J Korean Ophthalmol Soc JKOS Journal of the Korean Ophthalmological Society 0378-6471 2092-9374 The Korean Ophthalmological Society 10.3341/jkos.2017.58.12.1367 Original Article Factors Related to Refractory Macular Edema in Branch Retinal Vein Occlusion Park Ji Hyun MD Park Jung Min MD PhD Department of Ophthalmology, Maryknoll Medical Center, Busan, Korea. Address reprint requests to Jung Min Park, MD, PhD. Department of Ophthalmology, Maryknoll Medical Center, #121 Junggu-ro, Jung-gu, Busan 48972, Korea. Tel: 82-51-461-2540, Fax: 82-51-465-7470, pjm1438@hanmail.net 12 2017 14 12 2017 58 12 1367 1375 08 06 2017 13 11 2017 30 11 2017 ©2017 The Korean Ophthalmological Society 2017 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose

To evaluate the factors associated with refractory macular edema (ME) secondary to branch retinal vein occlusion (BRVO) after three times of intravitreal bevacizumab (IVB) injections.

 Methods

Ninety eyes of Ninety patients, who were retrospectively reviewed, were treated with IVB of 1.25 mg (0.05 mL) for ME secondary to BRVO, repeated three times at 4-week intervals and then followed-up for at least 4 months after the IVB. The patients were classified as refractory if there was an increase in the mean retinal thickness >150 µm when measured 1 month after the three injections. The patients were divided into two groups: a responsive group (46 eyes) and a refractory group (44 eyes).

 Results

In univariate logistic regression analyses, age, diabetes mellitus, hypertension, visual acuity, maximal combined response b wave amplitude (Max B amp), maximal combined response B/A ratio (Max B/A), cone response b wave amplitude, subfoveal choroidal thickness (SFCT), and the number of hyperreflective foci (HF) were risk factors for refractory ME of BRVO (p = 0.045, p = 0.010, p = 0.037, p = 0.034, p = 0.003, p = 0.004, p = 0.001, p = 0.001 and p = 0.001, respectively). In backward multivariate logistic regression analyses, age, Max B amp, Max B/A, SFCT and number of HF were risk factors for refractory ME of BRVO (p = 0.024, p = 0.004, p = 0.047, p = 0.033 and p = 0.049, respectively).

 Conclusions

Baseline age, Max B amp, Max B/A, SFCT and number of HF predicted the probability of refractory ME secondary to BRVO after IVB.

 Bevacizumab Branch retinal vein occlusion Electroretinogram Hyperreflective foci Subfoveal choroidal thickness

The authors have no conflicts to disclose.

 Ehlers JP Decroos FC Fekrat S Intravitreal bevacizumab for macular edema secondary to branch retinal vein occlusion Retina 2011 31 1856 1862 Rabena MD Pieramici DJ Castellarin AA Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to branch retinal vein occlusion Retina 2007 27 419 425 Prager F Michels S Kriechbaum K Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of prospective clinical trial Br J Ophthalmology 2009 93 452 456 Kohner EM Cappin JM Do medical conditions have an influence on central retinal vein occlusions? Proc R Soc Med 1974 67 1052 1054 Dodson PM Galton DJ Hamilton AM Blach RK Retinal vein occlusion and prevalence of lipoprotein abnormalities Br J Ophthalmol 1982 66 161 164 Lee YS Kim MS Yu SY Kwak HW Two-year results of intravitreal bevacizumab injection in retinal vein occlusion J Korean Ophthalmol Soc 2011 52 1039 1047 Karpe G The basis of clinical electroretinography Acta Ophthalmol Suppl 1945 24 1 118 Matsui Y Katsumi O Mehta MC Hirose T Correlation of electroretinogrphic and fluoresein angiographic findings in unilateral central retinal vein obstruction Graefes Arch Clin Exp Ophthalmol 1994 232 449 457 Kang KT Kim YC Kim KS Factors related to repeatability of intravitreal bevacizumab injections in branch retinal vein occlusion macular edema J Korean Ophthalmol Soc 2015 56 1580 1585 Schatz H Yannuzzi L Stransky TJ Retinal detachment secondary to branch vein occlusion: Part II Ann Ophthalmol 1976 8 1461 1471 Hoeh AE Ruppenstein M Ach T Dithmar S OCT patterns of macular edema and response to bevacizumab therapy in retinal vein occlusion Graefes Arch Clin Exp Ophthalmol 2010 248 1567 1572 Yuan A Ahmad BU Xu D Comparison of intravitreal ranibizumab and bevacizumab for the treatment of macular edema secondary to retinal vein occlusion Int J Ophthalmol 2014 7 86 91 Aiello LP Northrup JM Keyt BA Hypoxic regulation of vascular endothelial growth factor in retinal cells Arch Ophthalmol 1995 113 1538 1544 Tsuiki E Suzuma K Ueki R Enhanced depth imaging optical coherence tomography of the choroid in central retinal vein occlusion Am J Ophthalmol 2013 156 543 547.e1 Du KF Xu L Shao L Subfoveal choroidal thickness in retinal vein occlusion Ophthalmology 2013 120 2749 2750 Maharaj AS D'Amore PA Roles for VEGF in the adult Microvasc Res 2007 74 100 113 Saint-Geniez M Maldonado AE D'Amore PA VEGF expression and receptor activation in the choroid during development and in the adult Invest Ophthalmol Vis Sci 2006 47 3135 3142 Bolz M Schmidt-Erfurth U Deak G Optical coherence tomographic hyperreflective foci: a morphologic sign of lipid extravasation in diabetic macular edema Ophthalmology 2009 116 914 920 Coscas G De Benedetto U Coscas F Hyperreflective dots: a new spectral-domain optical coherence tomography entity for follow-up and prognosis in exudative age-related macular degeneration Ophthalmologica 2013 229 32 37 Lee HW Kim HC Correlation between visual outcomes and pre-treatment factors including hyperreflective foci in neovascular age-related macular degeneration J Korean Ophthalmol Soc 2015 56 1188 1194 Kang JW Lee HW Chung H Kim HC Correlation between optical coherence tomogrphic hyperreflective foci and visual outcomes after intravitreal bevacizumab for macular edema in branch retinal vein occlusion Graefes Arch Clin Exp Ophthalmol 2014 252 1413 1421 Horizontal sectional image of optical coherence tomography (OCT) in macular edema secodary to branch retinal vein occlusion. The OCT shows sparse exudates. Yellow arrow shows exudate smaller than 20 µm, blue arrows show exudates bigger than 40 µm and red arrows show exudates 20 µm to 40 µm, hyperreflective foci. Baseline characteristics of patients

Values are presented as mean ± SD or n (%) unless otherwise indicated. The patients were classified as refractory if there was an increase in the mean retinal thickness >150 µm when measured 1 month after the three injections. Baseline: At first visit. Group I: Responsive group, Group II: Refractory group.

DM = diabetes mellitus; HTN = hypertension; VA = visual acuity; SE = spherical equivalents.

*p < 0.05; †Mean ± standard deviation, Independent sample t-test p-value; ‡Chi-square test p-value.

 Comparison of baseline parameters of standard ERG and mean retinal thickness

Values are presented as mean ± SD unless otherwise indicated. The patients were classified as refractory if there was an increase in the mean retinal thickness >150 µm when measured 1 month after the three injections. Baseline: At first visit. Group I: Responsive group, Group II: Refractory group.

ERG = electroretinogram; Rod B amp = rod response b wave amplitude; Rod B/A = rod response B/A ratio; Max B amp = maximal combined response b wave amplitude; Max B/A = maximal combined response B/A ratio; OPs = average of oscillatory potentials; Cone B amp = cone response b wave amplitude; 30 HZ amp = 30 HZ flicker response amplitude; MRT = mean retinal thickness.

*p < 0.05; †Mean ± standard deviation, Independent sample t-test p-value.

 Comparison of subfoveal choroidal thickness, hyperreflective foci

Values are presented as mean ± SD unless otherwise indicated. The patients were classified as refractory if there was an increase in the mean retinal thickness >150 µm when measured 1 month after the three injections. Baseline: At first visit. IVB 3: When 1 month after 3 times of intravitreal bevacizumab injections. Group I: Responsive group, Group II: Refractory group.

SFCT = subfoveal choroidal thickness; No. of HF = number of hyperreflective foci; ELM = external limiting membrane; IS/OS = junction of inner and outer photoreceptor segments.

*p < 0.05; †Mean ± standard deviation, Independent sample t-test p-value; ‡Paired t-test p-value.

 Comparison of baseline hyperreflective foci, subretinal fluid

Values are presented as n (%) unless otherwise indicated. The patients were classified as refractory if there was an increase in the mean retinal thickness >150 µm when measured 1 month after the three injections. Baseline: At first visit. Group I: Responsive group, Group II: Refractory group.

No. of HF = number of hyperreflective foci; ELM = external limiting membrane; RPE = retinal pigment epithelium; NFL = nerve fiber layer; ONL = outer nuclear layer; No. of SRF = number of patients who have subretinal fluid; Yes = patients who have subretinal fluid; No = patients who don't have subretinal fluid.

*p < 0.05; †Chi-square test p-value.

 Comparison of position of hyperreflective foci in group I, II

Values are presented as n (%) unless otherwise indicated. The patients were classified as refractory if there was an increase in the mean retinal thickness >150 µm when measured 1 month after the three injections. Baseline: At first visit. IVB 3: When 1 month after 3 times of intravitreal bevacizumab injections. Group I: Responsive group, Group II: Refractory group.

ELM = external limiting membrane; RPE = retinal pigment epithelium; NFL = nerve fiber layer; ONL = outer nuclear layer.

*p < 0.05; †McNemar test p-value.

 Regression analyses of baseline characteristics for refractory macular edema secondary to branch retinal vein occlusion after 3 times of intravitreal bevacizumab injections

Baseline: At first visit.

OR = odds ratio; CI = confidence interval; DM = diabetes mellitus; HTN = hypertension; VA = visual acuity; SE = spherical equivalents; Rod B amp = rod response b wave amplitude; Rod B/A = rod response B/A ratio; Max B amp = maximal combined response b wave amplitude; Max B/A = maximal combined response B/A ratio; OPs = average of oscillatory potentials; Cone B amp = cone response b wave amplitude; 30 HZ amp = 30 HZ flicker response amplitude; MRT = mean retinal thickness; SFCT = subfoveal choroidal thickness; HF = hyperreflective foci; ORL = outer retinal layer (ELM-retinal pigment epithelium [RPE]); IRL = inner retinal layer (nerve fiber layer [NFL]-outer nuclear layer [ONL]); ELM = external limiting membrane; IS/OS = junction of inner and outer photoreceptor segments.

*p < 0.05; †Multivariate logistic regression analysis with backward method.