|Year : 2019 | Volume
| Issue : 1 | Page : 12-17
Choroidal thickness in type 2 diabetic patients with various stages of diabetic macular edema and retinopathy: A prospective study from central India
Shilpi H Narnaware1, Prashant K Bawankule1, Dhananjay V Raje2, Moumita Chakraborty2
1 Vitreo-Retina, Sarakshi Netralaya, Nagpur, Maharashtra, India
2 Data Analysis Group, MDS Bio Analytics Private Limited, Mumbai, Maharashtra, India
|Date of Submission||08-Mar-2018|
|Date of Acceptance||13-Jun-2018|
|Date of Web Publication||12-Mar-2019|
Shilpi H Narnaware
Sarakshi Netralaya, 19, Rajiv Nagar, Wardha Road, Nagpur - 440 025, Maharashtra
Source of Support: None, Conflict of Interest: None
Background: The objective of this study is to assess the changes in choroidal thickness in patients with type 2 diabetes with diabetic macular edema (DME) and diabetic retinopathy (DR), using enhanced-depth imaging (EDI) spectral domain optical coherence tomography (OCT). Materials and Methods: A total of 164 eyes from 104 patients were divided into no DR, DR without DME, and DR with DME. Eyes were also divided according to subtypes of DME. Subfoveal choroidal thickness (SFChT) and parafoveal choroidal thickness (PFChT) at 500 μm, 1000 μm and 1500 μm were measured using EDI-OCT and compared across groups. Results: A sample of 104 patients with diabetes consisted of 28 females and 76 males. The adjusted mean SFChT was 266.1 ± 42.40 μm in no DR eyes, 258.32 ± 39.52 μm in DR without DME eyes, and 246.11 ± 35.42 μm in DR with DME eyes (P = 0.028). The adjusted mean SFChT was 242.5 ± 33.04 μm in spongy edema eyes, 242.05 ± 39.73 μm in cystic edema eyes, and 247.9 ± 39.54 μm in serous retinal detachment eyes (P < 0.006). Conclusions: In eyes with DR, there is an overall thinning of the choroid on EDI-OCT. The subfoveal choroid was significantly thinner in eyes with DR and DME, specifically in cystic type of DME, as compared to those without DR. A decreased choroidal thickness may lead to tissue hypoxia and consequently increase the level of vascular endothelial growth factor, resulting in the breakdown of the blood-retinal barrier and development of macular edema.
Keywords: Choroidal thickness, diabetic macular edema, nonproliferative diabetic retinopathy, proliferative diabetic retinopathy
|How to cite this article:|
Narnaware SH, Bawankule PK, Raje DV, Chakraborty M. Choroidal thickness in type 2 diabetic patients with various stages of diabetic macular edema and retinopathy: A prospective study from central India. J Clin Ophthalmol Res 2019;7:12-7
|How to cite this URL:|
Narnaware SH, Bawankule PK, Raje DV, Chakraborty M. Choroidal thickness in type 2 diabetic patients with various stages of diabetic macular edema and retinopathy: A prospective study from central India. J Clin Ophthalmol Res [serial online] 2019 [cited 2020 Jan 20];7:12-7. Available from: http://www.jcor.in/text.asp?2019/7/1/12/253987
Diabetic macular edema (DME) and diabetic retinopathy (DR) are common sight-threatening retinopathies caused by abnormalities in retinal vessels and capillaries. DR occurs due to breakdown of retinal vasculature integrity and hemodynamic abnormalities., Choroidal vasculature, especially the choriocapillaries, provides oxygen and nutrients to outer retina, retinal pigment epithelium (RPE), and photoreceptors, which is responsible for maintaining highly metabolically active photoreceptor cells as evident from absence of retinal vasculature in the foveal region. Impairment of choriocapillaries may cause severe functional damage to tissues in foveal region. Existing histopathological studies reveal vascular abnormalities in choroidal layers in patients with diabetes, such as atrophy of choriocapillary endothelium. Circulatory studies also show decreased pulsatile ocular blood flow in patients with diabetes., Studies have shown decreased choroidal blood flow even before clinical manifestations of DR. Histological and circulatory studies indicate that there might occur changes in choroidal thickness along with retinal changes.
Spectral domain optical coherence tomography (SD-OCT) has improved resolution as compared with time domain OCT. Enhanced-depth imaging optical coherence tomography (EDI-OCT) is unique in having foveal tracking capability and is used to measure the thickness of the choroid in normal and pathological states.,,,,, Few studies reported choroidal thickness (ChT) changes in patients with various stages of DR and DME., A retrospective study by Kim et al. in Korean population demonstrated increasing ChT with increasing severity of retinopathy. Contradicting is an article by Querques et al. from Italy showing thinning of the subfoveal choroid in patients with diabetes as compared to controls. There are other reports that suggest choroidal thinning in patients with diabetes,,, and increasing thinning with progressive retinopathy. Sudhalkar et al. in their study on central Indian population observed that ChT decreases with increasing stages of DR.
The present study was conducted specifically on central Indian diabetic population to evaluate the changes in ChT not only in patients with various stages of DR but also in various subtypes of DME.
| Materials and Methods|| |
A prospective study was planned on patients with diabetes examined at one of the major tertiary care ophthalmology center from central India, between January 2016 and March 2017. Participants with the history of type 2 diabetes along with duration, recent control of diabetes as observed through fasting and postmeal blood sugar levels were considered. All patients underwent a complete ophthalmic examination, including best-corrected visual acuity (BCVA), slit lamp examination, applanation tonometry, and detailed dilated fundus examination with indirect ophthalmoscope and slit lamp biomicroscopy with 78 diopter (D) lens, by two retina specialists. Subsequently, they were subjected to fundus fluorescein angiography (FFA), SD-OCT-Zeiss, and EDI-OCT. Exclusion criteria were patients with the presence of refractive error >+/-three diopters, history of any ocular surgery except cataract extraction, history of PRP (Pan–Retinal Photo-coagulation) or focal/grid laser, intravitreal, or sub-tenons injections, DME with Epi-retinal Membrane/vitreomacular traction, combined retinal detachment, other retinal pathologies such as drusen, age-related macular degenerations, vein occlusions, choroidopathies such as central serous retinopathy or polypoidal choroidal vasculopathy or any other inflammatory retinal pathologies, and history of glaucoma or trauma. The ethics clearance was obtained from the central Ethics Committee and patient's consent were sought regarding sharing of their data for research purpose.
Patients were divided into No DR, DR without DME, and DR with DME based on detailed dilated fundus examination with Indirect Ophthalmoscope and Slit Lamp Bio-microscopy with 78 D lens, followed by FFA, and OCT findings. DME was further subclassified on OCT characteristics as: Type 1: cystoid edema, Type 2: diffuse or spongy edema, type 3: serous retinal detachment (SRD) with thickening of fovea.
Choroid was imaged by positioning SD-OCT device close enough to eye to obtain an inverted image. Four raster scans were taken through fovea at 45, 90, 135, 180 degrees. Choroid thickness was measured by 2 experienced retinal physicians, which were blinded to the diagnosis. ChT was measured manually, using caliper tool from hyper-reflective line of Bruch's membrane to the hyperreflective line of chorio-scleral interface. Measurements were made subfoveally and para-foveally (at 500, 1000, and 1500 um distance) in temporal, nasal, superior and inferior quadrants. The interobserver reliability of measurements was high; hence, values for parameters were averaged out and used for analysis.
The descriptive statistics for various patient's characteristics such as demography, biochemical, and clinical parameters were obtained and summarized according to the scale of measurement. Comparison of these characteristics was performed across three groups, namely, No DR, DR without DME, and DR with DME according to the scales of measurement. Eye was treated as a subject and the mean subfoveal choroidal thickness (SFChT) and parafoveal ChT (PFChT) at three distances (500, 1000, and 1500 um) were obtained in each quadrant for eyes in each of the three groups. The comparison across groups was performed using one-way analysis of variance (ANOVA), and the paired comparison was done using Tukey's post hoc test. The comparison of ChT was also performed in each quadrant across distances within each patient group. The measurements were pooled across distances as a result of statistical insignificance to obtain a representative thickness for each quadrant. Thickness values were adjusted with age, gender, duration of DM, and blood glucose levels using analysis of covariance (ANCOVA); and the adjusted mean thickness across groups were compared. Multiple testing correction was performed on different tests using Benjamini-Hochberg procedure, with a false discovery rate of 0.05. Accordingly, the adjusted P values were referred for deciding the statistical significance. All the analyses were performed using SPSS ver 20.0 (IBM Corp., Armonk, NY, USA) and R-3.2.3 (R Core Team 2015, Vienna, Austria).
| Results|| |
The descriptive statistics for baseline characteristics of 104 patients and their comparison across three groups are given in [Table 1]. The mean age of patients, gender distribution, and duration of DM differed insignificantly across groups. Both fasting and postmeal blood glucose levels across groups were significantly different as indicated by P = 0.007 and 0.005, respectively. The mean values were higher in DR without DME group as compared to other groups. The mean systolic and diastolic blood pressures were insignificantly different across three groups. The BCVA was significantly affected in DR groups as compared to No DR group for both right and left eyes as revealed by P = 0.018 and < 0.001, respectively.
|Table 1: Descriptive statistics and comparison of patient characteristics across no diabetic retinopathy, diabetic retinopathy without diabetic macular edema and diabetic retinopathy with diabetic macular edema groups|
Click here to view
The mean ChT in each quadrant at 500, 1000, and 1500 μm distances were obtained for patients in these three groups, with the results shown in [Table 2]. In the nasal quadrant, at 500 μm, the mean ChT in No DR group was higher as compared to DR groups with and without DME; and the difference was statistically significant (P = 0.03) after applying BH correction. Similar was the finding at 1000 μm, and 1500 μm with P = 0.029 and 0.022, respectively. The difference of mean ChT between No DR and DR with DME was more prominent at all the three distances as revealed through statistical significance using Tukey's post hoc test. Likewise, the mean ChT in temporal and superior quadrants at three distances, when compared across study groups, showed statistically significant differences after applying BH correction. In the inferior quadrant, at 500 μm, the difference of mean ChT was statistically significant (P = 0.042); however, at 1000 μm and 1500 μm, the differences were insignificant after applying BH correction.
|Table 2: Comparison of choroidal thickness at various distances in each quadrant across no diabetic retinopathy, diabetic retinopathy without diabetic macular edema, and diabetic retinopathy with diabetic macular edema groups|
Click here to view
The difference of mean ChT across three distances within each group and quadrant showed statistical insignificance. Therefore, the thickness values were pooled together to arrive at a single measure of mean ChT representing the quadrant and the study group. [Table 2] shows the unadjusted pooled means for four quadrants in each group, in addition to SFChT. One-way ANOVA resulted into statistically significant difference of mean ChTs across groups in subfoveal, nasal, temporal, and superior quadrants after applying BH correction. The difference between No DR and DR with DME groups contributed to overall significance, with the latter showing substantial thinning in subfoveal, nasal, and superior quadrants. The difference of means between No DR and DR without DME groups was statistically insignificant at subfoveal, nasal, superior, and inferior quadrants as per Tukey's post hoc test.
Although, the mean age, gender distribution and duration of DM did not differ significantly across three groups, considering their relevance with ChT, the thickness measurements were adjusted with these three covariates and blood sugar levels (fasting and postmeal) using ANCOVA. [Table 2] shows marginal change in the unadjusted means after performing ANCOVA in each quadrant and each group. The difference of adjusted means across groups showed statistical significance subfoveally; however, insignificance in other quadrants after applying BH correction. Despite insignificance, thinning was maximum in DME group. The next question was whether ChT of particular DME type differ significantly from that of No DR group. Accordingly, DME eyes were split into spongy, cystic, and SRD types constituting three groups. The comparison of these groups with No DR was performed separately excluding DR without DME group. The adjusted mean ChT values obtained are shown in [Table 3]. The analysis revealed that the mean thickness differed significantly at subfoveal, nasal, and superior regions after applying BH correction. The post hoc analysis indicated that the significance was mainly contributed by cystic and No DR group. In other words, thinning was maximum in cystic group among DME types. The mean thickness of other two DME types differed insignificantly than No DR group, as observed through post hoc analysis. Moreover, across DME types, the mean ChT differed insignificantly in every quadrant. In addition, the comparison of mean ChT was also performed between No DR and subgroups of DR. However, insignificant differences were observed across groups in all the quadrants [Supplementary Table 1S].
|Table 3: Comparison of adjusted choroidal thickness in various quadrants across patient groups with no diabetic retinopathy, and types of diabetic macular edema|
Click here to view
| Discussion|| |
DME has classically been attributed to inner capillary changes., However, some eyes do not develop macular edema in spite of marked macular capillary changes, suggesting that retinal capillary abnormalities are not only contributory factors but also coexisting changes in RPE, choroid, vitreous and/or systemic circulation might be necessary for the development of DME. Changes are observed in choroidal vasculature, which is an important source of blood supply to outer retina. The previous histological studies revealed increased tortuosity, focal vascular dilatation or narrowing, luminal narrowing of capillaries, atrophy, dropouts, and focal scarring., In addition, circulatory studies revealed decreased pulsatile ocular flow in patients with diabetes., Studies have shown that decreased choroidal blood flow may occur before clinical manifestations of DR. Few studies reported ChT changes in patients with various stages of DR and DME., A retrospective study by Kim et al. in Korean population demonstrated increasing ChT with the increasing severity of retinopathy. Contradictory is the finding by Q Querques et al. from Italy, showing significant thinning of the subfoveal choroid in patients with diabetes as compared to controls. Other studies also reported choroidal thinning in patients with diabetes,,, and increasing thinning with progressive retinopathy. The thinning of choroidal layers may have resulted from vascular constriction or chorio-capillary loss, secondary to hypoxia in association with diabetic choroidopathy and other mechanisms of DME.,, The decreased ChT leads to tissue hypoxia and increased levels of vascular endothelial growth factor (VEGF), resulting in the development of macular edema, due to breakdown of blood-retinal barrier.,,
A study conducted by Sudhalkar et al. in diabetic Indian population showed increasing stages of DR. Using EDI-OCT, we studied changes in ChT in various stages of DR and also subtypes of DME in central Indian population. There was a decrease in ChT with the increasing severity of DR; however, thinning was statistically insignificant [Table 2], while Sudhalkar et al. showed statistically significant choroidal thinning with increasing severity of DR. The decrease in ChT was seen in No DR group, if compared with age-matched controlled normative data available from other studies supporting the hypothesis that choroidal changes may occur before clinical manifestations of DR. Decreased ChT can be interpreted as a marker of compromised systemic vasculature. Clinically also, proliferative DR is associated with the increased risk of systemic vascular complications such as ischemic heart disease.
We also measured ChT in DME and it showed statistically significant decrease in subfoveal, nasal, and superior quadrants, while statistically nonsignificant thinning in the temporal and inferior quadrants between No DR and DME groups. We further studied ChT in subtypes of DME and maximum thinning was noticed in cystic variant. Cystic changes are suggestive of long-standing DME leading to degenerative cysts formation. Demographic factors in our study did not reveal any significance in relation to DR or DME. Plasma blood sugar levels were statistically significant as is well proven that poorer the control, earlier, and severe is the disease. Poor vision with increase in severity of disease is apparent because of progressive nature of the disease.
Although the present study has few matching results with the previous studies, the analysis of DME patients and subtypes of DME is the value addition. One of the limitations of this study is that normal nondiabetic population was not studied.
| Conclusions|| |
EDI-OCT is a novel and noninvasive technology for the assessment of choroidal vascular changes in patients with diabetes. In eyes with DR, there is an overall thinning of choroid and more with the development of DME. ChT is more substantially reduced in the cystic subtype of DME. This decrease in ChT may lead to tissue hypoxia leading to increase in VEGF level, resulting in breakdown of blood-retinal barrier and thereby development of edema. Probably, ChT might have a role in the future as a noninvasive marker for the assessment and prognosis of DME and DR. Combining OCT images with OCT Doppler flow maps may help establish the correlation between vascular flow and ChT. Future studies investigating changes in ChT with anti-VEGF treatment will help in better understanding.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Cunha-Vaz J, Faria de Abreu JR, Campos AJ. Early breakdown of the blood-retinal barrier in diabetes. Br J Ophthalmol 1975;59:649-56.
Ciulla TA, Harris A, Latkany P, Piper HC, Arend O, Garzozi H, et al.
Ocular perfusion abnormalities in diabetes. Acta Ophthalmol Scand 2002;80:468-77.
Alm A. Ocular circulation. In: Hart WM, editor. Adler's Physiology of the Eye. 9th
ed. St. Louis, MO: C.V. Mosby; 1992. p. 198-227.
Hidayat AA, Fine BS. Diabetic choroidopathy. Light and electron microscopic observations of seven cases. Ophthalmology 1985;92:512-22.
McLeod DS, Lutty GA. High-resolution histologic analysis of the human choroidal vasculature. Invest Ophthalmol Vis Sci 1994;35:3799-811.
Geyer O, Neudorfer M, Snir T, Goldstein M, Rock T, Silver DM, et al.
Pulsatile ocular blood flow in diabetic retinopathy. Acta Ophthalmol Scand 1999;77:522-5.
Langham ME, Grebe R, Hopkins S, Marcus S, Sebag M. Choroidal blood flow in diabetic retinopathy. Exp Eye Res 1991;52:167-73.
Nagaoka T, Kitaya N, Sugawara R, Yokota H, Mori F, Hikichi T, et al.
Alteration of choroidal circulation in the foveal region in patients with type 2 diabetes. Br J Ophthalmol 2004;88:1060-3.
Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496-500.
Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol 2009;147:811-5.
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;148:445-50.
Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina 2009;29:1469-73.
Spaide RF. Age-related choroidal atrophy. Am J Ophthalmol 2009;147:801-10.
Spaide RF. Enhanced depth imaging optical coherence tomography of retinal pigment epithelial detachment in age-related macular degeneration. Am J Ophthalmol 2009;147:644-52.
Esmaeelpour M, Považay B, Hermann B, Hofer B, Kajic V, Hale SL, et al.
Mapping choroidal and retinal thickness variation in type 2 diabetes using three-dimensional 1060-nm optical coherence tomography. Invest Ophthalmol Vis Sci 2011;52:5311-6.
Regatieri CV, Branchini L, Carmody J, Fujimoto JG, Duker JS. Choroidal thickness in patients with diabetic retinopathy analyzed by spectral-domain optical coherence tomography. Retina 2012;32:563-8.
Kim JT, Lee DH, Joe SG, Kim JG, Yoon YH. Changes in choroidal thickness in relation to the severity of retinopathy and macular edema in type 2 diabetic patients. Invest Ophthalmol Vis Sci 2013;54:3378-84.
Querques G, Lattanzio R, Querques L, Del Turco C, Forte R, Pierro L, et al.
Enhanced depth imaging optical coherence tomography in type 2 diabetes. Invest Ophthalmol Vis Sci 2012;53:6017-24.
Vujosevic S, Martini F, Cavarzeran F, Pilotto E, Midena E. Macular and peripapillary choroidal thickness in diabetic patients. Retina 2012;32:1781-90.
Esmaeelpour M, Brunner S, Ansari-Shahrezaei S, Nemetz S, Povazay B, Kajic V, et al.
Choroidal thinning in diabetes type 1 detected by 3-dimensional 1060 nm optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:6803-9.
Sudhalkar A, Chhablani JK, Venkata A, Raman R, Rao PS, Jonnadula GB, et al.
Choroidal thickness in diabetic patients of Indian ethnicity. Indian J Ophthalmol 2015;63:912-6.
] [Full text]
Bresnick GH. Diabetic macular edema. A review. Ophthalmology 1986;93:989-97.
Fine BS, Brucker AJ. Macular edema and cystoid macular edema. Am J Ophthalmol 1981;92:466-81.
Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res 2010;29:144-68.
Cunha-Vaz JG, Goldberg MF, Vygantas C, Noth J. Early detection of retinal involvement in diabetes by vitreous fluorophotometry. Ophthalmology 1979;86:264-75.
Mori F, Hikichi T, Takahashi J, Nagaoka T, Yoshida A. Dysfunction of active transport of blood-retinal barrier in patients with clinically significant macular edema in type 2 diabetes. Diabetes Care 2002;25:1248-9.
Vinores SA, Youssri AI, Luna JD, Chen YS, Bhargave S, Vinores MA, et al.
Upregulation of vascular endothelial growth factor in ischemic and non-ischemic human and experimental retinal disease. Histol Histopathol 1997;12:99-109.
Chhablani JK, Deshpande R, Sachdeva V, Vidya S, Rao PS, Panigati A, et al.
Choroidal thickness profile in healthy Indian children. Indian J Ophthalmol 2015;63:474-7.
] [Full text]
Tryniszewski W, Kuśmierczyk J, Maziarz Z, Goś R, Mikhailidis DP, Banach M, et al.
Correlation of the severity of diabetic retinopathy and the heart muscle perfusion in patients with type 2 diabetes. J Diabetes Complications 2011;25:253-7.
[Table 1], [Table 2], [Table 3]