CHOROIDAL VOLUME IN BRANCH RETINAL VEIN OCCLUSION BEFORE AND AFTER INTRAVITREAL ANTI-VEGF INJECTION YOUNG-KWON CHUNG, MD, JUNG-AH SHIN, MD, YOUNG-HOON PARK, MD, PHD Purpose: The aim of this study is to evaluate the subfoveal choroidal volume change in the patients with branch retinal vein occlusion before and after intravitreal anti-vascular endothelial growth factor injection using the enhanced depth imaging optical coherence tomography. Methods: We measured the bilateral subfoveal choroidal volume in 15 patients (mean age, 64.47 ± 7.13 years) with unilateral branch retinal vein occlusion by using the enhanced depth imaging methods of the Spectralis optical coherence tomography system. After an injection of intravitreal bevacizumab, we measured the subfoveal choroidal volume of the eye with regressed macular edema. Results: The mean subfoveal choroidal volume measured in 15 eligible eyes of 15 patients was 7.74 ± 0.70 mm3, which was significantly greater than the volume of the fellow eyes (6.38 ± 0.69 mm3; P = 0.001, Wilcoxon signed-rank test). The subfoveal choroidal volume of the eye with regressed macular edema was 6.56 ± 0.79 mm3, which was significantly lower than the volume before the treatment (P = 0.001, Wilcoxon signed-rank test). Conclusion: The subfoveal choroidal volume of the branch retinal vein occlusion eyes was significantly greater than the volume of the fellow eyes and decreased significantly after an intravitreal anti-vascular endothelial growth factor treatment. RETINA 35:1234–1239, 2015

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formed thickness measurement only in selected, usually subfoveal multiple single points of the macula. The volumetric analysis of the choroid is a novel manual segmentation technique using built-in, automated retinal segmentation software with enhanced depth imaging optical coherence tomography (EDI-OCT) using Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany). The choroidal volume measurement is highly reproducible and repeatable and is being used more frequently in ongoing studies.7 There is no report on the choroidal volume in retinal vein occlusion. The aim of this study is to measure and compare the choroidal volume in the eyes with BRVO and unaffected fellow eyes, and to measure the changes before and after an intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection.

etinal vein occlusion is one of the common causes of the retinal vascular disease.1–4 Patients with branch retinal vein occlusion (BRVO) present with a blurred vision or a field defect and a segmentally distributed intraretinal hemorrhage. Not only the hemorrhage in the macula but also macular edema may reduce the visual acuity. If there is little or no leakage on fluorescein angiography, macular ischemia because of vein occlusion may be the cause of macular edema. There are studies that demonstrate the correlation between retinal vein occlusion and choroidal thickness.5,6 However, there is a controversy over whether the correlation exists or not. These past studies perFrom the Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, South Korea. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Young-Hoon Park, MD, PhD, Department of Ophthalmology and Visual Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea #222 Banpo-daero, Seocho-gu, Seoul 137-701, Republic of Korea; e-mail: [email protected]

Methods The study was performed in adherence with the guidelines of the declaration of Helsinki and Good 1234

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Clinical Practice. The research activities were reviewed and approved by the Institutional Review Board of The Catholic University, Korea. A retrospective analysis was performed on 15 patients with newly diagnosed unilateral BRVO who were examined at our retinal outpatient department in the Seoul St. Mary’s Hospital from February 2010 to May 2013. The examination for the diagnosis of BRVO included slit-lamp biomicroscopy with a contact or a noncontact lens, fundus photography, macular OCT (Spectralis SD-OCT; Heidelberg Engineering, Heidelberg, Germany), and fluorescein angiography (Heidelberg Retinal Angiography; Heidelberg Engineering, Heidelberg, Germany). The patients with macular edema and decreased visual acuity were treated with a single intravitreal bevacizumab 1.25 mg/0.05 mL (Avastin; Genentech/Roche, San Francisco, CA) injection. The subfoveal choroidal volume was measured by Spectralis SD-OCT using the EDI technique. We gained 25 scan images from each examination and analyzed them with Heidelberg Eye Explorer Software (Heidelberg Engineering, Heidelberg, Germany). We moved the automated retinal segmentation line to the choroidal segmentation line making the dots at the internal limiting membrane line to move to the retinal pigmentation epithelium line and the dots at the retinal pigmentation line to the chorioscleral interface line. The choroidal volume in the Early Treatment Diabetic Retinopathy Study circle 6 mm was calculated by built-in software (Figure 1). To minimize the bias by inspectors, one ophthalmologist set the boundaries of the retinal pigment epithelium and the choroid and moved the segmentation points by himself. The subfoveal choroidal volume was measured again 4 weeks after the intravitreal bevacizumab injection. To figure out the difference between RVO in the superior area and that of the inferior area, the choroidal volume of the superior area was measured at the uppermost part in the Early Treatment Diabetic Retinopathy Study circle, whereas choroidal volume of inferior area was measured at the lowest part in the Early Treatment Diabetic Retinopathy Study

(Figure 2). We also measured the retinal thickness before and after the injection in the BRVO eye. The inclusion criteria were the newly diagnosed unilateral BRVO with macular edema involved in the superior or inferior arcade. To exclude the cases whose subfoveal choroids were not affected from the cramped area of retinal vein occlusion or the peripherality of the lesions, we included only the cases with the nonperfusion area over 5 disk diameters in fluorescein angiography. The exclusion criteria were a history of any other retinal disease, best-corrected visual acuity of the fellow eye under 16/20, anisometropia with .2 diopters (D) of a cylindrical and/or 4 D of a spherical refractive error, an intraocular pressure reading $22 mmHg, glaucomatous findings (optic disk change, retinal nerve fiber layer loss, visual field defect), and a history of previous intraocular surgery of laser therapy. Visual acuity was measured by decimal equivalents and logMAR equivalents. After the automated retinal layer segmentation software was disabled, choroidal segmentation was performed manually. An ophthalmologist observer moved the hyperreflective reference lines from the retinal pigment epithelium boundaries to the boundary of the scleral inner surface and moved the internal limiting membrane line to the retinal pigment epithelium line (Figure 1). After the movement of the boundaries, the choroidal volume could be measured by the automated built-in software. The data analysis was performed using the Statistical Package for the Social Sciences (Version 20; SPSS Inc, Chicago, IL). Measurements of the choroidal volume were analyzed using the Wilcoxon signed-rank test. For all tests, we considered P , 0.05 to be significant. Results There were 15 patients with unilateral BRVO. The mean age was 64.47 ± 7.13 years (range, 54–76 years). There were 5 male patients (33.33%) and 10 female patients (66.66%). Eleven patients had systemic diseases, 10 (66.66%) had hypertension, and 5 (33.33%)

Fig. 1. Enhanced depth imaging SD-OCT raster scan protocol (A), manual choroidal segmentation (B), standardized grid on the ETDRS circle (C), and average thickness and volume in the ETDRS circle 1, 3, 6 mm (D). ETDRS, Early Treatment Diabetic Retinopathy Study; SD-OCT, spectral domain optical coherence tomography.

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Fig. 2. The uppermost part (A, blue) and the lowest part (B, red) in the Early Treatment Diabetic Retinopathy Study circle.

had diabetes mellitus without retinopathy. The average duration from onset was 4.98 ± 4.59 months. The best-corrected visual acuity of all the patients was 0.51 ± 0.34 logMAR. Thirteen patients were treated with an intravitreal anti-VEGF injection to decrease macular edema and the subfoveal choroidal volume (Table 1). The best-corrected visual acuity of the patients treated with an anti-VEGF injection was 0.57 ± 0.33 logMAR before the treatment and 0.40 ± 0.26 logMAR after the treatment (Figure 3). There was a significant difference between the best-corrected visual acuity before and after the injection (P = 0.022, Wilcoxon signed-rank test). The baseline demographic and clinical characteristics of the BRVO eyes and fellow eyes are reported in Table 1. The retinal thickness before injection was 490 ± 167.40 mm, and it reduced to 306.53 ± 74.91 mm after the injection (P = 0.003 [Wilcoxon signed-rank test]). However, there is no significant correlation between the retinal thickness before the injection and the choroidal volume before the injection (r = 0.071, P = 0.817). No significant correlation was noted between the retinal thickness after the injection and the choroidal thickness after the injection (r = 0.115, P = 0.717). Compared with fellow eyes, the BRVO eyes showed significantly greater subfoveal choroidal volume (P = 0.001, Wilcoxon signed-rank test). The subfoveal choroidal volume was 7.74 ± 0.70 mm3 in the BRVO eyes and 6.38 ± 0.69 mm3 in the fellow eyes (Table 2). Figure 5 shows the EDI-OCT images of the choroid of 1 eye with BRVO and that of the unaffected fellow eye. In 13 patients with macula edema and decreased visual acuity, the subfoveal choroidal volume before the intravitreal bevacizumab therapy was significantly greater than that after the therapy (P = 0.001, Wilcoxon signed-rank test). The subfoveal choroidal volume in the BRVO eyes was 7.70 ± 0.75 mm3 before an intravitreal injection and 6.56 ± 0.79 mm3 after the intravitreal injection (Table 2, Figure 4). There was no significant difference between the

Fig. 3. Retinal vein occlusion eye (A), after anti-VEGF injection (B), fellow eye (C).

BRVO eyes after an injection (6.56 ± 0.79 mm3) and the fellow eyes (6.38 ± 0.69 mm3, P = 0.081, Wilcoxon signed-rank test). The choroidal volume of the superior area was 1.56 ± 0.32 mm3, whereas that of the inferior area was 1.36 ± 0.31 mm3. The choroidal volume of the superior or inferior area that involved with RVO was 1.49 ± 0.31 mm3, whereas the normal area was 1.43 ± 0.35 mm3. No significant difference was noted between the former and the latter (P = 0.683, Mann–Whitney U test). The duration from onset has no significant correlation with the retinal thickness before the injection (rho = 0.252, P = 0.385), the retinal thickness (rho = 0.002, P = 0.994), the choroidal volume before the injection (rho = 0.078, P = 0.791), the choroidal

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CHOROIDAL VOLUME IN BRVO  CHUNG ET AL Table 1. Baseline Demographic and Clinical Characteristics of the BRVO and Fellow Eyes

Case

Sex

Age (years)

Best-corrected Visual Acuity (logMAR)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Mean

M F F F F F M F M F F M M F F

55 56 61 76 68 65 61 76 68 54 63 74 59 66 65 64.47 ± 7.13

1.2 0.6 0.5 1.1 0.5 0.1 0.4 0.2 0.3 0.2 1.0 0.6 0.3 0.5 0.2 0.51 ± 0.34

Visual Acuity After a Single Anti-VEGF Injection 0.5 0.2 0.4 1.0 0.2 — 0.3 0.4 0.3 0.0 0.8 0.5 0.4 0.2 — 0.40 ± 0.26

Macular Edema

Systemic Disease

+ + + + + + + + + + + + + + +

HBP — HBP DM HBP HBP — DM, HBP — HBP, hyperlipidemia HBP HBP DM, HBP HBP —

Values are expressed as mean ± standard deviation. DM, diabetes mellitus; HBP, high blood pressure; logMAR, logarithm of the minimal angle of resolution equivalent.

volume after the injection (rho = 0.207, P = 0.518), and the fellow eye (rho = 0.140, P = 0.632) (Spearman’s rank correlation test).

Discussion Since Spaide et al8 described the EDI mode of the OCT for visualizing the choroid, an increasing number of studies have examined the choroidal thickness, its associated factors in normal eyes, and the eyes with various, retinal retinochoroidal disorders. Subsequently, the subfoveal choroidal thickness of patients with various diseases, such as central serous chorioretinopathy,9–11 macular hole,12 age-related macular degeneration,4,13–15 high myopia,16,17 and Vogt–Koyanagi–Harada disease,18 has been reported. There are ongoing studies examining the subfoveal choroidal thickness of patients with retinal vein occlusion. The subfoveal choroidal thickness of the BRVO eyes was significantly greater than that of the fellow eyes. It decreased after the intravitreal bevacizumab treatment in a retrospective study of patients with central retinal vein occlusion.19 A large study on the subfoveal choroidal thickness in retinal vein occlusion5 is in progress. The choroidal volume imaging can be analyzed manually and is very time-consuming. An automated choroidal volume analysis methodology has been developed, but it is neither generalized nor available commercially.6 For such reasons, few studies of the choroidal volume analysis in choroidal disease have been published. Notably, no choroidal volume study in RVO patients has been published.

The BRVO eye showed a significantly greater choroidal volume (P = 0.001). Tsuiki et al19 have suggested that hyperpermeability and VEGF expression after retinal hypoxia cause fluid collection and increase ocular blood flow, which results in the choroidal volume expansion. Because of the tissue hypoxia after the occlusion of the retinal vein, VEGF expression increases in the inner retina. Inducing vessel dilation and increasing ocular blood flow by the production of nitric oxide, VEGF expression has an effect on both the outer retina and the choroid.20–22 We postulate that there is a likelihood of the hypothesis of Tsuiki et al explaining this observation. The hypothesis of Tsuiki et al explains this phenomenon not only in patients with central retinal vein occlusion but also in BRVO patients. The choroidal volume after an intravitreal injection was significantly lower than that before the injection. However, there was no significant difference between the choroidal volume in the BRVO-affected eye and the fellow eye. Suppose both eyes have the same choroidal volume before the occlusion of the retinal vein, this means that the choroidal volume can be recovered to the normal volume as if it had no retinal vein occlusion. The choroidal blood flow accounts for 70% of the whole ocular blood flow to satisfy more than the outer retina and the choroid normally demand.23,24 This is the reason why choroidal hypoxic damage rarely occurs. This result supports that the VEGF expression or nitric oxide production from retinal hypoxic damage causes the choroidal volume expansion without the choroidal damage. An

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429 383 362 171 262 295 317 324 256 209 296 288 258 211 356 294.47 ± 70.25

378 195 238 149 165 304 224 327 174 255 300 334 272 237 274 255.07 ± 66.92



842 472 470 585 282 349 752 574 512 460 419 381 289 332 680 493.27 ± 167.36

337 233 432 187 256 — 279 344 282 450 258 335 267 325 — 306.54 ± 74.91

Inf Sup Inf Inf Sup Inf Inf Inf Sup Sup Sup Inf Sup Inf Sup

Fig. 4. A comparison of the subfoveal choroidal volume between the BRVO eyes and fellow eyes.

Values are expressed as mean ± standard deviation. Inf, inferior; Sup, superior.

2 months 2 weeks 3 months 1 year 1 year 1 week 2 months 10 months 2 months 1 year 3 months 7 months unknown 3 months 1 months 4.98 ± 4.59 months 7.39 6.22 6.4 5.18 6.65 — 7.8 6.89 5.56 6.3 6.95 6.10 7.77 6.09 — 6.56 ± 0.79 7.55 5.42 6.67 5.98 6.34 6.21 7.43 6.37 5.33 5.77 6.23 5.97 6.84 6.12 7.44 6.38 ± 0.69

Onset Case

1 8.77 2 7.69 3 7.83 4 6.14 5 8.22 6 7.94 7 8.24 8 8.08 9 7.54 10 8.33 11 7.77 12 6.43 13 7.89 14 7.12 15 8.10 Mean 7.74 ± 0.70

Superior Choroidal Thickness (mm) Location of RVO Lesion Retinal Thickness After Bevacizumab Injection (mm) Retinal Thickness (mm) After a Single Bevacizumab Injection (mm3) Fellow Eye (mm3) The Eye With BRVO (mm3)

Table 2. The Volume of the Fellow Eyes and the BRVO Eye, Before and After the Bevacizumab Treatment

Inferior Choroidal Thickness (mm)

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immediate intravitreal anti-VEGF injection can solve the problem of choroidal volume changes by suppressing only the activity of VEGF. No significant difference was noted between the choroidal volume of the superior or inferior area that involved with RVO, and that of the normal area. It shows that ischemia influences not only the choroid volume right beneath the local lesion but also that in the surrounding area. The produced VEGF does not remain local but spread around. The choroidal volume results in this study are lower than those observed in another study (normal choroidal volume: 8.678.79 mm3).7 The age difference of the patients causes the difference between the studies. Although the mean age of patients in our study was 64.47 ± 7.13 years, it was approximately 44 years in the other study. The difference in their racial distribution is another possible reason. All the patients in our study were Asians; those of the other study were nearly exclusively white (81%). This study has several limitations. The first is a small sample size caused by a long analysis time. Selection bias could occur as a result of choosing a small group. The second is the short-term follow-up. As the

Fig. 5. A comparison of the subfoveal choroidal volume both before and 4 weeks after the bevacizumab injection.

CHOROIDAL VOLUME IN BRVO  CHUNG ET AL

analysis took a long time to be done, we could not follow it up for a long period. There were measurement errors in the volume analysis because we used a manual technique. It is important that the novel volume analysis is more accurate than the preexisting choroidal thickness analysis technique. After an automated choroidal volume analysis software is developed in the near future, further studies should be performed on a large number of subjects. The factors which are known to have interactions with the choroidal volume, such as age, axial length, refractive error, and sex, must be considered in further studies. In conclusion, the subfoveal choroidal volume of the BRVO eyes was significantly greater than that of the fellow eyes and decreased significantly after an intravitreal bevacizumab treatment. We can expect that EDI-OCT and the choroidal volume measurement technique could be used to evaluate the chorioretinal diseases and could be helpful in their treatment or the estimation of their severity. Key words: branch retinal vein occlusion, retinal vein occlusion, choroidal volume, choroidal thickness, enhanced depth imaging, optical coherence tomography, bevacizumab, anti-vascular endothelial growth factor. References 1. The Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984;98:271–282. 2. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. A randomized clinical trial. Branch Vein Occlusion Study Group. Arch Ophthalmol 1986;104:34–41. 3. Shilling JS, Jones CA. Retinal branch vein occlusion: a study of argon laser photocoagulation in the treatment of macular oedema. Br J Ophthalmol 1984;68:196–198. 4. Spaide RF. Enhanced depth imaging optical coherence tomography of retinal pigment epithelial detachment in age-related macular degeneration. Am J Ophthalmol 2009;147:644–652. 5. Du KF, Xu L, Shao L, et al. Subfoveal choroidal thickness in retinal vein occlusion. Ophthalmology 2013;120:2749–2750. 6. Zhang L, Lee K, Niemeijer M, et al. Automated segmentation of the choroid from clinical Sd-Oct. Invest Ophthalmol Vis Sci 2012;53:7510–7519. 7. Chhablani J, Barteselli G, Wang H, et al. Repeatability and reproducibility of manual choroidal volume measurements using enhanced depth imaging optical coherence tomography. Invest Ophthalmol Vis Sci 2012;53:2274–2280.

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8. Spaide RF, Koizumi H, Pozzoni MC. Enhanced depth imaging spectral-domain optical coherence tomography. Am J Ophthalmol 2008;146:496–500. 9. Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina 2009;29: 1469–1473. 10. Maruko I, Iida T, Sugano Y, et al. One-year choroidal thickness results after photodynamic therapy for central serous chorioretinopathy. Retina 2011;31:1921–1927. 11. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness in fellow eyes of patients with central serous chorioretinopathy. Retina 2011;31:1603–1608. 12. Reibaldi M, Boscia F, Avitabile T, et al. Enhanced depth imaging optical coherence tomography of the choroid in idiopathic macular hole: a cross-sectional prospective study. Am J Ophthalmol 2011;151:112–117. 13. Chung SE, Kang SW, Lee JH, Kim YT, Choroidal thickness in polypoidal choroidal vasculopathy and exudative age-related macular degeneration. Ophthalmology 2011;118:840–845. 14. Koizumi H, Yamagishi T, Yamazaki T, et al. Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2011;249:1123–1128. 15. Maruko I, Iida T, Sugano Y, et al. Subfoveal retinal and choroidal thickness after verteporfin photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2011; 151:594–603. 16. Fujiwara T, Imamura Y, Margolis R, et al. Enhanced depth imaging optical coherence tomography of the choroid in highly myopic eyes. Am J Ophthalmol 2009;148:445–450. 17. Rogers SL, Mcintosh RL, Lim L, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1094–1101. 18. Maruko I, Iida T, Sugano Y, et al. Subfoveal choroidal thickness after treatment of Vogt-Koyanagi-Harada disease. Retina 2011;31:510–517. 19. Tsuiki E, Suzuma K, Ueki R, et al. Enhanced depth imaging optical coherence tomography of the choroid in central retinal vein occlusion. Am J Ophthalmol 2013;156:543–547. 20. Tilton RG, Chang KC, Lejeune WS, et al. Role for nitric oxide in the hyperpermeability and hemodynamic changes induced by intravenous VEGF. Invest Ophthalmol Vis Sci 1999;40: 689–696. 21. Ku DD, Zaleski JK, Liu S, Brock TA, Vascular endothelial growth factor Induces Edrf-dependent relaxation in coronary arteries. Am J Physiol 1993;265:586–592. 22. Aiello LP, Northrup JM, Keyt BA, et al. Hypoxic regulation of vascular endothelial growth factor in retinal cells. Arch Ophthalmol 1995;113:1538–1544. 23. Linsenmeier RA, Padnick-Silver L. Metabolic dependence of photoreceptors on the choroid in the normal and detached retina. Invest Ophthalmol Vis Sci 2000;41:3117–3123. 24. Nickla DL, Wallman J. The multifunctional choroid. Prog Retin Eye Res 2010;29:144–168.

Choroidal volume in branch retinal vein occlusion before and after intravitreal anti-VEGF injection.

The aim of this study is to evaluate the subfoveal choroidal volume change in the patients with branch retinal vein occlusion before and after intravi...
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