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Abstract
Aims To investigate the progression pattern of diffuse chorioretinal atrophy (DCA) among Chinese participants with high myopia.
Methods This is a longitudinal, non-interventional study. Participants with high myopia, defined as ≤−6 diopters spherical power, were included and followed up for 4 years, and underwent cycloplegic autorefraction, best-corrected visual acuity (BCVA) and fundus photography examinations. Newly established DCA, enlargement of existing DCA and development of other lesions of myopic maculopathy were regarded as DCA progression.
Results Of the 484 participants with a mean age of 21.5±12.7 years (range, 6.8–69.7 years), 68 eyes (14.0%) showed DCA progression, with 88 lesion changes. The first appearance of DCA was identified in 21 eyes (23.9%). Of 88 eyes with DCA at baseline, 47 eyes (53.4%) showed progression, with 67 lesion changes, including 45 eyes (67.2%) with enlargement of DCA, 17 (25.3%) with a first appearance of lacquer cracks, 4 (6.0%) with development of patchy chorioretinal atrophy and 1 (1.5%) with increased numbers of lacquer cracks. Longer axial length (p<0.001), baseline DCA (p=0.005) and baseline DCA closer to the fovea (p=0.013) predicted DCA progression. Eyes had poorer BCVA at the follow-up if DCA was enlarging (p<0.001) or DCA was closer to the fovea at baseline (p=0.028) after adjusting for age,gender and cataract.
Conclusion Approximately half of the participants with DCA had progression over a 4-year follow-up. Enlargement and newly developed DCA were common progression patterns. Larger areas of DCA and foveal involvement with DCA could be indicators of a worse BCVA later.
- Retina
- Epidemiology
- Optics and Refraction
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INTRODUCTION
The prevalence of high myopia is increasing,1–5 especially in working-age people in Asian populations.6–9 High myopia is linked to myopic maculopathy, which can cause irreversible bilateral visual impairment and blindness.10 Increases in myopic severity lead to excessive axial length (AL) elongation and subsequent stretching of the posterior wall of eyeball. This, in turn, leads to various complications, including diffuse chorioretinal atrophy (DCA), patchy chorioretinal atrophy, Fuchs spots, lacquer cracks, posterior staphyloma and so on.11
The definition of DCA is usually a yellowish-white appearance of the posterior pole; this is one of the key lesions that differentiates DCA from other lesions of myopic maculopathy. DCA generally appears first in the temporal area of the optic disc and then, with older age and increasing AL gradually extends to the macular area and, ultimately, the entire posterior pole area.12 13
An association between DCA and thinning of the choroid has been documented.14 15 It is said that choroidal thickness in eyes with DCA is decreased by half when myopic maculopathy progresses from tessellation to DCA. DCA pathogenesis then leads to progressive degenerative changes, such as marked thinning of the choroid due to mechanical stretching caused by the axial elongation. However, few studies have focused on understanding the biological history and underlying mechanisms of DCA progression.
Our study aimed to evaluate the progression of DCA in high myopes based on fundus photographs over a follow-up of 4 years.
METHODS
The Guangzhou Zhongshan Ophthalmic Center–Brien Holden Vision Institute (ZOC-BHVI) High Myopia Cohort Study was a prospective, observational cohort study. Ethics approval (2012KYNL002) was obtained from the Board Ethics Committee of Zhongshan Ophthalmic Center, Sun Yat-sen University in China. The research adhered to the Declaration of Helsinki and Chinese law, and informed consent was acquired from all subjects.
Participants
The study’s details have been previously described.16 Participants with bilateral high myopia (defined as ≤−6 diopters (D) refractive error) were enlisted from the optometry clinic of Zhongshan Ophthalmic Center in China. A total of 884 participants underwent baseline examinations from November 2011 to October 2012. Of these, 494 (56.1%) received follow-up examinations for 4 years, while the remaining 388 (43.9%) either declined further participation or were lost during follow-up.
Examination
Comprehensive ophthalmic examinations were conducted at the baseline and follow-up visits for both eyes of all participants. AL was assessed with a Lenstar LS900 instrument (Haag-Streit AG, Koeniz, Switzerland). Cycloplegic autorefraction was measured with a Topcon KR-8800 device (Topcon Corp, Tokyo, Japan). The spherical equivalent (SE) was referred to spherical power+cylindrical power multiplying by 1/2. Best-corrected visual acuity (BCVA) was acquired by an ETDRS logarithm of the minimum angle of resolution E-chart (Precision Vision, La Salle, IL, USA). Colour fundus photographs were taken with Canon CX-1 (Canon, Tokyo, Japan).
Image grading
For each eye, the macular centered fundus photograph was graded by ophthalmologists (ZXL, RL, OX and XXG) for myopic maculopathy using the meta-analyses of the pathologic myopia (META-PM) study classification.11 In brief, the ophthalmologists identified myopic maculopathy lesions, including DCA, patchy chorioretinal atrophy, macular atrophy, Fuch’s spots, lacquer cracks and choroidal neovascularisation (CNV) secondary to myopia.
The progression of DCA was defined as a first appearance of DCA, enlargement of a previously affected area of DCA or a first appearance of other lesions in eyes with pre-existing DCA. Finally, a qualitative comparison between baseline and follow-up visit data was performed. The fundus images taken at baseline and follow-up were analysed using a well-established software program (EVision Registration System for Fundus Image, EVision Technology Co, Beijing). This program could automatically adjust their geometric positions and align the images to dynamically demonstrate the progress when multiple fundus images of the same participant photographed at different visits were imported. The video of flipping images is provided as online supplemental file 1.
Supplemental material
An online ETDRS grid (figure 1; http://v201eyegrader.com) was used to explore the location of the lesions relative to the foveal region. In this ETDRS grid, the radius of the outer circle was referred to the distance between the temporal boundary of the optic disc and the fovea. The brightness, background pigmentation and contrast were also taken into consideration in the grading of images.
Based on the ETDRS grid, the extent of DCA seen in the images was used to divide the eyes into the following four subgroups: D0 (not affecting any of the circles), D1 (affecting the outer circle), D2 (affecting the middle circle) and D3 (affecting the inner circle). The area of DCA in relation to the area of the optic disc was determined for each eye and sorted into one of the four subgroups: ≤1 disc area (DA), 1–≤5 DA, 5–≤10 DA and >10 DA.
Diffuse chorioretinal atrophy affected area was graded using the ETDRS grid, centred on the fovea. The participant eyes were divided into four groups based on the area affected by diffuse atrophy: D0 showed no effect in the outer circle, D1 showed effects in the outer circle but outside the middle circle, D2 had effects in the middle circle but outside the inner circle and D3 had effects in the inner circle (http://v201eyegrader.com).
Statistical analyses
Each participant’s right eye was included for analysis in this study. Differences in eyes with and without DCA in terms of age, gender, baseline AL, SE and BCVA were analysed using Pearson’s χ2 test, and the distribution of characteristics between eyes with DCA progression and those without was assessed. The extent and area of DCA in the baseline and follow-up visit were also evaluated, and the BCVA in the follow-up was analysed by different DCA area. Pearson’s χ2 test was adopted for the comparison of categorical variables. Multiple logistic regression models were adopted to determine the risk factors for DCA progression and the reduction of BCVA. A p value of <0.05 was considered statistically significant. All data analyses were conducted with Stata software, version 14.0 (Stata Corp, College Station, TX, USA).
RESULTS
Of the 496 participants who were examined at baseline examination and at the 4-year follow-up visit, 12 were excluded. The exclusions were due to poor image quality (n=2), baseline patchy chorioretinal atrophy (n=8), baseline macular atrophy (n=1) and baseline CNV (n=1). Ultimately, 484 participants were included for the analyses in the current study, including 257 females (53.1%) and 227 males (46.9%). The mean AL and SE were 27.3±1.52 mm and −9.7±3.14 D, respectively.
Baseline characteristics
Of 484 right eyes, 88 had DCA at baseline. Table 1 shows the characteristics of eyes by the presence of baseline DCA. An increasing trend was noted for the presence of DCA in the older age groups (p<0.001), but gender differences between eyes with and without DCA were not statistically significant (p=0.683). As AL became longer or SE became more myopic, the presence of DCA increased (all p<0.001). DCA was present in only 15.8% of the eyes (n=71) with a BCVA of ≥20/40, and for eyes with a BCVA of <20/40, the presence of DCA was 47.2% (n=17, p<0.001).
Baseline characteristics of highly myopic eyes with and without diffuse chorioretinal atrophy
DCA progression
Of the 484 included eyes, a total of 68 (14.0%) had DCA progression, with 88 lesion changes (table 2). Overall, 21 eyes (23.9%) had a first appearance of DCA. Among the 88 eyes with baseline DCA, progression was identified in 47 (53.4%), with 67 lesion changes, including 45 (67.2%) with DCA enlargement, 17 (25.3%) with a first appearance of lacquer cracks, 4 (6.0%) with patchy chorioretinal atrophy development and 1 (1.5%) with an increasing number of lacquer cracks. Typical images are displayed in figure 2.
Comparison of characteristics of highly myopic eyes with and without diffuse chorioretinal atrophy (DCA) progression at the 4-year follow-up
Typical changes of the fundus photographs of participants with diffuse chorioretinal atrophy at baseline. (A, B) The appearance of patchy atrophy, development of lacquer cracks and enlargement of diffuse atrophy. Simple retinal haemorrhage at different locations at baseline and at the follow-up visit. (C, D) The appearance of lacquer cracks with simple retinal haemorrhage and enlargement of diffuse atrophy. (E, F) Increase in lacquer cracks, absorption of simple retinal haemorrhage and enlargement of diffuse atrophy.
Characteristics of DCA progression
We explored the characteristics of DCA progression by further dividing eyes into three groups: group 1 were eyes without DCA at baseline but with DCA progression; group 2 were eyes with DCA at baseline but with no DCA progression; and group 3 were eyes with DCA at baseline and with progression. Participants aged 40–70 years were the most likely to have DCA progression (37.7%), followed by those aged 7–11 years (19.2%). Gender differences among the three groups were not statistically significant.
The DCA progression rate was increasing with a longer baseline AL, from 2.7% in eyes having a baseline AL of <27.0 mm to 53.5% in eyes having a baseline AL of ≥29.0 mm. The distribution of AL in the three groups at the follow-up visit was similar. Participants with a baseline SE ≤−10 D had the highest rates of DCA progression (33.8%), and those with a baseline SE ≤−8 to −10 D had a DCA progression rate of 9.0%. The proportion of DCA progression in eyes with BCVA ≥20/40 was 11.3%, which increased to 41.9% in eyes with BCVA <20/40.
Change of the extent and affected area of DCA
The extent of DCA at baseline was as follows: 396 eyes (81.8%) were graded D0, 34 as D1 (7.0%), 36 as D2 (7.5%) and 18 as D3 (3.7%). Table 3 shows a comparison of the extent of DCA at baseline and at follow-up for the 88 eyes with DCA at baseline. Involvement from D1 to D3 was identified in 6 eyes (17.6%) and from D2 to D3 in 18 eyes (50.0%). In addition, for eyes with a first appearance of DCA (n=21), 7 (33.3%) increased from D0 to D1, 11 increased from D0 to D2 (52.4%) and 3 increased from D0 to D3 (14.3%).
Comparison of eyes with different extents of diffuse chorioretinal atrophy at baseline and at the 4-year follow-up
In eyes with DCA at baseline, the DCA-affected area was categorised as ≤1 DA in 12 eyes (13.6%), 1–≤5 DA in 55 eyes (62.5%), 5–≤10 DA in 15 eyes (17.1%) and >10 DA in 6 eyes (6.8%). The changes in the affected areas for these eyes are displayed in table 4. The affected area for eyes with a first appearance of DCA were ≤1 DA in 5 eyes (23.8%), 1–≤5 DA in 11 eyes (52.4%), 5–≤10 DA in 3 eyes (14.3%) and >10 DA in 2 eyes (9.5%).
Comparison of eyes with different affected areas of diffuse chorioretinal atrophy at baseline and at the 4-year follow-up
BCVA by baseline extent and area of DCA
Table 5 displays the assessment of BCVA at the 4-year follow-up visit based on the differences from the baseline DCA extent or area categories. A significant increase was noted in BCVA <20/40, with a DCA approaching the fovea (p=0.003), and the highest rates of BCVA <20/40 were identified in eyes with DCAs of 5–≤10 DA; the lowest rate was in eyes with a DCA of ≤1 DA (p=0.012).
Comparison of best-corrected visual acuity (BCVA) at the 4-year follow-up according to the characteristics of diffuse chorioretinal atrophy at baseline
Risks factors for DCA progression and reduction of BCVA
The relationships between age, gender, SE, presence of baseline DCA, baseline extent and area of DCA, and DCA progression were explored. In the multiple logistic regression analysis, after adjusting for age and gender, DCA progression was more frequently found in eyes with more myopic SE (OR 1.25, p<0.001) or longer AL (OR 1.89, p<0.001), presence of baseline DCA (OR 1.62, p=0.005) and baseline DCA that involved the middle or inner circle of the ETDRS grid (OR 4.31, p=0.013).
DCA progression (OR 2.10, p<0.001) and DCA closer to the fovea at baseline (OR 4.0, p=0.028) were associated with worse BCVA in the follow-up, after adjusting for age, gender and cataract.
The results of regression analyses among participants of <40 years were similar; DCA progression was increased with more SE (OR 1.25, p<0.001) or longer AL (OR 1.72, p<0.001) and baseline DCA that involved the middle or inner circle of the ETDRS grid (OR 4.92, p=0.036). After adjusting for age, gender and cataract, DCA progression (OR 1.36, p=0.032) and presence of DCA at baseline (OR 6.05, p=0.005) were significant predictors for worse BCVA.
DISCUSSION
Our study explored the progression of DCA in a Chinese bilateral high myopia cohort over a 4-year period. Overall, 14.0% of the participants showed DCA progression. The most common progression pattern was enlargement of DCA, followed by the first appearance of DCA and lacquer cracks. The presence of DCA progression was associated with an increasing AL or a more severe SE, presence of baseline DCA, and baseline DCA closer to the fovea. Eyes with DCA progression showed a trend toward having poor BCVA. Involvement of the fovea and an increasing area of DCA at the baseline led to a worse BCVA at the follow-up visit.
In our study, DCA progression presented in 14.0% of all high myopic participants and in 67.2% of those who had DCA at baseline. In Tokyo, Hayashi et al 17 included 429 participants with pathologic myopia, defined as an AL of ≥26.5 mm or a refractive power <−8 D, for a minimum 5-year follow-up to explore myopic maculopathy progression. In the subgroup of patients with DCA, they found that a total of 49.2% in the eyes having DCA progressed over the follow-up period. However, the observations in our study are novel and cannot be directly compared with the study of Hayashi et al 17 due to differences in the study populations, in the definitions of high myopia, in the participant ethnicities, and in the follow-up periods between the two studies.
Notably, participants aged ≤11 years demonstrated a significantly different pattern of DCA progression. When compared to the 12–18 age group and the 19–39 age group, the 7–11 age group had much higher proportion rate of DCA progression. Many researches demonstrated DCA and even more severe lesions of myopic maculopathy were not uncommon among children.18–20 High myopia, occurring at the age of 7–11 years, is usually regarded as early-onset high myopia. Genetic factors play a key role in underlying early-onset high myopia, and it trends toward the development of ocular degeneration.9 19 While the children were between 12 and 18 years old, the rate of early-onset high myopia in this age group was dramatically decreased with the swelling number of acquired high myopia, which involves fewer genetic factors and has less risk for development of fundus disorders.9
Statistical comparisons of the characteristics of eyes with DCA progression suggested that participants with DCA progression were significantly older and had significantly longer ALs or a more myopic SE. These findings indicate that increasing age, longer AL and more myopic SE might be risk factors for DCA progression.
The involvement of the fovea or increases in the DCA-affected area at baseline predicted a poorer BCVA at the follow-up visit. Traditionally, CNV and macular atrophy are viewed as lesions that cause severe visual impairment. However, our results suggested that 25% (22/88) of the patients with baseline DCA had a BCVA of <20/40 over the 4-year follow-up. The decline in BCVA might be caused by ischaemia during the thinning of the choroid due to axial elongation. This ischaemia would affect the function of the retinal pigment epithelium cells and retinal neuroepithelial layer cells by reduced blood supply.
The strengths of our study were its prospective and longitudinal nature, which allowed exploration of the historical progression of DCA in patients with high myopia. As far as we know, it was the first research to investigate longitudinal changes of DCA in participants with bilateral high myopia. In addition, the relationship of lesion changes to BCVA was examined.
Limitations
However, our study also had several limitations. In any longitudinal study, the proportion of nonparticipants influences the analysis results. A total of 884 participants were included in the baseline examination, but only 496 (55.9%) were re-examined at the follow-up visit 4 years later. At baseline, the nonparticipants tended to be younger (p<0.001), whereas there were no gender or SE differences between follow-up participants and nonparticipants (p=0.798 and 0.249, respectively), which indicates that selection bias may not have affected the results of this study. The age range of participants included in this study was wide (7–70 years), and the study sample size was large (n=496), which would be a representative of highly myopes. In this study cohort, 61% of the included participants were 7–18 years old. Now we analysed the data and presented the regression analyses in all participants and among those aged <40 years, respectively. These two analyses gave similar results. We also envisaged that a generalisation of findings among elderly people with high myopia may require further studies that should include more elderly participants with high myopia. In our exploration of the progression pattern of DCA, we also excluded eyes with poor quality images or severe myopic maculopathy, including patchy atrophy, macular atrophy and CNV. These may have led to an underestimation of the DCA progression rate. However, the effect would be very small, as only 2.4% of the participants (12 of 496) were excluded for these reasons.
In conclusion, we found that an overall rate of 14.0% in highly myopic eyes demonstrated DCA progression, and the progression rate in eyes with DCA of baseline was as high as 53.4%. The progression patterns included enlargement of pre-existing DCA, a first appearance of DCA, the onset of lacquer cracks, the formation of patchy atrophy and an increasing number of lacquer cracks. Our results suggest the presence of DCA progression was associated with an older age, an increasing AL and a more severe SE Baseline DCA enlargement and involvement of the fovea predicted a poorer BCVA at follow-up. Further investigation into the pathogenesis and mechanisms of DCA will allow us to obtain a better understanding of the historical course of DCA.
REFERENCES
Footnotes
Contributors MH had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: ZXL, MH. Data acquisition, analysis or interpretation: all authors. Drafting of the manuscript: ZXL. Critical revision of the manuscript for important intellectual content: MH. Statistical analysis: ZXL, JZ. Obtained funding: MH. Study supervision: JZ, MH.
Funding This work was supported by the National Key R&D Program of China (2018YFC0116500), the Fundamental Research Funds of the State Key Laboratory in Ophthalmology, National Natural Science Foundation of China (81420108008) and Science and Technology Planning Project of Guangdong Province in China (2013B20400003). The sponsor or funding organiszation had no role in the design or conduct of this research.
Competing interests None declared.
Ethics approval Ethics approval (2012KYNL002) was obtained from the Board Ethics Committee of Zhongshan Ophthalmic Center, Sun Yat-sen University in China. The research adhered to the Declaration of Helsinki and Chinese law, and informed consent was acquired from all subjects.
Provenance and peer review Not commissioned; internally peer reviewed.
Data availability statement Data are available upon reasonable request.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.
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