Background
High myopia is one of the main causes of visual impairment worldwide [
1]. It has been reported that about 1 % of the population suffers from this disease [
2]. High myopia is always accompanied by pathological structural changes, such as axial elongation, posterior scleral staphyloma, lacquer crack formation, thinning of the retina and chorioid, and choroidal neovascularization (CNV) [
3‐
5]. Excessive axial elongation of the eyeball is thought to be one of the main causes of the ocular complications mentioned above. Among these complications, chorioretinal atrophy, augmented by choroidal thinning, can lead to photoreceptor cell death, which results in the consequent loss of central visual function. Another notable complication threatening visual function is CNV [
4]. Myopic CNV develops into secondary chorioretinal central atrophy and leads to central scotoma [
6].
As we all know, in high myopic eyes, the earliest changes begin in the choroid [
7]; recent interest has focused on the choroid as an important structure involved in the pathophysiology of high myopia [
8]. Choroidal thickness may be an important parameter in studying the pathogenesis of high myopia. With the enhanced depth imaging (EDI) technique of optical coherence tomography (OCT) instruments, images of the choroid have improved, making it possible to measure choroidal thickness more accurately, safely, and simply [
9‐
13]. Several researchers have found that in high myopic eyes, the choroidal thickness is significantly thinner than in normal eyes [
14‐
17]. However, most of these studies failed to adjust for potential compounding factors such as axial length (AL) and spherical equivalent (SE), which have been proven to have a negative correlation with choroidal thickness [
18,
19].
Therefore, the aim of this study was to evaluate the macular choroidal thickness in Chinese patients with high myopia and normal subjects and to determine the correlation with clinical factors in high myopic eyes. In addition, because of the myopic CNV and the lacquer crack, which would develop into secondary chorioretinal central atrophy, we compare the subfoveal choroidal thickness (SFCT) in high myopic eyes with or without CNV and with or without lacquer cracks. Finally, given the data accumulated, we sought to conduct a comprehensive meta-analysis to calculate the differences in SFCT between high myopic eyes and normal control eyes quantificationally.
Methods
Subjects and enrollment criteria
This study was approved by the Ethical Review Committee of Aier Eye Hospital and adhered to the provisions of the Declaration of Helsinki for research involving human subjects. Written informed consent was obtained from the participants before the study began. All the subjects were from a Chinese Han population, and they were prospectively and consecutively recruited for this study between October 2012 and November 2014.
In the high myopia group, the inclusion criteria were as follows: (1) high myopia was defined as an SE > −6 diopters (D); (2) all eyes had clear ocular media; (3) a clear image was obtained to enable precise measurement of the choroidal thickness. Patients were excluded from this study if they presented with any retinal abnormalities other than high myopia such as diabetic retinopathy, uveitis, drusen, retinal vascular abnormalities, age-related macular degeneration, or other eye diseases such as the history of amblyopia or glaucoma. Patients who had a history of intraocular surgery, refractive surgery, or intravitreal injection were also excluded from the study. Patients with systemic diseases were also excluded. In the control group, the inclusion criterion was healthy eyes with an SE between −3 D to 3 D.
Examination
All subjects underwent a refractive error examination without pupil dilation using autorefraction (NIDEK, AR-310A, Japan). SE was calculated as the sum of the spherical power and half of the cylinder power [
20]. All the eyes of the subjects also underwent a thorough ophthalmic evaluation, including intraocular pressure (IOP) measurement, slit-lamp biomicroscopy, dilated ophthalmoscopy fundus examination, and color fundus photographs (Canon, Retinal Camera CR-DGi, Japan). B-scanning was also performed. AL measurements were taken using partial optical coherence interferometry (IOL-Master; Carl Zeiss Meditec, La Jolla, CA, USA). All the repeat measurements used the median for the analysis. Demographic data on each subject’s age and sex were collected.
EDI-OCT examination
All subjects were examined with a commercial OCT machine with an EDI mode (RS-3000 SD-OCT; Nidek, Japan). Choroidal imaging was performed as described in a previous study [
10]. In brief, the vertical and horizontal sections going directly through the centre of the fovea were used for final analysis. Choroidal thickness was defined as the distance between the retinal pigment epithelium (outermost hyperreflective line) to the inner margin of the sclera. Choroidal thicknesses were measured at the subfovea, 1 mm and 3 mm, nasally, temporally, superiorly, and inferiorly. All measurements were taken by a single experienced ophthalmologist who was masked to the clinical diagnosis of the subjects and was not involved in the data analysis. The images were obtained with the best visualization of the border between the choroid and the sclera known as the choroidal–scleral interface (CSI). If neither image had a clearly identifiable CSI, additional images were taken to produce the best possible view of the CSI. To avoid possible diurnal variation in choroidal thickness [
21], all EDI-OCT examinations were performed between 9 AM and 12 AM.
Statistical analysis
Statistical analysis was performed with SPSS software package version 17 (SPSS Inc, Chicago, IL, USA). Categorical covariates were assessed individually with the chi-square test. The demographics and ocular parameters between highly myopic and control eyes were compared using independent t-tests. One-way analysis of variance with the Bonferroni post-test was used to calculate the difference between the mean choroidal thicknesses of different locations. Univariate and multivariate regression analysis was used to evaluate the potential factors associated with SFCT in high myopia subjects. Univariate regression analyses were performed separately for each variable. Variables with a probability value ≤0.10 in univariate analyses were included in the multivariate analysis using a stepwise method. In high myopic eyes, subgroup analysis of macular choroidal thickness was performed in eyes with or without lacquer cracks and CNV using an independent-sample t test. For all the tests, P < 0.05 was considered significant.
Literature searches were performed in the following databases: PubMed, ISI Web of Science, EMBASE in English and in the Chinese National Knowledge Infrastructure (CNKI) (
http://www.cnki.net/), VIP (
http://www.cqvip.com/), and Wan Fang (
http://www.wanfangdata.com.cn) in Chinese. The following search strategy was performed in PubMed: ((Choroidal[All Fields] AND thickness[All Fields]) OR ("choroid"[MeSH Terms] OR "choroid"[All Fields])) AND (("myopia"[MeSH Terms] OR "myopia"[All Fields]) OR ("myopia"[MeSH Terms] OR "myopia"[All Fields] OR "myopic"[All Fields])). The search results were supplemented by reviews of reference lists for all relevant studies and review articles. If there were several studies published by the same population, the recent study was included. The final literature search was updated December 2014, with no restrictions on publication year, language, or methodological filter.
Studies that met the following criteria were included in this meta-analysis: (a) cross-sectional or case–control design; (b) choroidal thickness measured by OCT; (c) differences in choroidal thickness between patients with high myopia and controls reported. The exclusion criteria were as follows: (a) duplicate data; (b) no control population; (c) abstracts, comments, letters, case report, reviews, or editorial articles; (d) insufficient data on choroidal thickness. Two observers independently extracted the following information from the included studies, using a standardized data extraction form: first author, year of publication, number of high myopia patients and controls, definition of high myopia, the SE criteria of control subjects, and differences in choroidal thickness. Any discrepancies were addressed by having a discussion to reach a consensus.
To arrive at a conservative estimate of the effect of potential population differences among the studies, we chose a random-effect model to calculate pooled weighted mean differences (WMDs) in the meta-analysis. Statistical heterogeneity among the studies was evaluated using Cochran’s Q test and the I
2 statistic. For the Q statistic,
P < 0.05 was considered to indicate statistically significant heterogeneity [
22,
23]. To explore the source of heterogeneity, subgroup analyses were done according to the instrument used, the mean age of included subjects, and the source of control. To evaluate the influence of an individual data set on the pooled results, one study was deleted at a time, and the combined estimates were recalculated based on the remaining studies. Potential publication bias was evaluated using funnel plots, Begg’s test, and Egger’s test [
24,
25]. A
P value less than 0.05 was considered statistically significant in the test results for overall effect. The meta-analyses were conducted using the Stata software package (Version 12.0; Stata Corp., College Station, TX).
Discussion
In this cross-sectional study, we measured the macular choroidal thickness in high myopic eyes and normal control eyes. The mean SFCT of the high myopia group in this study was 200.54 ± 69.39 μm. Compared with the normal eyes, the results of this study revealed that the choroidal thickness was significantly smaller in the high myopic eyes. A thinning of the choroid in high myopic eyes has been demonstrated in several other studies [
14‐
17]. More importantly, these findings are supported by the results of the present meta-analysis, which showed that the SFCT of high myopic eyes was significantly thinner than that of the normal control eyes with the pooled WMD of −116.30 μm (95 % CI: −145.68, −86.92). This was not surprising. It has been reported that in high myopic eyes, excessive axial elongation of the eyeballs can cause biomechanical stretching and thinning of the choroid, retina, and sclera [
29,
30]. Thus, the thinner choroid is a long-term correlate of myopic axial elongation of the eye. In their previous studies, Gupta et al. [
14] found that high myopic eyes have significantly thinner choroid than that of emmetropic eyes. However, they failed to adjust for relative compounding factors such as AL and SE, and we do not know whether the thinning choroid is because of the longer AL or an independent factor. Chen et al. [
15] and Ohsugi et al. [
17] both obtained results similar to those of Gupta et al. However, they also failed to adjust for any potential compounding factors that might affect the choroidal thickness such as age, AL, and SE. Thus, in the present study, we investigated whether the thinner choroid in high myopic eyes might be due to longer AL and larger SE. Surprisingly, after adjusting for the AL and SE by multivariate linear regression analysis, we found that the diagnosis was not associated with SFCT. Therefore, we concluded that the thinner SFCT in high myopic eyes might be secondary in its effects to the longer AL, but it is not an independent factor.
In this study, we also performed a meta-analysis to calculate the difference in the SFCT between high myopic eyes and normal control eyes quantificationally. After a systematic literature search of several databases, we reviewed seven studies, including ours, to compare the SFCT in high myopic eyes with that of normal control eyes. Our findings of significance were also reflected in the meta-analysis, even across different subgroups, which are less prone to chance results, indicating the robustness of our findings. It is also worth mentioning that the "leave-one-out" sensitivity analyses did not affect the pooled results of the meta-analysis, which illustrated that the present meta-analysis results were stable and reliable.
The formation of lacquer cracks is considered a risk factor for developing CNV [
31,
32]. A previous study reported that the high myopic eyes with lacquer cracks had a less choroidal thickness than those without lacquer cracks [
33]. El and associates [
34] reported that macular choroidal thinning was also observed in high myopic eyes with CNV. In order to test whether the presence of CNV or lacquer cracks in high myopic eyes affected the SFCT, based on the relative large sample size, we divided the high myopic eyes into subgroups according to the presence or absence of CNV and lacquer cracks. The results showed that the subgroups with CNV and with lacquer cracks both had longer AL, larger SE, and more importantly, a thinner choroid. In order to determine whether the thinner choroid is secondary to the longer AL or the larger SE, we performed the univariate and multivariate linear regression analysis again. In the univariable analysis, the results showed that SE, AL, the presence of lacquer cracks, and the presence of CNV were significantly associated with SFCT. After adjusting for the SE and AL by multivariate linear regression analysis, the mean SFCTs of the eyes with lacquer cracks and CNV were still significantly thinner than those where these were absent. This implies that the thinner choroid in the presence of CNV and the presence of lacquer cracks were not secondary to the longer AL or the larger SE but rather was an independent factor. This result might indirectly prove once again that myopic CNV and lacquer cracks could develop into secondary chorioretinal central atrophy. The SFCT could be a good indicator and predictor of the clinical significance and severity of the disease in these high myopic eyes.
Our results show that the average SFCT in high myopic eyes was 200.54 ± 69.39 μm, which is much thicker than previous findings indicating a mean SFCT of 111.1 ± 45.0 μm [
15] and 115.0 ± 85.3 μm [
16]. It was also significantly thicker than the pooled results of the present meta-analysis (−116.30 μm). Considering this difference, we speculated that participants’ ages might be the main cause. It has been proven that age is negatively associated with choroidal thickness. In our study, the mean age of high myopia is only 22.23 years, which is younger than in other studies [
15‐
17]. Another important point is that, in all subjects, age was not associated with choroidal thickness, which is inconsistent with the findings of a large number of studies [
19,
35,
36]. One possible explanation for this is that in our study, the age distribution of patients included is limited to a young age group; further studies including patients from a wide range of ages are needed to shed light on this difference. Another possible explanation is that other factors' strong association with the SFCT, such as AL and SE, concealed the factor of age. In the present study, we performed the EDI-OCT examination using the RS-3000 SD-OCT machine, which is different from the machines used in other studies. However, the results of the subgroup analysis showed that different examination instruments had similar results. This implied that using a different OCT machine would not affect the results. In addition, the previous studies proved that the choroidal thickness measurements obtained with different SD-OCTs were highly correlated and could be used interchangeably [
37,
38].
Our study had a number of strengths. First, to date, the present study is the first synthesis exploring the association of choroidal thickness with high myopia. Second, the results of the present cross-sectional study were in accord with that of the corresponding meta-analysis. Third, our results are less prone to selection bias, in view of the low probability of publication bias.
It should be noted that the present study has a few limitations. First, in the meta-analysis, the SE of the control eyes included in the various studies was not uniform—it ranged from emmetropia to ± 6 D, which might affect the pooled results. Second, the small number of trials eligible for our meta-analysis made it difficult to acquire enough data to obtain meaningful results. Third, in the meta-analysis, substantial heterogeneity was observed among the studies. Although we performed analyses of the subgroups and sensitivity analyses, this heterogeneity could not be fully explained by the results. Fourth, the measurements of the choroidal thickness were performed manually, and automated software will be required for a more objective evaluation. However, the previous studies have proven that choroidal thickness measurement done using EDI-OCT is highly reproducible and repeatable [
39,
40]. Finally, given that factors other than AL and SE likely affect the choroidal thickness, our conclusion should be viewed with caution.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
All authors conceived of and designed the experimental protocol. SW and YW collected the data. All authors were involved in the analysis. SW wrote the first draft of the manuscript. SW and XG reviewed and revised the manuscript and produced the final version. All authors read and approved the final manuscript.