Int Ophthalmol DOI 10.1007/s10792-015-0066-6
ORIGINAL PAPER
Clinical, anatomical, and electrophysiological assessments of the central retina following intravitreal bevacizumab for macular edema secondary to retinal vein occlusion Eleni Loukianou • Dimitrios Brouzas • Klio Chatzistefanou • Chrysanthi Koutsandrea
Received: 18 December 2014 / Accepted: 23 March 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract The purpose of this study is to evaluate the long-term visual, anatomical and electrophysiological outcomes of repeated intravitreal injections of bevacizumab for macular edema due to retinal vein occlusion (RVO) and investigate any possible toxic effects on the central fovea. This is a prospective, noncomparative, interventional case series. Thirtythree eyes of 33 patients with macular edema secondary to RVO were treated with 1.25 mg/0.05 ml intravitreal bevacizumab. Nine patients had nonischemic central retinal vein occlusion (CRVO) and 24 patients had branch retinal vein occlusion (BRVO). The main outcome measures were best-corrected visual acuity, central retinal thickness (CRT), and multifocal electroretinography (mfERG) responses changes at baseline, 1 month after the third injection and at the end of the 2-year long follow-up period. Patients with CRVO had mean best-corrected Snellen visual acuity of 0.10 at baseline, which improved significantly to 0.31 after 2 years (P = 0. 028).The mean CRT at presentation was 756.28 lm and reduced significantly to 439.14 lm after 2 years (P = 0.05).
Patients with BRVO had mean best-corrected Snellen visual acuity of 0.19 at baseline, which improved significantly to 0.40 after 2 years (P \ 0.001). The mean CRT at presentation was 681.04 lm and reduced significantly to 369.81 lm after 2 years (P \ 0.001). Mean mfERG responses within central 10° (ring1, ring2) showed statistically significant differences on P1 parameters in terms of response density and implicit time after 2 years in both CRVO and BRVO patients. Repeated intravitreal bevacizumab injections for macular edema due to either CRVO or BRVO resulted in long-term improvement of visual acuity, a reduction in CRT and statistically significant changes in the mfERG responses with nondemonstrable toxic effects on the central fovea. Keywords Bevacizumab Macular edema Retinal vein occlusion Optical coherence tomography Multifocal electroretinography
Introduction E. Loukianou D. Brouzas K. Chatzistefanou C. Koutsandrea Department of Ophthalmology, University of Athens, Athens, Greece E. Loukianou (&) 100 Petrou Tsirou st., 3076 Limassol, Cyprus e-mail: [email protected]
Retinal vein occlusion (RVO) is the second most common cause of visual impairment due to retinal vascular disease after diabetic retinopathy [1, 2]. Branch retinal vein occlusion (BRVO) occurs 2–3 times more often than central retinal vein occlusion (CRVO) [3, 4]. It is currently estimated from pooled data that there are about 520 new cases of RVO per
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million of population, of which 440 BRVO cases and 80 CRVO cases [5]. RVO is associated with increased levels of intraocular vascular endothelial growth factor (VEGF), which vary with disease severity [6]. Increased levels of VEGF may lead to macular edema which is a major sight-threatening complication of RVO [7]. Beneficial treatment options for macular edema complicating RVOs include grid macular laser treatment (for BRVO), intravitreal injections of triamcinolone and dexamethasone, and most recently intravitreal anti-VEGF agents. According to Branch Vein Occlusion Study, patients with BRVO-associated edema and visual acuity of 20/40 or less showed statistically significant benefit when treated with macular grid laser compared with untreated patients [8]. On the contrary, patients with CRVO-associated macular edema did not show any significant benefit when treated with macular grid laser [9]. The efficacy of intravitreal triamcinolone was investigated in several studies which showed a visual acuity improvement, although there were significant side effects such as increased intraocular pressure (IOP) and cataract formation [10]. Similarly, intravitreal dexamethasone implant improved the visual acuity in patients with macular edema secondary to BRVO and CRVO [11]. Finally, several studies revealed the benefit of antiVEGF agents such as pegaptanib sodium, ranibizumab, bevacizumab, and recently aflibercept in patients with macular edema associated with BRVO and CRVO [12–15]. Bevacizumab (Avastin; Genentech) is a full-length monoclonal humanized antibody to all active isoforms of VEGF [16]. It is used off-label in many countries for the treatment of many retinal diseases and their complications including macular edema secondary to branch or CRVOs. In our study, we investigate the long-term visual, anatomic, and electrophysiologic responses of the central retina after repeated intravitreal bevacizumab injections for macular edema complicating RVO and also any possible toxic effect on the central fovea. In previous studies, Pai et al. evaluated the clinical, anatomic, and electrophysiologic responses after a single intravitreal injection of 1.25 mg of bevacizumab for macular edema secondary to RVO in a short-term study [17], and Shetty et al. found no measurable photoreceptor toxicity following intravitreal bevacizumab for macular edema based on fullfield electroretinography and mfERG recordings in the short term [18].
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Materials and methods From January 2008 until May 2010, all consecutive RVO cases presenting at the medical retinal department of our clinic were evaluated for inclusion in the study. Inclusion criteria were macular edema evident on clinical examination, confirmed by fluorescein angiography and optical coherence tomography (OCT) with central retinal thickness (CRT) greater than 350 lm and duration of RVO less than 6 months. Exclusion criteria were previously treated macular edema, ocular pathology like dense cataract and central corneal opacities and systemic diseases such as diabetes mellitus and renal failure that independently influence the results of the study. All cases that were included in the study were followed prospectively for 2 years. All the participants underwent thorough ophthalmic examination including best-corrected Snellen visual acuity (BCVA, decimal scale) assessment, IOP measurement with applanation tonometry, slit lamp biomicroscopy, CRT measurement by OCT, and functional evaluation of the central 10° of the macula at baseline and on follow-up visits every 6 weeks for a period of 2 years. The function of the macula could be elucidated by measurements of the retinal nerve fiber layer thickness and macular ganglion cell-inner plexiform layer thickness by spectral domain OCT or by microperimetric evaluation but in our clinic, we only have access to time domain OCT and electroretinography so we evaluated the function of the central 10° by multifocal electroretinography (mfERG). Fluorescein angiography was performed in all patients at baseline and then every 6 months unless it was suggested earlier from the examining team. Three intravitreal injections of 1.25 mg/0.05 ml bevacizumab were administered under aseptic conditions in the operating theater every 6 weeks. Patients were reinjected if there was visual acuity deterioration more than one line of Snellen optotype attributable to recurrent macular edema, if the central foveal thickness was [250 lm, and if there were cystic spaces in the macula even if the central foveal thickness was \250 lm. CRT was measured using Stratus OCT, Carl Zeiss Meditec, Dublin California, USA. All the eyes were scanned in a radial spoke pattern that was centered at the foveola, with a scan length of 6 mm. The participants were asked to gaze at the fixation light within the machine, and the foveolar fixation was
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confirmed by observing the retina through the infrared monitoring camera. The CRT was calculated as the distance between the vitreoretinal interface and the anterior surface of retinal pigment epithelium. Multifocal ERG recordings were performed using the EP-1000 model (Tomey, Nagoya, Japan), and mfERG recording parameters were in accordance with ISCEV standards [19]. The mfERG responses were recorded using a pseudorandom m-sequence with a stimulus matrix of 61 scaled hexagonal elements displayed on a cathode ray tube color monitor driven at a frame of 75 Hz. A field size of 27.7° was assessed. The P1 component of the first-order kernel of the mfERG from two concentric rings centered on the fovea (ring 1: 0°–5°, ring 2: 5°–10°) was averaged, and the data recorded included density and implicit time of response for every ring. The mean response density of P1 amplitude at ring 1 (RD1), the mean response density of P1 amplitude at ring 2 (RD2), the mean implicit time of P1 amplitude at ring 1 (IT1), and the mean implicit time of P1 amplitude at ring 2 (IT2) were studied at baseline, 1 month after the third injection, and at the end of the 2-year follow-up period. The statistical analysis was performed using SPSS, Inc, Chicago, IL (version 19). Due to the longitudinal design and the non-independence of the observations, the ANOVA for repeated measures with Bonferroni corrections was used to compare data before treatment with those obtained 1 month after the third injection and also baseline values with data at the end of the 2-year follow-up period. We also compared data 1 month after the third injection with values at the end of the 2-year followup period. A P value of 0.05 or less was considered statistically significant. All patients signed an informed consent to participate in the study. The study was conducted in accordance with the tenets of Helsinki and the requirements of the hospital Ethical Committee.
Results Thirty-three eyes of 33 patients were included in the study. There were 18 female (54.54 %) and 15 male (45.46 %) patients. The patient age ranged from 44 to 83 years. Nine patients had nonischemic CRVO, and 24 patients had BRVO.
The mean durations of the CRVO and BRVO on entry to the study were 20 and 22 weeks, respectively. Especially in the BRVO group, we were waiting for at least 3 months for spontaneous resolution of macular edema, and if the edema was persistent, the patients were included to the study. The mean number of injections during the 2-year follow-up period was nine injections per eye in both CRVO and BRVO groups. Last follow-up examination was performed 1 month after the last bevacizumab injection. Demographic characteristics are displayed in Table 1. All patients received three intravitreal injections of bevacizumab at the beginning, 6 weeks, apart. After the third injection, we observed recurrence of macular edema in eight patients with nonischemic CRVO (88.88 %) and in nineteen patients with BRVO (79.16 %). Six patients with macular edema due to CRVO (66.66 %) and thirteen patients with macular edema due to BRVO (54.16 %) needed continuous injections at constant time intervals. In patients who did not show a complete resolution of macular edema despite continuous treatment, we did not increase at a higher dose of the anti-VEGF agent and we continued with the same dose of 1.25 mg/0.05 ml intravitreal bevacizumab. Four patients exited the study after the third injection. One of these patients was lost to follow up, two of them were dissatisfied because of minimal improvement in visual acuity (0.005 and 0.1, respectively) and decided to discontinue the treatment, and one patient moved to another country and was lost to follow-up. Reinjections were administered according to the retreatment criteria described in methods section.
Table 1 Demographic characteristics of the patients at baseline Patient demographics CRVO
BRVO
Number of patients
9
24
Age
70.7 ± 10.05
63.7 ± 11.49
Sex (male/female)
5M/4F
10M/14F
Duration of occlusion (weeks)
20 ± 3
22 ± 3
Values are n or mean ± SD (standard deviation) CRVO central retinal vein occlusion, BRVO branch retinal vein occlusion
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Safety During the 2-year follow-up period, no severe ocular side effects such as retinal tears, retinal detachments, traumatic cataracts, vitreous hemorrhages, uveitis, or endophthalmitis were observed. Similarly, no severe systemic adverse events such as thromboembolic events, systemic hypertension, or kidney failure were reported. Angle, iris, optic disk, or retinal neovascularization was not observed in any of the study eyes. Clinical examination and fluorescein angiography revealed development of collateral vessels in 31 eyes. Two patients developed a lamellar macular hole during the treatment and had a final visual acuity of 0.5 and 0.7, respectively. One patient experienced diplopia after the third injection. The orthoptic evaluation showed limitation of abduction consistent with paralysis of the lateral rectus muscle of the injected eye. Further work-up for systemic causes of abducens palsy, including brain MRI, was unremarkable. There were no signs of resolution of abducens paralysis throughout the follow-up period.
Subgroup analysis
tested at the three time points of measurement (baseline, 1 month after the third injection and after 2 years) are shown in Table 2. The results after the Bonferroni-corrected pairwise comparisons for each analysis are shown in Table 3. In summary, the results for each characteristic in the CRVO group are as below: BCVA In the nonischemic CRVO group, mean baseline visual acuity was 0.10 (SD = 0. 08) which improved to mean 0.24 (SD = 0. 14) 1 month after the third injection and to 0.31 (SD = 0.18) after 2 years. There was a general significant increase in the level of BCVA from baseline to 1 month after the third injection (P = 0.033) as well as from baseline to the end of follow-up (P = 0.028). On the contrary, the difference in visual acuity from 1 month after the third
Table 2 Descriptives for all characteristics at the three time points (baseline, after the third injection, and after 2 years) in CRVO patients; n = 7 Characteristics
Mean
SD
BCVA_baseline
0.107
0.089
Patients with non-ischemic CRVO had mean BCVA of 0.10 at baseline which improved significantly to 0.31 after 2 years (P = 0.028). Patients with BRVO had mean BCVA of 0.19 at baseline which improved significantly to 0.40 after 2 years (P \ 0.001). The mean CRT in CRVO group at presentation was 756.28 lm and reduced significantly to 439.14 lm after 2 years (P = 0.05). The mean CRT in BRVO group at presentation was 681.04 lm and reduced significantly to 369.81 lm after 2 years (P \ 0.001). According to these results, the patients with macular edema complicating BRVO showed a better response to intravitreal bevacizumab injections compared to CRVO patients with greater improvement of BCVA and greater reduction of CRT. The results in details in each group are shown below.
BCVA_third injection
0.243
0.140
BCVA_2 years
0.314
0.186
CRT_baseline
756.286
118.840
CRT_third injection
513.857
137.540
CRT_2 years
439.143
95.244
RD1_baseline
67.000
25.794
RD1_third injection
92.714
26.631
RD1_2 years
102.571
32.979
RD2_baseline
54.800
15.515
RD2_third injection
71.200
19.186
RD2_2 years IT1_baseline
74.086 45.300
17.607 4.426
IT1_third injection
41.971
3.225
CRVO group
BCVA best-corrected visual acuity, CRT central retinal thickness, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2, SD standard deviation
Descriptives (mean, standard deviation) for each of the parameters (BCVA, CRT, RD1, RD2, IT1, and IT2)
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IT1_2 years
39.314
3.414
IT2_baseline
52.343
2.893
IT2_third injection
46.843
4.843
IT2_2 years
46.543
5.707
Int Ophthalmol Table 3 Multiple comparisons with Bonferroni corrections— CRVO group
RD1
Characteristics
Time
BCVA
1–2
-0.136*
1–3
-0.207*
0.028
2–3
0.029
0.140
The mean RD1 changed from 67.00 nV/deg2 (SD = 25.79) to 92.71 nV/deg2 (SD = 26.63) 1 month after the third injection and to 102.57 nV/deg2 (SD = 32.97) after 2 years. The difference from baseline was statistically significant 1 month after the third injection (P = 0.002) or at the end of the follow up period. (P = 0.003). The difference from 1 month after the third injection to the end of the 2-year follow-up period was not statistically significant (P = 0.215).
CRT
RD1
RD2
IT1
IT2
Mean difference
P values 0.033
1–2
242.429*
0.001
1–3
317.143*
0.005
2–3
42.219
0.382 0.002
1–2
-25.714*
1–3
-35.571*
0.003
2–3
-9.857
0.215
1–2
-16.400*
\0.001
1–3
-19.286*
\0.001
2–3
-2.886
0.369
1–2
3.329*
0.004
1–3
5.986*
0.018
2–3 1–2
2.657 5.500*
0.190 0.005
1–3
5.800*
0.049
2–3
0.300
1.000
* The mean difference is significant Time 1, baseline; time 2, after the third injection; time 3, after 2 years BCVA best-corrected visual acuity, CRT central retinal thickness, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2
injection to the end of the 2-year follow-up period was not statistically significant (P = 0.140).
CRT The mean CRT was reduced from 756.28 lm (SD = 118.84) at baseline to 513.85 lm (SD = 137.54) 1 month after the third intravitreal bevacizumab injection and to 439.14 lm (SD = 95.24) after 2 years. The difference of either post-treatment time points (1 month after the third injection, end of 2-year follow-up period) from baseline was statistically significant (P = 0.001and P = 0.005, respectively). On the contrary, the difference in CRT 1 month after the third injection compared to the end of the 2-year follow-up period was not statistically significant (P = 0.382).
RD2 The mean RD2 changed from 54.80 nV/deg2 (SD = 15.51) to 71.20 nV/deg2 (SD = 19.18) 1 month after the third injection to 74.08 nV/deg2 (SD = 17.60) after 2 years. A statistically significant difference was observed from baseline and 1 month after the third injection (P \ 0.001) and from baseline to the end of the follow-up period. (P \ 0.001). The difference from 1 month after the third injection to the end of the 2-year follow-up period was not statistically significant (P = 0.369). IT1 The mean IT1 was 45.30 ms (SD = 4.42) at baseline and 41.97 ms (SD = 3.22) 1 month after the third injection. The difference was statistically significant (P = 0.004). At the end of the follow-up period, the mean implicit time of P1 was 39.31 (SD = 3.41) and the difference from baseline was also statistically significant (P = 0.018). The difference from 1 month after the third injection to the end of the 2-year followup period was not statistically significant. (P = 0.190). IT2 The mean implicit time of P1 response at ring 2 was 52.34 ms (SD = 2.89) at baseline, 46.84 ms (SD = 4.84) 1 month after the third injection, and 46.54 (SD = 5.70) at the end of the follow-up period. The difference of either post-treatment time points (1 month after the third injection, end of 2-year follow-up period) from baseline was statistically significant (P = 0.005 and P = 0.049, respectively). On the contrary, the difference from 1 month after the
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Int Ophthalmol Fig. 1 Profile plots for BCVA and CRT in CRVO group. Follow up period 1 = baseline, follow up period 2 = 1 month after the third injection, follow up period 3 = after 2 years, BCVA best corrected visual acuity, CRT central retinal thickness, CRVO central retinal vein occlusion
third injection to the end of the 2-year follow-up period was not statistically significant (P = 1.000). Profile plots for BCVA and CRT are shown in Fig. 1 and for RD1, RD2, IT1, and IT2 are shown in Fig. 2. The mean IOP was 18 mmHg at baseline and remained within normal limits during the 2-year long follow-up period.
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BRVO group Descriptives (mean, standard deviation) for each of the parameters (BCVA, CRT, RD1, RD2, IT1, and IT2) tested at the three time points of measurement (baseline, 1 month after the third injection and after 2 years) are shown in Table 4.
Int Ophthalmol Fig. 2 Profile plots for RD1, RD2, IT1, and IT2 in CRVO group. Follow up period 1 = baseline, follow up period 2 = 1 month fter the third injection, follow up period 3 = after 2 years, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2
The results after the Bonferroni-corrected pairwise comparisons for each analysis are shown in Table 5. In summary, the results for each characteristic in the BRVO group are as below: BCVA The mean baseline visual acuity was 0.19 (SD = 0.16) and improved to 0.38 (SD = 0.35) 1 month after the
third injection and to 0.40 (SD = 0.35) at 2 years. The difference in visual acuity from baseline compared to visual acuity 1 month after the third injection (P = 0.001) as well as from baseline to the end of follow-up (P = 0 \ 0.001) was statistically significant. On the contrary, the difference in visual acuity from 1 month after the third injection to the end of the 2-year follow-up period was not statistically significant (P = 0.288).
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Int Ophthalmol Fig. 2 continued
CRT The mean CRT was reduced from 681.04 lm (SD = 226.45) at baseline to 381.45 lm (SD = 100.15) 1 month after the third intravitreal bevacizumab injection and to 369.81 lm (SD = 114.83) after 2 years. The difference of either post-treatment time
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points (1 month after the third injection, end of 2-year follow-up period) from baseline was statistically significant (P \ 0.0001 and P \ 0.0001, respectively). On the contrary, the difference in CRT from 1 month after the third injection to the end of the follow-up period was not statistically significant (P = 1.0000).
Int Ophthalmol Table 4 Descriptives for all characteristics at the three time points (baseline, after the third injection, and after 2 years) in BRVO patients; n = 22 Characteristics
Mean
Table 5 Multiple comparisons with Bonferroni corrections— BRVO group Characteristics
Time
BCVA
Mean difference
P values
SD 1–2
-0.191*
0.001
BCVA_baseline
0.193
0.161
1–3
-0.214*
\0.001
BCVA_third injection
0.384
0.359
2–3
-0.023
BCVA_2 years
0.407
0.352
1–2
299.591*
\0.001
CRT_baseline
681.045
226.458
1–3
311.227*
\0.001
CRT_third injection
381.454
100.156
2–3
11.636
1.000
CRT_2 years
369.818
114.838
1–2
-7.273
0.535
RD1_baseline
94.545
32.951
1–3
-14.136*
0.048
RD1_third injection
101.818
18.466
2–3
-6.864*
0.002
RD1_2 years
108.682
19.529
1–2
-9.123*
\0.001
RD2_baseline
74.854
16.233
1–3
-13.262*
\0.001
RD2_third injection RD2_2 years
83.977 88.116
14.889 14.720
2–3
-4.139*
\0.001
1–2
2.945*
\0.001
IT1_baseline
41.186
3.785
1–3
3.573*
0.001
IT1_third injection
38.241
3.830
IT1_2 years
37.614
3.972
2–3 1–2
0.627 4.041*
1.000 \0.001
CRT
RD1
RD2
IT1
IT2
0.288
IT2_baseline
52.932
7.000
1–3
6.264*
\0.001
IT2_third injection
48.891
6.900
2–3
2.223*
\0.001
IT2_2 years
46.668
6.424
BCVA best-corrected visual acuity, CRT central retinal thickness, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2, SD standard deviation
RD1 The mean RD1 changed from 94.54 nV/deg2 (SD = 32.95) to 101.81 nV/deg2 (SD = 18.46) 1 month after the third injection and to 108.68 nV/deg2 (SD = 19.52) after 2 years. The difference from baseline to 1 month after the third injection was not statistically significant (P = 0.535).On the contrary, the difference from baseline to the end of the follow-up period and from 1 month after the third injection to the end of the 2-year follow-up period was statistically significant (P = 0.048 and P = 0.002, respectively). RD2 The mean RD2 changed from 74.85 nV/deg2 (SD = 16.23) to 83.97 nV/deg2 (SD = 14.88) 1 month after the third injection and to 88.11 nV/deg2 (SD = 14.72) after 2 years. The difference was statistically
* The mean difference is significant Time 1 = baseline, Time 2 = after the third injection, Time 3 = after 2 years BCVA best-corrected visual acuity, CRT central retinal thickness, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2
significant from baseline to 1 month after the third injection (P \ 0.001) and from baseline to the end of the follow-up period (P \ 0.001) and also from 1 month after the third injection to the end of the 2-year follow-up period. (P \ 0.001). IT1 The mean IT1 was 41.18 ms (SD = 3.78) at presentation and 38.24 ms (SD = 3.83) 1 month after the third injection. The difference was statistically significant (P \ 0.001). At the end of the follow-up period, the mean implicit time of P1 was 37.61 (SD = 3.97) which was statistically different from baseline (P = 0.001). The difference from 1 month after the third injection to the end of the 2-year followup period was not statistically significant (P = 1.000).
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Int Ophthalmol Fig. 3 Profile plots for BCVA and CRT in BRVO group. Follow up period 1 = baseline, follow up period 2 = 1 month after the third injection, follow up period 3 = after 2 years, BCVA best corrected visual acuity, CRT central retinal thickness, BRVO branch retinal vein occlusion
IT2 The mean implicit time of P1 response at ring 2 was 52.93 ms (SD = 7.00) at baseline, 48.89 ms (SD =
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6.90) 1 month after the third injection, and 46.66 (SD = 6.42) at the end of the follow-up period. The difference of either post-treatment time points (1 month after the third injection, end of 2-year follow-up period)
Int Ophthalmol Fig. 4 Profile plots for RD1, RD2, IT1, and IT2 in BRVO group. Follow up period 1 = baseline, follow up period 2 = 1 month after the third injection, follow up period 3 = after 2 years, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2, BRVO branch retinal vein occlusion
from baseline was statistically significant (P \ 0.001). The difference from 1 month after the third injection to the end of the 2-year follow-up period was also statistically significant (P \ 0.001). Profile plots for BCVA and CRT are shown in Fig. 3 and for RD1, RD2, IT1, and IT2 are shown in Fig. 4.
The mean IOP was 17 mmHg at baseline and remained within normal limits during the study. Figure 5a–d show the OCT scans of a 67-year-old male with macular edema due to BRVO at presentation and during the follow-up period after four bevacizumab injections.
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Int Ophthalmol Fig. 4 continued
Also, Fig. 6a–i show mfERG responses in ring 1 and 2 of the same patient.
Discussion Macular edema is the main sight-threatening complication of RVO [8, 20]. The natural history of CRVO as
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reported by the Central Vein Occlusion Study (CVOS) Group shows a generally poor visual outcome [21, 22]. Loss of visual acuity is usually more pronounced with ischemic than with nonischemic CRVO, although vision also tends to be poor in eyes with the nonischemic type [23]. The Branch Vein Occlusion Study (BVOS) reported that 20 % of untreated eyes experienced significant visual deterioration over time.
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Fig. 5 The OCT scans of a 67-year-old patient with macular edema due to BRVO treated with intravitreal bevacizumab injections. We can observe the gradual resolution of the edema over time (a baseline, b 1 month after the first bevacizumab
injection, c 1 month after the third bevacizumab injection, and d after 2 years) and the reduction in central retinal thickness as documented by optical coherence tomography during the 2-year follow-up period
Approximately 50 % of untreated eyes with BRVO retained a VA of 6/12 or better, while in 25 % of cases, final VA was less than 6/60 [12, 24]. Treatment options include grid laser treatment (for BRVO), intravitreal injection of steroids, surgical procedures, and, most recently, treatment with intravitreal antiVEGF agents. Gregori et al. first reported on the longterm effectiveness of intravitreal bevacizumab in fiftyseven eyes with macular edema due to CRVO. In their study, visual acuity improved by a mean of 14 letters (P = 0.001) at 1 month, 13 letters at 3 months (P = 0.001), nine letters at 6 months (P = 0.001), and nine letters at 12 months (P = 0.004), and the mean OCT thickness decreased by 299 lm at 1 month (P = 0.001), 144 lm at 3 months, (P = 0.001), 127 lm at 6 months (P = 0.011), and 276 lm at 12 months (P = 0.001) [25]. The mean (range) number of injections at 1, 3, 6, and 12 months was 1.4 (1–2), 2.1 (1–4), 2.7 (1–5), and 3.2 (1–6), respectively. Rabena et al. showed anatomic and visual acuity improvements and lack of serious adverse side effects after intravitreal bevacizumab in 27 consecutive patients with macular edema secondary to BRVO after a mean of two injections per patient (range 1–3 injections) and a mean follow-up period of 5.3 months.They noted improvement in mean visual acuity from
20/200 at baseline to 20/100 at 1 month and 20/100 at 3 months and last follow-up (P = 0.001). The mean central macular thickness was 478 lm at baseline and decreased to 310, 336, and 332 lm at 1 month, 3 months, and last follow-up examination, respectively (P = 0.001) [26]. Ehlers et al. postulated that early treatment (within 6 months) resulted in a greater improvement in visual acuity compared with delayed treatment [27]. Hsu et al. concluded that intravitreal bevacizumab was beneficial in patients with macular edema associated with CRVO but the benefits were not sustained without repeated injections. In their study, thirty eyes of 29 patients had intravitreal bevacizumab injections and the mean follow-up was 18.1 weeks. No significant changes in visual acuity were found 4 months after the last injection, and worsening visual acuity occurred in all cases by 5 months after the most recent injection [28]. Our noncomparative prospective, interventional study investigated the long-term effectiveness of repeated intravitreal injections of bevacizumab when initiated relatively early in the course of macular edema related to nonischemic CRVO and BRVO. The median duration of the RVO on entry to the study was less than 6 months in both groups. We chose to
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Fig. 6 The mf ERG responses of the central retina of the patient in Fig. 1 on presentation (a–c), after the three injections (d– f) and at the end of the second year (g–i). The mean mfERG responses in every ring are documented (a, d, g). In the central two rings (ring 1, ring 2), we can see the gradual increase of P1
wave (nV/deg2) and the gradual improvement of the implicit time (ms) over time, which were statistically insignificant. The mfERG traces are recorded (c, f, i), and the mfERG responses are shown in 3D graphs (b, e, h) also
compare the visual and anatomic parameters at baseline in each group (CRVO, BRVO) with their respective values 1 month after the three intravitreal bevacizumab injections which resulted in a maximal response in most of the cases and also with the values at the end of the follow-up period to investigate if the maximal achievable response was sustainable for up to 2 years with continued treatment. In order to support sustainability, we also compared data after the third injection with values at the end of the 2-year follow-up period. Our data show that clinical improvement in terms of BCVA was statistically significant in both groups 1 month after the third intravitreal bevacizumab injection and this improvement was sustained for up
to 2 years with continued treatment. CRT decreased in all patients after intravitreal bevacizumab injections compared to baseline and this result was statistically significant in both groups and maintained for 2 years with continued treatment. Although repeated injections were required to maintain the outcomes, no serious adverse events were encountered. Furthermore, in order to evaluate the long-term safety of repeated bevacizumab injections, mfERG testing was performed for functional evaluation of the central 10° of the macula. There is limited evidence in the literature on multifocal ERG changes after intravitreal bevacizumab. Park et al. suggested that there is a potential role for mfERG in evaluating the effect of
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intravitreal bevacizumab injection on retinal function [29]. Maturi et al. first reported an improvement in mfERG responses after intravitreal bevacizumab for the treatment of exudative age-related macular degeneration (AMD) [30]. This finding is consistent with ours and suggests that a successful treatment of macular edema may lead to improvement in mfERG responses in the involved areas. Later on, Moschos et al. evaluated the macular function by mfERG before and after the intravitreal use of bevacizumab in patients with choroidal neovascularization due to AMD and did not find any statistically significant functional change of the macula 3 months after treatment [31]. Pedersen et al. also assessed the alteration of retinal function by multifocal and fullfield electroretinography in patients with AMD treated with intravitreal bevacizumab and concluded that no signs of focal toxicity in the central retina were shown in the short term [32]. However, RVO and AMD are completely different diseases in their pathogenesis and in visual and clinical outcomes, so it is possible to obtain different retinal function changes after intravitreal bevacizumab. Recently, Torres-Soriano et al. reported on the short-term safety of intravitreal bevacizumab, assessed by mfERG and postulated that no short-term cone photoreceptor toxicity was demonstrable after a single intravitreal bevacizumab injection in patients with AMD, RVO, and diabetic retinopathy [33]. Finally, Park et al. concluded that intravitreal bevacizumab injections in BRVO patients improved effectively the functional and structural outcomes not only of the central fovea but also of the extrafoveal macula [34]. In our study, the mean response density of P1 at rings 1 and 2 increased after the three loading bevacizumab injections in both RVO groups and the improvement was statistically significant at the end of the follow-up period. Also the mean implicit time of P1 response at rings 1 and 2 decreased over time to a statistically significant degree. The improvement in macular function can be attributed to the restoration of the inner blood retinal barrier which might be involved in the re-establishment of normal foveal anatomy. We can speculate that these changes resulted also in the improvement in central vision and reduction in CRT. According to ISCEV standards, mfERG testing provides a topographic measure of electrophysiological activity from the cone driven retina only [19]. The improved
macular cone photoreceptor electrophysiological activity observed in our study after repeated intravitreal bevacizumab injections suggests that the above treatment is nontoxic for these cells. In our study, we could not evaluate rod, ganglion, and optic nerve fiber layer function, so it is impossible to draw any firm conclusions regarding their activity. Cheng et al. suggested that intravitreal injection of bevacizumab poses no risk to retinal ganglion cells also, even after repeated application [35]. Some limitations of the study are the small number of patients especially in the CRVO group, the retrospective design of the study, the absence of control group, and the fact that the investigators and the patients were not masked and some patients exited the study at an early stage. However, the conclusion is that early treatment with repeated intravitreal bevacizumab injections in patients with macular edema complicating RVO resulted in long-term improvement of visual acuity, reduction in CRT, and statistically significant changes in the mfERG responses with nondemonstrable toxic effects on cone photoreceptors in either CRVO or BRVO patients. Further studies are needed to evaluate the rod photoreceptor cells and optic nerve fiber layer function after repeated intravitreal bevacizumab injections.
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22. Central Vein Occlusion Study Group (1995) A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion: the Central Vein Occlusion Study Group N report. Ophthalmology 102:1434–1444 23. McIntosh RL, Rogers SL, Lim L, Cheung N, Wang JJ, Mitchell P, Kowalski JW, Nguyen HP, Wong TY (2010) Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology 117: 1094–1123 24. Branch Vein Occlusion Study Group (1986) Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion: a randomized clinical trial. Arch Ophthalmol 104:34–41 25. Gregori NZ, Gaitan J, Rosenfeld PJ, Puliafito CA, Feuer W, Flynn HW Jr, Berrocal AM, Al-Attar L, Dubovy S, Smiddy WE, Schwartz SG, Lee WH, Murray TG (2008) Long-term safety and efficacy of intravitreal bevacizumab (Avastin) for the management of central retinal vein occlusion. Retina 28:1325–1337 26. Rabena MD, Pieramici DJ, Castellarin AA, Nasir MA, Avery RL (2007) Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to branch retinal vein occlusion. Retina 27:419–425 27. Ehlers JP, Decroos FC, Fekrat S (2011) Intravitreal bevacizumab for macular edema secondary to branch retinal vein occlusion. Retina 31:1856–1862 28. Hsu J, Kaiser RS, Sivalingam A, Abraham P, Fineman MS, Samuel MA, Vander JF, Regillo CD, Ho AC (2007) Intravitreal bevacizumab (Avastin) in central retinal vein occlusion. Retina 27:1013–1019 29. Park JY, Kim SH, Park TK, Ohn YH (2011) Multifocal electroretinogram findings after intravitreal bevacizumab injection in choroidal neovascularization of age-related macular degeneration. Korean J Ophthalmol 25(3):161–165 30. Maturi RK, Bleau LA, Wilson DL (2006) Electrophysiologic findings after intravitreal bevacizumab (Avastin) treatment. Retina 26:270–274 31. Moschos MM, Brouzas D, Apostolopoulos M, Koutsandrea C, Loukianou E, Moschos M (2007) Intravitreal use of bevacizumab (Avastin) for choroidal neovascularization due to ARMD: a preliminary multifocal—ERG and OCT study. Multifocal- ERG and OCT study. Multifocal-ERG after use of bevacizumab in ARMD. Doc Ophthalmol 114(1):37–44 32. Pedersen KB, Møller F, Sjølie AK, Andre´asson S (2010) Electrophysiological assessment of retinal function during 6 months of bevacizumab treatment in neovascular agerelated macular degeneration. Retina 30(7):1025–1033 33. Torres-Soriano ME, Cubas-Lorenzo V, Garcı´a-Aguirre G, Herna´ndez-Rojas M, Kon-Jara V, Dı´az-Rubio JL, FromowGuerra J, Quiroz-Mercado H, Jime´nez-Sierra JM (2011) Multifocal electrophysiologic findings after intravitreal bevacizumab (Avastin) treatment. Retina 32(5):972–976 34. Park S, Cho IH, Park TK, Nam WH, Ohn YH (2013) Extrafoveal changes following intravitreal bevacizumab injections for macular edema secondary to branch retinal vein occlusion: an mfERG and OCT study. Doc Ophthalmol 126(2):137–148 35. Cheng CK, Peng PH, Tien LT, Cai YJ, Chen CF, Lee YJ (2009) Bevacizumab is not toxic to retinal ganglion cells after repeated intravitreal injection. Retina 29(3):306–312
ORIGINAL PAPER
Clinical, anatomical, and electrophysiological assessments of the central retina following intravitreal bevacizumab for macular edema secondary to retinal vein occlusion Eleni Loukianou • Dimitrios Brouzas • Klio Chatzistefanou • Chrysanthi Koutsandrea
Received: 18 December 2014 / Accepted: 23 March 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract The purpose of this study is to evaluate the long-term visual, anatomical and electrophysiological outcomes of repeated intravitreal injections of bevacizumab for macular edema due to retinal vein occlusion (RVO) and investigate any possible toxic effects on the central fovea. This is a prospective, noncomparative, interventional case series. Thirtythree eyes of 33 patients with macular edema secondary to RVO were treated with 1.25 mg/0.05 ml intravitreal bevacizumab. Nine patients had nonischemic central retinal vein occlusion (CRVO) and 24 patients had branch retinal vein occlusion (BRVO). The main outcome measures were best-corrected visual acuity, central retinal thickness (CRT), and multifocal electroretinography (mfERG) responses changes at baseline, 1 month after the third injection and at the end of the 2-year long follow-up period. Patients with CRVO had mean best-corrected Snellen visual acuity of 0.10 at baseline, which improved significantly to 0.31 after 2 years (P = 0. 028).The mean CRT at presentation was 756.28 lm and reduced significantly to 439.14 lm after 2 years (P = 0.05).
Patients with BRVO had mean best-corrected Snellen visual acuity of 0.19 at baseline, which improved significantly to 0.40 after 2 years (P \ 0.001). The mean CRT at presentation was 681.04 lm and reduced significantly to 369.81 lm after 2 years (P \ 0.001). Mean mfERG responses within central 10° (ring1, ring2) showed statistically significant differences on P1 parameters in terms of response density and implicit time after 2 years in both CRVO and BRVO patients. Repeated intravitreal bevacizumab injections for macular edema due to either CRVO or BRVO resulted in long-term improvement of visual acuity, a reduction in CRT and statistically significant changes in the mfERG responses with nondemonstrable toxic effects on the central fovea. Keywords Bevacizumab Macular edema Retinal vein occlusion Optical coherence tomography Multifocal electroretinography
Introduction E. Loukianou D. Brouzas K. Chatzistefanou C. Koutsandrea Department of Ophthalmology, University of Athens, Athens, Greece E. Loukianou (&) 100 Petrou Tsirou st., 3076 Limassol, Cyprus e-mail: [email protected]
Retinal vein occlusion (RVO) is the second most common cause of visual impairment due to retinal vascular disease after diabetic retinopathy [1, 2]. Branch retinal vein occlusion (BRVO) occurs 2–3 times more often than central retinal vein occlusion (CRVO) [3, 4]. It is currently estimated from pooled data that there are about 520 new cases of RVO per
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million of population, of which 440 BRVO cases and 80 CRVO cases [5]. RVO is associated with increased levels of intraocular vascular endothelial growth factor (VEGF), which vary with disease severity [6]. Increased levels of VEGF may lead to macular edema which is a major sight-threatening complication of RVO [7]. Beneficial treatment options for macular edema complicating RVOs include grid macular laser treatment (for BRVO), intravitreal injections of triamcinolone and dexamethasone, and most recently intravitreal anti-VEGF agents. According to Branch Vein Occlusion Study, patients with BRVO-associated edema and visual acuity of 20/40 or less showed statistically significant benefit when treated with macular grid laser compared with untreated patients [8]. On the contrary, patients with CRVO-associated macular edema did not show any significant benefit when treated with macular grid laser [9]. The efficacy of intravitreal triamcinolone was investigated in several studies which showed a visual acuity improvement, although there were significant side effects such as increased intraocular pressure (IOP) and cataract formation [10]. Similarly, intravitreal dexamethasone implant improved the visual acuity in patients with macular edema secondary to BRVO and CRVO [11]. Finally, several studies revealed the benefit of antiVEGF agents such as pegaptanib sodium, ranibizumab, bevacizumab, and recently aflibercept in patients with macular edema associated with BRVO and CRVO [12–15]. Bevacizumab (Avastin; Genentech) is a full-length monoclonal humanized antibody to all active isoforms of VEGF [16]. It is used off-label in many countries for the treatment of many retinal diseases and their complications including macular edema secondary to branch or CRVOs. In our study, we investigate the long-term visual, anatomic, and electrophysiologic responses of the central retina after repeated intravitreal bevacizumab injections for macular edema complicating RVO and also any possible toxic effect on the central fovea. In previous studies, Pai et al. evaluated the clinical, anatomic, and electrophysiologic responses after a single intravitreal injection of 1.25 mg of bevacizumab for macular edema secondary to RVO in a short-term study [17], and Shetty et al. found no measurable photoreceptor toxicity following intravitreal bevacizumab for macular edema based on fullfield electroretinography and mfERG recordings in the short term [18].
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Materials and methods From January 2008 until May 2010, all consecutive RVO cases presenting at the medical retinal department of our clinic were evaluated for inclusion in the study. Inclusion criteria were macular edema evident on clinical examination, confirmed by fluorescein angiography and optical coherence tomography (OCT) with central retinal thickness (CRT) greater than 350 lm and duration of RVO less than 6 months. Exclusion criteria were previously treated macular edema, ocular pathology like dense cataract and central corneal opacities and systemic diseases such as diabetes mellitus and renal failure that independently influence the results of the study. All cases that were included in the study were followed prospectively for 2 years. All the participants underwent thorough ophthalmic examination including best-corrected Snellen visual acuity (BCVA, decimal scale) assessment, IOP measurement with applanation tonometry, slit lamp biomicroscopy, CRT measurement by OCT, and functional evaluation of the central 10° of the macula at baseline and on follow-up visits every 6 weeks for a period of 2 years. The function of the macula could be elucidated by measurements of the retinal nerve fiber layer thickness and macular ganglion cell-inner plexiform layer thickness by spectral domain OCT or by microperimetric evaluation but in our clinic, we only have access to time domain OCT and electroretinography so we evaluated the function of the central 10° by multifocal electroretinography (mfERG). Fluorescein angiography was performed in all patients at baseline and then every 6 months unless it was suggested earlier from the examining team. Three intravitreal injections of 1.25 mg/0.05 ml bevacizumab were administered under aseptic conditions in the operating theater every 6 weeks. Patients were reinjected if there was visual acuity deterioration more than one line of Snellen optotype attributable to recurrent macular edema, if the central foveal thickness was [250 lm, and if there were cystic spaces in the macula even if the central foveal thickness was \250 lm. CRT was measured using Stratus OCT, Carl Zeiss Meditec, Dublin California, USA. All the eyes were scanned in a radial spoke pattern that was centered at the foveola, with a scan length of 6 mm. The participants were asked to gaze at the fixation light within the machine, and the foveolar fixation was
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confirmed by observing the retina through the infrared monitoring camera. The CRT was calculated as the distance between the vitreoretinal interface and the anterior surface of retinal pigment epithelium. Multifocal ERG recordings were performed using the EP-1000 model (Tomey, Nagoya, Japan), and mfERG recording parameters were in accordance with ISCEV standards [19]. The mfERG responses were recorded using a pseudorandom m-sequence with a stimulus matrix of 61 scaled hexagonal elements displayed on a cathode ray tube color monitor driven at a frame of 75 Hz. A field size of 27.7° was assessed. The P1 component of the first-order kernel of the mfERG from two concentric rings centered on the fovea (ring 1: 0°–5°, ring 2: 5°–10°) was averaged, and the data recorded included density and implicit time of response for every ring. The mean response density of P1 amplitude at ring 1 (RD1), the mean response density of P1 amplitude at ring 2 (RD2), the mean implicit time of P1 amplitude at ring 1 (IT1), and the mean implicit time of P1 amplitude at ring 2 (IT2) were studied at baseline, 1 month after the third injection, and at the end of the 2-year follow-up period. The statistical analysis was performed using SPSS, Inc, Chicago, IL (version 19). Due to the longitudinal design and the non-independence of the observations, the ANOVA for repeated measures with Bonferroni corrections was used to compare data before treatment with those obtained 1 month after the third injection and also baseline values with data at the end of the 2-year follow-up period. We also compared data 1 month after the third injection with values at the end of the 2-year followup period. A P value of 0.05 or less was considered statistically significant. All patients signed an informed consent to participate in the study. The study was conducted in accordance with the tenets of Helsinki and the requirements of the hospital Ethical Committee.
Results Thirty-three eyes of 33 patients were included in the study. There were 18 female (54.54 %) and 15 male (45.46 %) patients. The patient age ranged from 44 to 83 years. Nine patients had nonischemic CRVO, and 24 patients had BRVO.
The mean durations of the CRVO and BRVO on entry to the study were 20 and 22 weeks, respectively. Especially in the BRVO group, we were waiting for at least 3 months for spontaneous resolution of macular edema, and if the edema was persistent, the patients were included to the study. The mean number of injections during the 2-year follow-up period was nine injections per eye in both CRVO and BRVO groups. Last follow-up examination was performed 1 month after the last bevacizumab injection. Demographic characteristics are displayed in Table 1. All patients received three intravitreal injections of bevacizumab at the beginning, 6 weeks, apart. After the third injection, we observed recurrence of macular edema in eight patients with nonischemic CRVO (88.88 %) and in nineteen patients with BRVO (79.16 %). Six patients with macular edema due to CRVO (66.66 %) and thirteen patients with macular edema due to BRVO (54.16 %) needed continuous injections at constant time intervals. In patients who did not show a complete resolution of macular edema despite continuous treatment, we did not increase at a higher dose of the anti-VEGF agent and we continued with the same dose of 1.25 mg/0.05 ml intravitreal bevacizumab. Four patients exited the study after the third injection. One of these patients was lost to follow up, two of them were dissatisfied because of minimal improvement in visual acuity (0.005 and 0.1, respectively) and decided to discontinue the treatment, and one patient moved to another country and was lost to follow-up. Reinjections were administered according to the retreatment criteria described in methods section.
Table 1 Demographic characteristics of the patients at baseline Patient demographics CRVO
BRVO
Number of patients
9
24
Age
70.7 ± 10.05
63.7 ± 11.49
Sex (male/female)
5M/4F
10M/14F
Duration of occlusion (weeks)
20 ± 3
22 ± 3
Values are n or mean ± SD (standard deviation) CRVO central retinal vein occlusion, BRVO branch retinal vein occlusion
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Safety During the 2-year follow-up period, no severe ocular side effects such as retinal tears, retinal detachments, traumatic cataracts, vitreous hemorrhages, uveitis, or endophthalmitis were observed. Similarly, no severe systemic adverse events such as thromboembolic events, systemic hypertension, or kidney failure were reported. Angle, iris, optic disk, or retinal neovascularization was not observed in any of the study eyes. Clinical examination and fluorescein angiography revealed development of collateral vessels in 31 eyes. Two patients developed a lamellar macular hole during the treatment and had a final visual acuity of 0.5 and 0.7, respectively. One patient experienced diplopia after the third injection. The orthoptic evaluation showed limitation of abduction consistent with paralysis of the lateral rectus muscle of the injected eye. Further work-up for systemic causes of abducens palsy, including brain MRI, was unremarkable. There were no signs of resolution of abducens paralysis throughout the follow-up period.
Subgroup analysis
tested at the three time points of measurement (baseline, 1 month after the third injection and after 2 years) are shown in Table 2. The results after the Bonferroni-corrected pairwise comparisons for each analysis are shown in Table 3. In summary, the results for each characteristic in the CRVO group are as below: BCVA In the nonischemic CRVO group, mean baseline visual acuity was 0.10 (SD = 0. 08) which improved to mean 0.24 (SD = 0. 14) 1 month after the third injection and to 0.31 (SD = 0.18) after 2 years. There was a general significant increase in the level of BCVA from baseline to 1 month after the third injection (P = 0.033) as well as from baseline to the end of follow-up (P = 0.028). On the contrary, the difference in visual acuity from 1 month after the third
Table 2 Descriptives for all characteristics at the three time points (baseline, after the third injection, and after 2 years) in CRVO patients; n = 7 Characteristics
Mean
SD
BCVA_baseline
0.107
0.089
Patients with non-ischemic CRVO had mean BCVA of 0.10 at baseline which improved significantly to 0.31 after 2 years (P = 0.028). Patients with BRVO had mean BCVA of 0.19 at baseline which improved significantly to 0.40 after 2 years (P \ 0.001). The mean CRT in CRVO group at presentation was 756.28 lm and reduced significantly to 439.14 lm after 2 years (P = 0.05). The mean CRT in BRVO group at presentation was 681.04 lm and reduced significantly to 369.81 lm after 2 years (P \ 0.001). According to these results, the patients with macular edema complicating BRVO showed a better response to intravitreal bevacizumab injections compared to CRVO patients with greater improvement of BCVA and greater reduction of CRT. The results in details in each group are shown below.
BCVA_third injection
0.243
0.140
BCVA_2 years
0.314
0.186
CRT_baseline
756.286
118.840
CRT_third injection
513.857
137.540
CRT_2 years
439.143
95.244
RD1_baseline
67.000
25.794
RD1_third injection
92.714
26.631
RD1_2 years
102.571
32.979
RD2_baseline
54.800
15.515
RD2_third injection
71.200
19.186
RD2_2 years IT1_baseline
74.086 45.300
17.607 4.426
IT1_third injection
41.971
3.225
CRVO group
BCVA best-corrected visual acuity, CRT central retinal thickness, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2, SD standard deviation
Descriptives (mean, standard deviation) for each of the parameters (BCVA, CRT, RD1, RD2, IT1, and IT2)
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IT1_2 years
39.314
3.414
IT2_baseline
52.343
2.893
IT2_third injection
46.843
4.843
IT2_2 years
46.543
5.707
Int Ophthalmol Table 3 Multiple comparisons with Bonferroni corrections— CRVO group
RD1
Characteristics
Time
BCVA
1–2
-0.136*
1–3
-0.207*
0.028
2–3
0.029
0.140
The mean RD1 changed from 67.00 nV/deg2 (SD = 25.79) to 92.71 nV/deg2 (SD = 26.63) 1 month after the third injection and to 102.57 nV/deg2 (SD = 32.97) after 2 years. The difference from baseline was statistically significant 1 month after the third injection (P = 0.002) or at the end of the follow up period. (P = 0.003). The difference from 1 month after the third injection to the end of the 2-year follow-up period was not statistically significant (P = 0.215).
CRT
RD1
RD2
IT1
IT2
Mean difference
P values 0.033
1–2
242.429*
0.001
1–3
317.143*
0.005
2–3
42.219
0.382 0.002
1–2
-25.714*
1–3
-35.571*
0.003
2–3
-9.857
0.215
1–2
-16.400*
\0.001
1–3
-19.286*
\0.001
2–3
-2.886
0.369
1–2
3.329*
0.004
1–3
5.986*
0.018
2–3 1–2
2.657 5.500*
0.190 0.005
1–3
5.800*
0.049
2–3
0.300
1.000
* The mean difference is significant Time 1, baseline; time 2, after the third injection; time 3, after 2 years BCVA best-corrected visual acuity, CRT central retinal thickness, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2
injection to the end of the 2-year follow-up period was not statistically significant (P = 0.140).
CRT The mean CRT was reduced from 756.28 lm (SD = 118.84) at baseline to 513.85 lm (SD = 137.54) 1 month after the third intravitreal bevacizumab injection and to 439.14 lm (SD = 95.24) after 2 years. The difference of either post-treatment time points (1 month after the third injection, end of 2-year follow-up period) from baseline was statistically significant (P = 0.001and P = 0.005, respectively). On the contrary, the difference in CRT 1 month after the third injection compared to the end of the 2-year follow-up period was not statistically significant (P = 0.382).
RD2 The mean RD2 changed from 54.80 nV/deg2 (SD = 15.51) to 71.20 nV/deg2 (SD = 19.18) 1 month after the third injection to 74.08 nV/deg2 (SD = 17.60) after 2 years. A statistically significant difference was observed from baseline and 1 month after the third injection (P \ 0.001) and from baseline to the end of the follow-up period. (P \ 0.001). The difference from 1 month after the third injection to the end of the 2-year follow-up period was not statistically significant (P = 0.369). IT1 The mean IT1 was 45.30 ms (SD = 4.42) at baseline and 41.97 ms (SD = 3.22) 1 month after the third injection. The difference was statistically significant (P = 0.004). At the end of the follow-up period, the mean implicit time of P1 was 39.31 (SD = 3.41) and the difference from baseline was also statistically significant (P = 0.018). The difference from 1 month after the third injection to the end of the 2-year followup period was not statistically significant. (P = 0.190). IT2 The mean implicit time of P1 response at ring 2 was 52.34 ms (SD = 2.89) at baseline, 46.84 ms (SD = 4.84) 1 month after the third injection, and 46.54 (SD = 5.70) at the end of the follow-up period. The difference of either post-treatment time points (1 month after the third injection, end of 2-year follow-up period) from baseline was statistically significant (P = 0.005 and P = 0.049, respectively). On the contrary, the difference from 1 month after the
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Int Ophthalmol Fig. 1 Profile plots for BCVA and CRT in CRVO group. Follow up period 1 = baseline, follow up period 2 = 1 month after the third injection, follow up period 3 = after 2 years, BCVA best corrected visual acuity, CRT central retinal thickness, CRVO central retinal vein occlusion
third injection to the end of the 2-year follow-up period was not statistically significant (P = 1.000). Profile plots for BCVA and CRT are shown in Fig. 1 and for RD1, RD2, IT1, and IT2 are shown in Fig. 2. The mean IOP was 18 mmHg at baseline and remained within normal limits during the 2-year long follow-up period.
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BRVO group Descriptives (mean, standard deviation) for each of the parameters (BCVA, CRT, RD1, RD2, IT1, and IT2) tested at the three time points of measurement (baseline, 1 month after the third injection and after 2 years) are shown in Table 4.
Int Ophthalmol Fig. 2 Profile plots for RD1, RD2, IT1, and IT2 in CRVO group. Follow up period 1 = baseline, follow up period 2 = 1 month fter the third injection, follow up period 3 = after 2 years, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2
The results after the Bonferroni-corrected pairwise comparisons for each analysis are shown in Table 5. In summary, the results for each characteristic in the BRVO group are as below: BCVA The mean baseline visual acuity was 0.19 (SD = 0.16) and improved to 0.38 (SD = 0.35) 1 month after the
third injection and to 0.40 (SD = 0.35) at 2 years. The difference in visual acuity from baseline compared to visual acuity 1 month after the third injection (P = 0.001) as well as from baseline to the end of follow-up (P = 0 \ 0.001) was statistically significant. On the contrary, the difference in visual acuity from 1 month after the third injection to the end of the 2-year follow-up period was not statistically significant (P = 0.288).
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Int Ophthalmol Fig. 2 continued
CRT The mean CRT was reduced from 681.04 lm (SD = 226.45) at baseline to 381.45 lm (SD = 100.15) 1 month after the third intravitreal bevacizumab injection and to 369.81 lm (SD = 114.83) after 2 years. The difference of either post-treatment time
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points (1 month after the third injection, end of 2-year follow-up period) from baseline was statistically significant (P \ 0.0001 and P \ 0.0001, respectively). On the contrary, the difference in CRT from 1 month after the third injection to the end of the follow-up period was not statistically significant (P = 1.0000).
Int Ophthalmol Table 4 Descriptives for all characteristics at the three time points (baseline, after the third injection, and after 2 years) in BRVO patients; n = 22 Characteristics
Mean
Table 5 Multiple comparisons with Bonferroni corrections— BRVO group Characteristics
Time
BCVA
Mean difference
P values
SD 1–2
-0.191*
0.001
BCVA_baseline
0.193
0.161
1–3
-0.214*
\0.001
BCVA_third injection
0.384
0.359
2–3
-0.023
BCVA_2 years
0.407
0.352
1–2
299.591*
\0.001
CRT_baseline
681.045
226.458
1–3
311.227*
\0.001
CRT_third injection
381.454
100.156
2–3
11.636
1.000
CRT_2 years
369.818
114.838
1–2
-7.273
0.535
RD1_baseline
94.545
32.951
1–3
-14.136*
0.048
RD1_third injection
101.818
18.466
2–3
-6.864*
0.002
RD1_2 years
108.682
19.529
1–2
-9.123*
\0.001
RD2_baseline
74.854
16.233
1–3
-13.262*
\0.001
RD2_third injection RD2_2 years
83.977 88.116
14.889 14.720
2–3
-4.139*
\0.001
1–2
2.945*
\0.001
IT1_baseline
41.186
3.785
1–3
3.573*
0.001
IT1_third injection
38.241
3.830
IT1_2 years
37.614
3.972
2–3 1–2
0.627 4.041*
1.000 \0.001
CRT
RD1
RD2
IT1
IT2
0.288
IT2_baseline
52.932
7.000
1–3
6.264*
\0.001
IT2_third injection
48.891
6.900
2–3
2.223*
\0.001
IT2_2 years
46.668
6.424
BCVA best-corrected visual acuity, CRT central retinal thickness, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2, SD standard deviation
RD1 The mean RD1 changed from 94.54 nV/deg2 (SD = 32.95) to 101.81 nV/deg2 (SD = 18.46) 1 month after the third injection and to 108.68 nV/deg2 (SD = 19.52) after 2 years. The difference from baseline to 1 month after the third injection was not statistically significant (P = 0.535).On the contrary, the difference from baseline to the end of the follow-up period and from 1 month after the third injection to the end of the 2-year follow-up period was statistically significant (P = 0.048 and P = 0.002, respectively). RD2 The mean RD2 changed from 74.85 nV/deg2 (SD = 16.23) to 83.97 nV/deg2 (SD = 14.88) 1 month after the third injection and to 88.11 nV/deg2 (SD = 14.72) after 2 years. The difference was statistically
* The mean difference is significant Time 1 = baseline, Time 2 = after the third injection, Time 3 = after 2 years BCVA best-corrected visual acuity, CRT central retinal thickness, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2
significant from baseline to 1 month after the third injection (P \ 0.001) and from baseline to the end of the follow-up period (P \ 0.001) and also from 1 month after the third injection to the end of the 2-year follow-up period. (P \ 0.001). IT1 The mean IT1 was 41.18 ms (SD = 3.78) at presentation and 38.24 ms (SD = 3.83) 1 month after the third injection. The difference was statistically significant (P \ 0.001). At the end of the follow-up period, the mean implicit time of P1 was 37.61 (SD = 3.97) which was statistically different from baseline (P = 0.001). The difference from 1 month after the third injection to the end of the 2-year followup period was not statistically significant (P = 1.000).
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Int Ophthalmol Fig. 3 Profile plots for BCVA and CRT in BRVO group. Follow up period 1 = baseline, follow up period 2 = 1 month after the third injection, follow up period 3 = after 2 years, BCVA best corrected visual acuity, CRT central retinal thickness, BRVO branch retinal vein occlusion
IT2 The mean implicit time of P1 response at ring 2 was 52.93 ms (SD = 7.00) at baseline, 48.89 ms (SD =
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6.90) 1 month after the third injection, and 46.66 (SD = 6.42) at the end of the follow-up period. The difference of either post-treatment time points (1 month after the third injection, end of 2-year follow-up period)
Int Ophthalmol Fig. 4 Profile plots for RD1, RD2, IT1, and IT2 in BRVO group. Follow up period 1 = baseline, follow up period 2 = 1 month after the third injection, follow up period 3 = after 2 years, RD1 response density of P1 amplitude at ring 1, RD2 response density of P1 amplitude at ring 2, IT1 implicit time of P1 amplitude at ring 1, IT2 implicit time of P1 amplitude at ring 2, BRVO branch retinal vein occlusion
from baseline was statistically significant (P \ 0.001). The difference from 1 month after the third injection to the end of the 2-year follow-up period was also statistically significant (P \ 0.001). Profile plots for BCVA and CRT are shown in Fig. 3 and for RD1, RD2, IT1, and IT2 are shown in Fig. 4.
The mean IOP was 17 mmHg at baseline and remained within normal limits during the study. Figure 5a–d show the OCT scans of a 67-year-old male with macular edema due to BRVO at presentation and during the follow-up period after four bevacizumab injections.
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Int Ophthalmol Fig. 4 continued
Also, Fig. 6a–i show mfERG responses in ring 1 and 2 of the same patient.
Discussion Macular edema is the main sight-threatening complication of RVO [8, 20]. The natural history of CRVO as
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reported by the Central Vein Occlusion Study (CVOS) Group shows a generally poor visual outcome [21, 22]. Loss of visual acuity is usually more pronounced with ischemic than with nonischemic CRVO, although vision also tends to be poor in eyes with the nonischemic type [23]. The Branch Vein Occlusion Study (BVOS) reported that 20 % of untreated eyes experienced significant visual deterioration over time.
Int Ophthalmol
Fig. 5 The OCT scans of a 67-year-old patient with macular edema due to BRVO treated with intravitreal bevacizumab injections. We can observe the gradual resolution of the edema over time (a baseline, b 1 month after the first bevacizumab
injection, c 1 month after the third bevacizumab injection, and d after 2 years) and the reduction in central retinal thickness as documented by optical coherence tomography during the 2-year follow-up period
Approximately 50 % of untreated eyes with BRVO retained a VA of 6/12 or better, while in 25 % of cases, final VA was less than 6/60 [12, 24]. Treatment options include grid laser treatment (for BRVO), intravitreal injection of steroids, surgical procedures, and, most recently, treatment with intravitreal antiVEGF agents. Gregori et al. first reported on the longterm effectiveness of intravitreal bevacizumab in fiftyseven eyes with macular edema due to CRVO. In their study, visual acuity improved by a mean of 14 letters (P = 0.001) at 1 month, 13 letters at 3 months (P = 0.001), nine letters at 6 months (P = 0.001), and nine letters at 12 months (P = 0.004), and the mean OCT thickness decreased by 299 lm at 1 month (P = 0.001), 144 lm at 3 months, (P = 0.001), 127 lm at 6 months (P = 0.011), and 276 lm at 12 months (P = 0.001) [25]. The mean (range) number of injections at 1, 3, 6, and 12 months was 1.4 (1–2), 2.1 (1–4), 2.7 (1–5), and 3.2 (1–6), respectively. Rabena et al. showed anatomic and visual acuity improvements and lack of serious adverse side effects after intravitreal bevacizumab in 27 consecutive patients with macular edema secondary to BRVO after a mean of two injections per patient (range 1–3 injections) and a mean follow-up period of 5.3 months.They noted improvement in mean visual acuity from
20/200 at baseline to 20/100 at 1 month and 20/100 at 3 months and last follow-up (P = 0.001). The mean central macular thickness was 478 lm at baseline and decreased to 310, 336, and 332 lm at 1 month, 3 months, and last follow-up examination, respectively (P = 0.001) [26]. Ehlers et al. postulated that early treatment (within 6 months) resulted in a greater improvement in visual acuity compared with delayed treatment [27]. Hsu et al. concluded that intravitreal bevacizumab was beneficial in patients with macular edema associated with CRVO but the benefits were not sustained without repeated injections. In their study, thirty eyes of 29 patients had intravitreal bevacizumab injections and the mean follow-up was 18.1 weeks. No significant changes in visual acuity were found 4 months after the last injection, and worsening visual acuity occurred in all cases by 5 months after the most recent injection [28]. Our noncomparative prospective, interventional study investigated the long-term effectiveness of repeated intravitreal injections of bevacizumab when initiated relatively early in the course of macular edema related to nonischemic CRVO and BRVO. The median duration of the RVO on entry to the study was less than 6 months in both groups. We chose to
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Fig. 6 The mf ERG responses of the central retina of the patient in Fig. 1 on presentation (a–c), after the three injections (d– f) and at the end of the second year (g–i). The mean mfERG responses in every ring are documented (a, d, g). In the central two rings (ring 1, ring 2), we can see the gradual increase of P1
wave (nV/deg2) and the gradual improvement of the implicit time (ms) over time, which were statistically insignificant. The mfERG traces are recorded (c, f, i), and the mfERG responses are shown in 3D graphs (b, e, h) also
compare the visual and anatomic parameters at baseline in each group (CRVO, BRVO) with their respective values 1 month after the three intravitreal bevacizumab injections which resulted in a maximal response in most of the cases and also with the values at the end of the follow-up period to investigate if the maximal achievable response was sustainable for up to 2 years with continued treatment. In order to support sustainability, we also compared data after the third injection with values at the end of the 2-year follow-up period. Our data show that clinical improvement in terms of BCVA was statistically significant in both groups 1 month after the third intravitreal bevacizumab injection and this improvement was sustained for up
to 2 years with continued treatment. CRT decreased in all patients after intravitreal bevacizumab injections compared to baseline and this result was statistically significant in both groups and maintained for 2 years with continued treatment. Although repeated injections were required to maintain the outcomes, no serious adverse events were encountered. Furthermore, in order to evaluate the long-term safety of repeated bevacizumab injections, mfERG testing was performed for functional evaluation of the central 10° of the macula. There is limited evidence in the literature on multifocal ERG changes after intravitreal bevacizumab. Park et al. suggested that there is a potential role for mfERG in evaluating the effect of
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intravitreal bevacizumab injection on retinal function [29]. Maturi et al. first reported an improvement in mfERG responses after intravitreal bevacizumab for the treatment of exudative age-related macular degeneration (AMD) [30]. This finding is consistent with ours and suggests that a successful treatment of macular edema may lead to improvement in mfERG responses in the involved areas. Later on, Moschos et al. evaluated the macular function by mfERG before and after the intravitreal use of bevacizumab in patients with choroidal neovascularization due to AMD and did not find any statistically significant functional change of the macula 3 months after treatment [31]. Pedersen et al. also assessed the alteration of retinal function by multifocal and fullfield electroretinography in patients with AMD treated with intravitreal bevacizumab and concluded that no signs of focal toxicity in the central retina were shown in the short term [32]. However, RVO and AMD are completely different diseases in their pathogenesis and in visual and clinical outcomes, so it is possible to obtain different retinal function changes after intravitreal bevacizumab. Recently, Torres-Soriano et al. reported on the short-term safety of intravitreal bevacizumab, assessed by mfERG and postulated that no short-term cone photoreceptor toxicity was demonstrable after a single intravitreal bevacizumab injection in patients with AMD, RVO, and diabetic retinopathy [33]. Finally, Park et al. concluded that intravitreal bevacizumab injections in BRVO patients improved effectively the functional and structural outcomes not only of the central fovea but also of the extrafoveal macula [34]. In our study, the mean response density of P1 at rings 1 and 2 increased after the three loading bevacizumab injections in both RVO groups and the improvement was statistically significant at the end of the follow-up period. Also the mean implicit time of P1 response at rings 1 and 2 decreased over time to a statistically significant degree. The improvement in macular function can be attributed to the restoration of the inner blood retinal barrier which might be involved in the re-establishment of normal foveal anatomy. We can speculate that these changes resulted also in the improvement in central vision and reduction in CRT. According to ISCEV standards, mfERG testing provides a topographic measure of electrophysiological activity from the cone driven retina only [19]. The improved
macular cone photoreceptor electrophysiological activity observed in our study after repeated intravitreal bevacizumab injections suggests that the above treatment is nontoxic for these cells. In our study, we could not evaluate rod, ganglion, and optic nerve fiber layer function, so it is impossible to draw any firm conclusions regarding their activity. Cheng et al. suggested that intravitreal injection of bevacizumab poses no risk to retinal ganglion cells also, even after repeated application [35]. Some limitations of the study are the small number of patients especially in the CRVO group, the retrospective design of the study, the absence of control group, and the fact that the investigators and the patients were not masked and some patients exited the study at an early stage. However, the conclusion is that early treatment with repeated intravitreal bevacizumab injections in patients with macular edema complicating RVO resulted in long-term improvement of visual acuity, reduction in CRT, and statistically significant changes in the mfERG responses with nondemonstrable toxic effects on cone photoreceptors in either CRVO or BRVO patients. Further studies are needed to evaluate the rod photoreceptor cells and optic nerve fiber layer function after repeated intravitreal bevacizumab injections.
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