Optical coherence tomography (OCT) provides cross-sectional, three-dimensional, high-resolution views of the retina in vivo in a noninvasive, reproducible manner.1 Spectral-domain OCT (SD-OCT) permits fast scanning speeds of up to 52,000 A-scans per second, and with improvements in SD-OCT technology such as image averaging and enhanced depth imaging (EDI), imaging through the choroid is now possible.2–6 The choroidal thickness has been evaluated using SD-OCT in both normal and diseased states such as in patients with high myopia, age-related macular degeneration (AMD), central serous chorioretinopathy (CSCR), and age-related choroidal atrophy.7–10
AMD is the leading cause of irreversible visual impairment among the elderly worldwide.11,12 OCT-generated macular thickness maps have proven useful in monitoring the progression and response to treatment in neovascular AMD after anti-vascular endothelial growth factor (VEGF) treatment, and more recently, SD-OCT and EDI are being used to examine the choroid of patients with AMD.10,13,14 Choroidal thinning has been described in patients with AMD compared to age-matched controls; however, there has not been significant investigation regarding the change in the subfoveal choroidal thickness of AMD patients over time.10,15,16 The purpose of this study is to examine the change in subfoveal choroidal thickness in patients with neovascular AMD and dry AMD over a 6-month time period using SD-OCT.
Patients and Methods
This is a retrospective, observational study investigating the change in subfoveal choroidal thickness in patients with both neovascular and dry AMD over a time period of 6 months. This study was approved by the institutional review board of Tufts Medical Center and was conducted in adherence to the tenets of the Declaration of Helsinki. Patients previously diagnosed with AMD who were monitored for 6 months at the New England Eye Center, Tufts Medical Center, between November 2009 and November 2010 were included in this study. All study participants underwent a comprehensive ophthalmologic examination with fundus biomicroscopy, color fundus photography, best corrected Snellen visual acuity, and OCT imaging. OCT imaging was performed using Cirrus HD-OCT software version 4.5 (Carl Zeiss Meditec, Dublin, CA). The software version allows for the acquisition of high-definition one-line raster scans that are constructed from 20 B-scans obtained at the same location and processed using a unique selective pixel profiling system. The one-line raster scan, which is a 6-mm line scan consisting of 4,096 A-scans, has an axial resolution of 5 to 6 μm and a transverse resolution of 15 to 20 μm. Images were taken with the vitreoretinal interface adjacent to the zero delay and were not inverted to bring the choroid adjacent to zero delay because image inversion using the Cirrus software results in a low-quality image. These high-definition images provide increased definition of retinal layers as well as more posterior structures, such as the choroid-sclera junction. All reviewed scans had an intensity of 6/10 or greater and were taken as close to the fovea as possible, with adequate visualization of the choroid-sclera boundary.
The subfoveal choroidal thickness was measured manually using the Cirrus linear measurement tool. The measurements were taken from the base of the hyperreflective retinal pigment epithelium to the hyporeflective line corresponding to the sclera-choroidal interface junction. The same scan was used for all patients, and the readers were masked from each other’s results. Two measurements were taken at baseline and at 6 months by three independent observers (JGF, VM, LAB), and the average data were compared for each patient. Chart review was performed to collect information regarding duration of disease, number of intravitreal anti-VEGF injections, visual acuity, and concomitant retinal pathology. Highly myopic patients (> 6 D) were excluded due to known choroidal thinning.8
The results were also compared with age-matched controls, using data from a previous study by this same group. All statistics were calculated using SPSS software version 17.0 for Windows. The paired t-test was used to correlate mean subfoveal choroidal thickness values at baseline and at 6 months. Data are expressed as means ± standard error of the mean. P values less than or equal to .05 were considered to be significant.
Of the initial 65 eyes of 52 patients identified, 16 eyes were excluded due to lack of follow-up, incomplete choroidal penetration on subsequent OCT scans, or follow-up scans with inadequate signal strength. There was one patient excluded because the outer boundary of the choroid was not visualized. This patient had a history of neovascular AMD and was noted to have a scar with fibrosis along with subretinal hemorrhage and intraretinal fluid on initial enrollment. On subsequent examination, the choroidal scleral boundary was not visualized secondary to poor penetration through the scar. Patients were subclassified as having dry AMD if there was no evidence of neovascularization such as intraretinal or subretinal fluid at any visit time point. This group included patients with geographic atrophy, drusen, and drusenoid or serous pigment epithelial detachments not associated with choroidal neovascularization. The dry AMD patients were not further categorized to assess for severity of disease. Patients were subclassified as having neovascular AMD if there was evidence of neovascularization such as intraretinal or subretinal fluid at any follow-up visit. All patients classified with neovascular AMD had subfoveal neovascularization. Patients were treated by different attending physicians with a combination of treat-and-extend and as-needed regimens with anti-VEGF therapy. In total, 49 eyes of 39 patients had adequate 6-month follow-up. Of these, 30 eyes (61%) had neovascular AMD, and 19 eyes (39%) had dry AMD; 22 were women (56%) and 17 men (44%), with an average age of 78.5 years (range: 59–93 years). Three patients had one eye included in the dry AMD group and one eye included in the neovascular AMD group. Of the patients with neovascular AMD, no patients were treatment-naïve: 23 eyes had received intravitreal ranibizumab, 12 eyes intravitreal bevacizumab, two eyes intravitreal pegaptanib, one eye intravitreal triamcino-lone, and five eyes either photodynamic therapy (PDT) or laser. Of patients who received PDT, two eyes had one session, three eyes three sessions, and one eye four sessions. None of these sessions were during or shortly before the 6-month study period. Three of the PDT-treated eyes had thinner than average choroidal thickness.
Of the 30 eyes with neovascular AMD, 14 eyes had received between one and five injections, five eyes between five and 10 injections, and 10 eyes between 11 and 20 injections prior to enrollment in the study. Ten eyes received a combination of treatments listed above prior to study enrollment.
For the entire cohort of AMD patients, there was a statistically significant thinning of the subfoveal choroidal thickness at 6 months compared to baseline (181.2 ± 75 μm to 173.4 ± 63 μm; P = .049) (Figure 1, page 33, and Table). This finding was driven by the subgroup of neovascular AMD patients. In the subgroup of dry AMD eyes, subfoveal choroidal thickness did not demonstrate statistically significant change between baseline and 6 months (192.2 ± 70 μm to 190.8 ± 60 μm; P = .824) (Table, Figures 1 and 2). In the subgroup of neovascular AMD eyes, there was a statistically significant difference between subfoveal choroidal thickness at baseline and at 6-month follow-up (182.8 ± 77 μm to 169.1 ± 62 μm; P = .015) (Table, Figures 1 and 3).
Graphical representation of the subfoveal choroidal thickness in subjects with age-related macular degeneration (AMD) over 6 months with comparison to age-matched controls. Total of 49 eyes with AMD from 39 patients. Thirty eyes (61%) had neovascular AMD, and 19 eyes (39%) had dry AMD at the start of the study.
Subfoveal Choroidal Thickness by AMD Type
Choroidal thickness in a patient with dry AMD. High-definition Cirrus one-line raster scans (A, C) and color fundus photographs (B, D) from a patient with a history of dry AMD over 6 months.
Choroidal thickness in a patient with neovascular AMD. High-definition Cirrus one-line raster scans (A, C) and color fundus photographs (B, D) from a patient with a history of neovascular AMD over 6 months.
In the neovascular AMD group, which consisted of 30 eyes of 27 patients, 10 eyes (33%) demonstrated increased subfoveal choroidal thickness and 20 eyes (66%) demonstrated a decrease in subfoveal choroidal thickness at 6-month follow-up. The opposite pattern was observed in the subgroup of dry AMD patients, which consisted of 19 eyes of 14 patients. Twelve eyes (63%) demonstrated an increase in subfoveal choroidal thickness, and seven eyes (37%) demonstrated a decrease in subfoveal choroidal thickness at 6-month follow-up (Figure 4, page 36).
Scatter plot of the change in subfoveal choroidal thickness between baseline and 6 months in neovascular AMD (A) and dry AMD (B) subgroups.
When the above data were analyzed including both the dry and neovascular AMD patients, there was a statistically significant decrease in the subfoveal choroidal thickness over 6 months compared to baseline (P = .049). On subgroup analysis, however, it was clear that the neovascular AMD patients, who made up the 61% of the cohort, drove this finding. The dry AMD patients did not demonstrate a statistically significant decrease over 6 months when examined as a subgroup. Although in both dry and neovascular AMD groups there were some eyes that demonstrated an increase in choroidal thickness over 6 months, there was overall a statistically significant trend towards decreased choroidal thickness in the group considered as a whole. The increase in subfoveal thickness, which was observed in both subgroups, may represent an error intrinsic to manual measurements, or a natural variation in choroidal thickness. The choroid is a highly vascular structure whose thickness varies with intraocular pressure, perfusion pressure, nitric oxide production, and vasoactive substances such as circulating catecholamines and is believed to be highly sensitive to small vessel disease. Therefore, it may be expected that there is some natural fluctuation of subfoveal choroidal thickness over time.20–23
There is also known diurnal variation in choroidal thickness, with the choroid being thickest at night and thinnest during the day. A recent study by Chakraborty et al demonstrated an average choroidal thickness of 0.256 ± 0.049 mm with a diurnal fluctuation of 0.029 ± 0.016 mm. Patients included in this study had OCT imaging performed at various times throughout the day, so there may be some choroidal thickness variation due to differences when the measurements were taken.24 In normal eyes on the Cirrus OCT, Manjunath et al reported a subfoveal choroidal thickness of 272 ± 81 μm with a sample size of 34 subjects and a mean age of 51.1 years (range: 22 to 78 years), as well as demonstrating the reproducibility of choroidal thickness measurements by the same technique described in this study, with strong inter-observer correlation (r = 0.92, P < .0001).17 Previous studies have demonstrated a 1.56-μm decline in choroidal thickness per year of life, so based on the normative data obtained on the Cirrus HD-OCT by Manjunath et al, the average choroidal thickness expected in normal patients with an average age of 78.5 years would be 229 μm, which is significantly thicker than what was observed in both the dry and neovascular AMD cohorts in our study.17,25
More recent work by the same group demonstrated a mean subfoveal choroidal thickness of 194.6 μm (SD 88.4; n = 40) in patients with neovascular AMD versus 213.4 μm (SD 92.2; n = 17) in patients with dry AMD, with a mean age of 78.6 years.10 Our data demonstrate similar baseline subfoveal choroidal thickness for patients with neovascular AMD (182.8 ± 77 μm) and dry AMD (192.2 ± 70 μm), confirming that both the dry and neovascular AMD patients have thinner than average choroids compared to age-matched healthy patients.
There are two hypotheses to explain the choroidal thinning observed in this investigation. Patients with neovascular AMD may have accelerated choroidal thinning due to vascular or metabolic factors, which may contribute to the pathogenesis of AMD. Another possibility is that treatment for neovascular AMD, intravitreal anti-VEGF agents, may cause choroidal thinning.
VEGF is expressed in the retinal pigment epithelium of normal eyes, where it is thought to be a trophic factor for the choriocapillaris and play a role in choriocapillaris survival and permeability. VEGF-A is a glycoprotein that is thought to have an important role in the regulation of the choroidal vasculature.18,26,27
Therefore, continuous VEGF blockage used in the treatment of neovascular AMD through the use of anti-VEGF agents may negatively affect the maintenance of the choroid. Clinically it has been demonstrated that retinal pigment epithelial cells undergo progressive atrophy in patients with neovascular AMD undergoing treatment with intravitreal anti-VEGF therapy, although it is unclear if this is related to anti-VEGF treatment or the natural history of the disease. 28,29
Rahman et al found no correlation between subfoveal choroidal thickness and treatment with anti-VEGF agents in a small case series of 15 patients who were treated with 3 months of intravitreal anti-VEGF medication and compared to 15 treatment-naïve neovascular AMD patients. However, this was a very small sample size, and choroidal thickness was not analyzed over time.30 Conflicting data were found by Forte et al, who examined 34 patients with macular edema injected with intravitreal bevacizumab. Retinal and choroidal thickness was measured before and after 1 year of treatment, and in 24% of these patients, there was statistically significant choroidal thinning at 1-year follow-up, suggesting that VEGF blockade may play a role in choroidal thinning.19
There are several limitations to the present study. This examination did not subclassify dry AMD patients using AREDS criteria to assess disease severity, as the sample size was small and the study was not powered to detect a difference in the subcohorts of patients. It may be that patients with more advanced dry AMD have a rate of decrease in subfoveal choroidal thickness comparable to the neovascular AMD group. A greater number of subjects with dry AMD would be necessary to investigate this. Dry AMD also has a different clinical time course than neovascular AMD, so it may be that choroidal thinning occurs, but at a slower rate that would not be significant over a 6-month study. Future studies employing long-term follow-up would help elucidate choroidal thickness changes during the natural history of this disease process.
Another limitation is that with Cirrus OCT, there is no way to be sure that the same retinal location is scanned at differing time points. This issue may be exacerbated in patients with poor fixation due to low vision. It is also difficult to determine the central foveal scan in the setting of retinal edema or choroidal neovascularization. This may contribute to choroidal thickness fluctuation that is unrelated to underlying disease process. In addition, measurements were manually performed; automated software would enable a more objective evaluation of choroidal thickness.
In conclusion, this study suggests that there is a decrease in subfoveal choroidal thickness in subjects with neovascular AMD over 6 months that was not observed in those with dry AMD over the same time period. It is unclear whether this decrease represents the natural history of neovascular AMD or is related to treatment with anti-VEGF agents. Continued advances in OCT technology such as choroidal segmentation will allow for more accurate measurements of the choroid in the future and hopefully aid in further understanding the role of the choroid in disease processes such as age-related macular degeneration.
- Huang D, Swanson EA, Lin CP, et al. Optical coherence tomography. Science. 1991;254(5035):1178–1181. doi:10.1126/science.1957169 [CrossRef]
- Drexler W, Fujimoto JG. State-of-the-art retinal optical coherence tomography. Prog Retina Eye Res. 2008;27(1):45–88. doi:10.1016/j.preteyeres.2007.07.005 [CrossRef]
- Potsaid B, Gorczynska I, Srinivasan VJ, et al. Ultrahigh speed spectral / Fourier domain OCT ophthalmic imaging at 70,000 to 312,500 axial scans per second. Opt Express. 2008;16(19):15149–169. doi:10.1364/OE.16.015149 [CrossRef]
- Sander B, Larsen M, Thrane L, et al. Enhanced optical coherence tomography imaging by multiple scan averaging. Br J Ophthalmol. 2005;89(2):207–212. doi:10.1136/bjo.2004.045989 [CrossRef]
- Ferguson RD, Hammer DX, Paunescu LA, Beaton S, Schuman JS. Tracking optical coherence tomography. Opt Lett. 2004;29(18):2139–2141. doi:10.1364/OL.29.002139 [CrossRef]
- Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol. 2008;146(4):496–500. doi:10.1016/j.ajo.2008.05.032 [CrossRef]
- Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina. 2009;29(10):1469–1473. doi:10.1097/IAE.0b013e3181be0a83 [CrossRef]
- Fujiwara T, Imamura Y, Margolis R, Slakter JS, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am J Ophthalmol. 2009;148(3):445–450. doi:10.1016/j.ajo.2009.04.029 [CrossRef]
- Spaide RF. Age-related choroidal atrophy. Am J Ophthalmol. 2009;147(5):801–810. doi:10.1016/j.ajo.2008.12.010 [CrossRef]
- Manjunath V, Goren J, Fujimoto J, Duker JS. Analysis of Choroidal thickness in Age-Related Macular Degeneration Using Spectral-Domain Optical Coherence Tomography. Am J Ophthalmol. 2011;152(4):663–668. doi:10.1016/j.ajo.2011.03.008 [CrossRef]
- Congdon N, O’Colmain B, Klaver CC, et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122(4):477–485. doi:10.1001/archopht.122.4.477 [CrossRef]
- Li Y, Xu L, Wang YX, You QS, Yang H, Jonas JB. Prevalence of age-related maculopathy in the adult population in China: the Beijing eye study. Am J Ophthalmol. 2006;142(5):788–793. doi:10.1016/j.ajo.2006.06.001 [CrossRef]
- Kaiser PK, Blodi BA, Shapiro H, Acharya NRMARINA Study Group. Angiographic and optical coherence tomographic results of the MARINA study of ranibizumab in neovascular age-related macular degeneration. Ophthalmology. 2007;114(10):1868–1875. doi:10.1016/j.ophtha.2007.04.030 [CrossRef]
- Spaide RF. Enhanced depth imaging optical coherence tomography of retinal pigment epithelial detachment in age-related macular degeneration. Am J Ophthalmol. 2009;147(4):644–652. doi:10.1016/j.ajo.2008.10.005 [CrossRef]
- Koizumi H, Yamagishi T, Yamazaki T, Kawasaki R, Kinoshita S. Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol. 2011;249(8):1123–1128. doi:10.1007/s00417-011-1620-1 [CrossRef]
- Chung SE, Kang SW, Lee JH, Kim YT. Choroidal thickness in polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Ophthalmology. 2011;118(5):840–845. doi:10.1016/j.ophtha.2010.09.012 [CrossRef]
- Manjunath V, Taha M, Fujimoto JG, Duker JS. Choroidal thickness in normal eyes measured using Cirrus HD optical coherence tomography. Am J Ophthalmol. 2010;150(3):325–329. doi:10.1016/j.ajo.2010.04.018 [CrossRef]
- Adamis AP, Shima DT. The role of vascular endothelial growth factor in ocular health and disease. Retina. 2005;25(2):111–118. doi:10.1097/00006982-200502000-00001 [CrossRef]
- Forte R, Cennamo G, Breve MA, Vecchio EC, de Crecchio G. Functional and Anatomic Response of the Retina and the Choroid to Intravitreal Bevacizumab for Macular Edema. J Ocul Pharmacol Ther. 2012;28(1):69–75. doi:10.1089/jop.2010.0181 [CrossRef]
- Kiel JW. Modulation of choroidal autoregulation in the rabbit. Exp Eye Res. 1999;69(4):413–429. doi:10.1006/exer.1999.0717 [CrossRef]
- Kiel JW, Shepherd AP. Autoregulation of choroidal blood flow in the rabbit. Invest Ophthalmol Vis Sci. 1992;33(8):2399–2410.
- Kiel JW, van Heuven WA. Ocular perfusion pressure and choroidal blood flow in the rabbit. Invest Ophthalmol Vis Sci. 1995;36(3):579–585.
- Reiner A, Zagvazdin Y, Fitzgerald ME. Choroidal blood flow in pigeons compensates for decreases in arterial blood pressure. Exp Eye Res. 2003;76(3):273–282. doi:10.1016/S0014-4835(02)00316-0 [CrossRef]
- Chakraborty R, Read SA, Collins MJ. Diurnal Variations in Axial Length, Choroidal Thickness, Intraocular Pressure, and Ocular Biometrics. Invest Ophthalmol Vis Sci. 2011;52(8):5121–5129. doi:10.1167/iovs.11-7364 [CrossRef]
- Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Opthalmol. 2009;147(5):811–815. doi:10.1016/j.ajo.2008.12.008 [CrossRef]
- Marneros AG, Fan J, Yokoyama Y, et al. Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol. 2005;167(5):1451–1459. doi:10.1016/S0002-9440(10)61231-X [CrossRef]
- Nishijima K, Nh YS, Zhong L, et al. Vascular endothelial growth factor-A is a survival factor for retinal neurons and a critical neuroprotectant during the adaptive response to ischemic injury. Am J Pathol. 2007;171(1):53–67. doi:10.2353/ajpath.2007.061237 [CrossRef]
- Brown DM, Michels M, Kaiser PK, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009;116(1):57–65. doi:10.1016/j.ophtha.2008.10.018 [CrossRef]
- McBain VA, Kumari R, Townend J, Lois N. Geographic atrophy in retinal angiomatous proliferation. Retina. 2011;31(6):1043–1052. doi:10.1097/IAE.0b013e3181fe54c7 [CrossRef]
- Rahman W, Chen FK, Yeoh J, da Cruz L. Enhanced depth imaging of the choroid in patients with neovascular age-related macular degeneration treated with anti-VEGF therapy versus untreated patients. Graefes Arch Clin Exp Ophthalmol. 2013;251(6):1483–1488. doi:10.1007/s00417-012-2199-x [CrossRef]
Subfoveal Choroidal Thickness by AMD Type
|AMD Variant||Subfoveal Choroidal Thickness (μm)||Total||P Value|
|Dry||192.2 ± 69.91||190.8 ± 60.27||19 eyes||.824|
|Neovascular||182.8 ± 76.71||169.1 ± 61.98||30 eyes||.015|
|All AMD||181.2 ± 74.82||173.4 ± 62.73||49 eyes||.049|