Graefes Arch Clin Exp Ophthalmol
DOI 10.1007/s00417-014-2845-6
RETINAL DISORDERS
Subthreshold grid laser versus intravitreal bevacizumab
as second-line therapy for macular edema in branch retinal vein
occlusion recurring after conventional grid laser treatment
M. Battaglia Parodi & P. Iacono & F. Bandello
Received: 2 July 2014 / Revised: 22 October 2014 / Accepted: 24 October 2014
# Springer-Verlag Berlin Heidelberg 2014
Abstract
Purpose To compare the effects of subthreshold grid laser
treatment (SGLT) and intravitreal bevacizumab injection
(IVBI) for the treatment of macular edema (ME) secondary
to branch retinal vein occlusion (BRVO) recurring after con-
ventional grid laser photocoagulation.
Methods Thirty-five eyes were considered in this prospective,
randomised, interventional study and treated with micropulse
diode laser (SGLT subgroup) or IVBI (IVBI subgroup). SGLT
was administered once, whereas IVBI (1.25 mg) was given at
baseline and then on a pro re nata regimen according to ME
presence on optical coherence tomography (OCT), performed
at monthly examinations over a 12-month follow-up. Primary
outcome measures were the mean BCVA changes over the
follow-up and the decrease in mean central foveal thickness
(CFT) on optical coherence tomography (OCT). Secondary
outcomes included the proportion of eyes that gained at least
15 letters (approximately three lines) at the 12-month
examination.
Results Eighteen and 17 patients were assigned to SGLT and
IVBI subgroups, respectively. At baseline, the subgroups were
similar with regard to mean ME duration, BCVA, and CFT. At
month 12, mean CFT significantly improved from 484 μm to
271 μm in the IVBI subgroup, whereas it was unchanged in
the SGLT subgroup. Mean BCVA changed from 0.92±0.3
(LogMAR) to 0.99±0.2 in the SGLT subgroup; in the IVBI
The authors have no proprietary/financial interest in any of the products
mentioned in the study.
M. B. Parodi (*) : F. Bandello
Department of Ophthalmology, University Vita-Salute, San Raffaele
Scientific Institute, Via Olgettina, 60, 20132 Milano, Italy
e-mail: maubp@yahoo.it
P. Iacono
Fondazione G. B. Bietti per l’Oftalmologia, IRCCS (Istituto di
Ricovero e Cura a Carattere Scientifico), Roma, Italy
subgroup, mean BCVA showed a statistically significant im-
provement from 0.94±0.3 to 0.72±0.2. Ten patients in the
IVBI subgroup (58 %) and no patient in the SGLT subgroup
gained at least three lines.
Conclusion At the 1-year follow-up, IVBI provided a signif-
icant functional and anatomical improvement, whereas SGLT
failed to demonstrate any beneficial effects. IVBI might be a
useful approach in the treatment of recurrent ME secondary to
BRVO already treated with conventional grid laser
photocoagulation.
UMIN registry, number UMIN000005014, URL:
http://www.umin.ac.jp/ctr/index.htm
Keywords Branch retinal vein occlusion . Macular edema .
Laser treatment
Introduction
The management of macular edema (ME) secondary to branch
retinal vein occlusion (BRVO) has greatly improved in recent
times with the introduction of a therapy based on intravitreal
injection of anti-vascular endothelial growth factor (VEGF)
molecules and steroids [1]. The Branch Vein Occlusion Study
Group had previously demonstrated that conventional grid
laser photocoagulation could improve the visual outcome
[2]. Unfortunately, this approach tended to offer limited func-
tional improvement and was associated with several compli-
cations, especially regarding the development of visible laser
scars, which tended to enlarge progressively over the follow-
up [3–5]. Moreover, ME might recur even after successful
grid laser treatment. As such, the management of recurrent
ME related to BRVO has remained controversial. Further laser
treatment is a potential option, but the application of addition-
al laser spots in a macular area already subjected to grid laser
photocoagulation would lead to greater chorioretinal damage.

Subthreshold grid laser treatment (SGLT) or intravitreal anti-
VEGF and steroid injections are possible alternatives, bearing
in mind the positive results achieved in the management of
primary ME related to BRVO [6–16]. However, no study
exists specifically designed to assess the best therapeutic
approach for recurrent ME secondary to BRVO after previous
grid laser treatment.
The aim of the present study is to compare the effects of
SGLT and intravitreal bevacizumab injection (IVBI) for the
treatment of ME secondary to BRVO recurring after conven-
tional grid laser photocoagulation.
Methods
A prospective randomized clinical trial was drawn up that
would compare the effects of SGLT with infrared micropulse
diode laser and IVBI in eyes that were both affected by
recurrent ME secondary to BRVO and had been previously
s uc c es s f u l l y t r ea t e d b y c on v e nt i o n al g r i d la s e r
photocoagluation.
The research adhered to the tenets of the Declaration of
Helsinki, and institutional review board approval was obtain-
ed. Each patient was carefully informed about the purpose of
the research, providing signed consent for all procedures. The
investigation was registered in the UMIN registry with the
number UMIN000005014. Patients affected by recurrent ME
related to BRVO observed in the outpatient department be-
tween April 2009 and April 2010 were prospectively enrolled.
Inclusion criteria were ME secondary to BRVO, previous
conventional grid laser photocoagulation with documented
resolution of ME and subsequent recurrence of ME over the
follow-up, best corrected visual acuity (BCVA) between 20/
400 and 20/40, and central foveal thickness (CFT) of at least
250 μm.
Exclusion criteria were detection of retinal capillary non-
perfusion more than five disc diameters on fluorescein angi-
ography, coexistence of any other chorioretinal disease and
presence of cataracts.
Each patient underwent a complete ophthalmological ex-
amination, including refracted BCVA on standard Early
Treatment of Diabetic Retinopathy Study charts, optical co-
herence tomography (OCT) and fluorescein angiography,
with a planned follow-up of 12 months.
BCVA measurement and OCT were performed by masked
staff members, who were unaware of the purpose of the study.
OCT (Stratus, Carl Zeiss, Meditec Inc, Germany) was per-
formed using the fast macular thickness map protocol,
consisting of six 6-mm radial lines, oriented 30° apart and
centred on the fovea. CFT was defined as the distance between
the inner retinal surface and the inner border of the retinal
pigment epithelium (RPE).
Graefes Arch Clin Exp Ophthalmol
The patient randomisation to either SGLT or IVBI was
performed by means of computer-generated, sequentially
numbered envelopes, which were stored by an investigator
unaware of the purpose of the study. A permuted block
randomisation was carried out with a final allocation ratio of
1:1.
SGLT was performed using an infrared diode laser (Iris
Medical Oculight, SLx Photocoagulator, Iridex Corp,
Mountain View, CA, USA). The laser parameters were
125 μm laser spot diameter, 0.3 s exposure and 15 % duty
cycle, while laser power was determined by means of a single
“medium” white test burn in a continuous wave. In each case,
laser burns were delivered in a contiguous mode with no free
space between the spot applications, thus covering the whole
area affected by the ME, except the zones showing the old
laser scars. Patients randomised to IVBI were treated in the
operating theatre under sterile conditions. Intravitreal
bevacizumab (1.25 mg) was injected 3.5 mm and 4.0 mm
posterior to the limbus, in pseudophakic and phakic eyes,
respectively. After the first IVBI, further injections were per-
formed in a pro re nata (PRN) regimen based on the detection
of ME on OCT.
All the patients underwent a monthly ophthalmological
examination, including OCT, over a planned follow-up of
12 months. Fluorescein angiography was carried out every
3 months.
The primary outcome measures were the decrease in mean
CFT on OCT and the mean BCVA changes over the follow-
up. Secondary outcomes included the proportion of eyes that
gained at least 15 letters (approximately three lines) at the 12-
month examination.
The study was designed to detect a difference in the CFT of
150 μm with an SD of 100 μm, as extrapolated from previous
studies applying SGLT and bevacizumab for the treatment of ME
secondary to BRVO and from an exploratory analysis carried out
by our centre [6, 17, 18]. About 20 patients (10 eyes in each arm
per group) were required to detect this difference (90 % power,
two-sided with 5 % significance level). The recruitment target
was expanded to 30 patients to compensate for possible patient
drop-out during the 12-month follow-up.
Statistical analysis was performed using the Student t-test
(paired and unpaired depending upon the groups) to evaluate
the changes of BCVA and CFT with Bonferroni corrections
employed to account for multiple comparisons. The Chi-
square test was applied for the comparison of proportion. All
tests were two-tailed and the level of significance was taken at
p <0.05.
Results
Thirty-seven patients affected by recurrent ME related to
BRVO were considered for the study, but only 35 patients
Graefes Arch Clin Exp Ophthalmol

(35 eyes) were enrolled, because two patients were found to
have cortico-nuclear cataract. The mean age of the patients
was 66.8±5.9 SD. General history revealed that 21 patients
were affected by hypertension (60 %) and five had diabetes
mellitus (13 %). Overall, the mean duration of BRVO was
29.5±4 SD months, whereas the mean duration of ME from
its onset was 27.3±4.3 SD months. In all the cases conven-
tional grid laser treatment had been performed within 6 months
from the onset of ME, resulting in the resolution of ME. ME
recurrence occurred 12.1 +/− 1.3 months after conventional
laser application.
Eighteen patients were randomly assigned to SGLT and 17
patients to IVBI (1.25 mg). All the patients were regularly
followed up and completed the 12-month study. Complete
demographic characteristics are listed in Table 1. Fluorescein
angiography showed no evidence of capillary nonperfusion at
baseline and over the follow-up.
The two groups showed similar baseline characteristics
with regard to mean age, gender distribution, duration of
ME, BCVA, and CFT. Data concerning CFT and BCVA
changes over the 12-month follow-up are recorded in Figs. 1
and 2. The results at 12 months revealed that the mean CFT
significantly improved only in the subgroup treated with
IVBI, passing from 484 μm to 271 μm (p<0.001), whereas
it was practically unmodified in the SGLT subgroup (from
485 μm to 445 μm). Indeed, CFT decreased by 44 % and 8 %
in IVBI and SGLT, respectively. At the end of the follow-up
the comparison between the two subgroups revealed a statis-
tically significant difference in favour of the IVBI subgroup (p
= 0.001).
Mean BCVA changed from 0.92 +/− 0.3 LogMAR (ap-
proximately 20/160 Snellen equivalent) to 0.99 +/− 0.2
LogMAR (approximately 20/200 Snellen equivalent, p =
0.12) in the subgroup treated with SGLT and from 0.94 +/−
0.3 LogMAR (approximately 20/160 Snellen equivalent) to
0.72 +/− 0.2 LogMAR (approximately 20/100 Snellen equiv-
alent) in the IVBI subgroup. At the end of the follow-up a,
statistically significant difference was registered in the sub-
group treated with IVBI (p = 0.0015), and a comparison of
BCVA outcomes between the two treatment subgroups
favoured the IVBI arm (p = 0.0085).
Ten patients in the IVBI subgroup (58 %) and no patient in
the SGLT subgroup gained at least three lines at the end of the
follow-up (p<0.05). The mean number of line changes was
−0.1 and +2.2 in the SGLT and IVBI subgroups, respectively.
The mean number of injections over the 12-month follow-up
in the IVBI subgroup was 6±3.2 (range 2–12).
OCT documented the persistence of ME in all the eyes
treated with SGLT, and in five eyes (29 %) treated with IVBI.
No complications secondary to the intravitreal injection or
SGLT were registered over the follow-up. Moreover, no sign
of progressive capillary non-perfusion was detected in eyes
receiving the IVBI treatment.
Discussion
Grid laser photocoagulation was previously considered the
standard of care for ME secondary to BRVO, according to
the Branch Vein Occlusion Study Group [2]. Unfortunately,
this approach afforded only limited functional improvement,
causing visible laser burns, and leading to the formation of
scars within the macular region, which invariably evolved
towards a progressive chorioretinal atrophy. The recent advent
of the intravitreal approach with anti-VEGF molecules and
steroids has completely revolutionized the management of
BRVO-related ME, significantly improving visual
outcomes[1]. An unexplored aspect concerns the treatment
of ME recurring after a successful grid laser photocoagulation.
Indeed, at present there is a distinct lack of information re-
garding the management of recurrent ME secondary to
BRVO. Re-treatments of conventional visible laser applica-
tion would cause further atrophic damage to the macular area,
and therefore, in theory, should be avoided. A laser approach
other than conventional grid laser treatment seems to offer
advantages, avoiding as it does the development of macular
scars. In a previous study, we demonstrated that SGLT was as
effective as conventional grid laser photocoagulation in eyes
with primary ME secondary to BRVO, without any visible
laser scar [6, 7]. However, anti-VEGF and steroid approaches
for primary ME have been found to ensure a greater visual
acuity improvement, greatly surpassing the results achievable
by means of laser application [1, 8–16].
In order to cast light on the management of ME recurring in
eyes that have already undergone conventional laser treat-
ment, we designed a pilot, randomized clinical trial comparing

Table 1 Main demographic and

clinical characteristics of the pa-
tients affected by branch retinal
vein occlusion
Subthreshold grid laser treatment
Age (years) 66.6 +/− 6.7
Gender (females/males) 5/7
Duration of macular edema 28.5 +/− 4.8 months
Recurrence of macular edema 12.1 +/− 1.4 months
Baseline best-corrected visual acuity 0.92 +/− 0.31 LogMAR
Baseline central foveal thickness 485.5 +/− 87
Intravitreal bevacizumab injection
67 +/− 5.3
8/5
26.2 +/− 5.5 months
12.0 +/− 1.3 months
0.94 +/− 0.32 LogMAR
484.2 +/− 90
 Graefes Arch Clin Exp Ophthalmol

Fig. 1 Mean central foveal

thickness (CFT) (μm) values over
the follow-up. A statistically
significant improvement in the
CFT in comparison with the
baseline values was demonstrated
in IVBI groups from the 3-month
examination on. A substantial
stabilization in the mean CFT was
noted in the SGLT group over the
follow-up. (IVBI, intravitreal
bevacizumab injection; SGLT,
subthreshold grid laser treatment)

SGLT and IVBI. Our results clearly indicate that the IVBI
approach can yield a positive outcome, attaining a three-line
gain in 58 % of cases, even in eyes already treated with
conventional grid laser photocoagulation. These data are con-
sistent with the results of previous studies scheduling anti-
VEGF or steroids, including the BRAVO, SCORE,
GENEVA, and RABAMES trials [1, 8–16].
Nevertheless, our investigation also points out that SGLT is
completely ineffective in the management of recurrent ME.
Although it is hard to tell exactly why this should be so, we
believe that the presence of a retinal pigment epithelium
(RPE) exhibiting prior damage caused by long-term persis-
tence of ME and the previous laser treatment may limit the
efficacy of SGLT, which is thought to stimulate RPE cells,
rather than destroy them [19]. IVBI acts in a different manner
compared with SGLT, the underlying mechanism being the
vascular endothelial growth factor antagonism on vascular
permeability. It is worth noting that the overall BCVA
improvement turned out to be limited even in the subgroup
randomised to IVBI, with a mean change from 20/160 to 20/
100 at the end of the follow-up, probably depending on the
advanced stage of ME.
We are aware that our study has several limitations. The
design did not include a treatment masking, but only a masked
assessment of the effects. A more precise study design might
have also included sham-injection or sham-SGLT in both
subgroups. On the other hand, this analysis was designed as
a pilot study providing material for future research, for in-
stance, into the potential of intraocular steroid injection.
Moreover, our SGLT treatment protocol, with its single laser
application over the whole follow-up, could be inappropriate.
In particular, bearing in mind the previous conventional grid
laser treatment and consequent development of macular atro-
phic scars, we considered the number of retinal cells likely to
be sensitive to subthreshold laser would be limited and thus
potentially require longer for the clinical effects to become

Fig. 2 Best-corrected visual

acuity (BCVA, LogMAR) values
over the follow-up. In comparison
with the baseline values, BCVA
significantly improved at
12 months only in the subgroups
receiving IVBI. (IVBI,
intravitreal bevacizumab
injection; SGLT, subthreshold
grid laser treatment)
Graefes Arch Clin Exp Ophthalmol
visible. We, therefore, decided to allow the SGLT to develop
its effects within 12 months. However, in view of the almost
complete absence of effects, we believe that even a different
approach with repeated SGLT applications would not yield
more beneficial results.
In essence, IVBI can be regarded as a useful option in the
treatment of recurrent ME secondary to BRVO that has al-
ready been treated with conventional grid laser photocoagu-
lation, whereas SGLT is not able to ensure the resolution of
ME. Further studies are warranted in order to establish the best
therapeutic approach for recurrent ME secondary to BRVO.
Conflict of Interest Statement All authors contributing to the present
paper certify that they have no financial interest or non-financial interest
in the subject matter or materials discussed in this manuscript.
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