Current Eye Research, Early Online, 1–5, 2014 ! Informa Healthcare USA, Inc. ISSN: 0271-3683 print / 1460-2202 online DOI: 10.3109/02713683.2014.952827
RESEARCH REPORT
Bevacizumab Treatment for Acute Branch Retinal Vein Occlusion Accompanied by Subretinal Hemorrhage
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Lin Zhao*, Bingzhen Li*, Kang Feng, Liang Han, Zhizhong Ma and Yuling Liu Department of Ophthalmology, Peking University Third Hospital; Peking University Eye Center, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing, P.R. China
ABSTRACT Purpose: The purpose of this study was to compare the efficacy of intravitreal bevacizumab (IVB) in the treatment of acute (53 months [mo]. duration) macular edema (ME), with or without subretinal hemorrhage (SRH), resulting from branch retinal vein occlusion (BRVO). Materials and methods: We conducted a retrospective review of 33 consecutive patients (n = 33 eyes) with ME caused by acute BRVO. All patients received an injection of IVB at baseline examination. All patients were followed monthly, with administration of additional IVB injections if there was persistent or recurrent ME. Specific patterns of ME were investigated using spectral-domain optical coherence tomography (SD-OCT). Results: SD-OCT revealed serous retinal detachments in the fovea of 15 eyes, 10 of which had accompanying foveal SRH. Based on initial detection of foveal SRH, patients were divided into SRH-negative (n = 23 eyes) or SRH-positive (n = 10 eyes) groups. Initial best-corrected visual acuity (BCVA) did not differ between the two groups. In the SRH-negative group, both BCVA and central macular thickness (CMT) improved significantly after IVB injections (mean, 2.3 injections) at the 6-mo. follow-up examination. In the SRH-positive group, there was no significant improvement in BCVA after IVB injections (mean, 2.0 injections), although there was a significant decrease in CMT. The final BCVA of the SRH-positive group was significantly poorer than that of the SRH-negative group (p = 0.001). Conclusion: The presence of foveal SRH may be a negative predictor of IVB treatment outcomes for BRVO patients with ME. Keywords: Bevacizumab, branch retinal vein occlusion, macular edema, optical coherence tomography, subretinal hemorrhage
INTRODUCTION
optimal results following intravitreal bevacizumab (IVB) treatment. Spectral-domain optical coherence tomography (SD-OCT) is a useful tool for assessing and measuring changes in morphologic parameters, and a number of tomographic baseline characteristics have been considered as being possible prognostic factors for BRVO-induced ME.5–8 However, reports of BRVO-induced subretinal hemorrhage (SRH) are limited. The aim of the present study was to analyze
Branch retinal vein occlusion (BRVO) is a common retinal vascular disorder, with macular edema (ME) being the major resultant cause of associated visual loss. Numerous studies have reported an increase in the use of bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, for the treatment of BRVO patients.1–4 However, not all patients have
*These authors contributed equally to this work. Received 9 December 2013; revised 25 June 2014; accepted 3 August 2014; published online 20 October 2014 Correspondence: Yuling Liu, Department of Ophthalmology, Peking University Third Hospital, Peking University Eye Center, Key Laboratory of Vision Loss and Restoration, Ministry of Education, No. 49 North Garden Road, Haidian District, Beijing 100191, P.R. China. Tel/Fax: 0086 10 82265010. E-mail: [email protected]
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the impact and relationship of SRH on IVB treatment outcomes in BRVO patients.
MATERIALS AND METHODS
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Patients This retrospective research protocol was approved by the Institutional Review Board of Peking University Third Hospital, Beijing, China. All procedures conformed to the tenets of the Declaration of Helsinki. Enrolled in the study were 33 patients (17 women, 16 men) (n = 33 eyes) with BRVOinduced ME. All patients had received IVB treatment at the Medical Retina Service of the Department of Ophthalmology, Peking University Third Hospital, Beijing, between February 2012 and August 2013. The medical records of all enrolled patients were retrospectively analyzed. Inclusion criteria included (i) symptomatic BRVO, with retinal hemorrhage and retinal edema extending to the macula; (ii) duration of symptoms prior to initial examination of 512 weeks; (iii) best-corrected vision acuity (BCVA) of 0.3 log MAR units; (iv) central subfield macular thickness (CMT) as measured by SD-OCT of 4320 mm at baseline visit; and (v) a minimum follow-up of 6 months (mo) after the initial visit. Exclusion criteria included (i) clinically significant media opacity; (ii) retinal, optic disc, or iris neovascularization; (iii) any previous laser therapy or intravitreal injection of anti-angiogenic drugs or steroids; (iv) other macular diseases affecting central vision; (v) uncontrolled hypertension; (vi) any recent history of myocardial infarction; (vii) or cerebral vascular accident within the past 6 mo.
Clinical Parameters Baseline examination included a comprehensive ophthalmologic examination, including measurement of BCVA (as described in the Early Treatment Diabetic Retinopathy Study and converted to logMAR units), measurement if intraocular pressure (IOP), slit-lamp biomicroscopy, color fundus retinography, fluorescein angiography (Zeiss ff450), and spectral domain optical coherence tomography (SD-OCT) (SpectralisOCT, Heidelberg Engineering, Heidelberg, Germany). Using SD-OCT images, we accomplished quantitative measurements and morphologic evaluations of the fovea. CMT was recorded as the central 1-mm circle of the macular map generated by the regular macular thickness SD-OCT mapping protocol.9 Using these results, cystoid spaces, serous retinal detachments (SRDs), and subretinal hemorrhages (SRHs) of each patient were evaluated as being either within or
outside the foveal area. If foveal cystoid spaces were found, they were examined for the presence of hemorrhage. During the baseline visit, the study eye was prepared according to standard clinical practice for eyes undergoing intravitreal injections. IVB (1.25 mg/0.05 ml) was injected via the pars plana, 3.5 mm posterior to the limbus. The ability to count fingers was assessed 5 min after injection, and IOP was measured 60 min after injection. After the initial IVB treatment, all patients were scheduled for monthly follow-up visits, which included BCVA examination and SD-OCT analysis. At each visit, re-treatments were performed if there was any intraretinal or subretinal fluid, as determined by SD-OCT. After the acute phase of the BRVO was considered to have passed and any intraretinal hemorrhage had been largely resorbed, fluorescein angiography was undertaken to delineate any large segments of capillary non-perfusion. If any non-perfused areas were detected, grid laser was performed 1 week after the IVB. We hypothesized that age, sex, duration of symptoms prior to initial examination, initial BCVA, initial CMT, foveal cystoids, hemorrhage within foveal cystoid spaces, foveal sub-retinal detachments, and foveal SRH are factors relevant to increased BCVA (i.e. 15 ETDRS letters). All such signs were evaluated as independent variables in the main outcomes criteria, i.e. increase/no increase in BCVA 15 ETDRS letters after several injections.
Statistical Analysis An independent-samples t- test was used to determine if there was a statistical significance in the initial and final measurement values between two groups classified by initial detection of foveal SRH. Multiple logistic models were developed to estimate odds ratios (ORs) and 95% confidence intervals (CIs), using variables that had been determined by Univariate Analysis to be significant. The statistical level of significance was pre-set at p = 0.05. Data were analyzed using Version 17.0 SPSS statistical software (SPSS, Inc, Chicago, IL).
RESULTS About 33 patients (17 women, 16 men) enrolled in the study, n = 33 eyes; (21 OD, 11 OS), mean ages of 60.5 ± 9.1 (range, 40–76) years old). Table 1 shows initial measurements of all patients included in the study. At baseline visits, all eyes showed intra-retinal hemorrhage and ME. Mean CMT was 608.3 ± 205.6 mm (range, 342.0–1026.0). Of the 33 eyes, cystoid spaces Current Eye Research
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Bevacizumab for the Treatment of Acute BRVO 3 were seen in 27 eyes and foveal SRDs in 15 eyes. OCT sections revealed hemorrhagic foveal cystoid spaces in 15 of 27 (55.6%) eyes. Hemorrhage within these foveal cystoid spaces often created a niveau formation and sometimes appeared as amorphous hyper-reflectivity. Ten of the 15 eyes with foveal SRD had accompanying SRH within the sub-retinal spaces. Here, the SRHs appeared as either homogenous hyper-reflectivity or as amorphous mild-to-moderate hyper-reflectivity10 (Figure 1). At the final visit, BCVA had improved significantly, from 0.8 ± 0.3 to 0.4 ± 0.3 (p = 0.001), and the mean CMT had decreased from 608.3 ± 205.6 mm (range, 342.0–1026) to 335.0 ± 122.0 mm (range, 203.0–731.0; p = 0.001). Predictive factors associated with unfavorable outcomes, i.e. no increase in BCVA of 15 ETDRS letters, included presence of hemorrhage within the
foveal cystoid spaces (OR = 16.000, p = 0.003), SRD (OR = 7.500, p = 0.014), and SRH (OR = 60.000, p = 0.001) at initial examination (Table 2). The multiple logistic model we developed indicated that initial foveal SRH was closely correlated with an unfavorable outcome, i.e. no increase in BCVA of 15 ETDRS letters (OR = 36.700, p = 0.024) (Table 3). Patients were classified into one of two groups depending on whether or not foveal SRH was detected at the initial visit (Table 4). Although the initial BCVA, mean CMT, and final mean CMT did not differ between the two groups (p = 0.343, p = 0.186, p = 0.654, respectively), the final BCVA (0.7 ± 0.2) of the SRH-positive group was significantly poorer than that (0.4 ± 0.2) of the SRH-negative group (p = 0.001).
DISCUSSION TABLE 1. Initial and final conditions of eligible patients with branch retinal vein occlusion. Age (years) 60.5 ± 9.1 (40.0–76.0) Gender (women/men) 16 (48.5%)/17 (51.5%) Duration of symptom 5.9 ± 3.4 (2.0–12.0) until initial examination (weeks) Right eye/left eye 21 (63.6%)/12 (36.4%) Initial examination Visual acuity (logMAR) 0.8 ± 0.3 (0.3–1.5) Central subfield 608.3 ± 205.6 (342.0–1026.0) thickness (mm) Foveal cystoid spaces 27 (82%) Hemorrhage within foveal 15 (45.5%) cystoid spaces Foveal SRD 15 (45.5%) Foveal SRH 10 (30.3%) Final examination Visual acuity (logMAR) 0.4 ± 0.3 (0 to 1.0) Central subfield thickness (mm) 335.0 ± 122.0 (203.0–731.0) logMAR logarithm of the minimum angle of resolution, SRD serous retinal detachment, SRH subretinal hemorrhage.
Intra-retinal hemorrhage is a prominent feature of acute BRVO, although SRH is also not uncommon. Several recent studies have reported on the nature of SRHs and their clinical relevance.10–14 Using OCT, Muraoka et al. reported on 18 BRVO eyes with foveal SRH; these patients had poor final visual function. We observed 33 eyes with acute BRVO, 15 with hemorrhage in the foveal cystoid space, and 10 subfoveally. These baseline features were closely correlated with the final BCVA. The difference between our study and that of Muraoka is that all of our patients received IVB injections, while their patients were treated with laser photocoagulation or pars plana vitrectomy, or received no treatment. Serous macular neuroretinal detachment is another common tomographic feature of retinal vein occlusion. SRD has been reported to be a limiting factor for visual gain in cases of central retinal vein occlusion or BRVO.15,16 In our study, the 15 eyes with SRD at baseline had the worse visual prognosis. However, there was SRH in 10 of these eyes. In our opinion,
FIGURE 1. Left eye of a 64-year-old man with superior temporal branch retinal vein occlusion. (A). Color fundus photograph. (B). Confocal scanning laser ophthalmoscopy (cSLO) infrared (IR) fundus imaging. (C). Spectral-domain optical coherence tomography (SDOCT) cross-sectional horizontal image at baseline. Hemorrhage within foveal cystoid spaces indicated by long arrow. Subretinal hemorrhage marked with arrowhead. !
2014 Informa Healthcare USA, Inc.
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damages to retinal circulation that are associated with retinal vein occlusion may be related to SRH and SRD. If SRH and SRD exist simultaneously, it follows that the inner blood-retinal barrier (BRB) plays a significant role in SRD formation. Previous studies had reported that iron, in the form of ferritin, is the primary toxic agent released when there is SRH,17 and that increased iron in the photoreceptor outer segments exerts a toxic effect. In the current study, initial BCVA did not differ between the SRH-positive and SRH-negative groups. Foveal SRH may chronically damage the photoreceptor layer, thus leading to poor visual function even after resorption of the hemorrhage. Eyes with BRVO-induced macular ischemia have greater foveal thickness and poorer visual acuities.18 However, for the acute phase of the BRVO, it is difficult to differentiate between vascular perfusion/ non-perfusion status by fluorescein angiography,
TABLE 2. Univariate logistic analysis of final visual acuity (increase in BCVA 15 ETDRS letters or not)with measurement values obtained at initial examination.
because the extensive SRH blocks the view of the retinal vessels. Thus, SRH could be a confounding variable that masks a real association between perfusion status and visual outcome. The present study had several limitations, the most important one of which was the lack of a control group. Another limitation of this study included a sample pool that was somewhat small (33 cases) for the multiple logistic model, although it was large enough with respect to the three independent variables. In addition, the study compared SD-OCT images and BCVA only between baseline and final examinations. Finally, this study did not report monthly evaluations of patients during the 6-mo follow-up period. Despite these limitations, an important finding of this study is that foveal SRH is not uncommon in acute BRVO and is, conceivably, responsible for poor visual acuity even after resolution of retinal hemorrhage/retinal edema. Future prospective studies with larger sample sizes are needed to support the hypothesis that foveal SRH negatively affects final visual outcomes in acute BRVO patients. This study was conducted with the approval of Peking University Third Hospital Medical Ethics Committee.
95% CI p Value OR Lower Upper Age (years) Gender (women/men) Duration of symptom until initial examination (weeks) Right eye/left eye Initial examination Visual acuity (logMAR) Central subfield thickness (mm) Foveal cystoid spaces Hemorrhage within foveal cystoid spaces Foveal SRD Foveal SRH
0.722 0.895 0.161
0.9 1.1 0.8
0.9 1.0 0.2 4.5 0.6 1.0
0.224
2.5
0.5 10.9
0.115 0.462 0.106 0.003
7.0 0.9 0.2 16.0
0.6 0.9 0.0 2.5
0.014 0.001
7.5 60.0
1.4 37.6 5.4 658.7
80.3 1.0 1.3 98.7
BCVA best-corrected vision acuity, ETDRS Early Treatment Diabetic Retinopathy Study, IVB intravitreal bevacizumab, logMAR logarithm of the minimum angle of resolution, SRD serous retinal detachment, SRH subretinal hemorrhage.
TABLE 3. Risk factors for development of final visual acuity (increase in BCVA 15 ETDRS letters or not) with measurement values obtained at initial examination in Multivariate Logistic Model.
Hemorrhage within foveal cystoid spaces Foveal SRD Foveal SRH
p Value
OR
95% CI Lower Upper
0.6
2.0
0.1 37.1
0.9 0.0
0.9 36.7
0.1 14.6 1.6 842.3
BCVA best-corrected vision acuity, ETDRS Early Treatment Diabetic Retinopathy Study, IVB intravitreal bevacizumab, SRD serous retinal detachment, SRH subretinal hemorrhage.
TABLE 4. Comparisons of initial visual acuity and final measurement values between two groups classified by initial detection of foveal subretinal hemorrhage.
Age Duration of symptom until initial Examination (weeks) Times of injection Initial visual acuity (logMAR) Final visual acuity (logMAR) Initial central subfield thickness (mm) Final central subfield thickness (mm)
Initial SRH ( ) 23 eyes Mean ± SD
Initial SRH ( + ) 10 eyes Mean ± SD
p Value
61.2 ± 10.1
59.0 ± 6.6
0.537
5.4 ± 3.0 2.4 ± 0.6 0.9 ± 0.3 0.4 ± 0.2 576.8 ± 193.6 328.6 ± 123.4
7.2 ± 4.0 2.0 ± 0.5 0.7 ± 0.3 0.7 ± 0.2 680.8 ± 224.3 349.8 ± 123.8
0.148 0.083 0.343 0.001 0.186 0.654
logMAR logarithm of the minimum angle of resolution, SRH subretinal hemorrhage. Current Eye Research
Bevacizumab for the Treatment of Acute BRVO 5
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
AUTHOR’S CONTRIBUTIONS
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The first two authors (LZ and BL) contributed equally to this work. The experiment was conceived and designed by: LZ, BL, ZM and YL. The experiments were performed by: LZ, BL, and LH. The data were analyzed by: LZ, BL and KF. This paper was written by: LZ and BL.
REFERENCES 1. Gregori NZ, Rattan GH, Rosenfeld PJ, Puliafito CA, Feuer W, Flynn HJ, et al. Safety and efficacy of intravitreal bevacizumab (avastin) for the management of branch and hemiretinal vein occlusion. Retina 2009; 29:913–925. 2. Prager F, Michels S, Kriechbaum K, Georgopoulos M, Funk M, Geitzenauer W, et al. Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial. Br J Ophthalmol 2009;93:452–456. 3. Figueroa MS, Contreras I, Noval S, Arruabarrena C. Results of bevacizumab as the primary treatment for retinal vein occlusions. Br J Ophthalmol 2010;94:1052–1056. 4. Demir M, Oba E, Gulkilik G, Odabasi M, Ozdal E. Intravitreal bevacizumab for macular edema due to branch retinal vein occlusion: 12-month results. Clin Ophthalmol 2011;5:745–749. 5. Jaissle GB, Szurman P, Feltgen N, Spitzer B, Pielen A, Rehak M, et al. Predictive factors for functional improvement after intravitreal bevacizumab therapy for macular edema due to branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2011;249:183–192. 6. 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.
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7. Chung EJ, Hong YT, Lee SC, Kwon OW, Koh HJ. Prognostic factors for visual outcome after intravitreal bevacizumab for macular edema due to branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2008;246: 1241–1247. 8. Poon YC, Chen CH, Kuo HK, Chen YJ, Wu PC, Chen YH, et al. Clinical implications of serous retinal detachment in branch retinal vein occlusion and response after primary intravitreal bevacizumab injection. J Ocul Pharmacol Ther 2013;29:319–324. 9. Murakami T, Nishijima K, Sakamoto A, Ota M, Horii T, Yoshimura N. Foveal cystoid spaces are associated with enlarged foveal avascular zone and microaneurysms in diabetic macular edema. Ophthalmology 2011;118:359–367. 10. Muraoka Y, Tsujikawa A, Murakami T, Ogino K, Miyamoto K, Yoshimura N. Branch retinal vein occlusion-associated subretinal hemorrhage. Jpn J Ophthalmol 2013;57:275–282. 11. Rogers SL, Mcintosh RL, Lim L, Mitchell P, Cheung N, Kowalski JW, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1094–1101. 12. Spaide RF, Lee JK, Klancnik J, Gross NE. Optical coherence tomography of branch retinal vein occlusion. Retina 2003; 23:343–347. 13. Lerche RC, Schaudig U, Scholz F, Walter A, Richard G. Structural changes of the retina in retinal vein occlusion – imaging and quantification with optical coherence tomography. Ophthalmic Surg Lasers 2001;32:272–280. 14. Tsujikawa A, Sakamoto A, Ota M, Kotera Y, Oh H, Miyamoto K, et al. Serous retinal detachment associated with retinal vein occlusion. Am J Ophthalmol 2010;149: 291–301. 15. Cinal A, Ziemssen F, Bartz-Schmidt KU, Gelisken F. Intravitreal bevacizumab for treatment of serous macular detachment in central retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2011;249:513–520. 16. Gallego-Pinazo R, Dolz-Marco R, Pardo-Lopez D, Martinez-Castillo S, Lleo-Perez A, Arevalo JF, et al. Ranibizumab for serous macular detachment in branch retinal vein occlusions. Graefes Arch Clin Exp Ophthalmol 2013;251:9–14. 17. Steel DH, Sandhu S. Submacular haemorrhages associated with neovascular age-related macular degeneration. Br J Ophthalmol 2011;95:1051–1057. 18. Murakami T, Tsujikawa A, Miyamoto K, Sakamoto A, Ota M, Ogino K, et al. Relationship between perifoveal capillaries and pathomorphology in macular oedema associated with branch retinal vein occlusion. Eye (Lond) 2012;26:771–780.
RESEARCH REPORT
Bevacizumab Treatment for Acute Branch Retinal Vein Occlusion Accompanied by Subretinal Hemorrhage
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Lin Zhao*, Bingzhen Li*, Kang Feng, Liang Han, Zhizhong Ma and Yuling Liu Department of Ophthalmology, Peking University Third Hospital; Peking University Eye Center, Key Laboratory of Vision Loss and Restoration, Ministry of Education, Beijing, P.R. China
ABSTRACT Purpose: The purpose of this study was to compare the efficacy of intravitreal bevacizumab (IVB) in the treatment of acute (53 months [mo]. duration) macular edema (ME), with or without subretinal hemorrhage (SRH), resulting from branch retinal vein occlusion (BRVO). Materials and methods: We conducted a retrospective review of 33 consecutive patients (n = 33 eyes) with ME caused by acute BRVO. All patients received an injection of IVB at baseline examination. All patients were followed monthly, with administration of additional IVB injections if there was persistent or recurrent ME. Specific patterns of ME were investigated using spectral-domain optical coherence tomography (SD-OCT). Results: SD-OCT revealed serous retinal detachments in the fovea of 15 eyes, 10 of which had accompanying foveal SRH. Based on initial detection of foveal SRH, patients were divided into SRH-negative (n = 23 eyes) or SRH-positive (n = 10 eyes) groups. Initial best-corrected visual acuity (BCVA) did not differ between the two groups. In the SRH-negative group, both BCVA and central macular thickness (CMT) improved significantly after IVB injections (mean, 2.3 injections) at the 6-mo. follow-up examination. In the SRH-positive group, there was no significant improvement in BCVA after IVB injections (mean, 2.0 injections), although there was a significant decrease in CMT. The final BCVA of the SRH-positive group was significantly poorer than that of the SRH-negative group (p = 0.001). Conclusion: The presence of foveal SRH may be a negative predictor of IVB treatment outcomes for BRVO patients with ME. Keywords: Bevacizumab, branch retinal vein occlusion, macular edema, optical coherence tomography, subretinal hemorrhage
INTRODUCTION
optimal results following intravitreal bevacizumab (IVB) treatment. Spectral-domain optical coherence tomography (SD-OCT) is a useful tool for assessing and measuring changes in morphologic parameters, and a number of tomographic baseline characteristics have been considered as being possible prognostic factors for BRVO-induced ME.5–8 However, reports of BRVO-induced subretinal hemorrhage (SRH) are limited. The aim of the present study was to analyze
Branch retinal vein occlusion (BRVO) is a common retinal vascular disorder, with macular edema (ME) being the major resultant cause of associated visual loss. Numerous studies have reported an increase in the use of bevacizumab, an anti-vascular endothelial growth factor (VEGF) agent, for the treatment of BRVO patients.1–4 However, not all patients have
*These authors contributed equally to this work. Received 9 December 2013; revised 25 June 2014; accepted 3 August 2014; published online 20 October 2014 Correspondence: Yuling Liu, Department of Ophthalmology, Peking University Third Hospital, Peking University Eye Center, Key Laboratory of Vision Loss and Restoration, Ministry of Education, No. 49 North Garden Road, Haidian District, Beijing 100191, P.R. China. Tel/Fax: 0086 10 82265010. E-mail: [email protected]
1
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L. Zhao et al.
the impact and relationship of SRH on IVB treatment outcomes in BRVO patients.
MATERIALS AND METHODS
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Patients This retrospective research protocol was approved by the Institutional Review Board of Peking University Third Hospital, Beijing, China. All procedures conformed to the tenets of the Declaration of Helsinki. Enrolled in the study were 33 patients (17 women, 16 men) (n = 33 eyes) with BRVOinduced ME. All patients had received IVB treatment at the Medical Retina Service of the Department of Ophthalmology, Peking University Third Hospital, Beijing, between February 2012 and August 2013. The medical records of all enrolled patients were retrospectively analyzed. Inclusion criteria included (i) symptomatic BRVO, with retinal hemorrhage and retinal edema extending to the macula; (ii) duration of symptoms prior to initial examination of 512 weeks; (iii) best-corrected vision acuity (BCVA) of 0.3 log MAR units; (iv) central subfield macular thickness (CMT) as measured by SD-OCT of 4320 mm at baseline visit; and (v) a minimum follow-up of 6 months (mo) after the initial visit. Exclusion criteria included (i) clinically significant media opacity; (ii) retinal, optic disc, or iris neovascularization; (iii) any previous laser therapy or intravitreal injection of anti-angiogenic drugs or steroids; (iv) other macular diseases affecting central vision; (v) uncontrolled hypertension; (vi) any recent history of myocardial infarction; (vii) or cerebral vascular accident within the past 6 mo.
Clinical Parameters Baseline examination included a comprehensive ophthalmologic examination, including measurement of BCVA (as described in the Early Treatment Diabetic Retinopathy Study and converted to logMAR units), measurement if intraocular pressure (IOP), slit-lamp biomicroscopy, color fundus retinography, fluorescein angiography (Zeiss ff450), and spectral domain optical coherence tomography (SD-OCT) (SpectralisOCT, Heidelberg Engineering, Heidelberg, Germany). Using SD-OCT images, we accomplished quantitative measurements and morphologic evaluations of the fovea. CMT was recorded as the central 1-mm circle of the macular map generated by the regular macular thickness SD-OCT mapping protocol.9 Using these results, cystoid spaces, serous retinal detachments (SRDs), and subretinal hemorrhages (SRHs) of each patient were evaluated as being either within or
outside the foveal area. If foveal cystoid spaces were found, they were examined for the presence of hemorrhage. During the baseline visit, the study eye was prepared according to standard clinical practice for eyes undergoing intravitreal injections. IVB (1.25 mg/0.05 ml) was injected via the pars plana, 3.5 mm posterior to the limbus. The ability to count fingers was assessed 5 min after injection, and IOP was measured 60 min after injection. After the initial IVB treatment, all patients were scheduled for monthly follow-up visits, which included BCVA examination and SD-OCT analysis. At each visit, re-treatments were performed if there was any intraretinal or subretinal fluid, as determined by SD-OCT. After the acute phase of the BRVO was considered to have passed and any intraretinal hemorrhage had been largely resorbed, fluorescein angiography was undertaken to delineate any large segments of capillary non-perfusion. If any non-perfused areas were detected, grid laser was performed 1 week after the IVB. We hypothesized that age, sex, duration of symptoms prior to initial examination, initial BCVA, initial CMT, foveal cystoids, hemorrhage within foveal cystoid spaces, foveal sub-retinal detachments, and foveal SRH are factors relevant to increased BCVA (i.e. 15 ETDRS letters). All such signs were evaluated as independent variables in the main outcomes criteria, i.e. increase/no increase in BCVA 15 ETDRS letters after several injections.
Statistical Analysis An independent-samples t- test was used to determine if there was a statistical significance in the initial and final measurement values between two groups classified by initial detection of foveal SRH. Multiple logistic models were developed to estimate odds ratios (ORs) and 95% confidence intervals (CIs), using variables that had been determined by Univariate Analysis to be significant. The statistical level of significance was pre-set at p = 0.05. Data were analyzed using Version 17.0 SPSS statistical software (SPSS, Inc, Chicago, IL).
RESULTS About 33 patients (17 women, 16 men) enrolled in the study, n = 33 eyes; (21 OD, 11 OS), mean ages of 60.5 ± 9.1 (range, 40–76) years old). Table 1 shows initial measurements of all patients included in the study. At baseline visits, all eyes showed intra-retinal hemorrhage and ME. Mean CMT was 608.3 ± 205.6 mm (range, 342.0–1026.0). Of the 33 eyes, cystoid spaces Current Eye Research
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Bevacizumab for the Treatment of Acute BRVO 3 were seen in 27 eyes and foveal SRDs in 15 eyes. OCT sections revealed hemorrhagic foveal cystoid spaces in 15 of 27 (55.6%) eyes. Hemorrhage within these foveal cystoid spaces often created a niveau formation and sometimes appeared as amorphous hyper-reflectivity. Ten of the 15 eyes with foveal SRD had accompanying SRH within the sub-retinal spaces. Here, the SRHs appeared as either homogenous hyper-reflectivity or as amorphous mild-to-moderate hyper-reflectivity10 (Figure 1). At the final visit, BCVA had improved significantly, from 0.8 ± 0.3 to 0.4 ± 0.3 (p = 0.001), and the mean CMT had decreased from 608.3 ± 205.6 mm (range, 342.0–1026) to 335.0 ± 122.0 mm (range, 203.0–731.0; p = 0.001). Predictive factors associated with unfavorable outcomes, i.e. no increase in BCVA of 15 ETDRS letters, included presence of hemorrhage within the
foveal cystoid spaces (OR = 16.000, p = 0.003), SRD (OR = 7.500, p = 0.014), and SRH (OR = 60.000, p = 0.001) at initial examination (Table 2). The multiple logistic model we developed indicated that initial foveal SRH was closely correlated with an unfavorable outcome, i.e. no increase in BCVA of 15 ETDRS letters (OR = 36.700, p = 0.024) (Table 3). Patients were classified into one of two groups depending on whether or not foveal SRH was detected at the initial visit (Table 4). Although the initial BCVA, mean CMT, and final mean CMT did not differ between the two groups (p = 0.343, p = 0.186, p = 0.654, respectively), the final BCVA (0.7 ± 0.2) of the SRH-positive group was significantly poorer than that (0.4 ± 0.2) of the SRH-negative group (p = 0.001).
DISCUSSION TABLE 1. Initial and final conditions of eligible patients with branch retinal vein occlusion. Age (years) 60.5 ± 9.1 (40.0–76.0) Gender (women/men) 16 (48.5%)/17 (51.5%) Duration of symptom 5.9 ± 3.4 (2.0–12.0) until initial examination (weeks) Right eye/left eye 21 (63.6%)/12 (36.4%) Initial examination Visual acuity (logMAR) 0.8 ± 0.3 (0.3–1.5) Central subfield 608.3 ± 205.6 (342.0–1026.0) thickness (mm) Foveal cystoid spaces 27 (82%) Hemorrhage within foveal 15 (45.5%) cystoid spaces Foveal SRD 15 (45.5%) Foveal SRH 10 (30.3%) Final examination Visual acuity (logMAR) 0.4 ± 0.3 (0 to 1.0) Central subfield thickness (mm) 335.0 ± 122.0 (203.0–731.0) logMAR logarithm of the minimum angle of resolution, SRD serous retinal detachment, SRH subretinal hemorrhage.
Intra-retinal hemorrhage is a prominent feature of acute BRVO, although SRH is also not uncommon. Several recent studies have reported on the nature of SRHs and their clinical relevance.10–14 Using OCT, Muraoka et al. reported on 18 BRVO eyes with foveal SRH; these patients had poor final visual function. We observed 33 eyes with acute BRVO, 15 with hemorrhage in the foveal cystoid space, and 10 subfoveally. These baseline features were closely correlated with the final BCVA. The difference between our study and that of Muraoka is that all of our patients received IVB injections, while their patients were treated with laser photocoagulation or pars plana vitrectomy, or received no treatment. Serous macular neuroretinal detachment is another common tomographic feature of retinal vein occlusion. SRD has been reported to be a limiting factor for visual gain in cases of central retinal vein occlusion or BRVO.15,16 In our study, the 15 eyes with SRD at baseline had the worse visual prognosis. However, there was SRH in 10 of these eyes. In our opinion,
FIGURE 1. Left eye of a 64-year-old man with superior temporal branch retinal vein occlusion. (A). Color fundus photograph. (B). Confocal scanning laser ophthalmoscopy (cSLO) infrared (IR) fundus imaging. (C). Spectral-domain optical coherence tomography (SDOCT) cross-sectional horizontal image at baseline. Hemorrhage within foveal cystoid spaces indicated by long arrow. Subretinal hemorrhage marked with arrowhead. !
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4
L. Zhao et al.
damages to retinal circulation that are associated with retinal vein occlusion may be related to SRH and SRD. If SRH and SRD exist simultaneously, it follows that the inner blood-retinal barrier (BRB) plays a significant role in SRD formation. Previous studies had reported that iron, in the form of ferritin, is the primary toxic agent released when there is SRH,17 and that increased iron in the photoreceptor outer segments exerts a toxic effect. In the current study, initial BCVA did not differ between the SRH-positive and SRH-negative groups. Foveal SRH may chronically damage the photoreceptor layer, thus leading to poor visual function even after resorption of the hemorrhage. Eyes with BRVO-induced macular ischemia have greater foveal thickness and poorer visual acuities.18 However, for the acute phase of the BRVO, it is difficult to differentiate between vascular perfusion/ non-perfusion status by fluorescein angiography,
TABLE 2. Univariate logistic analysis of final visual acuity (increase in BCVA 15 ETDRS letters or not)with measurement values obtained at initial examination.
because the extensive SRH blocks the view of the retinal vessels. Thus, SRH could be a confounding variable that masks a real association between perfusion status and visual outcome. The present study had several limitations, the most important one of which was the lack of a control group. Another limitation of this study included a sample pool that was somewhat small (33 cases) for the multiple logistic model, although it was large enough with respect to the three independent variables. In addition, the study compared SD-OCT images and BCVA only between baseline and final examinations. Finally, this study did not report monthly evaluations of patients during the 6-mo follow-up period. Despite these limitations, an important finding of this study is that foveal SRH is not uncommon in acute BRVO and is, conceivably, responsible for poor visual acuity even after resolution of retinal hemorrhage/retinal edema. Future prospective studies with larger sample sizes are needed to support the hypothesis that foveal SRH negatively affects final visual outcomes in acute BRVO patients. This study was conducted with the approval of Peking University Third Hospital Medical Ethics Committee.
95% CI p Value OR Lower Upper Age (years) Gender (women/men) Duration of symptom until initial examination (weeks) Right eye/left eye Initial examination Visual acuity (logMAR) Central subfield thickness (mm) Foveal cystoid spaces Hemorrhage within foveal cystoid spaces Foveal SRD Foveal SRH
0.722 0.895 0.161
0.9 1.1 0.8
0.9 1.0 0.2 4.5 0.6 1.0
0.224
2.5
0.5 10.9
0.115 0.462 0.106 0.003
7.0 0.9 0.2 16.0
0.6 0.9 0.0 2.5
0.014 0.001
7.5 60.0
1.4 37.6 5.4 658.7
80.3 1.0 1.3 98.7
BCVA best-corrected vision acuity, ETDRS Early Treatment Diabetic Retinopathy Study, IVB intravitreal bevacizumab, logMAR logarithm of the minimum angle of resolution, SRD serous retinal detachment, SRH subretinal hemorrhage.
TABLE 3. Risk factors for development of final visual acuity (increase in BCVA 15 ETDRS letters or not) with measurement values obtained at initial examination in Multivariate Logistic Model.
Hemorrhage within foveal cystoid spaces Foveal SRD Foveal SRH
p Value
OR
95% CI Lower Upper
0.6
2.0
0.1 37.1
0.9 0.0
0.9 36.7
0.1 14.6 1.6 842.3
BCVA best-corrected vision acuity, ETDRS Early Treatment Diabetic Retinopathy Study, IVB intravitreal bevacizumab, SRD serous retinal detachment, SRH subretinal hemorrhage.
TABLE 4. Comparisons of initial visual acuity and final measurement values between two groups classified by initial detection of foveal subretinal hemorrhage.
Age Duration of symptom until initial Examination (weeks) Times of injection Initial visual acuity (logMAR) Final visual acuity (logMAR) Initial central subfield thickness (mm) Final central subfield thickness (mm)
Initial SRH ( ) 23 eyes Mean ± SD
Initial SRH ( + ) 10 eyes Mean ± SD
p Value
61.2 ± 10.1
59.0 ± 6.6
0.537
5.4 ± 3.0 2.4 ± 0.6 0.9 ± 0.3 0.4 ± 0.2 576.8 ± 193.6 328.6 ± 123.4
7.2 ± 4.0 2.0 ± 0.5 0.7 ± 0.3 0.7 ± 0.2 680.8 ± 224.3 349.8 ± 123.8
0.148 0.083 0.343 0.001 0.186 0.654
logMAR logarithm of the minimum angle of resolution, SRH subretinal hemorrhage. Current Eye Research
Bevacizumab for the Treatment of Acute BRVO 5
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
AUTHOR’S CONTRIBUTIONS
Curr Eye Res Downloaded from informahealthcare.com by Michigan University on 10/31/14 For personal use only.
The first two authors (LZ and BL) contributed equally to this work. The experiment was conceived and designed by: LZ, BL, ZM and YL. The experiments were performed by: LZ, BL, and LH. The data were analyzed by: LZ, BL and KF. This paper was written by: LZ and BL.
REFERENCES 1. Gregori NZ, Rattan GH, Rosenfeld PJ, Puliafito CA, Feuer W, Flynn HJ, et al. Safety and efficacy of intravitreal bevacizumab (avastin) for the management of branch and hemiretinal vein occlusion. Retina 2009; 29:913–925. 2. Prager F, Michels S, Kriechbaum K, Georgopoulos M, Funk M, Geitzenauer W, et al. Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial. Br J Ophthalmol 2009;93:452–456. 3. Figueroa MS, Contreras I, Noval S, Arruabarrena C. Results of bevacizumab as the primary treatment for retinal vein occlusions. Br J Ophthalmol 2010;94:1052–1056. 4. Demir M, Oba E, Gulkilik G, Odabasi M, Ozdal E. Intravitreal bevacizumab for macular edema due to branch retinal vein occlusion: 12-month results. Clin Ophthalmol 2011;5:745–749. 5. Jaissle GB, Szurman P, Feltgen N, Spitzer B, Pielen A, Rehak M, et al. Predictive factors for functional improvement after intravitreal bevacizumab therapy for macular edema due to branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2011;249:183–192. 6. 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.
!
2014 Informa Healthcare USA, Inc.
7. Chung EJ, Hong YT, Lee SC, Kwon OW, Koh HJ. Prognostic factors for visual outcome after intravitreal bevacizumab for macular edema due to branch retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2008;246: 1241–1247. 8. Poon YC, Chen CH, Kuo HK, Chen YJ, Wu PC, Chen YH, et al. Clinical implications of serous retinal detachment in branch retinal vein occlusion and response after primary intravitreal bevacizumab injection. J Ocul Pharmacol Ther 2013;29:319–324. 9. Murakami T, Nishijima K, Sakamoto A, Ota M, Horii T, Yoshimura N. Foveal cystoid spaces are associated with enlarged foveal avascular zone and microaneurysms in diabetic macular edema. Ophthalmology 2011;118:359–367. 10. Muraoka Y, Tsujikawa A, Murakami T, Ogino K, Miyamoto K, Yoshimura N. Branch retinal vein occlusion-associated subretinal hemorrhage. Jpn J Ophthalmol 2013;57:275–282. 11. Rogers SL, Mcintosh RL, Lim L, Mitchell P, Cheung N, Kowalski JW, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1094–1101. 12. Spaide RF, Lee JK, Klancnik J, Gross NE. Optical coherence tomography of branch retinal vein occlusion. Retina 2003; 23:343–347. 13. Lerche RC, Schaudig U, Scholz F, Walter A, Richard G. Structural changes of the retina in retinal vein occlusion – imaging and quantification with optical coherence tomography. Ophthalmic Surg Lasers 2001;32:272–280. 14. Tsujikawa A, Sakamoto A, Ota M, Kotera Y, Oh H, Miyamoto K, et al. Serous retinal detachment associated with retinal vein occlusion. Am J Ophthalmol 2010;149: 291–301. 15. Cinal A, Ziemssen F, Bartz-Schmidt KU, Gelisken F. Intravitreal bevacizumab for treatment of serous macular detachment in central retinal vein occlusion. Graefes Arch Clin Exp Ophthalmol 2011;249:513–520. 16. Gallego-Pinazo R, Dolz-Marco R, Pardo-Lopez D, Martinez-Castillo S, Lleo-Perez A, Arevalo JF, et al. Ranibizumab for serous macular detachment in branch retinal vein occlusions. Graefes Arch Clin Exp Ophthalmol 2013;251:9–14. 17. Steel DH, Sandhu S. Submacular haemorrhages associated with neovascular age-related macular degeneration. Br J Ophthalmol 2011;95:1051–1057. 18. Murakami T, Tsujikawa A, Miyamoto K, Sakamoto A, Ota M, Ogino K, et al. Relationship between perifoveal capillaries and pathomorphology in macular oedema associated with branch retinal vein occlusion. Eye (Lond) 2012;26:771–780.
