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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 21  |  Issue : 2  |  Page : 122-126

Anatomical and functional significance of choroidal thickness changes after anti-vascular endothelial growth factors injection in diabetic macular edema


Ophthalmology Department, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Submission25-Oct-2019
Date of Decision06-Dec-2019
Date of Acceptance26-Dec-2019
Date of Web Publication26-Jun-2020

Correspondence Address:
MD Shaimaa A Arfeen
7308, 83 Street, Al Mokattam, Cairo 11571
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/DJO.DJO_57_19

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  Abstract 


Purpose The aim of this study was to evaluate the choroidal thickness (CT) changes and its effect on the early functional and anatomic outcome in eyes with diabetic macular edema (DME) following intravitreal injection of bevacizumab by using enhanced depth imaging optical coherence tomography.
Design This is a prospective interventional study.
Patients and methods A total of 40 eyes (of 27 patients) with clinically significant DME were included in the present study. Evaluation of CT at different points before and after three intravitreal injections of bevacizumab was done by using enhanced depth imaging optical coherence tomography. Patients were classified according to the anatomic and functional outcome to responder and nonresponder groups.
Results There was a significant decrease in the mean subfoveal CT from 425.47±96.61 to 374.75±99.71 μm following the three intravitreal injections (P<0.001). All examined quadrants of the choroid (nasal, temporal, superior, and inferior) showed significant decrease in thickness from 306.29±66.29, 313.85±65.01, 322.14±66.03, and 314.64± 62.93 μm, respectively, to 267.85±69.49, 273.00±71.76, 279.75±64.36, and 275.91±57.89 μm, respectively. There was a significant decrease in CT in the anatomic responder group (mean change was 49.68 μm compared with 21.43 μm in the nonresponder group; P=0.023), as well as in the functional responder group (mean change was 49.68 μm compared with 21.43 μm in the nonresponder group; P=0.023).
Conclusion Over a 3-month period, the use of intravitreal bevacizumab was associated with significant thinning of the choroid in DME which did not correlate with visual acuity changes. The responder groups showed significant reduction in CT as compared with the nonresponder groups. CT changes following bevacizumab injection might represent secondary nonspecific changes with no definite predictive value on the outcome.

Keywords: bevacizumab, choroidal thickness, diabetic macular edema, optical coherence tomography


How to cite this article:
Abd-Elmohsen MN, Dahab AA, Arfeen SA, Raafat KA, Elrakhawy K. Anatomical and functional significance of choroidal thickness changes after anti-vascular endothelial growth factors injection in diabetic macular edema. Delta J Ophthalmol 2020;21:122-6

How to cite this URL:
Abd-Elmohsen MN, Dahab AA, Arfeen SA, Raafat KA, Elrakhawy K. Anatomical and functional significance of choroidal thickness changes after anti-vascular endothelial growth factors injection in diabetic macular edema. Delta J Ophthalmol [serial online] 2020 [cited 2020 Jul 4];21:122-6. Available from: http://www.djo.eg.net/text.asp?2020/21/2/122/287461




  Introduction Top


Diabetic macular edema (DME) is one of the major causes of visual impairment in patients with diabetes mellitus [1],[2]. Although retinal microvascular changes play the main role in the pathogenesis of DME, many studies investigated the role of choroidal vasculopathy, for example, vascular degenerations, choroidal aneurysms, and obstruction of choriocapillaries, and suggested its role as a contributing factor in the pathogenesis of diabetic retinopathy [3].

With the introduction of enhanced depth imaging technique, examination of choroidal changes in retinal and choroidal diseases became possible with a simple noninvasive highly repeatable procedure [4],[5].

Many studies had evaluated choroidal thickness (CT) in diabetics and reported thinning of the choroid as compared with healthy individuals. Other studies, also, compared the CT in different stages of diabetes and its correlation to macular thickness. Based on the previous reports, many theories had been suggested explaining the vascular and metabolic effect of choroidal thinning on the retina as a contributing factor with retinal ischemia and vascular endothelial growth factors (VEGF) elaboration [6],[7],[8],[9].

The effect of treatment on this vital structure has been investigated with many studies focusing on anti-VEGF therapy, being the most preferred treatment nowadays. These studies reported decrease in CT after intravitreal injection of anti-VEGF for different causes of macular edema [10],[11],[12]. Despite these studies, the clinical significance of CT changes in DME is still unclear.

In this study, the CT changes after intravitreal bevacizumab injection were evaluated, and its relationship to functional and anatomic outcome was studied.


  Patients and methods Top


The study adhered to the tenets of the Declaration of Helsinki. The study was approved by the Local Ethical Committee of Cairo University Faculty of Medicine. All patients signed a written informed consent to participate in the study and for publication of data before enrollment in the study.

A total of 40 eyes of 27 patients were included in this study, which was conducted from August 2014 till July 2016. It included patients with clinically significant center-involving DME defined according to the early treatment diabetic retinopathy study criteria. Exclusion criteria were previous treatment for DME (anti-VEGF, corticosteroids, or retinal photocoagulation); previous surgery (pars plana vitrectomy or cataract extraction); and other macular disorders, for example, age-related macular degeneration, ischemic diabetic maculopathy, suspected or confirmed glaucoma, high myopia, and any media opacity that may affect imaging. All patients underwent full ophthalmological examination including dilated fundus examination. Fundus fluorescein angiography imaging was done to exclude ischemic diabetic maculopathy and to classify macular edema into focal and diffuse types. Spectral domain optical coherence tomography (SD-OCT) for assessment of both macular and CT was done at baseline and 4 weeks following the last injection.

Each patient received three injections of 0.05 ml (1.25 mg/0.05 ml) of bevacizumab (Avastin, Genentech Inc., San Francisco, California, USA) 4 weeks apart. One day following each injection, every patient was assessed clinically for intraocular pressure, fundus, and best-corrected visual acuity (BCVA).

OCT scans were performed using EDI SD-OCT (Spectralis, HRA+OCT Heidelberg Engineering, Heidelberg, Germany). The images were generated using six macular radial scans, centered at the fovea at equally spaced angular orientations, with 20 raster lines, 200 μm apart. Using Spectralis linear measuring, two independent observers measured the CT vertically from the outer border of the hyper-reflective line corresponding to the retinal pigment epithelium to the inner border of the sclera subfoveally and at 500-μm intervals temporal, nasal, inferior, and superior to the fovea up to 1000 μm. Measurements were done before treatment and 4 weeks after the third injection ([Figure 1]). These measurements were done using the follow-up function. The follow-up function (also referred to as Auto Rescan) uses active eye tracking to automatically acquire OCT scans at the same location on the retina as during a previous examination. Measurements were performed in the same time frame for all patients between 12 pm and 2 pm to exclude the probable bias of diurnal variation in CT.
Figure 1 Choroidal thickness measurement using manual caliber, subfoveal, and 500 µm intervals inferior and superior (a), nasal and temporal (b) up to 1000 µm.

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Patient classification

Patients were classified regarding the response to treatment into responders (anatomic and functional) and nonresponders. Anatomic responders were defined as patients having a decrease in central macular thickness of more than or equal to 50 μm from baseline, whereas functional responders were patients with BCVA gain of more than or equal to one line from baseline.

Statistical analysis

Data were coded and entered using the Statistical Package for Social Sciences (SPSS), version 24 (SPSS, Chicago, Illinois, USA). Quantitative data were expressed in mean, SD, median, minimum, and maximum. Categorical data were expressed using frequency (count) and relative frequency (percentage). Nonparametric Mann–Whitney test was used for comparisons between quantitative variables. For comparison of serial measurements within each patient, the nonparametric Wilcoxon signed rank test was used. c2 test was performed for comparing categorical data. When the expected frequency was less than 5, exact test was performed instead. Linear regression was done to detect association between BCVA change and both pre-injection subfoveal CT and CT change. P values less than 0.05 were considered statistically significant.


  Results Top


A total of 40 eyes of 27 patients were included in this study (11 males and 16 females). The mean age of the patients was 56.89±7.55 years (31–68 years). Nine (22.5%) eyes had focal DME, whereas thirty one eyes had diffuse DME as classified by fundus fluorescein angiography.

The mean BCVA at baseline was 0.78±0.36 (1.9–0.2) Log MAR. After 3 monthly injections of bevacizumab, the mean BCVA was 0.56±0.26 (1.10–0.00). Twenty-seven (67.5%) eyes showed functional response.

There was a statistically significant decrease in the mean central subfield foveal thickness after the last injection. The mean pre-injection thickness was 425.47±96.61 μm (261–649 μm). Following injections, the mean subfield foveal thickness became 374.75±99.71 μm (223–583 μm) (P<0.001). Among the study groups, nine (22.5%) eyes showed anatomic response.

The CT was significantly thinner (P<0.001) at all measured points following anti-VEGF treatment ([Table 1]). There was a tendency for more thinning in the superior quadrants as compared with the other quadrants as 90% of the eyes showed decrease in the superior quadrant thickness (P=0.08).
Table 1 Choroidal thickness in different test points before and after injection

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There was a weak nonsignificant positive linear correlation between the change in subfoveal CT and the change in BCVA before and after injections (R=0.001, P=0.844).

No statistically significant difference was detected between the mean baseline subfoveal CT in the anatomic responder group and the nonresponder group (327±69.9 and 315.19±63.55 μm, respectively, P=0.364). However, there was a significant decrease in the mean subfoveal CT in the responder group as compared with the nonresponder group following treatment. The mean change was 49.68 and 21.43 μm, respectively (P=0.041, [Table 2]).
Table 2 Subfoveal choroidal thickness in anatomical responders and nonresponders groups

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Similarly, there was no statistically significant difference between the mean baseline subfoveal CT in the functional responder and nonresponder groups (330.41±54.23 and 300.85±84.67 μm, respectively; P=0.142). Again, a significant decrease occurred in the functional responder group following treatment (mean change was 49.68 μm compared with 21.43 μm in the nonresponder group; P=0.023, [Table 3]).
Table 3 Subfoveal choroidal thickness in functional responders and nonresponders groups

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  Discussion Top


This study assessed the effect of monthly intravitreal bevacizumab injection for 3 months on CT and the effect of these changes on the short-term outcome. Choroidal thickness was measured subfoveally, 500 and 1000 μm away from the fovea in the four cardinal directions to detect the points where the CT change mostly occurred to standardize a routine protocol of examination for these patients in the future and to avoid unnecessary lengthy procedures. A statistically significant decrease in CT was found in all examined points with a tendency of more thinning superiorly, which was statistically insignificant. The choroidal thinning after anti-VEGF treatment could be explained by blocking the VEGF trophic effect on choroidal vasculature previously proved by Kurihara et al. [13] who demonstrated loss of choriocapillaries after targeted deletion of VEGF in mice. Although choroidal thinning after anti-VEGF treatment was previously reported in different studies, the pathophysiological consequences of this thinning were not well investigated [10],[11],[14].

In the present study, patients were classified regarding their response to treatment into anatomic and functional responders and nonresponders to study the relationship between the choroidal thinning and the response to treatment. Both responders and nonresponders showed significant decline in CT after treatment. However, the responders (anatomical and functional) showed more significant thinning than the nonresponders. These results are consistent with what was reported by Rayess et al. [14]. However, contrary to their study, we could not find significant difference between both groups’ baseline CT as their report. Again, this might be owing to decreased VEGF burden with subsequent blockage of its effect on choroidal and retinal permeability. Despite that, this decrease in CT was not significantly correlated to the improvement in the BCVA. This can be explained by the presence of different confounding factors which contribute to the change in BCVA and macular thickness such as type and duration of macular edema, integrity of ellipsoid zone, and integrity of Muller’s fibers.

We suggest that choroidal thinning after intravitreal injection represents secondary nonspecific changes that differ in their pathophysiologic effect from those resulting from the diabetes mellitus itself, with no adverse effect on either the functional or anatomic outcome.

We recommend conducting a further study to evaluate the long-term effect of treatment on a larger sample size and to find out the importance of adding CT as a part of multimodal imaging in evaluating patients with DME.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Yau JW, Rogers SL, Kawasaki R, Lamoureux EL, Kowalski JW, Bek T et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012; 35:556–564.  Back to cited text no. 1
    
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Moss SE, Klein R, Klein BE. The 14-year incidence of visual loss in a diabetic population. Ophthalmology 1998; 105:998–1003.  Back to cited text no. 2
    
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Shiragami C, Shiraga F, Matsuo T, Tsuchida Y, Ohtsuki H. Risk factors for diabetic choroidopathy in patients with diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2002; 240:436–442.  Back to cited text no. 3
    
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Spaide RF, Koizumi H, Pozonni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008; 146:496–500.  Back to cited text no. 4
    
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Wong IY, Koizumi H, Lai WW. Enhanced depth imaging optical coherence tomography. Ophthalmic Surg Lasers Imaging 2011; 42:S75–S84.  Back to cited text no. 5
    
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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; 32:563–568.  Back to cited text no. 6
    
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Laíns I, Figueira J, Santos AR, Baltar A, Costa M, Nunes S et al. Choroidal thickness in diabetic retinopathy: the influence of antiangiogenic therapy. Retina 2014; 34:1199–1207.  Back to cited text no. 7
    
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El Ghonemy K, Rajab GZ, Ibrahim AM, Gohar IM. Comparison between choroidal thickness in patients with diabetic retinopathy and normal individuals using enhanced-depth imaging spectral-domain optical coherence tomography. Delta J Ophthalmol 2018; 19:53–57.  Back to cited text no. 8
    
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Hasan NA, Aldghaimy AH, Hamed MA, Eltaher AM. Correlation between choroidal thickness and central macular thickness measured by optical coherence tomography in nonproliferative diabetic retinopathy. Delta J Ophthalmol 2018; 19:201–204.  Back to cited text no. 9
  [Full text]  
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Kniggendorf VF, Novais EA, Kniggendorf SL, Xavier C, Cole ED, Regatieri CV. Effect of intravitreal anti-VEGF on choroidal thickness in patients with diabetic macular edema using spectral domain OCT. Arq Bras Oftalmol 2016; 79:155–158.  Back to cited text no. 10
    
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Yiu G, Manjunath V, Chiu SJ, Farsiu S, Mahmoud TH. Effect of anti-vascular endothelial growth factor therapy on choroidal thickness in diabetic macular edema. Am J Ophthalmol 2014; 158:745–751.  Back to cited text no. 11
    
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Sonoda S, Sakamoto T, Yamashita T, Otsuka H, Shirasawa M, Kakiuchi N et al. Effect of intravitreal triamcinolone acetonide or bevacizumab on choroidal thickness in eyes with diabetic macular edema. Invest Ophthalmol Vis Sci 2014; 55:3979–3985.  Back to cited text no. 12
    
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Kurihara T, Westenskow PD, Bravo S, Aguilar E, Friedlander M. Targeted deletion of VEGFa in adult mice induces vision loss. J Clin Invest 2012; 122:4213–4217.  Back to cited text no. 13
    
14.
Rayess N, Rahimy E, Ying GS, Bagheri N, Ho AC, Regillo CD et al. Baseline choroidal thickness as a predictor for response to anti-vascular endothelial growth factor therapy in diabetic macular edema. Am J Ophthalmol 2015; 159:85–91.e1-3.  Back to cited text no. 14
    


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  [Table 1], [Table 2], [Table 3]



 

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