessel density in On the other hand, the study showed that only at the the highly myopic eyes with tessellated fundus with respect nasal quadrant, there was a statistically negative correlation to the control eyes [7]. In another study, it was revealed that between the peripapillary vessel density and AL in the stud- in the highly myopic eyes with peripapillary intrachoroidal ied groups, indicating that the elongation of the globe cavitation (PICC), peripapillary, inferotemporal, and super- affected nasal retinal vasculature significantly. A wide range otemporal vessel density was lower than in that without of previous studies has already shown a decreased peripapil- PICC [12]. lary perfusion in the greater myopic eyes. Wang and col- With OCTA, Fan et al. studied 91 eyes from emmetropia leagues in their vascular-related OCTA research showed a to high myopia, including pathologic myopic eyes with 8 Journal of Ophthalmology

Table 4: Comparison of OCT-based RNFL thickness studies in the myopic eyes.

Division Method Conclusion Reference Peripapillary RNFL thickness reduced significantly in high None OCTA Wang et al. 2016 [1] myopia compared to mild myopia. Peripapillary RNFL thickness was thinner at 1, 7, and 12 o’clock 12 o’clock OCT Leung et al. 2006 [9] sectors in the highly myopic eyes than in the mild myopic eyes. RNFL thickness of the 1, 2, 5, 6, and 12 o’clock sectors was 12 o’clock Cirrus HD-OCT Seo et al. 2017 [11] significantly thinner in moderate to high myopia than in mild myopia. Mean peripapillary RNFL thickness did not vary with myopic None OCT-1 Hoh et al. 2006 [14] SE or axial length for any OCT scan diameter investigated. The RNFL thickness in high myopia decreased 12 o’clock Stratus OCT Efendieva 2014 [10] significantly at 1, 5, 6, 7, 8, 9, 10, 11, and 12 o’clock. Average and temporal RNFLs increased significantly Quadrant/12 o’clock Cirrus HD-OCT Choi et al. 2014 [15] as the AL increased. Quadrant SD-OCT Global and the temporal RNFL were thicker in the myopia group. AttaAllah et al. 2017 [16] Six sectors SD-OCT RNFL thickness in children was not affected by myopia. Goh et al. 2017 [17]

Table 5: Comparison of OCTA-based fundus vasculature studies in the myopic eyes.

Division Method Conclusion Reference Peripapillary retinal perfusion (flow index and vessel density) was lower in None OCTA Wang et al. 2016 [1] higher myopia than emmetropia. Peripapillary retinal perfusion (flow index and vessel density) reduced in None OCTA Wang et al. 2016 [7] high myopia with tessellated fundus with respect to the control eyes. Peripapillary, IT, and ST vessel density in the highly myopic eyes with Six sectors OCTA Chen et al. 2017 [12] PICC was lower than the density in those without. Macular but not optic disc superficial and deep vascular density reduced None OCTA Fan et al. 2017 [13] as AL increased in the myopic eyes. None OCTA Retinal capillary density reduced while CC flow deficit increased in greater myopia. Al-Sheikh et al. 2017 [5] Retinal microvascular network alterations in the highly myopic eyes None OCTA Yang et al. 2016 [18] correlates with axial length elongation. Retinal microvascular decreased in the high myopia subjects with None OCTA Li et al. 2017 [19] unchanged retinal microvessel blood flow velocity. None OCTA SE and AL influence the size of the foveal avascular zone. Tan et al. 2016 [20] CC: choriocapillaris; PICC: peripapillary intrachoroidal cavitation. peripheral retinal degeneration, and revealed that superficial these graphical correlations in myopia disease development and deep vascular density in the macula negatively correlated remained unknown. Previous researchers have stated one with AL and the degree of myopia, but positively correlated possible hypothesis that thinning of peripapillary RNFL with ganglion cell complex (GCC) thickness [13]. However, may affect the vasculature network via autoregulatory mech- the vascular density had no difference in the optic disc area anisms [1]. Another explanation from the view of myopia among the groups, without any correlation with AL, SE, or pathology is that the elongation of the globe leads to the RNFL thickness [13]. Recently, using OCTA, Al-Sheikh decreased peripapillary RNFL and vessel density. However, et al. also showed that the density of retinal capillary micro- according to our results, the reducing trend of peripapillary vasculature was reduced and the area of flow deficit in chor- RNFL as myopia grows differs from that of peripapillary ves- iocapillaris (CC) is increased in the greater myopic eyes [5]. sel density at retina quadrants, which is in conflict with the These OCTA studies about vasculature changes in the myo- hypothesis. If the change of peripapillary RNFL directly con- pic eyes in literature have been summarized and compared tributes to the vessel distribution or the elongation of the (Table 5). myopic globe contributes to the loss of RNFL and vasculature Our findings agree with these previous descriptions about physically and structurally, the localization of changes of the peripapillary vessel density and go further to illustrate that two should be at similar retina quadrants. Thus, further the vasculature at the nasal quadrant of the retina may be studies are necessary to explain the disagreement between more vulnerable to myopia-related structural change than the patterns of peripapillary RNFL thickness, vessel density, that at other quadrants. However, the clear mechanism of and AL. Journal of Ophthalmology 9

The current study had several limitations. First, the cross- Acknowledgments sectional design of the study precluded a causative conclusion that AL elongation in myopia induced the thinning of The authors thank all the participants of the study. Yuanjun RNFL and vascular density at quadrants in the peripapillary Li was supported by the HKUST/CSU Joint MD-PhD Pro- area. Second, the sample size in the present study was rela- gram. This work was supported by the Natural Science Foun- tively small and from the same race within a narrow spec- dation of China (NSFC 81770930 and NSFC 81371012 to trum of age, mainly in twenties and thirties. Thus, the Bing Jiang), the Department of Science and Technology study is an exploratory and descriptive analysis, and its of Hunan (No. 2015TP2007), and the Natural Science conclusions may not be applicable to the other races or age Foundation of Hunan Province (2017jj2360 to Bing Jiang). spectrums, for example, Caucasian, African, children, or elderly. 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Koizumi et al., Choroidal blood relatively small, from 3 Å 3mmto6Å 6 mm, which limits flow visualization in high myopia using a projection artifact its usage in detecting the peripheral diseases. Moreover, method in optical coherence tomography angiography,” Ret- superficial large blood vessel could form artificial projection ina, vol. 37, no. 3, pp. 460–465, 2017. in the outer retina which is without blood vessels. Therefore, [7] X. Wang, Y. Zheng, X. Kong, L. Zhu, and X. Sun, “The charac- the development of the OCTA technique in the future should teristics of peripapillary retinal perfusion by optical coherence be focused on the following aspects: (1) to increase the imag- tomography angiography in tessellated fundus eyes,” PLoS ing speed, in order to lower the time of the patient kept fix- One, vol. 11, no. 7, article e0159911, 2016. ated and positioned; (2) to widen the scanning range of the [8] J. W. Shin, J. Lee, J. Kwon, J. Choi, and M. S. 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Research Article Long-Term Natural Outcomes of Simple Hemorrhage Associated with Lacquer Crack in High Myopia: A Risk Factor for Myopic CNV?

Bing Liu , Xiongze Zhang, Lan Mi, Ling Chen, and Feng Wen

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China

Correspondence should be addressed to Feng Wen; [email protected]

Received 3 September 2017; Revised 6 December 2017; Accepted 26 December 2017; Published 24 January 2018

Academic Editor: Malgorzata Mrugacz

Copyright © 2018 Bing Liu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To investigate the relationship between simple hemorrhage (SH) associated with lacquer crack (LC) and myopic choroidal neovascularization (CNV) in high myopia. Methods. A cross-sectional evaluation including best-corrected visual acuity (BCVA), axial length, refractive error, color fundus photography, and spectral domain optical coherence tomography (SD-OCT) was performed in patients diagnosed with high myopia and SH. Fundus fluorescein angiography and indocyanine green angiography were performed if the eye was suspected with CNV. Results. Thirty-three eyes of 27 patients with SH were enrolled in the study. None of the eyes developed CNV at final examination following the occurrence of hemorrhage. Recurrent hemorrhage was observed in 36.5% of the eyes. Compared with the initial BCVA, the final BCVA was significantly improved (P <0001) and correlated with the integrity of the ellipsoid zone in SD-OCT. There was no significant difference in the final BCVA between group 1 (LC crossed the central fovea) and group 2 (no LC crossed the central fovea) (P =0299). Conclusions. SH associated with LC is not a risk factor for the development of myopic CNV in patients with high myopia. LCs have little influence on the final BCVA unless the integrity of the ellipsoid zone in the central fovea is disrupted.

1. Introduction developed myopic CNV [11–14]. Therefore, some retina specialists have hypothesized that SH may be a risk factor High myopia is a major cause of visual impairment and legal for the development of myopic CNV. Several previous blindness worldwide, especially in Asian countries [1–3]. studies have reported the prognosis of SH in highly myo- Among the various myopic fundus lesions, macular hemor- pic eyes but have not investigated the relationship between rhage is a common vision-threatening complication in high SH associated with LC and myopic CNV; in addition, the myopia [4, 5]. Based on the presence of choroidal neovascu- results of these studies are limited by their short follow-up larization (CNV), macular hemorrhage can be categorized times [6, 15–17]. into two types, hemorrhage secondary to myopic CNV and Thus, this study aims to investigate whether SH associ- simple hemorrhage (SH). ated with LC is related to myopic CNV in highly myopic eyes. There may be a relationship between SH and myopic The long-term visual outcomes of highly myopic eyes with CNV because the formation of both lesions is related to SH in a natural history are also evaluated in this study. lacquer cracks (LCs) [6–8]. The occurrence of SH is generally associated with the formation of new LCs or progres- 2. Materials and Methods sion of primary LCs [5, 6, 9, 10]. Most myopic CNVs seem to emanate from LCs or at least the areas adjacent We performed a cross-sectional study. Patients with high to LCs, and the extension of LCs accompanies newly myopia and SH who were referred to the Zhongshan 2 Journal of Ophthalmology

Ophthalmic Center in Guangzhou, China, between Janu- 3. Results ary 1, 2010, and May 31, 2014, were enrolled. The study fi protocol was approved by the institutional review board 3.1. Patients. We screened 319 les, and 58 patients were eli- of Zhongshan Ophthalmic Center of Sun Yat-sen Univer- gible. Among these patients, 3 could not be contacted, and 28 sity. The study was conducted in accordance with the refused to participate in this study because of good visual tenets of the Declaration of Helsinki. Written informed acuity. Thus, 33 eyes of 27 patients with SH were enrolled ff consent was obtained from all patients in this study prior in the study. There were no di erences in age, gender, or geo- to enrollment. graphic location between those who participated and those Pathologic myopia was defined as a refractive error < −6 who did not participate. The clinical characteristics of the diopters (D) or an axial length > 26.0 mm. The diagnosis of 27 patients are summarized in Table 1. The study included SH was confirmed by ophthalmoscopic examination and 13 men and 14 women. The mean duration since the initial ± fundus fluorescein angiography (FFA). The exclusion criteria visit was 50.4 16.3 months, with a range of 36 months to included a history of other ocular disorders, such as dense 87 months. For all patients, the clinical diagnosis was made cataract, glaucoma, diabetic retinopathy or other retinal vas- within 1 month from the onset of their visual symptoms, fi cular diseases, and age-related macular degeneration (AMD), such as blurred vision and a xed shadow in the front of and a history of vitreoretinal surgery, which might affect the eye with or without distorted vision. visual acuity. Because this study aimed to determine the natural course of SH in highly myopic eyes, patients who 3.2. Patient Clinical Data Collected from Medical Records. received any treatments for myopic fundus lesions following The size of hemorrhages ranged from 0.25 to 1.5 disc diame- SH were also excluded. ters (DDs), and all hemorrhages covered the central fovea. Patient demographics, initial best-corrected visual acuity The mean hemorrhage duration was 3.0 ± 1.0 months, with (BCVA), axial length, refractive error, color fundus photog- a range of 1 month to 6 months. raphy, FFA imaging, and a history of follow-up were LCs were identified by ophthalmoscopy and FFA in 17 recorded from patient medical records. eyes (51.5%) at the initial examination. After hemorrhage A cross-sectional evaluation of all patients was per- absorption, LCs were observed in 32 eyes (97.0%) at the loca- formed and included BCVA using a Snellen chart, axial tion of the initial hemorrhage, and the mean BCVA length using IOL Master (Carl Zeiss Meditec, Oberkochen, improved to 0.38 ± 0.26 logMAR (0 to 1.0 logMAR) from Germany), refractive error, slit lamp examination, dilated the initial examination. The difference in BCVA between fundus examination by indirect ophthalmoscopy (+90 D), the two time points was significant (P <0001). color fundus photography, and spectral domain optical Recurrent hemorrhages were recorded in 12 eyes (36.4%) coherence tomography (SD-OCT; Spectralis HRA + OCT, from the medical records. Of these eyes, 3 had 3 recurrent Heidelberg Engineering, Heidelberg, Germany) between hemorrhages, 1 had 2 recurrent hemorrhages, and 8 had June 1, 2017, and June 30, 2017. If the diagnosis of CNV fi fl one recurrent hemorrhage. The recurrent hemorrhages could not be con rmed by SD-OCT (hyperre ective area almost completely resolved within 4 months. above the damaged retinal pigment epithelial level with intraretinal fluid/increased foveal thickness and/or serous foveal detachment), FFA and indocyanine green angiogra- 3.3. Patient Clinical Data at Cross-Sectional Examination. phy (ICGA) (Spectralis HRA + OCT, Heidelberg Engineer- The mean refractive error was −14.7 ± 4.6 D, and the mean ing, Heidelberg, Germany) were performed. SD-OCT axial length was 30.1 ± 1.4 mm at the final examination. scanning and analysis of all study eyes were performed by There were significant differences in both the refractive error one experienced investigator. Horizontal and vertical SD- and axial length between the initial and final examinations OCT scans of 6 or 3 mm were centered on the fovea and (all P <0001). the location of SH. The integrity of the ellipsoid zone within None of the eyes developed CNV at the final examination the 1 mm centered fovea was evaluated as continuous or following the occurrence of hemorrhage. discontinuous. In addition, the eyes were divided into group At the final examination, LCs were observed in 32 1 (LC passed the central fovea) and group 2 (no LC passed eyes (97.0%), and 12 (37.5%) LCs crossed the central the central fovea). Differences in visual acuity between the fovea. No LC was detected in 1 eye from the initial to two groups were investigated. the final examination. Compared with the initial mean BCVA, the final mean 2.1. Statistical Analysis. Data were processed and analyzed BCVA was significantly improved (0.26 ± 0.21 logMAR; using SPSS 16.0 software (Inc., Chicago, IL, USA). For the P <0001). The distributions of the initial and final Snellen analysis, Snellen BCVA data were transformed into equiva- VA are shown in Figures 1 and 2. The initial Snellen VA lent logarithms of the minimum angle of resolution (log- was 20/40 or greater in 6 eyes (18.2%), 20/200 to 20/40 in MAR) values. To evaluate the differences in visual acuity 21 eyes (63.6%), and 20/200 or less in 6 eyes (18.2%). The between group 1 and group 2, we performed independent t- final Snellen VA was 20/40 or greater in 26 eyes (78.8%) tests for continuous variables and chi-square tests for cate- and 20/200 to 20/40 in 7 eyes (21.2%). There was a significant gorical variables. Changes in visual acuity at each follow-up difference in the number of eyes with a Snellen VA of 20/40 were analyzed using paired t-tests. A P value < 0.05 was con- or greater between the initial and final visits (P <0001). sidered statistically significant. Moreover, only two eyes had a worse VA at the final visit Journal of Ophthalmology 3

Table 1: Patient clinical characteristics (n =27). 100 Characteristics 18.2% ± Age (years) 39.0 8.5 80 Male/total (n, %) 13/27 (48.1) Bilateral hemorrhage (n, %) 6/27 (22.2) 60 78.8% Refractive error (diopters) 63.6% Initial −13.2 ± 4.3 (%) 40 Final −14.7 ± 4.6 Axial length (mm) Initial 28.7 ± 1.3 20 ± 21.2% Final 30.1 1.4 18.2% BCVA (logMAR) 0 Initial 0.68 ± 0.40 Initial Final Final 0.26 ± 0.21 >20/40 Mean duration since initial visit (months) 50.4 ± 16.3 20/200−20/40 Mean duration of hemorrhage (months) 3.0 ± 1.0 <20/200

Figure 2: Distribution of the initial and final Snellen BCVA in this study. 1.0 Table 2: Comparison of clinical characteristics between group 1 and group 2. 0.8 Group 1 Group 2 P 0.6 Eyes 12 20 — Age (year) 38.7 ± 8.1 38.1 ± 8.1 0.968 − ± − ± 0.4 Initial refractive error (diopters) 13.0 4.6 13.4 4.3 0.830 Initial axial length (mm) 28.3 ± 1.1 28.8 ± 1.5 0.339 Final visual acuity Final visual Initial BCVA (logMAR) 0.76 ± 0.45 0.58 ± 0.26 0.017 0.2 Final BCVA (logMAR) 0.30 ± 0.24 0.18 ± 0.14 0.299 Eyes with recurrent 5 (41.7%) 7 (35.0%) 0.800 0.0 hemorrhage (n,%) 0.0 0.2 0.4 0.6 0.8 1.0 Initial visual acuity significantly improved final BCVA (0.48 ± 0.35 logMAR Figure 1: Initial and final Snellen BCVA of patients in this study. versus 0.21 ± 0.13 logMAR; P <0001, Figures 3 and 4). Dots on the line indicate unchanged visual acuity, dots above the line indicate improved visual acuity, and dots below the line indicate worse visual acuity. 4. Discussion SH is a term used for macular hemorrhage without CNV that because of enlarged retinal pigment epithelium (RPE) and occurs in highly myopic eyes and is most likely caused by the choroid atrophy. mechanical rupture of Bruch’s membrane and choriocapillaris complex [15, 16]. Although some researchers have sus- 3.4. Relationship between the Final BCVA and Lacquer pected that SH may be a precursor of myopic CNV [15], fi Cracks. To investigate the relationship between the nal the evidence is insufficient. A better understanding of the BCVA and LCs, we divided 32 eyes with LCs into the follow- predictors of myopic CNV development may lead to more ing groups: group 1 (LC crossed the central fovea) and group personalized treatment and help improve clinical outcomes 2 (no LC crossed the central fovea). Although the initial and reduce recurrence [8, 18]. To investigate the relationship fi BCVA in group 1 was signi cantly greater than that in group between SH associated with LC and myopic CNV, we per- fi ff fi 2, no signi cant di erence was found in the nal BCVA formed a cross-sectional study. between the two groups (Table 2). In this study, no eyes with SH associated with LC developed CNV following hemorrhage occurrence. This result is 3.5. Relationship between the Final BCVA and OCT Findings. consistent with the results of several previous studies [15, Of the 33 eyes, 27 had a continuous ellipsoid zone in the cen- 16]. Goto et al. examined 20 eyes of 17 consecutive patients tral fovea in OCT. Compared with eyes with a discontinuous with SH and found that most of the patients had a good ellipsoid zone, eyes with a continuous ellipsoid zone had a recovery, and no eye in the SH group developed CNV during 4 Journal of Ophthalmology

(a) (b)

(e)

Figure 3: Multimodal imaging of an eye with a continuous ellipsoid zone. A 52-year-old woman was initially seen on September 2, 2011, with decreased visual acuity and a fixed shadow in her right eye. At the initial examination, the BCVA was 20/100, the refractive error was −8.75 D, and the axial length was 29.7 mm in her right eye. There was subretinal hemorrhage (white arrow) in the macular area of the right eye at the initial examination (a). The late phases of FFA and ICGA revealed a simple hemorrhage (b and c). During the follow-up period, recurrent hemorrhage and CNV were not detected. At the final examination (June 2, 2017), LCs were observed in the macular area by color fundus photography (d). An LC passing through the central fovea was easily observed with near-infrared reflectance imaging (e). Because the ellipsoid zone (white arrow) at the central fovea was continuous (e), the final BCVA of the eye was still good (20/25). Journal of Ophthalmology 5

(a) (b)

(e)

Figure 4: Multimodal imaging of an eye with a discontinuous ellipsoid zone. A 40-year-old woman was initially seen on December 3, 2013, with decreased visual acuity in her left eye. At the initial examination, the BCVA was 5/100, the refractive error was −16.5 D, and the axial length was 27.37 mm in her left eye. An obvious subretinal hemorrhage (white arrow) was observed in the macular area at the initial examination (a). The late phase of FFA indicated that it was a simple hemorrhage (white arrow) (b). SD-OCT showed that the hemorrhage (white arrow) was thick and reached beyond the ellipsoid zone (c). After 3 years of follow-up, no recurrent hemorrhage or CNV occurred. Because the ellipsoid zone (white arrow) at the central fovea was not continuous (e), the final BCVA of the eye was poor (20/100). 6 Journal of Ophthalmology the 1-year follow-up [15]. Moriyama et al. examined 31 eyes referral bias may exist. Second, a small number of patients of 28 patients with high myopia and SH; they also found that participated in this study. However, to the best of our knowl- no eye developed CNV during a mean follow-up of 17.7 edge, this study is the first to evaluate the relationship months [16]. These results may be explained by differences between SH associated with LC and myopic CNV in high in the pathogenesis between SH associated with LC and myo- myopia in a long-term natural history. pic CNV. LCs are caused by the mechanical rupture of In conclusion, in this study, we demonstrated that SH Bruch’s membrane. If both the choriocapillaris and Bruch’s associated with LC is not a risk factor for the development membrane rupture during formation or progression of LCs, of myopic CNV and that SH may recur in approximately then SH could be observed. The pathogenesis of myopic 1/3 of eyes with high myopia. The long-term visual outcome CNV remains controversial, and several theories, such as the of SH in high myopia was generally good, and it correlated mechanical theory, heredodegenerative theory, and hemody- with the integrity of the ellipsoid zone in OCT. In addition, namic changes in choroidal circulation [19–23], have been LCs that passed through the central fovea had little influence proposed. In our opinion, the development of myopic CNV on the final visual acuity unless the integrity of the ellipsoid may result from the interaction of multiple factors. LCs are zone in the central fovea was disrupted. necessary but not sufficient for the development of myopic CNV. The occurrence of myopic CNV may require other con- Conflicts of Interest ditions mentioned above. Therefore, SH associated with LC is not a risk factor for the development of myopic CNV. The authors declare no conflicts of interest. The visual prognosis of the myopic eyes with SH may be fair during a short follow-up period unless the hemorrhage Acknowledgments recurs, atrophic scars develop, or retinochoroidal degeneration progresses [17]. In this study, similar results were This research was supported by the National Natural observed in the long-term natural history. Most patients Science Foundation of China (Grant no. 81570831) and had good visual outcomes after at least 3 years of observation the Fundamental Research Funds of State Key Laboratory ff except for two eyes in which severe di use retinochoroidal of Ophthalmology. atrophy was detected in the posterior fundus. In addition, recurrent hemorrhages were detected in 12 eyes (36.4%), indicating a high prevalence of recurrent hemorrhage in References highly myopic eyes. [1] L. Xu, Y. Wang, Y. Li et al., “Causes of blindness and visual In this study, we also evaluated the relationship between fi fi impairment in urban and rural areas in Beijing: the Beijing nal visual acuity and fundus changes. There was a signi - Eye Study,” Ophthalmology, vol. 113, no. 7, pp. 1134.e1– cant correlation between the visual outcome and OCT find- 1134.e11, 2006. ings. At the last visit, eyes with a continuous ellipsoid zone [2] A. Iwase, M. Araie, A. Tomidokoro et al., “Prevalence and in the central fovea usually had better visual outcomes. This causes of low vision and blindness in a Japanese adult popula- result is compatible with the findings of previous reports tion: the Tajimi study,” Ophthalmology, vol. 113, no. 8, [15, 16, 24, 25]. For eyes with a discontinuous ellipsoid zone, pp. 1354–1362.e1, 2006. the SH may be thick and reach beyond the ellipsoid zone; [3] X. He, R. Zhao, P. 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[10] K. Ohno-Matsui and T. Tokoro, “The progression of lacquer [24] T. Asai, Y. Ikuno, and K. Nishida, “Macular microstructures cracks in pathologic myopia,” Retina, vol. 16, no. 1, pp. 29– and prognostic factors in myopic subretinal hemorrhages,” 37, 1996. Investigative Ophthalmology & Visual Science, vol. 55, no. 1, – [11] R. Axer-Siegel, D. Cotlear, E. Priel, I. Rosenblatt, M. Snir, pp. 226 232, 2014. and D. Weinberger, “Indocyanine green angiography in [25] P. Milani, M. Pellegrini, A. Massacesi et al., “Is ellipsoid zone high myopia,” Ophthalmic Surgery, Lasers and Imaging, integrity essential for visual recovery in myopic neovasculari- vol. 35, pp. 139–145, 2004. zation after anti-VEGF therapy?,” Graefe's Archive for Clinical – [12] Y. Ikuno, K. Sayanagi, K. Soga et al., “Lacquer crack formation and Experimental Ophthalmology, vol. 255, no. 9, pp. 1713 and choroidal neovascularization in pathologic myopia,” 1720, 2017. Retina, vol. 28, no. 8, pp. 1124–1131, 2008. [13] Y. M. Kim, J. U. Yoon, and H. J. Koh, “The analysis of lacquer crack in the assessment of myopic choroidal neovascularization,” Eye, vol. 25, no. 7, pp. 937–946, 2011. [14] H. M. Kang and H. J. Koh, “Ocular risk factors for recurrence of myopic choroidal neovascularization: long-term follow-up study,” Retina, vol. 33, no. 8, pp. 1613–1622, 2013. [15] S. Goto, K. Sayanagi, Y. Ikuno, Y. Jo, F. Gomi, and K. Nishida, “Comparison of visual prognoses between natural course of simple hemorrhage and choroidal neovascularization treated with intravitreal bevacizumab in highly myopic eyes: a 1-year follow-up,” Retina, vol. 35, no. 3, pp. 429–434, 2015. [16] M. Moriyama, K. Ohno-Matsui, N. Shimada et al., “Correla- tion between visual prognosis and fundus autofluorescence and optical coherence tomographic findings in highly myopic eyes with submacular hemorrhage and without choroidal neovascularization,” Retina, vol. 31, no. 1, pp. 74–80, 2011. [17] S. Hayasaka, M. Uchida, and T. Setogawa, “Subretinal hemorrhages with or without choroidal neovascularization in the maculas of patients with pathologic myopia,” Graefe's Archive for Clinical and Experimental Ophthalmology, vol. 228, no. 4, pp. 277–280, 1990. [18] N. Leveziel, D. Gaucher, S. Baillif et al., “Understanding the determinants of myopic choroidal neovascularization and response to treatment,” European Journal of Ophthalmology, vol. 26, no. 6, pp. 511–516, 2016. [19] K. Neelam, C. M. G. Cheung, K. Ohno-Matsui, T. Y. Y. Lai, and T. Y. Wong, “Choroidal neovascularization in pathological myopia,” Progress in Retinal and Eye Research, vol. 31, no. 5, pp. 495–525, 2012. [20] T. Wakabayashi and Y. Ikuno, “Choroidal filling delay in choroidal neovascularisation due to pathological myopia,” The British Journal of Ophthalmology, vol. 94, no. 5, pp. 611–615, 2010. [21] N. Leveziel, Y. Yu, R. Reynolds et al., “Genetic factors for choroidal neovascularization associated with high myopia,” Investigative Ophthalmology & Visual Science, vol. 53, no. 8, pp. 5004–5009, 2012. [22] Y. Akagi-Kurashige, K. Kumagai, K. Yamashiro et al., “Vascu- lar endothelial growth factor gene polymorphisms and choroidal neovascularization in highly myopic eyes,” Investigative Ophthalmology & Visual Science, vol. 53, no. 4, pp. 2349– 2353, 2012. [23] M. Miyake, K. Yamashiro, H. Nakanishi et al., “Evaluation of pigment epithelium–derived factor and complement factor I polymorphisms as a cause of choroidal neovascularization in highly myopic eyes,” Investigative Ophthalmology & Visual Science, vol. 54, no. 6, pp. 4208–4212, 2013. Hindawi Journal of Ophthalmology Volume 2018, Article ID 4694789, 8 pages https://doi.org/10.1155/2018/4694789

Review Article Modern Diagnostic Techniques for the Assessment of Ocular Blood Flow in Myopia: Current State of Knowledge

Ewa Grudzińska and Monika Modrzejewska

Department of Ophthalmology, Pomeranian Medical University in Szczecin, Szczecin, Poland

Correspondence should be addressed to Monika Modrzejewska; [email protected]

Received 6 October 2017; Accepted 21 December 2017; Published 21 January 2018

Academic Editor: Malgorzata Mrugacz

Copyright © 2018 Ewa Grudzińska and Monika Modrzejewska. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Myopia is the most common refractive error and the subject of interest of various studies assessing ocular blood flow. Increasing refractive error and axial elongation of the eye result in the stretching and thinning of the scleral, choroid, and retinal tissues and the decrease in retinal vessel diameter, disturbing ocular blood flow. Local and systemic factors known to change ocular blood flow include glaucoma, medications and fluctuations in intraocular pressure, and metabolic parameters. Techniques and tools assessing ocular blood flow include, among others, laser Doppler flowmetry (LDF), retinal function imager (RFI), laser speckle contrast imaging (LSCI), magnetic resonance imaging (MRI), optical coherence tomography angiography (OCTA), pulsatile ocular blood flowmeter (POBF), fundus pulsation amplitude (FPA), colour Doppler imaging (CDI), and Doppler optical coherence tomography (DOCT). Many researchers consistently reported lower blood flow parameters in myopic eyes regardless of the used diagnostic method. It is unclear whether this is a primary change that causes secondary thinning of ocular tissues or quite the opposite; that is, the mechanical stretching of the eye wall reduces its thickness and causes a secondary lower demand of tissues for oxygen. This paper presents a review of studies assessing ocular blood flow in myopes.

1. Introduction the sclera, choroid and retina, and retinal vasoconstriction. The thickness of the choroid in myopes is reduced compared Myopia is the most common refractive error. Its preva- to subjects without this refractive error [4] and at the same lence has increased significantly over the last 50 years to time correlates significantly with the axial length [5, 6]. In about 70% of the population in developed countries. Cur- myopia, photoreceptors and choriocapillaris are rarefied, rently, the global prevalence of myopia is estimated at and the retinal pigment epithelium is diffusely depigmented about 1.4 billion people, and this figure is expected to [7]. In the retina, the density of the superficial and deep increase to 4.7 billion by 2050 (50% of the global population) vascular network is reduced [8, 9]. The thinning and disap- [1]. Myopia is associated with an increased risk of ophthal- pearance of the choroid and retinal structures further reduce mic complications, such as retinal detachment and choroidal their oxygen demand, resulting in decreased blood flow [10]. neovascularization [2]. The above medical conditions can Disorders of ocular blood flow in myopia have still not lead to a significant deterioration of visual acuity, which cre- been fully explained and are quite rarely described in the ates serious economic and social problems [3]. The aetiology literature. A search of available databases (MEDLINE, Web of myopia has not been explained in detail despite many of Science, Google Scholar) for published papers revealed studies on its pathogenesis. Literature data show that several dozen publications dealing with a similar problem both genetic and environmental factors are involved in as discussed here. Therefore, the authors reviewed the litera- its onset [2]. ture with a focus on currently used diagnostic methods used High-grade myopia is associated with axial elongation of for the analysis of changes in the haemodynamics of ocular the eye, which is accompanied by changes in the structure of blood flow in subjects with myopia. 2 Journal of Ophthalmology

The eyeball is supplied with blood through the ophthalmic stimulus. This method should be used, rather, to compare artery (OA) and its branches. In blood flow disorders affecting changes in the patient than as a comparison of different the ocular artery, blood may be supplied to the eyeball by an patients, because there is significant variation in the scatter- anastomosis between the middle meningeal and the lacrimal ing of light between subjects. The device is very sensitive to arteries and between the angular and dorsal nasal arteries. head- and eye-movement artifacts, and it cannot analyze The central retinal artery (CRA) is the first branch of the ocu- the blood flow in relation to the eye that moves along with lar artery, an anatomically terminal artery supplying blood to it. Studies employing this method were conducted by Shi- the inner layers of the retina. The other branches of the oph- mada et al. [16]. Measurements were taken using a Canon thalmic artery are short and long posterior ciliary arteries that laser blood flowmeter, which is a combination of LDV and reach the choroid and ciliary body. In addition, blood is RVA, with an eye-tracking system for measuring flow supplied to the anterior segment by the anterior ciliary velocity and vessel diameter, and blood flow was expressed arteries [11]. The total ocular blood flow is estimated to in μl/min. The study showed significant reduction of be approx. 1 ml/min, most of which supplies the vasculature vessel diameter in eyes with myopia compared to those of the uvea and only 2–5% supplying the retina [12]. without refractive error. Retinal blood flow was signifi- Ocular blood flow is affected by local factors and systemic cantly decreased in highly myopic eyes (>−8.0 diopters) factors, as well as autoregulation mechanisms. The latter compared with emmetropic eyes (±3.0 diopters) or mild mechanisms maintain constant blood flow in the eye despite myopic eyes (−3.0 to −8.0 diopters). A similar difference changes in perfusion pressure which depend on fluctuations was observed when comparing mild myopic eyes with eyes in arterial blood pressure but also in intraocular pressure or without refractive error. The mean velocity of ocular blood metabolic parameters [13]. Ocular factors known to affect flow decreased with increasing refractive error, but the changes in blood flow include intraocular pressure, biorheol- correlation was not statistically significant. Shimada et al. ogy, axial length, and diseases such as glaucoma or diabetic attributed these differences to increased axial length causing retinopathy. It was also found that the ocular blood flow mechanical stretching and thinning of the retina. Changes can be altered because of blood pressure, changes in body in the morphology of the eye structures observed by the posture, air composition, and medications [14]. Ocular blood authors may lead to straightening and decreasing vascular flow is also affected by external and environmental factors diameter, with a simultaneous reduction in metabolic such as temperature, brightness, air quality, and altitude. demand of tissues for oxygen and nutrients. Another hypothesis explaining this process is the facilitated transport of 2. Diagnostic Techniques oxygen into the retina via choroid of reduced density and thickness, which results in secondary retinal vasoconstriction Currently, many methods are available for the assessment of [16]. Other researchers cooperating with Benavente-Perez ocular blood flow. As indicated in the literature, measure- observed decreased choroidal blood velocity in myopic eyes ments of ocular circulation performed using different when using the above diagnostic method. They found also a methods show similar results, but each of these methods has higher response to hypercapnia in myopes consisting of its limitations. Diagnostic techniques and tools include the significant increase in choroidal blood velocity [17]. laser Doppler flowmeter (LDF), laser Doppler velocimetry (LDV), retinal vessel analyzer (RVA), retinal function imager 2.2. Laser Doppler Velocimetry. The blood velocity in selected (RFI), laser speckle contrast imaging (LSCI), magnetic vessels can be measured using a variant of the laser Doppler resonance imaging (MRI), optical coherence tomography velocimetry (LDV) method. Riva et al. applied successfully angiography (OCTA), pulsatile ocular blood flowmeter this method in the study of retinal arteries and veins. The (POBF), fundus pulsation amplitude (FPA), colour Doppler essence of LDV is the observation of two collimated laser imaging (CDI), Doppler optical coherence tomography light beams, directed and focused inside the vessel in one (DOCT), fluorescein and indocyanine angiography (FA and intersection point. As a result, the interfered light appears, ICG), retinal oximetry, blue light entopic phenomenon, and which then can be reflected by flowing blood cells, and its infrared thermography. Using MEDLINE, Google Scholar, fluctuations can be observed by specialized sensors. The inci- and Web of Science online databases, an analysis of the dent and reflected light are shifted in Doppler sense, which available blood flow studies conducted in myopic patients can be expressed proportionally as a velocity. The method was performed. All techniques and findings in myopia are assumes light’s coherence; thus, one light splitted into two summarized in Table 1. bundles is commonly used [18]. The authors found no data about the use of this method in myopic patients. 2.1. The Laser Doppler Flowmeter. allows for the continuous measurement of blood flow in retinal capillaries. The essence 2.3. Retinal Vessel Analysis. Retinal vessel analysis (RVA) is a of this method is the use of a coherent laser light source and novel technique for the measurement of retinal vessel diam- measurement of the beat frequency for light, which is par- eter in relation to time. Vessel diameter determines retinal tially scattered by moving blood cells and partially by sur- blood flow by the change of vascular resistance. In this rounding tissue. In case of moving cells, the Doppler shift method, the coefficients of light reflection and absorption in for source frequency is observed [15]. The readings are retinal vessels are measured. The erythrocytes tend to absorb expressed in relative flow units, so this technique is mainly the light bundle with the wavelength of 400–620 nm, in used to evaluate changes in blood flow in response to a opposite to the vessel tissues that mostly reflect it. The results Journal of Ophthalmology 3

Table 1: Table summarizing the techniques of ocular blood ﬂow measurement in myopia.

Methods Principle of each method Findings in myopia Measurement of blood cells traversing Retinal blood flow is decreased in Laser Doppler flowmeter (LDF) volume which are reflecting the light, highly and mild myopic eyes and the light undergoes a Doppler shift Doppler shift for interfered lights Laser Doppler velocimetry (LDV) No data reflected from blood cells In high myopia, the vessels at the posterior Measurement of the diameter of retinal Retinal vessel analyzer (RVA) pole have smaller diameter but are vessels in relation to time and location functionally comparable to control subjects Measurement of the haemodynamic parameters such as retinal blood flow velocity, oximetric state, No significant difference in retinal metabolic responses to photic activation, Retinal function imager (RFI) microcirculation blood flow velocity in and generation of capillary perfusion maps (CPM); either arterioles or venules RFI maps the retina to the resolution of single red blood cells moving through capillaries Measurement of velocity distributions which Decreased optic nerve microcirculation Laser speckle contrast imaging (LSCI) are coded as speckle contrast variations in eyes with myopic optic discs Measurement with the use of a pneumotonometer, In high myopes, pulsatile ocular blood flow Pulsatile ocular blood which registers changes in intraocular pressure as well as ocular blood flow amplitude flowmeter (POBF) during each cardiac cycle and volume is decreased Measurement of the distance between the Decrease in the FPA index along with Fundus pulsation amplitude (FPA) cornea and the retina during the cardiac cycle increased axial length with the use of laser interferometry Examining the circulation of the retina and Fluorescein and indocyanine choroid using a fluorescent dye and a Delayed blood flow in highly myopic eyes angiography (FA, ICG) specialized camera Reduced perfusion in the peripapillary Optical coherence tomography Measurement of laser light reflectance of the retina and decreased superficial and deep angiography (OCTA) surface of moving red blood cells retinal vascular density in annular zone of myopic eyes Measurement of backscattered signals as a Decreased blood flow velocity in the Colour Doppler imaging (CDI) function of the motion of the erythrocytes retrobulbar vessels, increased resistance toward or away from the transducer index in central retinal artery Measuring the phase changes between two Doppler optical coherence scans which is a quantitative value for the DOCT could indicate choroidal tomography (DOCT) velocity if the time between the two neovascularization in pathological myopia measurements is known Measurement of the optical densities of retinal Retinal oximetry vessels for two wavelengths and their ratio, which Reduced saturation in high myopia is known to be proportional to the oxygen saturation Method that provides structural, physiological, In severe myopia, blood flow Magnetic resonance imaging and functional image of tissue with the use of is markedly reduced magnetic properties of certain atomic nuclei Measurement of average leukocyte velocity Blue light entoptoscopy in area around the foveola by the use No data of entoptic phenomenon Measurement of infrared energy emitted Ocular surface temperature (OST) No data from object are the local diameters of measured arteries or veins pre- analysis. The light stimulation results in percent change of sented in UM units. The Gullstrand standard eye model is baseline diameter [19]. used to determine the relation of UM unit as 1 μm; however, In studies conducted by La Spina C. and company based for nonemmetropic eyes, the corrective values have not been on static and dynamic tests, the reduction of vessel diameter specified. One of the disadvantages of the RVA method is the at the retinal posterior pole was observed in patients with necessity of the patient’s pupil dilation prior to measurement. high myopia. The results indicated that the functions of reti- Moreover, during the measurement, patient fixations on a nal vessels were comparable to a group of control subjects. strobe light is required in order to provoke vascular tone They explained it by the reduction of oxygen consumption changes and allow proper retinal vascular functionality in the myopic group [20]. 4 Journal of Ophthalmology

2.4. Retinal Function Imaging. Retinal function imaging Moreover, it cannot be used for peripheral retinal assessment (RFI) is the next noninvasive technique which allows to and, unlike traditional angiography, does not allow for the assess several haemodynamic parameters such as oximetric visualization of vascular leakage. This device measures many state, retinal blood flow velocity, capillary perfusion map, parameters such as flow index, macular vessel area density, and functional metabolic responses to photic activation. and thickness of the foveal avascular zone and central macula. The principle of this technique is multispectral, high- The flow index estimates both vessel area and blood velocity resolution imaging which is capable of switching up four illu- [26]. Wang et al. used OCTA and confirmed that myopic eyes mination wavelengths allowing multiple image acquisition. It had reduced perfusion in the peripapillary retina, which may provides acquisition of images from small vessels, even the cause their increased susceptibility to vascular diseases. They information about a single red blood cell in the capillary. It is also reported a negative correlation between the axial length also integrated with a stimulus generator which is useful for and the peripapillary flow index [27]. Other researchers used functional imaging [21]. Li and coworkers with the use of the same method and observed decreased superficial and deep RFI found no difference in retinal microvessel blood flow retinal vascular density in the annular zone between 0.6 and velocity in myopes compared to the control group [8]. 2.5 mm from the foveal centre in myopic patients [8, 28].

2.5. Laser Speckle Contrast Imaging. Aizawa and coworkers in 2.8. Pulsatile Ocular Blood Flowmeter. Pulsatile Ocular Blood their study observed for the first time the microcirculation Flowmeter (POBF) is a well-known diagnostic technique for within the optic disc in myopic patients, using the laser the evaluation of the volume of blood supplied to the retina speckle contrast imaging (LSCI) method. The results have and choroid. Measurements are taken using a pneumoton- been expressed by mean blur rate coefficients, which refer ometer, which registers changes in intraocular pressure to local contrast variations of the speckles and indirectly indi- during each cardiac cycle. The results are expressed as the cate the blood flow in the imaged area. The method is based pulsation amplitude, reflecting the flow of blood into the on the fact that a collimated laser beam reflected from an eye; the volume of pulsation, that is, the amount of blood; irregular mutable surface produces random interferences, and the frequency of pulsation, that is, the frequency of which can be observed as intensity fluctuations and inform ocular flow caused by heart contraction. A study by Yang indirectly about object movement. In order to establish this and Koh indicated decreased pulsation amplitude and blood relation, an image with a longer exposure time than a speckle flow volume in myopic eyes compared with emmetropic eyes single fluctuation has to be captured. Thus, for selected pixels [29]. Benavente-Pérez et al. and two other research groups of the image, the velocity can be expressed in linear relation used the same technique in young patients with myopia. to contrast changes. Aizawa and coworkers noticed that eyes They confirmed lower pulsatile ocular blood flow as well as with myopic optic discs had decreased optic nerve microcir- lower ocular blood flow amplitude and volume in high culation compared to the normal group [22, 23]. myopes compared to other refractive groups [30–32].

2.6. Magnetic Resonance Imaging. Magnetic resonance imag- 2.9. Fundus Pulsation Amplitude. Tests relying on fundus ing (MRI) is the technique which uses magnetic properties of pulsation amplitude (FPA) allow for the measurement of certain atomic nuclei. It provides structural and metabolic the distance between the cornea and the retina during the information without depth limitation. It could image blood cardiac cycle with the use of laser interferometry. The value flow by the use of intravenous contrast or by magnetically of this index reflects the status of the choroidal circulation. labeling blood water. The main disadvantage of this tech- A study conducted by Berisha et al. showed a significant nique is low spatial resolution which prevents analysis of decrease in the FPA index along with increased axial length. blood flow in different layers of the eyeball. It is sufficient Their study, however, proves experimentally that the to measure total blood flow and its stimuli responses in the decrease in pulsation amplitude, fundus pulsation amplitude, entire retina and choroid. Blood flow of the choroid is 8–10 and pulsatile ocular blood flow in myopic eyes is related to times higher than the retina. MRI provides quantitative value the ocular volume and indicates that in fact, pulsatile ocular of blood flow, but there is no gold standard how to validate it. blood flow is not reduced [33]. It is vulnerable to eye movements [24]. San Emeterio Nateras et al. in their study suggested 2.10. Colour Doppler Imaging. The use of colour Doppler that in severe myopia, blood flow is markedly reduced. imaging (CDI) for testing ocular blood flow was first men- Their observation was made only on two patients with tioned in the 1980s. This method has become popular in a severe myopia [25]. very short time due to its numerous advantages, including the repeatability and reliability of measurement, availability, 2.7. Optical Coherence Tomography Angiography. Optical the low cost of testing, and suitability for nontranslucent Coherence Tomography Angiography (OCTA) is another optical structures. CDI is a noninvasive diagnostic method modern noninvasive test method that does not require con- and is most frequently used for the analysis of retrobulbar trast enhancement and allows for the monitoring of the con- vessels: ophthalmic artery (OA), central retinal artery stant ocular microcirculation. It requires multiple scans of (CRA), posterior ciliary arteries (PCAs) including temporal the same vessel to detect motion. This method has limited PCA (TPCA), and nasal PCA (NPCA). Testing PCAs applicability and is unsuitable in eyes with nontranslucent requires a lot of experience from the operator because of their optical centres, lack of fixation, narrow pupil, and nystagmus. small diameter and anatomical variability. Parameters Journal of Ophthalmology 5 evaluated with CDI include peak systolic velocity (PSV), end- was no significant difference between groups with small diastolic velocity (EDV), mean velocity (MV), resistance (<−3D) and moderate or high myopia (>−3D) [48]. index (RI), and pulsatile index (PI). The most reliable param- Angiography is a gold standard for the assessment of eters, due to their independence of the Doppler angle, are the retinal and choroidal circulation when leak is suspected. It PSV/EDV ratio and RI [30]. RI was first described by Pource- is invasive because of the need to administer contrast agents. lot, and it could be calculated as RI = (PSV − EDV)/PSV. It is There are two kinds of angiography depending on the used for evaluating peripheral vascular resistance [34]. Vas- contrast agent: indocyanine green (ICG) and fluorescein cular resistance is also related to vessel radius, vessel length, angiography (FA). Fluorescein is used mainly to visualize and blood viscosity, because it is consistent with the retinal vessels whereas indocyanine allows to imagine deeper Hagen–Poiseuille law [35]. choroidal vessels. It can be used to assess blood velocity, due to measurement of the time that it takes for the dye to pass 8μLQ ΔP = R4, 1 through the vessels. In myopia, Avetisov and Savitskaya π found delayed blood flow with the use of fluorescein angiography [49]. It is also very helpful in degenerative myopia where ΔP is the pressure difference between the two where it is used for evaluating development of CNV as well ends, L is the length of the vessel, μ is the dynamic vis- as RPE atrophy. ICG is better in evaluating delineation of lac- cosity, Q is the volumetric flow rate, and R is the vessel quer cracks and localization of the CNV in lacquer cracks radius. than FA in highly myopic eyes [50]. The results of the available studies using CDI indicate The blue field entoptic phenomenon is produced by the decreased blood flow velocity in the retrobulbar vessels corre- different light absorption by erythrocytes and leukocytes lated with greater axial length, increased refractive error, or when the retina is illuminated by blue light. One could progressive retinal degeneration, particularly in combination observe the motion of one’s own white blood cells flowing with chorioretinal atrophy in the peripapillary region of the in retinal vessels. In this method, the patient looks constantly optic nerve II [30, 36–41]. It should be stressed that in myo- at the screen displaying alternatingly two different images. pic patients, haemodynamic disorders in PCAs are associated One of them presents a solid blue surface and the other one with greater severity of degenerative fundus changes. At the presents an animation of moving dots. The patient’s task is same time, the extent of degenerative processes and their to select the number and minimum and maximum speeds advancement is directly proportional to the deterioration of of the generated dots in reference to one’s own leukocytes; flow parameters in CRA [42, 43]. The most pronounced therefore, it is a subjective method. The principle of this changes in blood flow have been observed in subjects with technique is the assumption that leukocyte flux is propor- moderate and high myopia, that is, >8.0 diopters [41]. In tional to retinal blood flow; however, it assess the blood addition, increased RI in CRA is associated with both flow only in the perimacular region [51]. The authors greater axial length and refractive error, which may explain found no studies with the use of the above described method the pathomechanism of myopic retinopathy [36]. It should in myopic patients. also be emphasized that differences in flow parameters in Measurement of ocular surface temperature (OST) OA are not statistically significant with respect to retinal becomes an important examination in modern ophthalmol- degeneration [42]. ogy. There are several known algorithms to acquire the Doppler optical coherence tomography (DOCT) is a OST that can be used for the diagnosis of ocular diseases. method which consists of a combination of optical coher- The thermal imaging technique, known as thermography, is ence tomography with the Doppler principle. It provides the method of indirect, noninvasive measurement of body high-resolution images of both static and moving compo- heat radiation by the use of an infrared camera. In oph- nents which transmits information not only about volu- thalmology, it provides patterns (images) of temperature metry of blood flow (direction and velocity) but also distribution and changes in the vascular tissues within about vascular anatomy. It provides three-dimensional the eye and adnexa. Some studies revealed a correlation information, and it is capable of generating a microvascu- between ocular blood flow and OST. Gugleta et al. in their lature tissue map [44]. There are almost no data about studies noticed a relation of corneal temperature and retro- findings of DOCT in myopia. The authors found only few bulbar haemodynamics, where OST decreased along with images which show pathological neovascularization in high the ocular circulation [52]. The authors found no studies myopia [45]. using this method in assessment of myopic patients. Retinal oximetry is the technique which measures oxygen saturation. It is based on the simultaneous capture of two images with different light wavelengths. The comparison of 3. Discussion these images with software algorithm provides estimation of oxygen saturation, because there is a difference in light Currently, there are many available methods for the assess- absorption by oxygenated and deoxygenated hemoglobin. ment of ocular blood flow. Each one has advantages and [46]. Zheng and other researchers observed reduced arteriole limitations, but none of them is suitable for the direct saturation and smaller difference in arterio-venosus satura- assessment of retinal and choroidal vasculature. Each device tion in patients with high-grade myopia [47]. However, in a measuring ocular blood flow presents results in different study by Yang conducted on a Chinese population, there units, either relative or absolute, which makes measurements 6 Journal of Ophthalmology inconsistent, nonstandardized, and sometimes impossible to decreased perfusion in the peripapillary retina. In myopic compare against other techniques. eyes, there is lower retinal vascular density in the annular Many available techniques rely on the use of laser light of zone. Researchers showed also a smaller diameter of retinal various wavelengths in the process of measurement, which is vessels as well as decreased arteriole saturation compared a serious limitation in the case of eyes with nontranslucent to controls. optical structures or narrow pupils. CDI is the only technique These differences are probably due to mechanical stretch- relying on ultrasound waves for measurement, which makes ing and thinning of the tissues related to elongation of the it suitable for use in any patient, regardless of the translu- eyeball. These changes are believed to cause a reduction in cency of the optical structures and visual acuity that allows metabolic demand of tissues for oxygen and nutrients. for proper fixation. Another theory suggests that reduced circulation leads to In the reviewed literature, other methods of measuring secondary thinning of the tissues. tissue metabolism and providing indirect information about ocular blood flow volume were recorded, but they are not easily available. These include retinal oximetry, ocular sur- 4. Summary face temperature, and retinal functional imager. Myopia is an increasingly common refractive error and a Angiography is one of the oldest techniques but still subject of interest for many researchers. The newly developed commonly used, because of its availability and being sensitive diagnostic techniques are also used for the assessment of ocu- to leakage. This method should not be performed as routine lar blood flow in myopia. Reduced ocular blood flow in myo- examination due to its invasive nature. Other methods are pia has been detected using various diagnostic techniques, noninvasive, but some of them, for example, POBF, require and the introduction of new ones allows for more accurate physical contact of the cornea with the sensor. It may cause measurements. a risk of transmission of the infection. Many researchers consistently reported lower blood flow The major challenge of blood flow measurement is its fi parameters in myopic eyes regardless of the used diagnostic quanti cation. Only two of the described methods allow fully method. It is unclear whether this is a primary change that quantitative volumetric information. These are DOCT and fl causes secondary thinning of ocular tissues or quite the MRI. Both provide information about blood ow together opposite; that is, the mechanical stretching of the eye wall with structural anatomy. Nevertheless, DOCT has a higher fl reduces its thickness and causes a secondary lower demand resolution than MRI and allows assessment of blood ow of tissues for oxygen. with precise depth gating. Other techniques measure some of the volumetric blood flow component. Combin- ing techniques which assess velocity with measurements Conflicts of Interest of vessel diameters are possible, but these procedures fl are very time-consuming; therefore, they cannot be used in The authors declare that there is no con ict of interest a clinical setting. regarding the publication of this paper. There are two techniques which allow to obtain high- resolution images of retinal vessels with information about References blood flow: OCTA and DOCT. 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Research Article Prevalence and Related Factors for Myopia in School-Aged Children in Qingdao

1 2 1 1 3 Jin Tao Sun , Meng An , Xiao Bo Yan, Guo Hua Li , and Da Bo Wang

1Department of Ophthalmology, Qingdao Economic and Technological Development Area First People’s Hospital, Qingdao, Shandong 266555, China 2Department of Ophthalmology, Qingdao Traditional Chinese Medical Hospital of Huangdao District, Qingdao, Shandong 266500, China 3Department of Ophthalmology, The Aﬃliated Hospital of Qingdao University, Qingdao, Shandong 266000, China

Correspondence should be addressed to Da Bo Wang; [email protected]

Received 26 July 2017; Accepted 10 December 2017; Published 8 January 2018

Academic Editor: Malgorzata Mrugacz

Copyright © 2018 Jin Tao Sun et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. To investigate the prevalence and related factors for myopia in school-aged children in the Economic and Technological Development Zone of Qingdao, Eastern China. Methods. A total of 4890 (aged 10 to 15 years) students were initially enrolled in this study. 3753 (76.75%) students with completed refractive error and questionnaire data were analyzed. The children underwent a comprehensive eye examination. Multiple logistic regression models were applied to assess possible factors associated with myopia. Results. The prevalence of myopia increased as the children’s grade increased (χ2 = 560 584, P <0001). Low myopia was the main form of myopia in adolescent students (30.22%). With the growth of age, students spent significantly more time on near work (P =003) and less time on outdoor activity (P <0001). In multivariate models, only the following variables were significantly associated with myopia: age, two myopic parents, outdoor activity time, and continuous near work without 5 min rest. Conclusions. The prevalence of myopia increased as the grade increased. Age, two myopic parents, and continuous near work time without 5 min rest were risk factors for myopia. Outdoor activities had protective effect for myopia.

1. Introduction In recent years, Chinese scientific research institutions have carried out large-scale epidemiological survey on Myopia has become a major global public health problem, myopia in the northern and southern areas. Numerous particularly in East Asia [1]. The direct cost of providing eye- cross-sectional studies have provided information on the glasses to people who need refractive correction are also pattern of prevalence and risk factors for myopia. Although enormous. In the United States, the National Health and the exact pathogenic mechanism of myopia is still unclear, Nutrition Examination Survey (NHANES) reported the most scholars believe that myopia is the result of a combina- annual direct cost of correcting distance vision impairment tion of genetic and environmental factors. Recent epidemio- due to refractive errors to be between US$3.9 and US$7.2 logical surveys have shown that the prevalence of myopia billion [2]. The prevalence of myopia is generally highest in varies widely, depending on age, gender, geography, and populations of East Asian, particularly in urban locations ethnicity [8–11]. What is more, some studies have explored such as Guangzhou [3], Taiwan [4], Hong Kong [5], and other relevant influencing factors, including more time spent Korea [6]. Affected by many factors, such as visual function, on near work activity [12], higher educational level [13], and psychology, aesthetics, and economy, the quality of life in less time participating in outdoor activities [14]. Whereas the patients of myopia was seriously impaired [7]. evidence on this issue is controversial, a cross-sectional study 2 Journal of Ophthalmology in Beijing demonstrated that a higher prevalence of myopia mydriasis (a minimum pupil diameter of 6 mm and disap- in high school students was associated with shorter near pearance of papillary light reflex). work distance [15]. Lin et al. [16] reported that outdoor activities were associated with less myopic refraction, but they did 2.4. Questionnaire Survey. A standardized myopia question- not find any significant association between near work and naire, which was modified from the Sydney Myopia Study myopic refraction in this study. Furthermore, Low et al. (SMS) group, was adapted and applied to this study. The [17] reported that neither near work nor outdoor activity questionnaire was translated by ophthalmologists, an epide- was found to be associated with early myopia. The conflict miologist, and a statistician in our study group. It is com- results are mainly attributed to the following aspects: (1) posed of two parts: the parental version and the children’s There are no uniform questionnaire. (2) The results of ques- version. A pilot study in the Anyang Childhood Eye Study tionnaire survey are affected by geography, culture, cognitive (ACES) proved that this questionnaire is valid and reliable ability, and memory biases of the respondents. (3) The [19]. In order to ensure the quality of investigation, school outcome used to reflect myopia was mainly noncycloplegic mobilization was implemented in selected school sampling autorefraction. Recently, a standardized myopia question- units by project members through a meeting in which the naire, which was developed by the Sydney Myopia Study details regarding the questionnaire were explained to the group, was used to acquire information on near work/out- parents and guardians. Primary school students were allowed door activities, habitual reading distance, and so on [18]. In to complete the questionnaire with the help of parents. The this study, we investigated the prevalence and the risk factors questionnaire was administered to obtain information on for myopia in schoolchildren in the eastern coastal city of near work time, continuous near work time without 5 min China, by the method of cluster sampling, with particular rest, near work distance, outdoor activities, and so on. Paren- attention to variables such as the duration and type of tal refractive status was also obtained from the questionnaire. outdoor activities and near work. Average hours spent on near work (<50 cm working distance) were summed from questions regarding drawing, homework, reading, making handicrafts, and handheld com- 2. Methods puter use. Time spent on outdoor activities was based on 2.1. Study Participants. The Childhood Errors of Refraction questions about playing outdoors, family picnics, taking a Study was a cross-sectional epidemiological study investi- walk, bicycle riding, hiking, and outdoor sports after school gating the prevalence of refractive error in 10–15-year- on weekdays and weekends. To assess the duration of contin- old school-aged children conducted from December uous reading, children were asked about the time they 2015 to January 2016. The sample calculation formula spent in continuous reading or other near work before 2 taking a break of 5 minutes or longer. They were then classi- n = μα/δ p 1 − p was used to estimate the number of sam- fied into five categories: category A: 0–15 min; category B: ples. With a stratified-clustered sampling method, 6 primary 15–30 min; category C: 30–45 min; category D: 45–60 min; (aged 7 to 12 years) and 4 secondary (aged 13 to 15 years) and category E: >60 min. From response to a question schools including 4890 students (2529 [51.72%] male) were “How far did you often write your homework,” the distance randomly selected from 22 primary and 19 secondary from objects when doing near work was classified into four schools. This met the sample number criteria for total categories: category A: >30 cm; category B: 20–30 cm; number of samples, providing a representative sample of category C: 10–20 cm; and category D: <10 cm. Economic and Technological Development Zone of Qingdao primary and secondary schools. 2.5. Quality Control. The equipment was checked and cali- brated daily. All examiners were senior clinical ophthalmolo- 2.2. Ethics Statement. The study was approved by the Ethics gists. Data entry was completed by well-trained staff. Committee of the Review Board of the Qingdao Economic ’ and Technological Development Area First people s Hospital 2.6. Definitions and Data Analysis. Spherical equivalent (SE) and adhered to the Declaration of Helsinki. Written was calculated with the following equation: SE = spherical informed consent was obtained from parents or guardians. diopter +0.5 × cylinder diopter. Myopia, emmetropia, and hyperopia was defined as the SE < −0.50 D (low myo- 2.3. Examination. The children underwent a comprehensive pia < −0.5 to >−3.0 D, moderate myopia ≤−3.0 to >−6.0 D, eye examination, including measurement of visual acuity, and high myopia ≤−6.0 D), −0.50 D ≤ SE ≤ +0.50 D, and color vision, assessment of ocular motility, slit-lamp exam- SE > + 0.50 D, respectively [20]. Statistical analysis was ination, autorefraction, cycloplegic autorefraction, and fun- performed using a commercially available statistical software dus examination using a direct ophthalmoscope (YZ6E; package (SPSS for Windows, version 20.0, IBM-SPSS, Six Six Vision Corp., Suzhou, China). The cycloplegic Chicago, Illinois, USA). First, we examined the associations autorefraction was measured by a binocular open-field between the prevalence of myopia and other parameters in a autorefractor (RM-8000A, Topcon, Japan) with a measure- univariate analysis. Multiple logistic regression analysis was ment range of −25 to +22 diopters (D). Cycloplegia was then used to determine independent factors. Odds ratios induced in each eye by instillation of three drops of (OR) and their 95% confidence intervals (CI) for myopia were 0.5% tropicamide 5 min apart. Extra tropicamide (1 or 2 calculated. All P values were 2-sided and were considered drops) was also used in some children to obtain adequate statistically significant when the values were less than 0.05. Journal of Ophthalmology 3

3. Result Table 1: The prevalence of myopia in different age groups. The mean refractive error was −1.62 (±1.82) D, and the over- Age (years) Number (n) Myopia (n) Myopia (%) all prevalence of myopia was 52.02%. The prevalence of myo- 10 690 156 22.61 χ2 = 560 58 P <0001 pia in students increased with age ( , ); 11 678 222 32.74 the prevalence of myopia in students at 10 years old was 12 671 307 45.75 only 22.61%, as it increased to 56.93% in students at 13 13 685 390 56.93 years old, and the rate was the highest (69.34%) in students at 15 years old (Table 1). There was no significant 14 1080 716 66.30 statistical difference in prevalence of myopia between boys 15 1086 753 69.34 and girls (χ2 =0709, P =0400, Table 2). Total 4890 2544 52.02 In addition, we found that low myopia was still the main form of adolescent myopia. The proportion of high myopia Table ff ff increased with age (χ2 = 567 054, P <0001, Table 3). 2: The prevalence of myopia of di erent genders in di erent Table 4 presents the time that students spent on near work age groups. fi and outdoor activities. The older children had spent signi - Male Female Age (years) cantly more time on near work (P =003) and less time on n Myopia (%) n Myopia (%) P <0001 outdoor activities than the young ones ( ). 10 361 94 (26.0) 329 62 (18.8) The results of univariate and multivariate analyses of factors associated with myopia are shown in Table 5. Univar- 11 348 119 (34.2) 330 103 (31.2) iate analysis showed that the following variables were signif- 12 351 156 (44.4) 320 151 (47.2) icantly associated with myopia: age, one myopic parent, two 13 344 199 (57.8) 341 191 (56.0) myopic parents, near work distance, near work time, outdoor 14 560 346 (61.8) 520 370 (71.2) activity time, and continuous near work without 5 min rest. 15 565 387 (68.5) 521 366 (70.2) In multivariate models, only the following variables were Total 2529 1301 (51.4) 2361 1243 (52.6) significantly associated with myopia: age, two myopic parents, outdoor activity time, and continuous near work without 5 min rest. Table 3: The prevalence of low, moderate, and high myopia in different age groups. 4. Discussion Moderate High No myopia Low myopia The prevalence of myopia around the world has increased Age (years) myopia myopia recently. Previous studies have shown that 9 to 16 years of n % n % n % n % age is the fastest growing period for adolescent myopia 10 534 77.39 130 18.84 17 2.46 9 1.30 [21]. Other than genetic factors, environment is also an 11 456 67.26 162 23.89 50 7.37 10 1.47 important contributing factor in the development of myopia [22]. Scholars from all over the world have done a lot of 12 364 54.25 192 28.61 89 13.26 26 3.87 research on the environmental factors, but the specific mech- 13 295 45.07 226 32.99 117 17.08 47 6.86 anism and extent of this impact remain controversial. 14 364 33.70 380 35.19 247 22.87 89 8.24 Consistent with previous studies, we found that the 15 333 30.66 388 35.73 266 24.49 99 9.12 prevalence of myopia in students persistently increased as Total 2346 47.98 1478 30.22 786 16.07 280 5.73 the age increased. Interestingly, this result is lower than that in urban areas in Guangzhou [23], which is higher than that in rural areas in Yangxi [24]. In addition, low myopia is the Table main form of myopia, but the properation of high myopia 4: Near work and outdoor activity time (hours per day) of the students. increased as the age increased. We consider that this might be related to the social and economic environment in this Near work (h/d) Outdoor activity (h/d) Age (years) n region. From another point of view, the importance of (Mean ± SD) (Mean ± SD) environmental factors for myopia is explained. 10 562 3.32 ± 1.32 2.28 ± 1.21 At present, there is no unified conclusion about the 11 559 3.42 ± 1.56 2.24 ± 1.26 prevalence of myopia among male or female. The current ± ± results revealed that girls were no more likely to suffer from 12 536 3.41 1.82 2.06 1.32 myopia than boys. This is consistent with many previous 13 561 3.78 ± 1.42 1.88 ± 1.12 studies [8, 25]. Particularly, in the COMET study, although 14 752 4.32 ± 1.84 1.64 ± 1.14 there is no difference in the prevalence of myopia between 15 783 4.62 ± 1.26 1.42 ± 0.96 boys and girls, boys had a slower progression (by 0.16 D) P value P =003 P <0001 than girls [26]. They considered that any relationship with sex, if it existed, would occur early in the course of myopia and would not be sustained over time. We think that this 4 Journal of Ophthalmology

Table 5: Associations between myopia and possible risk factors.

Univariate analysis Multivariate analysis Variables Odds ratio 95% CI P Odds ratio 95% CI P ∗ ∗ Age 1.43 1.34–1.52 0.012 1.23 1.18–1.27 <0.001 Sex Boys 1 1 Girls 1.64 0.48–2.21 0.14 1.68 0.42–1.92 0.12 Parental myopia None 1 1 ∗ One myopic 1.47 1.24–1.96 0.01 1.62 0.71–2.34 0.12 ∗ ∗ Two myopic 2.32 1.72–3.28 <0.001 2.58 1.76–3.46 <0.001 Near work distance (cm) >30 1 1 ∗ 20–30 1.27 1.02–1.54 <0.001 1.12 0.69–1.38 0.23 ∗ 10–20 2.46 1.52–4.76 <0.001 1.76 0.49–2.74 0.18 0–10 1.29 1.08–1.54 0.04 1.21 0.84–1.41 0.32 Trend test 0.16 0.21 ∗ Near work time (h/d) 1.28 1.04–1.86 <0.001 1.42 0.79–2.04 0.16 ∗ ∗ Outdoor activity time (h/d) 0.67 0.46–0.78 0.03 0.74 0.53–0.92 <0.001 5 min rest after continuous near work time (min) 0–15 1 1 15–30 0.94 0.72–1.12 0.24 1.02 0.92–1.08 0.12 ∗ ∗ 30–45 1.19 1.02–1.31 0.02 1.24 1.14–1.32 <0.001 ∗ ∗ 45–60 1.36 1.12–1.49 <0.001 1.34 1.28–1.38 0.03 ∗ ∗ >60 2.12 1.76–2.72 <0.001 2.48 1.92–3.24 <0.001 ∗ ∗ Trend test <0.001 <0.001 ∗ indicates a significant statistical significance (P <005). explanation may be reasonable. Taking into account the age regression analysis, we found that near work time and near group of the participants in the study, we believe that this work distance were not significantly related to myopia. explanation is reasonable. Perhaps, as Lin et al. [16] assumed, there was a special “satu- Previous studies showed that parental myopia, in even ration effect” between them. only one parent, leads to an increased risk for juvenile myo- Consistent with previous study [33], we found that pia. In Australia, in six-year-old children, there was 3.16- and children whose continuous near work time > 30 min with- 3.33-fold increased risk of incident myopia than no parental out 5 min rest were more likely to have myopia than those myopia, respectively [25]. One interesting finding of this 0–15 min group. Perhaps, we could put forward such a study was that although one or two parental myopia was a hypothesis that there was a “dose reponse” between myo- risk factor for myopia in univariate analysis, only two paren- pia and the duration of continuous near work. In other tal myopia was a risk factor after multiple regression analysis. words, as long as near work time reached a certain inten- This result may provide us with some valuable information sity, it would have an impact on myopia, which meaned about the relationship between heredity and myopia. that the intensity of near work rather than the total time Previous numerous cross-sectional studies had reported was an important factor for myopia. However, it should that schoolchildren engaged in near work were more likely be pointed out that some scholars considered that there to have myopia than those who spent less time on near work was a positive association between a higher education level [27, 28] and whose distance of near work were shorter than and myopia [34]. However, we thought that a higher 30 cm [29, 30]. However, there were also some studies that academic level was highly correlated with near work time have reported lack of association between near work and and it should not be listed separately. myopia [31, 32]. Thus, the findings are equivocal. In this In Singapore, a cross-sectional study was conducted to study, with the growth of age, students spent significantly analyze the effect of outdoor activities on 1249 teenagers aged more time on near work than before. The near work time 11–20 years. They found a significant negative association increased from 3.32 h/d in the 10-year-old children to between myopia and outdoor activities. Adjusting for the 4.62 h/d in the 15-year-old children. However, after multiple confounders, for each hour increase in outdoor activities Journal of Ophthalmology 5 per day, SE increased by 0.17 D and the axial length In conclusion, the prevalence of myopia in adolescent decreased by 0.06 mm [35]. Some scholars had also come students increased as the grade increased. Age, two myopic up with the quantitative standard of outdoor activity time. parents, and continuous near work time without 5 min rest Jones et al. [36] found that there might be a threshold of were risk factors for myopia. Longer time spent on outdoor around 2-3 hours per day spent outdoors that was needed activities was significantly associated with a lower risk of to prevent myopia. Smith et al. [37] found that high ambient myopia. These associations may indicate that low intensity lighting retarded the development of experimental myopia in near work and more outdoor activities may be important monkeys. The possible explanations included that high for future trials of intervention on myopia. ambient lighting could regulate the release of dopamine from the retina and stimulate the synthesis of vitamin D in the Conflicts of Interest body [38, 39]. In the present study, the outdoor activity time decreased from 2.28 h/d in the 10-year-old children to 1.42 h/ The authors declare that they have no conflicts of interest. d in the 15-year-old children. Similar to previous studies, we found that the more time spent outdoors was associated with References a lower prevalence of myopia. Although the specific mechanism remained to be further studied, the increase of outdoor [1] I. G. Morgan, K. Ohno-Matsui, and S. M. 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Research Article The Influence of Environmental Factors on the Prevalence of Myopia in Poland

Maciej Czepita, Damian Czepita, and Wojciech Lubiński

2nd Department of Ophthalmology, Pomeranian Medical University, al. Powstańców Wlkp. 72, 70-111 Szczecin, Poland

Correspondence should be addressed to Damian Czepita; [email protected]

Received 30 August 2017; Accepted 2 November 2017; Published 19 November 2017

Academic Editor: Malgorzata Mrugacz

Copyright © 2017 Maciej Czepita et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Purpose. In the paper, we describe and discuss the results of epidemiological studies concerning myopia carried out in Poland. Materials and Methods. Results from the examination of 5601 Polish school children and students (2688 boys and 2913 girls) aged 6 to 18 years were analyzed. The mean age was 11.9 ± 3.2 years. Every examined student had undergone the following examinations: distance visual acuity testing, cover test, anterior segment evaluation, and cycloplegic retinoscopy after instillation of 1% tropicamide, and a questionnaire was taken. Results. We have found that (1) intensive near work (writing, reading, and working on a computer) leads to a higher prevalence of myopia, (2) watching television does not inﬂuence the prevalence of myopia, and (3) being outdoors decreases the prevalence of myopia. Conclusions. The results of our study point to insuﬃciency of accommodation contributing to the pathogenesis of myopia.

1. Introduction 2. Materials and Methods

Myopia is a major and still unresolved health problem in the In this paper, we describe and discuss the results of epidemi- world. It is currently estimated that more than 22% of the ological studies concerning myopia carried out in Szczecin, world population has myopia. This means that 1.5 billion Poland. Special attention was put on the role of reading, writ- people have myopia. In East Asian countries, the prevalence ing, and visual work using a computer and outdoor activity. of myopia is at 70–80%. In Western countries, 25–40% has The studies were carried out from October 2000 till myopia. In the United States, the number of myopes has March 2009. Results from the examination of 5601 Polish double in the past 30 years [1–3]. school children and students (2688 boys and 2913 girls) aged Myopia is determined by genetic and environmental 6 to 18 years were analyzed. The mean age was 11.9 ± 3.2 factors [4]. Environmental factors include reading, years. The students examined were Caucasian, and there writing, and visual work when using a computer. Some were no children of mixed ethnicity. Every examined student researchers believe that even watching television has an had undergone the following examinations: distance visual inﬂuence on the development of myopia [5–17]. It is acuity testing, cover test, anterior segment evaluation, and currently believed that outdoor activity leads to a lower cycloplegic retinoscopy after instillation of 1% tropicamide, prevalence of myopia [10, 13, 14, 18–35]. and a questionnaire was taken. The methodology of the Research into the epidemiology of myopia is ongoing examination has been described in details in previous works throughout the entire world [1–3, 5–31]. In Poland, the as follows. Participation was voluntary. Before beginning the greatest achievements in myopia research belong to the examinations, the doctors met with the children, their par- Pomeranian Medical University in Szczecin [32, 33]. That ents, or legal guardians and teachers. It was explained what is why we decided to present our results. the examinations were about. The children, parents, or legal 2 Journal of Ophthalmology

10 10 9 9 8 8 7 7 6 6 5 5 4 4 3 3 2 2 1 1 0 0 −1 −1 −2 −2 −3 −3 −4 −4 − − Spherical equivalent (D) equivalent Spherical 5 5 −6 (D) equivalent Spherical −6 −7 −7 −8 −8 −9 −9 −10 −10 012345678910111213 012345678910 Time spent on reading and writing (hours/days) Time spent on watching television (hours/days)

Figure 1: Mean spherical equivalent in relation to reading and Figure 3: Mean spherical equivalent in relation to watching writing. television.

⁎ 10 y = 0.468 + 0.0088 × 9 10 8 9 7 8 6 7 6 5 5 4 4 3 3 2 2 1 1 0 0 −1 −1 −2 − − 2 −3 −3 −4 −4 −5 − (D) equivalent Spherical 6 Spherical equivalent (D) equivalent Spherical 5 −7 −6 −8 −7 −9 − −10 8 0 2 4 6 8 1012141618202224262830 −9 −10 Time spent on outdoor activity (hours/week) 012345678910111213 Time spent on computer work (hours/days) Figure 4: Mean spherical equivalent in relation to outdoor activity. Figure 2: Mean spherical equivalent in relation to using a computer. 0.5 DC. The mean SE was calculated after examination of both eyes [32, 33]. guardians and teachers had an opportunity to discuss the study with the experimenters prior to giving consent. 3. Results Informed consent as well as date of birth was obtained in each case from children, parents, or legal guardians and After having examined the 5601 students, it has been shown school principals. The studies were approved by the Bioethics that reading and writing lead to a higher prevalence of myo- Committee of the Pomeranian Medical University. The pia (p <0000001) [32] (Figure 1). research protocol adhered to the provisions of the Declara- It has also been observed that working on a computer tion of Helsinki for research involving human subjects. leads to a higher prevalence of myopia (p <0000001) Every examined person underwent retinoscopy under [32] (Figure 2). cycloplegia. Cycloplegia was induced with two drops of 1% It has been shown that watching television does not tropicamide administered 5 min apart. Thirty minutes after have an influence on the prevalence of myopia (p =031) the last drop, pupil dilation and the presence of light reflex [32] (Figure 3). was evaluated as later retinoscopy was performed. Retinos- Outdoor activity however leads to a lower prevalence of copy was performed in darkened school’s consulting rooms. myopia (p <0007) [33] (Figure 4). The refractive error readings were reported as a spherical equivalent (SE) (sphere power plus half-negative cylinder 4. Discussion power). Hyperopia was defined to be spherical equivalent higher than +0.5 D and emmetropia to be higher than Opinions concerning the influence of reading, writing, and −0.5 and lower than +0.5 D. Myopia was defined to be visual work when using a computer, watching television, with a SE lower than −0.5 D. Astigmatism did not exceed and outdoor activity are varied. Most authors accept that Journal of Ophthalmology 3

Table 1: Dependency between reading, writing, using a computer, or watching TV and myopia.

Dependency between reading Dependency between using a Dependency between Reference Country and writing and myopia computer and myopia watching TV and myopia Cole et al. [5] Australia + Czepita et l. [6] Poland + + Giloyan et al. [7] Armenia + Khader et al. [8] Jordan + + Kinge et al. [9] Norway + Konstantopoulos et al. [10] Greece + + Li et al. [11] China + + Mutti et al. [12] U.S.A. + Pärssinen et al. [13] Finland + + Saw et al. [14] China + Saxena et al. [15] India + + + Hong Wong et al. [16] + Kong You et al. [17] China + + +

Table 2: Dependence between outdoor activity and myopia. attributed to insufficiency of accommodation during visual Reference Country near work. It has also been observed that spasms of accommodation are considered the factors of myopia [4]. Dirani et al. [18] Singapore The results of these studies were confirmed by researchers French et al. [19] Australia from the Pomeranian Medical University in Szczecin, Guggenheim et al. [20] UK Poland, by achieving a coefficient of statistical significance Guo et al. [22] China p <0000001 [32]. Guo et al. [23] China During the years of 2005-2006, Buehren et al. [34] and Guo et al. [21] China Collins et al. [35] have showed that reading and visual work Jacobsen et al. [24] Denmark when using a computer leads to a change in the shape of the cornea, which may lead to the development of myopia. Jones et al. [25] U.S.A. The results obtained by the authors are in agreement with Lin et al. [26] China the hypothesis that lid-induced corneal aberrations may play Mutti et al. [12] U.S.A. a significant role in the development of myopia. Ngo et al. [27] Singapore Most authors believe that watching television does not Pärssinen et al. [13] Finland cause myopia. The argument behind this belief is that watch- Rose et al. [28] Australia ing television usually from a few meters away does not cause ffi Saxena et al. [15] India insu ciency of accommodation [4]. Research done at the Pomeranian Medical University in Szczecin, Poland, has also Shah et al. [29] UK proved that watching television does not lead to a higher You et al. [17] China prevalence of myopia (p =031) [32]. However, it happens Wu et al. [30] Taiwan that watching television does lead to a quicker development Zhou et al. [31] China of myopia when the television monitor is placed too close to the eye [4]. Currently, it is accepted that outdoor activity leads to a lower prevalence of myopia. This is probably due to the fact reading, writing, and visual work when using a computer that during distant visual work, there is no spasm of accom- lead to a higher prevalence of myopia. However, some modation [3, 4]. This relationship has been also proven by authors debate these relationships. Concerning watching research carried out at the Pomeranian Medical University television, most authors believe that it does not have an in Szczecin, Poland, achieving a coefficient of statistical influence on the development of myopia (Table 1). Out- significance of p <0007 [33]. door activity however decreases the prevalence of myopia It also has to be added that the results of our research are (Table 2) [3, 4, 32, 33]. reliable because they have been conducted on a large and It is accepted that the higher prevalence of myopia due homogenous group of people of the Caucasian race. Besides, to reading, writing, and visual work using a computer are our research was done after cycloplegia. 4 Journal of Ophthalmology

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