PURPOSE
To investigate the rate of structural and functional progression in different age groups of highly myopic glaucoma patients and identify risk factors associated with rate of change in functional parameters.
DESIGN
Retrospective clinical cohort study.
METHODS
This study included open-angle, normal-tension glaucoma (NTG) patients with high myopia who had been followed-up for at least 8 years. Patients were divided into two age groups, “younger (under age 40)” and “older (age 40 or over),” according to their age at presentation, and progression rates for visual field index (VFI), mean deviation (MD) and peripapillary retinal nerve fiber layer (RNFL) thickness were evaluated. Intergroup comparison was performed, and associations between age and progression rates for structural and functional parameters were assessed by scatter plots with linear regression and locally weighted scatterplot smoothing. Cox proportional hazards modeling was performed to identify factors for progression rate of functional parameters.
RESULTS
A total of 320 eyes of 320 highly myopic NTG patients (mean age at presentation, 38.7 ± 10.4 years) were included in this study with a mean follow-up duration of 13.1 ± 6.2 years. The rate of VFI, MD, and RNFL thickness change showed a positive correlation with the age at presentation ( P = .013, .002, and .003, respectively). The mean rate of MD change was −0.36 ± 0.39 dB/year in younger age group and −0.22 ± 0.27 dB/year in older age group ( P < .01). In the locally weighted scatterplot, the rate of change in VFI, MD, and RNFL thickness showed a fast-progressing pattern in those aged 19 to 29 years and 40 to 49 years, and a slow-progressing pattern in those aged 30 to 39 years and 50 years or older. Baseline IOP (β= −0.041; 95% CIs, −0.139-0.413; P = .047) and baseline VFI (β= 0.364; 95% CIs, 0.247-0.461; P < .01) was significantly related to the VF MD change rate.
CONCLUSIONS
The glaucoma progression rate in highly myopic NTG showed a bimodal pattern based on the age at presentation, younger patients exhibiting faster progression compared to older patients. Baseline IOP and VFI were significantly related to functional progression rate. The findings of this study may assist in deciding the treatment strategy for highly myopic NTG patients.
M yopia, particularly high myopia, is rapidly increasing among the young population. Worldwide prevalence of myopia is expected to increase to 5 billion people by the year 2050, and myopia is already an issue of concern in East Asia. Myopia not only imposes a socio-economic burden but also incurs the risk of visual disabilities including macular degeneration, cataract, and open-angle glaucoma (OAG), all of which affect quality of life.
As for the specific significant risk factor for glaucoma, eyes with increased axial length (AL) are considered to be more susceptible to higher deformability of the lamina cribrosa, leading to higher susceptibility to glaucomatous optic disc changes. , A recent meta-analysis reported an odds ratio of 2.46 for OAG in high myopia (refractive error ≤ −3 diopters). However, there is conflicting evidence concerning the role of myopia in glaucoma progression. Numerous studies have demonstrated myopia and high myopia to be the risk factors for glaucoma progression. Quigley et al reported that myopic patients exhibited more frequent visual field (VF) loss in ocular hypertension, and Perkins and Phelps found that progression of VF defect was accelerated in myopic patients compared with emmetropic or hyperopic patients. On the contrary, some studies have reported that myopia had no effect on glaucoma progression. ,
Myopic patients with glaucoma typically are younger aged with longer life expectancy. Old age also is a significant risk factor for glaucoma, and is associated with faster progression. , In order to properly treat these myopic populations, it is necessary to comprehend the clinical course of myopic glaucoma; however, investigations into the structural and functional changes of glaucoma according to age of occurrence are still insufficient. Such knowledge may aid understanding of the pathogenesis of glaucoma in highly myopic patients. Therefore, in the present study, we analyzed the rate of glaucoma progression based on the VF and optical coherence tomography (OCT) according to baseline age, and investigated the progression pattern in both younger and older normal tension glaucoma (NTG) patients with myopia. Additionally, we identified the risk factors associated with the rate of change in VF parameters.
METHODS
The study was approved by the Institutional Review Board of Seoul National University Hospital and followed the tenets of the Declaration of Helsinki. Informed consent was waived due to the retrospective nature of the study.
STUDY PARTICIPANTS
This observational cohort study included open-angle NTG patients with high myopia who had been examined at Seoul National University Hospital between January 1, 2000 and January 1, 2023. The participants were consecutively enrolled on the basis of a retrospective medical record review. They were divided into two groups, “younger (under age of 40)” and “older (age 40 or over),” according to their age of at presentation. The cut-off value of 40 years was chosen based on the overall mean age of the enrolled participants. Patients older than 18 years were included in the analysis.
All of the participants underwent a complete ophthalmic examination, including best-corrected visual acuity measurement, refraction, slit-lamp biomicroscopy, gonioscopy, intraocular pressure (IOP) measurement by Goldmann applanation tonometry (Haag-Streit), and dilated examination of the optic disc. They also underwent AL measurement (Axis II PR; Quantel Medical), stereo optic disc and red-free retinal nerve fiber layer photography (RNFL) (TRC-50IX; Topcon Corporation), optic nerve head (ONH) and macular imaging by Cirrus HD-OCT (version 9.5, Carl Zeiss Meditec), and standard automated perimetry (SAP) with central 24-2 (Humphrey Field Analyzer; Carl Zeiss Meditec). Percentage reduction in IOP was defined as 100 x (baseline IOP-mean IOP during treatment)/baseline IOP. Mean IOP was defined as the average value of all IOP measurements taken during the follow-up period of the study.
For a diagnosis of glaucoma, the following conditions had to be met: (1) presence of glaucomatous optic disc change (eg, focal notching or thinning of neuroretinal rim or RNFL defect); (2) glaucomatous visual field defect (VFD) corresponding to structural change; (3) an open angle. Eyes with glaucomatous VFD were defined as follows: (1) glaucoma hemifield test values outside the normal limit, (2) 3 or more abnormal cluster points on a pattern deviation plot with a probability of P < 5%, of which at least 1 point had a probability of P < 1%; (3) a pattern standard deviation (PSD) with P < 5% probability, as confirmed by at least 2 reliable examinations (false-positives and false-negatives < 15%, fixation losses < 20%).
The inclusion criteria were as follows: (1) high myopia defined as either AL greater than or equal to 26.0 mm or spherical equivalent less than or equal to −6 diopters; (2) open angle by gonioscopy; (3) maximal IOP without treatment ≤ 21 mmHg; (4) follow-up longer than 8 years after diagnosis of glaucoma; (5) at least five consecutive SAPs and OCTs taken during the follow-up period. When both eyes met the eligibility criteria, 1 eye was randomly selected as the study eye. The exclusion criteria were: (1) any history of ophthalmic surgery (except uncomplicated cataract surgery); (2) occurrence of ophthalmic comorbidities, other than glaucoma, that might affect visual function; (3) possibility of secondary or congenital glaucoma; (4) pathologic myopia, defined as 2 or higher with the presence of the plus sign (eg, lacquer crack, myopic choroidal neovascularization, or Fuch’s spot) or posterior staphyloma, based on the International Meta-Analysis for Pathological Myopia classification system.
ANALYSIS OF VF EXAMINATIONS
VF examinations were performed, with optical correction using either trial lenses or disposable hydrophilic contact lenses, in myopic eyes. Only reliable VF test results were included in the subsequent analysis (false-positives and false-negatives < 15%, fixation losses < 20%), and results showing explicit progression due to retinal or neurological pathologies were excluded. Two glaucoma specialists (J.L. and Y.K.K.) carefully reviewed the baseline VF data, accounting for any high-myopia-related defects or misinterpretation of VF results. Eyes with high-myopia-related VF abnormalities (eg, enlarged blind spot, vertical step, partial peripheral rim, or nonspecific defects) at baseline, but with no signs of significant glaucomatous VFD during follow-up, were excluded from the analysis. If participants underwent repeated VF tests, the test with the least serious defect (based on the mean deviation [MD] of the VF) was selected for the final analysis.
The rate of MD and visual field index (VFI) change were calculated by trend-based analysis using the Guided Progression Analysis (GPA) software from the Humphrey Field Analyzer. The rates of MD and VFI progression were recorded as dB change per year and % change per year, respectively.
ANALYSIS OF OCT IMAGING
Cirrus HD-OCT (version 9.5 software, Carl Zeiss Meditec) was used to acquire RNFL and macular GCIPL measurements. The measurements were taken by a single experienced examiner after mydriasis of the patients’ eyes. The circumpapillary RNFL layer was examined according to the optic disc cube 200 × 200 protocol, while the macular GCIPL layer was examined according to the macular cube 200 × 200 protocol, the scan area covering 6 mm × 6 mm. Based on each optic disc cube scan and macular scan, the RNFL thickness and GCIPL thickness, respectively, were analyzed. Results with poor image quality due to blinking artifacts or poor centration were excluded, as were those with a signal strength less than 7.
Referencing the optic disc scans, the GPA trend analysis from the Cirrus HD-OCT software calculated the rate of RNFL change by linear regression. The rate of RNFL progression was then recorded as the µm change per year.
STATISTICAL ANALYSIS
The independent t-test and χ 2 test were used to compare the clinical characteristics of the two groups. The data were recorded as the mean standard deviation (range) for the normally distributed continuous variables and as the frequency (percentage) for the categorical variables. The associations between age at presentation and the rate of progression of the structural and functional parameters were assessed by scatterplots with the linear function and locally weighted scatterplot smoothing. The rates of functional and structural parameter change were compared among the different age groups using one-way analysis of variance (ANOVA), and Bonferroni correction was applied to adjust the P values. Univariate and multivariate regression analyses were used to evaluate the risk factors associated with the rate of change in functional parameters. To avoid multicollinearity complications, the variance inflation factor was calculated, and variables with values above 10 were excluded. All of the statistical analyses were performed using statistical software (SPSS version 22.0; SPSS Inc.) and R software (version 3.5.2). A P value of <.05 was considered statistically significant.
RESULTS
DEMOGRAPHICS
Initially, 347 eyes were eligible for the analysis, and 31 eyes with low-quality RNFL photography (25 eyes with segmentation error, 4 eyes with low signal strength, 2 eyes with motion or blink artifact) along with 2 eyes with unreliable VF results were excluded. Thus, a total of 314 eyes (171 eyes of younger group and 143 eyes of older group) were included in the analysis. The mean age at presentation was 38.7 ± 10.4 years, and the mean follow-up duration was 13.1 ± 6.2 years. The mean baseline IOP was 15.2 ± 3.5 mmHg, the mean spherical equivalent was −7.70 ± 3.59 diopters, and the mean AL was 26.89 ± 1.27 mm. The baseline characteristics of the two age groups showed no significant differences and are summarized in Table 1 .
| Age (Years, n = 314) | P Value a | ||
|---|---|---|---|
| Younger Age <40 ( n = 171) | Older Age ≥40 ( n = 143) | ||
| Age (y) | 31.88 ± 6.52 | 48.54 ± 6.05 | <.01 b |
| Sex | |||
| Male, n (%) | 114 (66.7) | 68 (47.6) | .11 |
| Female, n (%) | 57 (33.3) | 75 (52.4) | .11 |
| Follow-up duration (y) | 13.52 ± 6.40 | 11.22 ± 5.64 | .10 |
| Ocular factors | |||
| Baseline IOP (mmHg) | 15.23 ± 3.27 | 15.18 ± 4.27 | .94 |
| IOP reduction (%) | 19.09 ± 0.19 | 16.06 ± 0.24 | .54 |
| No. of medication at final visit | 1.18 ± 0.87 | 1.29 ± 0.77 | .65 |
| Spherical Equivalent (diopters) | −7.83 ± 3.46 | −7.49 ± 3.77 | .40 |
| Axial Length (mm) | 26.99 ± 1.32 | 26.75 ± 1.20 | .11 |
| Central corneal thickness (µm) | 545.87 ± 38.36 | 544.00 ± 35.45 | .87 |
| Visual Field examination | |||
| Baseline VFI (%) | 88.81 ± 14.07 | 88.74 ± 14.65 | .96 |
| Baseline MD (dB) | −4.58 ± 5.38 | −5.04 ± 5.31 | .46 |
| Baseline PSD (dB) | 5.33 ± 4.32 | 5.48 ± 4.21 | .76 |
| OCT examination | |||
| Baseline RNFL thickness (µm) | 74.75 ± 10.95 | 76.72 ± 12.58 | .16 |
| Baseline GCIPL thickness (µm) | 67.58 ± 8.64 | 67.19 ± 9.73 | .72 |
a Comparison was performed using Student t tests for continuous variables, x2 or Fisher exact tests for categorical variables.
RATE OF FUNCTIONAL PROGRESSION AND AGE AT PRESENTATION
The overall mean rate of VFI change was −0.88 ± 1.02%/year, and the mean rate of MD change was −0.30 ± 0.35 dB/year. The rate of change in both of the functional parameters (VFI and MD) showed a positive correlation with age at presentation ( P = .013 and 0.002, respectively). As summarized in Table 2 , the mean rate of VFI change was −1.00 ± 1.18%/year in the younger group and −0.74 ± 0.75%/year in the older group, which was a statistically significant difference ( P < .05). The mean rate of MD change was −0.36 ± 0.39 dB/year in the younger group and −0.22 ± 0.27 dB/year in the older group, which also was a significant difference ( P < .01) ( Table 2 ). In the subgroup analysis, the rate of VFI change was −1.31 ± 1.77%/year among those under 30 years of age ( n = 55), −0.80 ± 0.84%/year among those 30 to 39 years of age ( n = 116), −0.91 ± 0.88%/year among those 40 to 49 years of age ( n = 97), and −0.61 ± 0.58 among those 50 years of age or older ( n = 46) ( P = .045). There was a significant difference in the rate of VFI change between the under-30 group and the 50-years-or-older group according to a post hoc analysis ( P = .018). In the subgroup analysis, the rate of MD change was −0.43 ± 0.37 dB/year among those under 30 years of age ( n = 55), −0.31 ± 0.31 dB/year among those 30 to 39 years of age ( n = 116), −0.29 ± 0.32 dB/year among those 40 to 49 years of age ( n = 97), and −0.17 ± 0.19 dB/year among those 50 years of age or older ( n = 46). ( P = .310) ( Table 3 ). The associations between age and rate of change in VFI and MD are shown in Figure 1 . The slope for rate of VFI change and age at initial visit was 0.016 ( P = .013). The slope for rate of MD change and age at initial visit was 0.017 ( P = .002). In the locally weighted scatterplot, the rate of VFI change showed a fast-progressing pattern for those aged 20 to 29 years and those aged 40 to 49 years, and a slow-progressing pattern for those aged 30 to 39 years and those aged 50 years or older. The rate of MD change showed similar patterns among the different age groups ( Figure 2 ).
| Age (Years, n = 314) | |||
|---|---|---|---|
| Younger Age <40 ( n = 171) | Older Age ≥40 ( n = 143) | P Value a | |
| Rate of progression | |||
| VFI (%/y) | −1.00 ± 1.18 | −0.74 ± 0.75 | <.05 b |
| MD (dB/y) | −0.36 ± 0.39 | −0.22 ± 0.27 | <.01 b |
| RNFL thickness (µm/y) | −0.62 ± 0.84 | −0.34 ± 1.23 | <.05 b |
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