CHOROIDAL THICKNESS IN AGE-RELATED MACULAR DEGENERATION
Jonas, Jost B. MD; Forster, Tessa M.; Steinmetz, Philippe MD; Schlichtenbrede, Frank C. MD; Harder, Björn C. MD
Department of Ophthalmology, Medical Faculty Mannheim, Ruprecht-Karls-University, Heidelberg, Germany.
Reprint requests: Jost B. Jonas, MD, Universitäts-Augenklinik, Theodor-Kutzer-Ufer 1-3, Mannheim 68167, Germany; e-mail: firstname.lastname@example.org
None of the authors have any financial/conflicting interests to disclose.
J. B. Jonas and T. M. Forster equally contributed to the study and share the first authorship.
Purpose: To examine choroidal thickness in age-related macular degeneration (AMD).
Methods: The hospital-based case series study included patients with nonexudative or exudative AMD as study group, and the control group consisted of subjects with a normal fundus. Choroidal thickness was measured by enhanced depth imaging of spectral domain optical coherence tomography.
Results: The study group (126 patients; 204 eyes) included a nonexudative subgroup (n = 50 eyes) and an exudative subgroup (n = 154 eyes), differentiated into eyes with mostly retinal pigment epithelium detachment (n = 35), mostly retinal edema (n = 36), and a subretinal fibrotic scar (n = 83). For 29 patients with unilateral AMD, contralateral normal eyes were compared with affected eyes. The control group consisted of 189 patients (228 eyes). Comparing choroidal thickness between the affected eyes and contralateral unaffected eyes in patients with unilateral AMD revealed no statistically significant differences (all P > 0.20). After adjusting for age and refractive error, subfoveal choroidal thickness was not significantly (all P > 0.10) related with AMD neither as a whole nor with the nonexudative or exudative AMD subgroup nor with the single exudative AMD subtypes (except for the subretinal fibrotic scar subgroup; P = 0.03). Correspondingly, choroidal thickness at a horizontal distance of 1000 μm from the fovea was not significantly (all P ≥ 0.30) associated with any subgroup of AMD. In binary regression analysis, the presence of AMD or of its subtypes (except for subretinal fibrotic scar type) was not significantly (all P ≥ 0.20) associated with subfoveal or parafoveal choroidal thickness after adjustment for age and refractive error. After matching for age, refractive error, and axial length, study group and control group did not differ significantly (all P ≥ 0.25) in foveal or parafoveal choroidal thickness measurements.
Conclusion: After adjusting for age and refractive error, AMD, neither in its nonexudative form nor exudative form, was significantly associated with a marked thinning or thickening of the choroid in the foveal and parafoveal region.
Age-related macular degeneration (AMD) is characterized by changes in the retinal pigment epithelium and Bruch membrane.1 Since the retinal pigment epithelium and Bruch membrane are nourished by the choroidal blood vessels, it has been discussed that a choroidal vascular insufficiency may be associated with AMD.2–6 A decreased choroidal blood perfusion may be associated with thinning of the choroid. Since the landmark studies by Spaide et al on the technique of enhanced depth imaging by optical coherence tomography (OCT) to visualize and measure the choroid in its entire thickness,7,8 an increasing number of studies have measured the choroidal thickness in normal eyes and eyes with choroidal, retinal, and optic nerve diseases.9–17 Only few of these investigations were focused on the choroidal thickness in eyes with AMD.18–26 We therefore conducted this hospital-based study to assess the choroidal thickness in patients with AMD and to compare the values with those of normal subjects.
The hospital-based noninterventional study included a study group of patients with AMD and a control group consisting of patients who attended the hospital for cataract surgery or other reasons than macular or retinal diseases. The ethics committee II of the Medical Faculty Mannheim of the University of Heidelberg approved the study, and all study participants gave informed written consent according to the Declaration of Helsinki. As recently discussed in detail, AMD was defined by medium (≥63–125 μm) or large drusen of the retinal pigment epithelium, pigmentary abnormalities, chorioretinal neovascularization, or geographic atrophy within a foveal area of two optic disk diameters.1
All eyes with exudative AMD were under current therapy consisting of intravitreal injections of bevacizumab. The eyes with nonexudative AMD were treatment naive. Subfoveal choroidal thickness (SFCT) was measured using a spectral domain OCT (Spectralis, wavelength: 870 nm; Heidelberg Engineering Co, Heidelberg, Germany) with enhanced depth imaging modality after pupil dilation.7,8 Nineteen horizontal OCT sections were obtained in a 15° × 30° rectangle centered onto the fovea. The horizontal section running through the center of the fovea was selected for further analysis. Subfoveal choroidal thickness was defined as the vertical distance from the hyperreflective line of the Bruch membrane to the hyperreflective line of the inner surface of the sclera. The measurements were performed using the Heidelberg Eye Explorer software (version 188.8.131.52; Heidelberg Engineering Co, Heidelberg, Germany). The images were taken by an experienced technician and were assessed by two experienced examiners (T.M.F., P.S.). The reproducibility of the technique had previously been examined by a group of the other examiners and had revealed a relatively high reproducibility (Bland–Altman plot with 61 of 3233 points [1.9%] outside the 95% limits of agreement; intraclass coefficient, 1.00; mean coefficient of variation, 0.85 ± 1.48%).27
The whole group of patients with AMD was divided into eyes with nonexudative AMD characterized by drusen and/or pigmentary irregularities without exudation and eyes with exudative AMD, differentiated into subgroups of eyes with a detachment of the retinal pigment epithelium, eyes with mostly intraretinal and subretinal edema, and eyes with a fibrotic scar formation.
Statistical analysis was performed using a commercially available statistical software package (SPSS for Windows, version 20.0; IBM-SPSS, Chicago, IL). After calculating the mean values (presented as mean ± standard deviation) of the main parameters, we compared in the first step the choroidal thickness in the affected eyes and contralateral unaffected eyes in patients with unilateral AMD. In the second step, we performed a multivariate linear regression analysis, with choroidal thickness as a dependent parameter and the diagnosis of AMD as an independent parameter after adjusting for age and refractive error. In the previous studies, choroidal thickness was dependent on age, refractive error, or axial length.10,17 In the third step, we matched the study group and control group for age, refractive error, and axial length and compared choroidal thickness measurements between both matched groups. Odds ratios and 95% confidence intervals were presented. All P values were 2-sided and were considered statistically significant when P < 0.05.
The study group included 126 patients (204 eyes) with a mean age of 77.6 ± 7.1 years (median, 77.7 years; range, 52.8–91.8 years), mean refractive error of +0.19 ± 1.82 diopters (D) (median, 0.00 D; range, −6.00 to +3.88 D), and mean axial length of 23.30 ± 1.07 mm (range, 20.88–27.54 mm). The whole group of patients with AMD included 50 eyes with nonexudative AMD and 154 eyes with exudative AMD, differentiated into eyes with a detachment of the retinal pigment epithelium (n = 35), eyes with mostly intraretinal and subretinal edema (n = 36), and eyes with a fibrotic scar formation (n = 83). For 29 patients with unilateral AMD, the contralateral normal eye was compared with the affected eye. For additional 21 patients with unilateral AMD, OCT images of the contralateral eye were not available for the measurement of SFCT.
The control group consisted of 189 patients (228 eyes) with no abnormality of the fundus. Mean age was 71.7 ± 11.8 years (median, 74.4 years), mean refractive error was 0.18 ± 3.05 D (median, +0.25 D), and mean axial length was 23.33 ± 0.95 mm (median, 23.39 mm; range, 20.81–26.72 mm). The study group and control group differed significantly in age (P < 0.001), whereas refractive error (P = 0.18) and axial length did not vary significantly (P = 0.76). For direct comparison of both groups, we matched study and control group for age, refractive error, and axial length. For the multivariate analyses, we took the original groups and adjusted for age and refractive error.
In the first step of the statistical analysis, we compared choroidal thickness measurements between the affected eyes and contralateral unaffected eyes of the 29 patients with unilateral AMD. It revealed that the differences between affected eyes and unaffected eyes were not statistically significant (all P > 0.20) (Table 1).
In the second step of the statistical analysis, we analyzed the relationship between choroidal thickness and the diagnosis of AMD after adjusting for the other parameters. In the control group, choroidal thickness was significantly associated with younger age (P < 0.001) and less myopic refractive error (P = 0.001), whereas it was not significantly associated with gender (P = 0.32). We then included all study participants in the statistical analysis and conducted a multivariate regression analysis, in which we assessed the relationship between choroidal thickness and the diagnosis of AMD (as a whole group and separated into the subtypes of AMD) after adjusting for age and refractive error. It revealed that SFCT was not related with the diagnosis of AMD as a whole nor to the different subtypes of AMD (all P > 0.10), except for the subdiagnosis of exudative AMD with a subretinal fibrotic scar. The latter group of patients had significantly (P = 0.03) thinner SFCT measurements after adjustment for age and refractive error (Table 2). If the study group was divided only into a nonexudative subgroup and exudative subgroup, neither the nonexudative group (P = 0.70) nor exudative group (P = 0.11) was significantly associated with foveal choroidal thickness after adjusting for age and refractive error. If choroidal thickness measurements obtained at a distance of 1000 μm from the fovea were taken, neither the subgroups of AMD nor the whole group of AMD was significantly (all P ≥ 0.30) associated with choroidal thickness (Table 2).
In the third step of statistical analysis, we performed a binary regression analysis, with the presence or absence of AMD (or its subtypes) as a dependent parameter and age, axial length, and choroidal thickness as independent variables. It revealed that neither the presence of AMD as a whole nor the presence of the different subtypes of AMD was significantly associated with choroidal thickness after adjustment for age and refractive error (all P ≥ 0.20) (Table 3).
In the fourth step of statistical analysis, we compared the AMD group with the control group that was matched for age and axial length with the study group. The matched study group consisted of 86 patients and the matched control group included 102 subjects with no significant difference in age (P = 0.43), axial length (P = 0.44), and refractive error (P = 0.62). Study group and control group did not differ significantly (all P > 0.25) in any choroidal thickness measurement (Table 4).
Finally, we calculated post hoc the statistical power of the statistical analysis. With the given sample size and the mean value and standard deviation of choroidal thickness in the control group, the statistical power of the test to detect a difference of 20 μm and 15 μm between the control group and study group was 97% and 84%, respectively.
Since the landmark study by Spaide et al on the clinical use of enhanced depth imaging by OCT for imaging of the choroid,7,8 studies have measured choroidal thickness and have examined the factors associated with choroidal thickness in normal eyes and eyes with various retinal and retinochoroidal disorders.9–17 These studies have revealed that the mean SFCT in normal eyes is ∼250 μm in a population with a mean age of 65 years17; that choroidal thickness shows a pronounced interindividual variation with values as low as 8 μm in elderly highly myopic subjects and values as large as 854 μm in young hyperopic individuals; and that choroidal thickness decreases with age by ∼4 μm/year of age and with increasing myopia by 15 μm/D of myopia. Clinical studies also showed that patients with central serous chorioretinopathy have an abnormally thick SFCT in the affected eye and contralateral unaffected eye,12 and that patients with polypoidal vascular choroidopathy have an increased thickness of the subfoveal choroid in association with a dilatation of the large choroidal vessels.11,19–21 In this hospital-based study, we found that after adjustment for age and refractive error, choroidal thickness measured in the foveal region and the parafoveal area did not differ significantly between the affected eyes and unaffected eyes in patients with unilateral AMD and between patients with AMD and subjects of the control group matched for age and refractive error with the study group.
In a similar manner, Rahman et al26 reported that SFCT did not differ significantly between the 15 eyes affected by neovascular AMD and contralateral 15 eyes with early AMD. Other studies examined choroidal thickness in patients with AMD and patients with polypoidal vascular choroidopathy and found significantly thinner values in the AMD group.11,20,21 Since eyes with polypoidal vascular choroidopathy have an abnormally thick choroid with a dilatation of the choroidal vessels, the findings of these studies did not reveal whether the eyes with AMD had a normal choroidal thickness. In the study by Koizumi et al,20 23 affected eyes with neovascular AMD had a mean SFCT of 245 ± 75 μm, a value which was almost identical to the mean choroidal thickness found in the previous studies on normal eyes. In the study by Jirarattanasopa et al21 on 58 patients with typical AMD and 63 patients with polypoidal vascular choroidopathy, mean SFCT was significantly lower in eyes with AMD than that in eyes with polypoidal vascular choroidopathy. A normal control group was not available to be compared with the patients with AMD. In the study by Yamazaki et al,22 mean SFCT in 23 eyes with neovascular AMD was 244 ± 62 μm, again a value similar to the mean choroidal thickness found in the previous studies on normal eyes. Kim et al19 examined 37 eyes with nonexudative AMD, 24 eyes with neovascular AMD, and 29 control eyes. Mean SFCT was 187 ± 64 μm in the nonexudative AMD when compared with 242 ± 66 μm in the control group. If however in a post hoc analysis, an age difference of 10 years between the study group and control group is taken into account with a mean decrease in choroidal thickness by ∼5 μm/year of life (as suggested in the population-based Beijing Eye Study),17 the study group and control group would have almost identical SFCT measurements. If an age-related decline in choroidal decrease of only 2 μm/year of life is assumed, the difference between the mean of the AMD study group and control group would still be ∼50% of the standard deviations so that the difference between both groups would likely be not statistically significant. Mean SFCT in the group with exudative AMD was 226 ± 103 μm and did not differ from the value in the control group, as raw data or adjusted for age. In the recent study by Kim et al,23 mean SFCT was 185 ± 69 μm in the group of 24 eyes with exudative AMD, a mean age of 74 years, and a mean refractive error of +0.78 D. If, again in post hoc analysis, the choroidal thickness is adjusted for age, a value within the normal range results. In a histomorphometric study, Spraul et al28 examined 51 human enucleated globes with different stages of AMD and 40 age-matched control eyes. Eyes with AMD had fewer large choroidal vessels in the submacular region while the submacular choriocapillaris density was higher in eyes with AMD. Choroidal thickness was not measured.
Potential limitations of our study should be mentioned. First, a hospital-based study as ours carries the risk of a confounding effect because of a referral bias. The alternative would have been a study with a population-based design. With an assumed prevalence of exudative AMD of ∼1% to 2% or lower in the adult population, however, a population-based investigation would have had to include >5000 subjects to arrive at a sample size of 100 patients. Second, since choroidal thickness differences if at all a priori expected would have been small, selection bias may have been a major risk to cover a statistical significance of such a small difference. The study participants were however consecutively included into the study, depending on the availability of the two trained examiners and independently of clinical parameters. It may therefore not be very likely that a selection bias might have been present. Third, if a study concludes on the absence of a statistically significant difference between two groups, the statistical power of the analysis is important. In our study setting, the statistical power of the analysis to detect a difference of 20 μm and 15 μm between the control group and study group was 97% and 84%, respectively. We can therefore only conclude that the difference between the study group and control group was <20 μm with P = 97%. In addition, it has to be considered that OCT has an axial resolution of ∼4 μm, so that it is unlikely to detect a mean difference of ∼≤4 μm between the 2 groups if the Spectralis OCT is applied. Fourth, the previous studies revealed that the medical therapy of exudative AMD was associated with a reduction in SFCT by 10 μm to 20 μm.22 This study was contradicted by the investigation by Rahman et al26 who did not find a significant difference in the intereye difference in patients with unilateral neovascular AMD, if a treated group was compared with an untreated group. There may however be a possibility that the medical therapy supplied to the patients in this study may have slightly affected the choroidal thickness. Since the mean choroidal thickness values were slightly, however not significantly, lower in the study group than in the control group, and since the medical intravitreal treatment may potentially have led to this slight thinning, the medical pretreatment of the eyes in the study group may only serve to strengthen the conclusion of the study that the eyes with AMD did not have an abnormal choroidal thickness. Fifth, the previous studies by Tan et al,29 Usui et al30 and others have shown a circadian (diurnal) rhythm of ∼20 to 30 μm change in choroidal thickness measurements. The participants of our study underwent the OCT examinations at various times of the day. Since these examinations were performed in a randomized manner about when they were performed, it is unlikely that the dependence of choroidal thickness measurements during the daytime of examination may have introduced a bias into our study. In addition, the dependence of choroidal thickness during the daytime did not affect the intereye difference in choroidal thickness in the intraindividual comparison. Sixth, OCT measured only the whole choroidal thickness. The most important layer for the nourishment of the retinal pigment epithelium and the photoreceptors is however the choriocapillaris that makes out <5% of the choroid. It is therefore not possible to make conclusions on the blood flow in the choriocapillaris. Seventh, our study did not include patients with geographic atrophy for which a partial closure of the choriocapillaris has been described, similar to the closure of the choriocapillaris in beta zone of parapapillary atrophy.31 Our study can therefore not make any statements about the choroidal thickness in eyes with geographic atrophy. Finally, our study evaluated only the thickness of the choroid as a whole and did not assess the thickness of the choriocapillaris as a single entity. The study could therefore not address the question whether AMD, in particular geographic atrophy, is associated with thinning of the choriocapillaris as the main supplying layer of the choroid for the nourishment of the retinal pigment epithelium and the photoreceptors.
In conclusion, after adjusting for age and refractive error or axial length, AMD, neither in its nonexudative form nor exudative form, was significantly associated with a marked thinning or thickening of the choroid in the foveal and parafoveal region, neither in an intraindividual intereye comparison nor interindividual analysis.
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choroidal thickness; age-related macular degeneration; enhanced depth imaging; optical coherence tomography
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