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Purpose: To
investigate the clinical and electrophysiological effects of serial
intravitreal injections of dexamethasone implant and aflibercept for macular
edema after central retinal vein occlusion (CRVO).
Methods: Fifteen
patients with macular edema after CRVO were examined with full-field
electroretinography (ERG) within 1 month of symptom onset and 2 and 12 months
after the start of treatment. They were divided into a non-ischemic and an
ischemic CRVO group. All the CRVO patients had undergone clinical ophthalmological
examination at the CRVO debut, monthly for 6 months and then every second month
for 18 months.
The primary outcome measures were the change in the retinal function 2
and 12 months after treatment. Secondary outcome measures included best
corrected visual acuity, intraocular pressure, central foveal thickness (CFT)
and the presence of neovascular glaucoma (NVG).
Results: Of the
15 patients, 4 (27%) had non-ischemic and 11 (73%) had ischemic CRVO. A
significant reduction in CFT, compared with baseline values, was observed in
the whole group of CRVO patients at 2, 12 and 24 months (p=0.001, 0.017 and
0.022, respectively). A significant decrease in b-wave amplitudes of combined
rod-cone response and of single-flash cone response of the full-field ERG was
observed 12 months after treatment, while the reduction in the b-wave
amplitudes of 30 Hz flicker response of the full-field ERG was significant
compared with baseline values in all studied CRVO patients at both 2 and 12
months (p=0.046, 0.008, 0.021 and 0.030, respectively). Three of the eleven
patients with ischemic CRVO (27%) developed NVG, on average, 18 months after
CRVO debut.
Conclusion: This
study revealed a decrease in retinal function at 12 months in CRVO patients
undergoing serial intravitreal injections for macular edema after CRVO. The
treatment did not prevent the development of NVG in ischemic CRVO.
Keywords: Central retinal vein occlusion, Intravitreal injections, Full-field electroretinography, Retinal function
INTRODUCTION
Central retinal vein occlusion (CRVO) is a common sight-threatening retinal vascular disease in the elderly. CRVO affects 0.8 per 1000 persons and the incidence increases significantly with age [1]. Systemic hypertension and vascular disease are important risk factors for CRVO in patients older than 50 years [2]. Further risk factors for CRVO have been found to be diabetes mellitus, hyperlipidemia, black race, male sex, diagnosis of stroke, blood hyper viscosity and thrombophilia. Ophthalmic risk factors for CRVO have also been reported, including ocular hypertension, glaucoma and changes in the retinal arteries [2,3].
Studies on the natural visual outcome of CRVO have shown the major causes of vision loss to be macular edema and neovascularization with secondary neovascular glaucoma (NVG) and/or vitreous hemorrhages [4-6]. CRVO can be divided into non-ischemic and ischemic types. The risk of neovascular complications in patients with CRVO is related to the extent of retinal capillary non-perfusion, which can be evaluated with fluorescein angiography (FA) [7-9] and full-field electroretinography (full-field ERG). The cone b-wave implicit times, in both photopic and scotopic 30 Hz flicker ERG have been found to be significantly correlated with the degree of retinal ischemia [10-14], as well as with the concentration of vascular endothelial growth factor (VEGF) in the aqueous humor of CRVO eyes [15].
An evidence-based systemic study on
clinical course of CRVO showed that untreated CRVO eyes, including non-ischemic
CRVO, had poor visual acuity, which declined further over time. One third of
eyes with non-ischemic CRVO became ischemic over a 3 year period, while in 30%
of the non-ischemic CRVO eyes macular edema resolved and NVG was rare. In
ischemic CRVO eyes, NVG developed in at least 23% of the eyes within 10 months
and ischemic CRVO cases had poor baseline and final vision [16].
VEGF is a hypoxia-inducible angiogenic
peptide; a potent growth factor for vascular endothelial cells, which promotes
neovascularization and increases vascular permeability in patients with
ischemic retinal diseases [17-21]. Anti-VEGF therapy at an early stage of
retinal disease has been shown to be beneficial for visual recovery [19-21].
Retinal ischemia and vascular damage in CRVO eyes result in a breakdown of the
inner blood-retinal barrier and disruption of this barrier is associated with
complex cellular processes that lead to the release of angiogenic and
inflammatory cytokines [22]. These cytokines have been found to be
overexpressed in the aqueous humor or vitreous fluid of CRVO eyes [23-27]. Both
anti-VEGF-therapy and treatment with intravitreal corticosteroid-based agents
have been found to be effective in reducing the intraocular level of cytokines
and in the reduction of macular edema due to CRVO [25-27].
Since 2010, intravitreal anti-VEGF agents,
such as ranibizumab, bevacizumab and recently aflibercept and
corticosteroid-based agents, such as dexamethasone and preservative-free
triamcinolone, have been used for the treatment of macular edema-associated
with CRVO and replaced the recommendations of the Central Retinal Vein
Occlusion Study (CVOS) [28,29]. Three large prospective randomized controlled
studies on the treatment of macular edema after CRVO (CRUISE, GALILEO and
COPERNICUS) have demonstrated that repeated intravitreal injections of
ranibizumab (in the CRUISE study) and aflibercept (in the GALILEO and
COPERNICUS studies) improved visual and anatomic outcomes at follow-up compared
to observation [30-33].
Anti-VEGF intravitreal injections were
generally well tolerated and their use quickly replaced standard of care for
CRVO-associated macular edema recommended by CVOS [28,29,34-36]. However,
long-term results from the extension studies for CRUISE, COPERNICUS and GALILEO
demonstrated a decline in visual and anatomic improvements in CRVO eyes when
CRVO patients were monitored at least every 3 months and treated with fewer
anti-VEGF injections [37-39]. Corticosteroid-based intravitreal injections for
the treatment of macular edema-associated with CRVO, including the
dexamethasone implant and triamcinolone acetonide used as off-label agent,
decrease macular edema in CRVO eyes in the same way as anti-VEGF agents, by
reducing vascular permeability, downregulating inflammatory mediators and
inhibiting VEGF [40,41]. In the SCORE and GENEVA studies it has been found that
intravitreal injections of corticosteroids for the treatment of macular edema
associated with CRVO were superior to observation regarding visual and
anatomical improvements in CRVO eyes [40-42]. Long-term visual and anatomical
outcomes have been reported to be similar to those with dexamethasone implants
and anti-VEGF agents in CRVO eyes treated for macular edema [43]. However, intravitreal
corticosteroid treatment has been associated with a higher frequency of adverse
effects, including the elevation of intraocular pressure (IOP) and cataract
formation or progression [35,40,43-47].
It has been suggested that anti-VEGF
therapy may not only reduce macular edema in CRVO eyes and improve vision, but
may also prevent the deterioration of retinal perfusion and promote reperfusion
[48-51]. In contrast, the SCORE study and post hoc analysis of the pooled data
from the GENEVA study showed that intravitreal corticosteroid treatment was not
associated with lower incidences of neovascular events or less global
(peripheral and macular) non-perfusion compared with observation. The area of
global non-perfusion increased from baseline to the end of the studies and was
similar in treated and untreated eyes [52,53]. Using wide-field FA (WFFA), it
has been shown that the area of peripheral retinal non-perfusion may vary in
CRVO eyes and may affect the clinical course and the response to treatment of these
eyes [54]. Wykoff et al. [55] performed serial WFFA on 12 ischemic CRVO eyes
over a period of 3 years. All eyes demonstrated extensive areas of retinal
peripheral non-perfusion at baseline, and the area of retinal non-perfusion
increased in all eyes during treatment with ranibizumab, with a mean loss of
approximately 8.1% of the perfused retinal area per year.
The Rubeosis Anti-VEGF (RAVE) study [56]
and two retrospective studies [57,58] on neovascular events in eyes with CRVO
treated with anti-VEGF showed that anti-VEGF therapy could improve retinal
anatomy and vision in eyes with ischemic CRVO, but it did not prevent ocular
neovascularization.
Quantifying the extent of global retinal
non-perfusion in patients with CRVO using FA or WFFA is very difficult and very
subjective and an electrophysiological method such as full-field ERG may be a
more appropriate, objective method for the evaluation of the total retinal
function before and after anti-VEGF or intravitreal corticosteroid therapy for
macular edema associated with CRVO. Only a few studies have been performed to
evaluate the retinal function before and after intravitreal treatment of CRVO
patients using full-field ERG [59,60].
The aim of this prospective study was thus
to evaluate the retinal function and structure in patients with macular edema
due to non-ischemic and ischemic CRVO, using full-field ERG and optical
coherence tomography (OCT), before and after serial intravitreal injections.
PATIENTS AND METHODS
The study was approved by the Ethics Committee
of Lund University and all participants gave their written informed consent
according to the principles outlined in the Universal Declaration of Helsinki.
Fifteen patients with macular edema
secondary to CRVO who were examined with full-field ERG within 1 month of
symptom onset and treated with intravitreal injections (dexamethasone implant
and aflibercept) were included in this study. They were also examined with
full-field ERG 2 and 12 months after the start of the intravitreal treatment.
Patients with glaucoma, ocular inflammation or cloudy media due to cataract,
keratopathy or vitreous hemorrhage were excluded. The patients were divided
into two groups: a non-ischemic (n=4) and an ischemic CRVO group (n=11). Two
patients in the ischemic CRVO group did not undergo full-field ERG at 12
months; one because of death (not related to the intravitreal treatment) and
the other refused to undergo full-field ERG but completed all other tests at 12
months. All 15 patients received one intravitreal dexamethasone implant
injection at the beginning of the study, after which they had the possibility
to switch to aflibercept or continue with dexamethasone. Only three patients
continued with dexamethasone treatment (two of them had two intravitreal
dexamethasone implant injections and one of them had five intravitreal
dexamethasone implant injections before changing to aflibercept).
CRVO was classified as non-ischemic if the
cone b-wave implicit time in the 30 Hz flicker ERG was ≤ 37 ms and as ischemic
if the cone b-wave implicit time was >37 ms [11]. Visual and ophthalmoscopic
findings and capillary non perfusion findings on FA were also used to classify
CRVO in the present study [7-10]. Macular edema was retreated if the best
corrected visual acuity (BCVA) decreased by more than five ETDRS-letters and/or
the central foveal thickness in OCT increased by more than 100 µm. Patients
with 2 clock hours’ iris neovascularization or any angle neovascularization and
IOP greater than 22 mm Hg were defined as having NVG.
Ocular examination
All the CRVO patients had undergone
clinical ophthalmological examination including BCVA, Early Treatment Diabetic
Retunopathy Study (ETDRS-letters), measurement of IOP (Goldman applanation
tonometry), slit-lamp examination, biomicroscopy, gonioscopy and OCT
examination at the debut of CRVO and then monthly for 6 months, and thereafter
every two months for 18 months.
Full-field electroretinography
Full-field electroretinograms were recorded
with an Espion E2 analysis system (Diagnosys, LLC, Lowell, MA, USA) after the
pupil had been dilated with topical 1% cyclopentolate and 10% phenylephrine,
and the subject’s eyes had been dark-adapted for 40 min. After topical
anesthesia of the eye, a Burian-Allen bipolar contact lens was applied to the cornea,
and the ground electrode to the forehead. Responses were obtained with a
wide-band filter (-3 dB at 1 Hz and 500 Hz), while stimulating with brief (30
µs) full-field flashes of dim blue light (0.0045 cd•s/m2) to elicit
rod response and with white light (3 cd•s/m2) to elicit the combined
rod-cone response. Cone responses were obtained with 30 Hz flickering white
light (3 cd•s/m2) averaged over 20 sweeps and single-flash white
light (3 cd•s/m2). The background luminance was 30 cd/m2.
The recording procedures were the same as those prescribed in the standard
protocol for clinical electroretinography recommended by the International
Society for Clinical Electrophysiology of Vision (ISCEV) [61].
Optical coherence tomography
OCT was performed using the spectral domain
3D OCT-1000, version 3.00 software (Topcon, Tokyo, Japan). The 3D macular scan
option was used in all scans in this study, centered on the fovea, covering 6 ×
6 mm, with a resolution of 512 × 128, creating an image of the whole macular
area. The fast macular thickness scan protocol was used. The central foveal
thickness (CFT) was used in the analysis. The macular thickness measurements
are given as numerical values (μm).
The primary outcome measures were the
change in the total retinal function at 2 and 12 months after treatment, as
demonstrated by full-field ERG and the secondary outcome measures were BCVA,
IOP, CFT and presence of NVG.
Treatment procedure
All 15 patients received the initial
intravitreal dexamethasone implant injections (Ozurdex, Allergan; Inc., Irvine,
CA, USA) via the pars plana under sterile conditions. The patients were then
allowed to change to 2 mg intravitreal aflibercept injections (Bayer,
Healthcare Pharmaceuticals, Berlin, Germany) or continue with dexamethasone
implant injections as needed.
STATISTICAL ANALYSIS
The data were analyzed using SPSS version
21 (SPSS Inc., Chicago, IL, USA). The Wilcoxon signed-rank test was used to
determine whether significant changes had occurred between baseline, 2 and 12
months and the final examination within each CRVO group and the Mann-Whitney
U-test was used to compare ordinal parameters between the two study groups.
Categorical variables were compared between the two study groups using Fisher’s
exact test. Values of p ≤ 0.05 were considered to show statistical
significance.
RESULTS
Of the 15 patients studied 4 (27%) had
non-ischemic CRVO and 11 (73%) had ischemic CRVO. No significant difference was
observed between the non-ischemic and ischemic CRVO groups regarding sex, age,
time from CRVO debut to treatment, follow-up period, number of dexamethasone
implant or aflibercept injections, ocular complications or lens status (Table 1).
Analysis of the whole group
of CRVO patients
A significant improvement in BCVA
(ETDRS-letters) was observed, from 46.0 ± 17.0 letters to 60.0 ± 20.4 letters
(p=0.001) 2 months after the intravitreal injections. The mean BCVA decreased
at 12 months to 45.0 ± 28 letters (p=0.789) and was almost unchanged, 45.0 ±
27.0 letters, 24 months after retreatments, compared with baseline (p=0.972) (Figure 1 and Table 2). A significant
increase in IOP was observed, from 19.0 ± 6.0 mm Hg at baseline to 23.0 ± 8.0
mm Hg (p=0.045) 2 months after the intravitreal injection. The mean IOP
decreased both 12 and 24 months after treatment and there was no significant
difference compared with baseline (p=0.893 and 0.953, respectively) (Figure 2 and Table 2). The mean CFT
decreased significantly, from 679.0 ± 166.2 µm at baseline to 284.0 ± 107.1 µm
(p=0.001) 2 months after the intravitreal injection. A different but still
significant improvement in CFT was also observed both 12 and 24 months after
treatment, compared with baseline (p=0.017 and 0.022, respectively) (Figure 3 and Table 2).
The changes in full-field ERG response for the whole group of CRVO
patients during the study period are given in Table 3. The a- and b-wave amplitudes of combined rod-cone and
single-flash response and the b-wave of rod and 30 Hz flicker response of the
full-field ERG decreased both 2 and 12 months after treatment, compared with
baseline values (Figures 4-6 and Table
3). The b-wave amplitudes of combined rod-cone response and of single-flash
cone response were significantly decreased 12 months after treatment, compared
with baseline (p=0.046 and 0.008, respectively) (Figures 4 and 5 and Table 3). The b-wave amplitudes of 30 Hz
flicker response (cone response) decreased significantly in all CRVO patients
studied, both 2 and 12 months after treatment, compared with baseline (p=0.021
and 0.030, respectively) (Figure 6 and
Table 3).
Analysis of the group with
non-ischemic CRVO
No significant improvement in BCVA was observed 2 months after
treatment (73.3 ± 4.0 letters) compared with baseline values (58.0 ± 10.0
letters) (p=0.068) and the mean BCVA decreased slightly 12 and 24 months after
treatment, compared with baseline values (p=0.066 and 0.144) (Figure 1 and Table 2). No significant
changes in IOP were observed during the whole study period, compared with
baseline (Figure 2 and Table 2). The
mean CFT decreased from 641.0 ± 70 µm at baseline to 221.3 ± 49.0 µm 2 months
after treatment and increased slightly at 12 and 24 months after treatment,
compared with baseline values (p=0.068, 0.068 and 0.068, respectively) (Figure 3 and Table 2).
The b-wave amplitudes of rod, combined rod-cone and 30 Hz flicker
response of the full-field ERG increased 2 months after treatment, compared
with baseline, but the increase did not reach statistical significance
(p=0.460, 0.465 and 0.465, respectively) (Table
4). In contrast, the b-wave amplitudes of rod, combined rod-cone and 30 Hz
flicker response of the full-field ERG showed a decrease 12 months after
treatment, compared with baseline, but the decrease did not reach statistical
significance (p=0.099, 0.465 and 0.465, respectively) (Table 4).
Analysis of the group with
ischemic CRVO
A significant improvement was observed in BCVA, from 44.4 ± 17.0
letters at baseline to 55.1 ± 22.0 letters 2 months after the intravitreal
injection, compared with baseline values (p=0.007) (Table 2). No significant changes in IOP were observed at any point
in time during the study, compared with baseline values (Table 2). The mean BCVA decreased from 44.4 ± 17.0 letters at
baseline to 35.0 ± 26.4 letters at 12 months and to 37.4 ± 27.0 letters at 24
months (p=0.236 and 0.514, respectively) (Table
2).
The mean CFT decreased significantly, from 692 ± 191.0 µm at baseline
to 307.0 ± 115.0 µm 2 months after the intravitreal injection (p=0.003). No
significant improvement in CFT was observed after 12 or 24 months of treatment,
compared with baseline (0.083 and 0.114, respectively) (Table 2).
The a-wave and b-wave amplitudes of rod, combined rod-cone,
single-flash and the b-wave amplitudes of 30 Hz flicker response of the
full-field ERG decreased both 2 and 12 months after treatment, compared with
baseline, but the decrease was only statistically significant for b-wave
amplitudes of single-flash response 12 months after treatment, compared with
baseline values (p=0.008) and for b-wave amplitudes of 30 Hz flicker response
both 2 and 12 months after treatment, compared with baseline (p=0.006 and
0.033, respectively) (Table 5).
Three of 11 (27%) patients with ischemic CRVO developed NVG (8, 19 and
29 months after CRVO debut or after 18 months, on average). There were no
incidents of endophtalmitis, retinal tears or retinal detachment. No serious
non-ocular adverse events occurred.
DISCUSSION
Intravitreal injections of dexamethasone implant and aflibercept were
effective in bringing about a significant reduction of CFT, compared with
baseline values, in the whole group of CRVO patients during the treatment period
in the present study. Patients with non-ischemic CRVO showed a more marked
reduction in CFT than those with ischemic CRVO. A significant reduction in CFT,
compared with baseline values, has been reported 6 months after anti-VEGF
therapy, which was maintained 12 months after repeated ranibizumab injections
for macular edema following CRVO in the CRUISE study [30,31] and after repeated
aflibercept injections in the COPERNICUS study [32] and the GALILEO study [33].
The mean BCVA improved significantly 2 months after the treatment in
the whole group of CRVO patients, compared with baseline values, but the visual
gains were diminished 12 and 24 months after treatment, despite the monitoring
every two months and repeated aflibercept or dexamethasone implant injections
as needed. Patients with ischemic CRVO exhibited the greatest visual loss,
nearly 20 letters, both at 12 and 24 months, while patients with non-ischemic
CRVO showed insignificant visual loss, ≤ 3 letters, 12 and 24 months after
treatment. These findings are in contrast to the results of several previous
studies, where it was reported that visual gains achieved with 6 monthly
injections of ranibizumab, bevacizumab or aflibercept in patients with macular
edema after CRVO were maintained 12 months after treatment [30,31,59,62].
The reason for the poorer worse visual results observed after 12 months
in the present study could be the high percentage of patients with ischemic
CRVO. In the present study 73% of the patients had ischemic CRVO, while in the
COPERNICUS study [32] only 30% of the patients had ischemic CRVO, 14% in the
GALILEO study [33], 0.5% in the CRUISE study [31], while all the CRVO patients
in the study by Mayer et al. [62] had non-ischemic CRVO. The deterioration in
the visual acuity 12 months after treatment in the present study was unchanged
up to 24 months in both ischemic and non-ischemic CRVO patients. It has been
reported in other studies that neither the improvements in visual acuity nor
the reductions in the CFT were maintained after the first year of anti-VEGF and
dexamethasone therapy for macular edema after CRVO [37-39,63,64].
To the best of our knowledge, the present study is the first clinical
pilot study on the treatment of CRVO patients with both repeated dexamethasone
implant and aflibercept injections using full-field ERG to evaluate the total
retinal function 2 and 12 months after treatment. A significant decrease in the
b-wave amplitudes of combined rod-cone and of single-flash cone response was
observed 12 months after treatment, compared with baseline values in all
studied CRVO patients, while the reduction in b-wave amplitudes of 30 Hz
flicker response was significant compared with baseline values in all studied
CRVO patients of this study both 2 and 12 months after treatment. All patients
with ischemic CRVO also showed a significant reduction in b-wave amplitudes for
single-flash response 12 months after treatment and for b-wave amplitudes of 30
Hz flicker response 2 and 12 months after treatment.
The findings of the current study indicate a decrease in retinal
function in the whole group of CRVO patients studied, especially in patients
with ischemic CRVO, 12 months after treatment with repeated intravitreal
injections as needed. Previous electrophysiological studies on retinal function
after anti-VEGF treatment have revealed no significant changes in the scotopic
or the photopic full-field ERG amplitudes or implicit times at the end of the
follow-up period, compared with baseline values [65-68]. However, other studies
also showed a non-significant reduction in the b-wave amplitudes of the rod,
combined rod-cone and 30 Hz flicker response in scotopic full-field ERG at the
end of the follow-up period, compared with baseline values, indicating
long-term deterioration of photoreceptor function [69,70].
We have previously found a more marked reduction in retinal function in
patients with ischemic CRVO treated with bevacizumab and PRP than in those
treated with PRP only, 6 months after treatment [60]. In contrast, Topčić et
al. [59] reported significantly improved retinal function 6 and 12 months after
bevacizumab treatment of macular edema resulting from CRVO. After separating
ischemic from non-ischemic CRVO, the authors of the above study found no
improvement in the retinal function of patients with ischemic CRVO 12 months
after treatment.
There are two possible reasons for the decrease in retinal function in
CRVO patients after intravitreal injections in this study. The first could be
progressive ischemia associated with the natural development of CRVO. Hayreh et
al. [6] and McIntosh et al. [16] have reported that progressive ischemia
develop when CRVO is untreated. It has also been reported that up to 34% of
eyes with non-ischemic CRVO become ischemic CRVO over a 3 year period and that
23% of eyes with ischemic CRVO developed NVG within 15 months [16]. In the
present study, 3 of 11 of the patients with ischemic CRVO (27%) developed NVG
an average of 18 months after CRVO debut, and treatment with intravitreal
injections did not prevent the progression of retinal ischemia in the eyes of
these patients.
The second factor that could contribute to the decrease in retinal
function could be direct effects of the dexamethasone or aflibercept on the
function of the photoreceptors through damage to the choriocapillaris or the
photoreceptors, especially in patients with ischemic CRVO. A significant
reduction in choriocapillaris endothelial cell fenestration and segmental
occlusion by thrombocytes and leukocytes, which influenced circulation and
impaired nutritional provision to the photoreceptors, has been found in primate
eyes treated with bevacizumab [71].
Marneros et al. [72] have also shown that VEGF was essential for the
development and maintenance of the choriocapillaris. Mutant mice that lack VEGF
expression in the retinal pigment epithelium showed morphologic abnormalities
in the retinal pigment epithelium and photoreceptors. Furthermore, both a and b
wave amplitudes of scotopic full-field ERG response were significantly reduced
in these mice compared to the full-field ERG response of control mice [72].
VEGF-A has been recognized as an important survival factor for the retinal
neurons and a critical neuroprotectant during ischemic injury by increasing the
blood flow to the retina and decreasing the number of apoptotic retinal cells.
Chronic inhibition of VEGF-A by anti-VEGF agents reduces macular edema and the
neovascularization, but also simultaneously reduces the neuro protective effect
of VEGF-A [73]. Anti-VEGF injections have been associated with increased
apoptosis in retinal photoreceptor cells, reduced retinal thickness of the
inner and outer layer of the retina and a significant reduction in both a and b
wave amplitudes of full-field ERG response [74,75]. VEGF blocking may increase
the progression of retinal non perfusion and, secondarily, decrease retinal
function as measured by full-field ERG. However, it was not possible to
ascertain this it in the present study as we did not evaluate untreated CRVO
eyes longitudinally. Leaving patients untreated would be unethical.
Although a significant reduction in CFT was seen in CRVO patients
undergoing serial intravitreal injections in this study, the retinal function
was not improved at 12 months and the treatment did not prevent the development
of NVG in ischemic CRVO. NVG occurred in 27% of patients with ischemic CRVO
undergoing anti-VEGF therapy in this study an average of 18 months after CRVO
debut. Our findings concerning NVG are similar to those in previous studies on
CRVO patients undergoing serial anti-VEGF injections [56-58].
Ryu et al. [57] reported that NVG occurred at 19.7 months after CRVO
debut and they concluded that although anti-VEGF therapy for macular edema,
especially in patients with ischemic CRVO, does not prevent the development of
ocular neovascularization, it may be delayed compared to the natural
development of CRVO-associated neovascularization. The RAVE study [56] has also
shown that anti-VEGF therapy can improve retinal anatomy and vision in eyes
with ischemic CRVO, but neurovascular complications were not prevented by VEGF
inhibition, only delayed. The SCORE-study [52] has also shown that
triamcinolone treatment was not associated with lower incidences of
neurovascular events or non-perfusion status, compared with observation. In a
more recent study by Wykoff et al. [55] using WFFA, a progressive loss of the
retinal perfusion was observed in ischemic CRVO eyes undergoing anti-VEGF
therapy. However, Campochiaro et al. [48] reported anti-VEGF therapy to have a
protective effect on retinal vascular perfusion.
Our study has several limitations, including the small number of
patients in each group, the lack of a control group to evaluate untreated CRVO
eyes longitudinally and a short follow-up period.
CONCLUSION
This study revealed a decrease in total retinal function, measured by
full-field ERG, at 12 months in patients undergoing repeated intravitreal
injections of dexamethasone implant and aflibercept using as needed dosing. The
treatment did not prevent the development of NVG in ischemic CRVO. Further
electrophysiological studies with longer follow-up periods and a control group
consisting of untreated CRVO eyes are needed to clarify the long-term effects
of anti-VEGF therapy on the retinal photoreceptor cells, especially in retinal
diseases with severe retinal ischemia.
ACKNOWLEDGEMENT
This study was
supported by Stiftelsen för synskadade I f.d. Malmöhus län and Skane University
Hospital.
DISCLOSURE
The authors report no conflicts of interest in this work.
1.
Rogers
S, McIntosh RL, Cheung N, Lim L, Wang J, et al. (2010) The prevalence of
retinal vein occlusion: Pooled data from population studies from the United
States, Europe, Asia and Australia. Ophthalmology 117: 313-319.
2.
Stem
MS, Talwar N, Comer GM, Stein JD (2013) A longitudinal analysis of risk factors
associated with central retinal vein occlusion. Ophthalmology 120: 362-370.
3.
Kolar
P (2014) Risk factors for central and branch retinal vein occlusion: A
meta-analysis of published clinical data. J Ophthalmol 2014: 724780.
4.
The
Central Vein Occlusion Study Group (1997) Natural history and clinical
management of central retinal vein occlusion. Arch Ophthalmol 115: 486-491.
5.
Hayreh
SS, Podhajsky PA, Zimmerman MB (2011) Natural history of visual outcome in
central retinal vein occlusion. Ophthalmology 118: 119-133.
6.
Hayreh
SS, Zimmerman MB (2012) Ocular neovascularization associated with central and
hemi central retinal vein occlusion. Retina 32: 1553-1565.
7.
Magargal
LE, Brown GC, Augsburger JJ, Parrish RK (1981) Neurovascular glaucoma following
central retinal vein occlusion. Ophthalmology 88: 1095-1101.
8.
Evans
K, Wishart PK, McGalliard JN (1993) Neurovascular complications after central
retinal vein occlusion. Eye 7: 520-524.
9.
Laatikainen
L, Kohner EM (1976) Fluorescein angiography and its prognostic significance in
central retinal vein occlusion. Br J Ophthalmol 60: 411-418.
10.
Larsson
J, Bauer B, Cavallin-Sjöberg U, Andréasson S (1998) Fluorescein angiography
versus ERG for predicting the prognosis in central retinal vein occlusion. Acta
Ophthalmol Scand 76: 456-460.
11.
Larsson
J, Andréasson S, Bauer B (1998) Cone b-wave implicit time as an early predictor
of rubeosis in central retinal vein occlusion. Am J Ophthalmol 125: 247-249.
12.
Larsson
J, Andréasson S (2001) Photopic 30 Hz flicker ERG as a predictor for rubeosis
in central retinal vein occlusion. Br J Ophthalmol 85: 683-685.
13.
Kjeka
O, Bredrup C, Krohn J (2007) Photopic 30 Hz flicker electro retinography
predicts ocular neovascularization in central retinal vein occlusion. Acta
Ophthalmol Scand 85: 640-643.
14.
Kjeka
O, Jansson RW, Bredrup C, Krohn J (2013) Early pan retinal photocoagulation for
ERG-verified ischemic central retinal vein occlusion. Acta Ophthalmol 91:
37-41.
15.
Yasuda
S, Kachi S, Kondo M, Ushida H, Uetani R, et al. (2011) Significant correlation
between electro retinogram parameters and ocular vascular endothelial growth
factor concentration in central retinal vein occlusion eyes. Invest Ophthalmol
Vis Sci 52: 5737-5742.
16.
McIntosh
RL, Rogers SL, Lim L, Cheung N, Wang J, et al. (2010) Natural history of
retinal vein occlusion: An evidence-based systematic review. Ophthalmology 117:
1113-1123.
17.
Jin
KL, Mao XO, Greenberg DA (2000) Vascular endothelial growth factor: Direct
neuro protective effect in in vitro ischemia. PNAS 97: 10242-10247.
18.
Aiello
LP, Avery RL, Arrigg PG, Keyt BA, Jampel HD, et al. (1994) Vascular endothelial
growth factor in ocular fluid of patients with diabetic retinopathy and other
retinal disorders. N Engl J Med 331: 1480-1487.
19.
Adamis
AP, Shima DT, Tolentino MJ Gragoudas ES, Ferrara N, et al. (1996) Inhibition of
vascular endothelial growth factor prevents retinal ischemia-associated iris
neovascularization in a non-human primate. Arch Ophthalmol 114: 66-71.
20.
Pe’er
J, Folberg R, Itin A, Gnessin H, Hemo I, Keshet E (1998) Vascular endothelial
growth factor upregulation in human central retinal vein occlusion.
Ophthalmology 105: 412-416.
21.
Boyd
SR, Zachary I, Chakravarthy U, Allen GJ, Wisdom GB, et al. (2002) Correlation
of increased vascular endothelial growth factor with neovascularization and
permeability in ischemic central vein occlusion. Arch Ophthalmol 120:
1644-1650.
22.
Kaur
C, Foulds WS, Ling EA. (2008) Blood-retinal barrier in hypoxic ischemic
conditions: Basic concepts, clinical features and management. Prog Retin Eye
Res 27: 622-647.
23.
Noma
H, Funatsu H, Mimura T, Harino S, Hori S (2009) Vitreous levels of
interleukin-6 and vascular endothelial growth factor in macular edema with
central retinal vein occlusion. Ophthalmology 116: 87-93.
24.
Noma
H, Funatsu H, Harino S, Mimura T, Eguchi S, Hori S (2011) Vitreous inflammatory
factors in macular edema with central retinal vein occlusion. Jpn J Ophthalmol
55: 248-255.
25.
Jung
SH, Kim KA, Sohn SW, Yang SJ (2014) Association of aqueous humor cytokines with
the development of retinal ischemia and recurrent macular edema in retinal vein
occlusion. Invest Ophthalmol Vis Sci 55: 2290-2296.
26.
Shchuko
AG, Zlobin IV, Iureva TN, Ostanin AA, Chernykh ER, Mikhalevich IM (2015)
Intraocular cytokines in retinal vein occlusion and its relation to the
efficiency of anti-vascular endothelial growth factor therapy. Indian J
Ophthalmol 63: 905-911.
27.
Rezar-Dreindl
S, Eibenberger K, Pollreisz A, Bühl W, Greorgopoulos M, et al. (2017) Effect of
intravitreal dexamethasone implant on intra-ocular cytokines and chemokines in
eyes with retinal vein occlusion. Acta Ophthalmol 95: e119-e127.
28.
The
central vein occlusion study group N report (1995) A randomized clinical trial
of early pan retinal photocoagulation for ischemic central vein occlusion.
Ophthalmology 102: 1434-1444.
29.
The
central vein occlusion study group M report (1995) Evaluation of grid pattern
photocoagulation for macular edema in central vein occlusion. Ophthalmology
102: 1425-1433.
30.
Brown
DM, Campochiaro PA, Singh RP, Li Z, Gray S, et al. (2010) Ranibizumab for
macular edema following central retinal vein occlusion. Ophthalmology 117:
1124-1133.
31.
Campochiaro
PA, Brown DM, Awh CC, Lee Y, Gray S, et al. (2011) Sustained benefits from
ranibizumab for macular edema following central retinal vein occlusion: Twelve
month outcomes of a phase III study. Ophthalmology 118: 2041-2049.
32.
Brown
DM, Heier JS, Clark L, Boyer DS, Vitti R, et al. (2013) Intravitreal
aflibercept injection for macular edema secondary to central retinal vein
occlusion: 1 year results from the phase 3 COPERNICUS study. Am J Ophthalmol
155: 429-437.
33.
Korobelnik
J-F, Holz FG, Roider J, Ogura Y, Simader C, et al. (2014) Intravitreal
aflibercept injection for macular edema resulting from central retinal vein
occlusion: 1 year results of the phase 3 GALILEO study. Ophthalmology 121:
202-208.
34.
Ford
JA, Clar C, Lois N, Barton S, Thomas S, et al. (2014) Treatments for macular
edema following central retinal vein occlusion: Systematic review. BMJ Open 4:
e004120.
35.
Yeh S,
Kim SJ, Ho AC, Schoenberger S, Bakri S, et al. (2015) Therapies for macular
edema associated with central retinal vein occlusion. Ophthalmology 122:
769-778.
36.
Ho M,
Liu DTL, Lam DSC, Jonas JB (2016) Retinal vein occlusions, from basics to the
latest treatment. Retina 36: 432-448.
37.
Heier
JS, Campochiaro PA, Yau L, Li Z, Saroj N, et al. (2012) Ranibizumab for macular
edema due to retinal vein occlusions: long-term follow-up in the HORIZON trial.
Ophthalmology 119: 802-809.
38.
Heier
JS, Clark WL, Boyer DS, Brown DM, Vitti R, et al. (2014) Intravitreal
aflibercept injection for macular edema due to central retinal vein occlusion.
Ophthalmology 121: 1414-1420.
39.
Ogura
Y, Roider J, Korobelnik J-F, Holz FG, Simader C, et al. (2014) Intravitreal
aflibercept for macular edema secondary to central retinal vein occlusion: 18
month results of the phase 3 GALILEO study. Am J Ophthalmol 158: 1032-1038.
40.
Ip MS,
Scott IU, VanVeldhuisen PC, Oden NL, Blodi BA, et al. (2009) A randomized trial
comparing the efficacy and safety of intravitreal triamcinolone with
observation to treat vision loss associated with macular edema secondary to
central retinal vein occlusion. The standard care vs. corticosteroid for
retinal vein occlusion (SCORE) study report 5. Arch Ophthalmol 127: 1101-1114.
41.
Campochiaro
PA, Hafiz G, Mir TA, Scott AW, Sophie R, et al. (2015) Pro-permeability factors
after dexamethasone implant in retinal vein occlusion; the ozurdex for retinal
vein occlusion (ORVO) study. Am J Ophthalmol 160: 313-321.
42.
Haller
JA, Bandello F, Belfort R Jr, Blumenkrantz MS, Gillies M, et al. (2010)
Randomized, sham-controlled trial of dexamethasone intravitreal implant in
patients with macular edema due to retinal vein occlusion. Ophthalmology 117:
1134-1146.
43.
Chiquet
C, Dupuy C, Bron AM, Aptel F, Straub M, et al. (2015) Intravitreal
dexamethasone implant versus anti-VEGF injection for treatment-naïve patients
with retinal vein occlusion and macular edema: A 12 month follow-up study.
Graefes Arch Clin Exp Ophthalmol 253: 2095-2102.
44.
Capone
A Jr, Singer MA, Dodwell DG, Dreyer RF, Oh KT, et al. (2014) Efficacy and
safety of two or more dexamethasone intravitreal implant injections for
treatment of macular edema related to retinal vein occlusion (Shasta study).
Retina 34: 342-351.
45.
Reid
GA, Sahota DS, Sarhan M (2015) Observed complications from dexamethasone
intravitreal implant for the treatment of macular edema in retinal vein
occlusion over 3 treatment rounds. Retina 35: 1647-1655.
46.
Caillaux
V, Valtot F, Souied EH, Mimoun G (2015) Intraocular pressure after intravitreal
injection of dexamethasone implant for macular edema resulting from retinal
vein occlusion. Eur J Ophthalmol 25: 454-458.
47.
Garweg
JG, Zandi S. (2016) Retinal vein occlusion and the use of a dexamethasone
intravitreal implant (Ozurdex) in its treatment. Graefes Arch Clin Exp Ophthalmol
254: 1257-1265.
48.
Campochiaro
PA, Bhisitkul RB, Shapiro H, Rubio RG (2013) Vascular endothelial growth factor
promotes progressive retinal non-perfusion in patients with retinal vein
occlusion. Ophthalmology 120: 795-802.
49.
Sophie
R, Hafiz G, Scott AW, Zimmer-Galler I, Nguyen QD, et al. (2013) Long-term
outcomes in ranibizumab-treated patients with retinal vein occlusion; the role
of progression of retinal non-perfusion. Am J Ophthalmol 156: 693-705.
50.
Campochiaro
PA, Hafiz G, Mir TA, Scott AW, Solomon S, et al. (2015) Scatter
photocoagulation does not reduce macular edema or treatment burden in patients
with retinal vein occlusion. Ophthalmology 122: 1426-1437.
51.
Mir
TA, Kherani S, Hafiz G, Scott AW, Zimmer-Galler I, et al. (2016) Changes in
retinal non-perfusion associated with suppression of vascular endothelial
growth factor in retinal vein occlusion. Ophthalmology 123: 625-634.
52.
Chan
CK, Ip MS, van Veldhuisen PC, Oden NL, Scott I, et al. (2011) SCORE study
report 11: Incidences of neovascular events in eyes with retinal vein
occlusion. Ophthalmology 118: 1364-1372.
53.
Sadda
S, Danis RP, Pappuru RR, Keane PA, Jiao J, et al. (2013). Vascular changes in
eyes treated with dexamethasone intravitreal implant for macular edema after
retinal vein occlusion. Ophthalmology 120: 1423-1431.
54.
Singer
M, Tan CS, Bell D, Sadda SR (2014) Area of peripheral retinal non-perfusion and
treatment response in branch and central retinal vein occlusion. Retina 34:
1736-1742.
55.
Wykoff
CC, Brown DM, Croft DE, Major JC Jr, Wong TP (2015) Progressive retinal
non-perfusion in ischemic central retinal vein occlusion. Retina 35: 43-47.
56.
Brown
DM, Wykoff CC, Wong TP, Mariani AF, Croft DE Schuetzle KL (2014) Ranibizumab in
pre-proliferative (ischemic) central retinal vein occlusion: The rubeosis anti-VEGF
(RAVE) trial. Retina 34: 1728-1735.
57.
Ryu
CL, Elfersy A, Desai U, Hessburg T, Edwards P, Gao H (2014) The effect of
anti-vascular endothelial growth factor therapy on the development of
neovascular glaucoma after central retinal vein occlusion: A retrospective
analysis. J Ophthalmol 2014: 317694.
58.
DeCroos
FC, Todorich B, Alshareef R, Khuthaila M, Fekrat S, et al. (2014) Neovascular
events in eyes with central retinal vein occlusion undergoing serial
bevacizumab or ranibizumab intravitreal injections: A retrospective review. J
Ophthalmic Vis Res 9: 461-468.
59.
Gardašević
Topčić I, Šuštar M, Brecelj J, Hawlina M, Mekjavić P (2014) Morphological and
electrophysiological outcome in prospective intravitreal bevacizumab treatment
of macular edema secondary to central retinal vein occlusion. Doc Ophthalmol
129: 27-38.
60.
Wittström
E, Holmberg H, Hvarfner C, Andréasson S (2012) Clinical and electrophysiologic
outcome in patients with neovascular glaucoma treated with and without
bevacizumab. Eur J Ophthalmol 22: 563-574.
61.
McCulloch
DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, et al. (2015) ISCEV Standard
for full-field clinical electroretinography (2015 update). Doc Ophthalmol 130:
1-12.
62.
Mayer
WJ, Wolf A, Kernt M, Kook D, Kampik A, et al. (2013) Twelve-month experience
with Ozurdex for the treatment of macular edema associated with retinal vein
occlusion. Eye 27: 816-822.
63.
Campochiaro
PA, Sophie R, Pearlman J, Brown DM, Boyer DS, et al. (2014) Long-term outcomes
in patients with retinal vein occlusion treated with ranibizumab. The RETAIN
study. Ophthalmology 121: 209-219.
64.
Moisseiev
E, Goldstein M, Waisbourd M, Barak A, Loewenstein A (2013) Long-term evaluation
of patients treated with dexamethasone intravitreal implant for macular edema
due to retinal vein occlusion. Eye 27: 65-71.
65.
Lüke
M, Warga M, Ziemssen F, Gelisken F, Grisanti S, et al. (2006) Effects of
bevacizumab on retinal function in isolated vertebrate retina. Br J Ophthalmol
90: 1178-1182.
66.
Stahl
A, Feltgen N, Fuchs A, Bach M (2009) Electrophysiological evaluation of retinal
photoreceptor function after repeated bevacizumab injections. Doc Ophthalmol
118: 81-88.
67.
Ziemssen
F, Lüke M, Messias A, Beutel J, Tatar O, et al. (2008) Safety monitoring in
bevacizumab (Avastin) treatment: Retinal function assessed by psychophysical
(visual fields, color vision) and electrophysiological (ERG/EOG) tests in two
subgroups of patients. Int Ophthalmol 28: 101-109.
68.
Januschowski
K, Schnichels S, Hagemann U, Koch V, Hofmann J, et al. (2014)
Electrophysiological toxicity testing of VEGF Trap-Eye in an isolated perfused
vertebrate retina organ culture model. Acta Ophthalmol 92: e305-e311.
69.
Shetty
R, Pai SA, Vincent A, Shetty N, Narayana KM, et al. (2008) Electrophysiological
and structural assessment of the central retina following intravitreal
injection of bevacizumab for treatment of macular edema. Doc Ophthalmol 116:
129-135.
70.
Bjerg
Pedersen K, Møller F, Sjølie AK, Andréasson S (2010) Electrophysiological
assessment of retinal function during 6 months of bevacizumab treatment in neovascular
age-related macular degeneration. Retina 30: 1025-1033.
71.
Peters
S, Heiduschka P, Julien S, Ziemssen F, Fietz H, et al. (2007) Ultra structural
findings in the primate eye after intravitreal injection of bevacizumab. Am J
Ophthalmol 143: 995-1002.
72.
Marneros
AG, Fan J, Yokoyama Y, Gerber HP, Ferrara N, et al. (2005) Vascular endothelial
growth factor expression in the retinal pigment epithelium is essential for
choriocapillaris development and visual function. Am J Pathol 167: 1451-1459.
73.
Nishijima
K, Ng Y-S, Zhong L, Bradley J, Schubert W, et al. (2007) Vascular endothelial
growth factor-A is a survival factor for retinal neurons and a critical neuro
protectant during the adaptive response to ischemic injury. Am J Pathol 171:
53-67.
74.
Avci
B, Avci R, Inan ÜÜ, Kaderli B (2009) Comparative evaluation of apoptotic
activity in photoreceptor cells after intravitreal injection of bevacizumab and
pegaptanib sodium in rabbits. Invest Ophthalmol Vis Sci 50: 3438-3446.
75.
Saint-Geniez
M, Maharaj ASR, Walshe T, Tucker BA, Sekiyama E, et al. (2008) Endogenous VEGF
is required for visual function: Evidence for a survival role on Müller cells
and photoreceptors. PLoS 3: e3554.
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