JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS

Volume 28, Number 5, 2012

ª Mary Ann Liebert, Inc.
DOI: 10.1089/jop.2012.0035

Comparison of Needle Revision with Subconjunctival

Bevacizumab and 5-Fluorouracil Injection
of Failed Trabeculectomy Blebs

Tulay Simsek, Ali B. Cankaya, and Ufuk Elgin

Abstract

Purpose: To evaluate the efficacy and complications of bevacizumab versus 5-fluorouracil (5-FU)-augmented
bleb needling of failed filtration blebs following trabeculectomy.
Methods: Twenty-seven eyes of 27 patients with bleb failure were included. Patients were randomly assigned to
receive either 5-FU or bevacizumab. Needling was performed in the operating room under sterile conditions.
After the needling procedure, a viscoelastic material was injected subconjunctivally around the bleb area to
avoid the entrance of 5-FU or bevacizumab into the anterior chamber. Bevacizumab (1.25 mg/0.1 mL) was
injected into 12 eyes and 5-FU injected into 15 eyes subconjunctivally. All of the patients were controlled weekly
until a filtration bleb was maintained. Intraocular pressure (IOP), bleb appearance, and complications were
noted in each group. Success was defined as absolute if the IOP 21 mmHg or less without any medication or
surgical intervention at last visit, and qualified if the IOP 21 mmHg or less with topical antiglaucomatous
medications. The patients were followed from 11 to 26 (median, 17) months.
Results: The IOP decreased, from 31.2 – 3.2 mmHg to 16.1 – 2.1 mmHg, in the bevacizumab group on the first
postoperative day. The IOP was within normal limits in 1 (8.3%) patient without medication and controlled with
topical antiglaucomatous drops in 2 (16.7%) patients. The total success rate was 25% at the time of the last visit.
Success was not achieved in 9 (75%) eyes. The IOP was 32.0 – 4.6 mmHg preoperatively and 12.2 – 2.6 mmHg on
the first postoperative day in the 5-FU injected patients. The total success rate was 80%; 8 (53.3%) eyes showed
absolute success, whereas 4 (26.7%) eyes showed a qualified success. A statistically significant difference be-
tween groups in terms of success rates was observed (P = 0.04).
Conclusions: Subconjunctival 5-FU application is a more effective therapy than bevacizumab application for
needling procedures in failed trabeculectomy blebs.

Introduction effective in the early postoperative period.4–9 However,

these approaches fail to rescue bleb function in late bleb

T rabeculectomy is the most common filtration proce-

dure in the surgical treatment of glaucoma. The success
rate following trabeculectomy has been reported to be 67%–
94% in different studies.1 Despite the increasing use of an-
tifibrotic agents to modulate the wound-healing response,
bleb failure remains a common complication of glaucoma
filtration surgery. The rate of bleb failure has been reported
to be as high as 10%–20%.2–6 Subconjunctival and episcleral
fibrosis over the fistula represent the most common mech-
anism of bleb failure. Numerous approaches for managing
failed filtration blebs have been described. Massage, scleral
flap suture lysis, and releasable suture removal may be
failure.
Needle revision with or without antifibrotic agents is an
effective and simple method of restoring bleb function. 5-
fluorouracil (5-FU) inhibits fibroblast proliferation, modu-
lates the wound-healing process, and increases the success
rate of glaucoma filtration surgery.4,5 Subconjunctival 5-FU
application has been used in the early postoperative period
alone, or with needle revision in bleb failure following tra-
beculectomy.5,8 Adjuvant subconjunctival mitomycin-C
(MMC) application during bleb needle revision has also been
reported.7,9 Although MMC and 5-FU help to prevent scar
formation in the bleb area, they may cause widespread

Glaucoma Division, Ulucanlar Training and Research Eye Hospital, Ankara, Turkey.
This study was carried out at the Ulucanlar Training and Research Eye Hospital.

542
NEEDLING AND BEVACIZUMAB OR 5-FLUOROURACIL APPLICATION FOR FAILED BLEBS
nonselective cell death and apoptosis.10 Therefore, the use
of these agents is associated with sight-threatening compli-
cations such as hypotony, blebitis, endophthalmitis, and
wound leakage.
Bevacizumab is a full-length humanized monoclonal anti-
body directed against all isoforms of vascular endotelial
growth factor-A. It is extensively used for metastatic colo-
rectal cancer. Wound dehiscence at the colorectal anastomosis
has been reported several months to years after original sur-
gery in patients with metastatic colorectal cancer treated with
intravenous bevacizumab.11,12 Based on this situation, it has
been proposed that bevacizumab may inhibit the wound-
healing process in a long-term period. Recent studies showed
that subconjunctival injections of bevacizamub could reduce
scarring in animal models of glaucoma.13
The key players in generating scar tissue after trabecu-
lectomy are the fibroblasts in the Tenon’s capsule. It has been
demonstrated that bevacizumab affects both vascular and fi-
broblast proliferation directly in glaucoma filtration surgery. In
addition, it modulates the inflow of proinflammatory cyto-
kines into the bleb from surrounding vessels.14 For this reason,
anti-VEGF agents may also exhibit beneficial effects during
glaucoma surgery. The use of subconjunctival injections of
bevacizumab to salvage failing blebs has been described in a
small number of case reports.15,16 To our knowledge, no re-
ported study has compared 5-FU and bevacizumab for the
needle revision of failed filtration blebs. The purpose of this
study was to compare the efficacy and complications of needle
revision and subconjunctival 5-FU-versus-bevacizumab ap-
plication in bleb failure after trabeculectomy.
Methods
This is a prospective and comparative case series of pa-
tients who underwent needle revision augmented with
bevacizumab or 5-FU for failed trabeculectomy blebs be-
tween November 2008 and February 2011. Twenty-seven
eyes of 27 patients with bleb failure were included. All of the
eyes had failing filtering procedures with or without the use
of antifibrotic agents, and an intraocular pressure (IOP)
> 21 mmHg. Signs of a failed bleb included an unacceptably
high IOP, an open corneoscleral window at gonioscopy,
vascularization, thickening and flattening of the bleb, and
loss of the conjunctival microcysts. Patients were randomly
assigned to receive either 5-FU or bevacizumab.
Demographic properties of the patients, previous surger-
ies, the type of glaucoma, antimetabolite use in last trabe-
culectomy, the time interval between the last trabeculectomy,
and the needling procedure were noted. Visual acuity test-
ing, IOP measurements, anterior segment, and fundus ex-
aminations were then performed.
A single surgeon (T.S.) performed all of the bleb revisions
using a standard protocol. The procedure was performed in
the operating room under sterile conditions. A sterile cotton
swab soaked with proparacaine was placed over the super-
otemporal quadrant for approximately 5 min. Brimonidine
eye drops were used preoperatively to prevent bleeding
from the conjunctival vessel during the procedure. With the
eye infraducted, the subconjunctival space was entered at
least 5 mm from the site of the filtration bleb using a 29-
gauge needle. Multiple passes and back and forth sweeping
movements were performed to disrupt any episcleral fibro-
sis. Careful attention was given to avoid inadvertent perfo-
543
ration of the overlying conjunctiva and subconjunctival blood
vessels. Then, the needle was moved into the bleb cavity,
underneath the scleral flap, until the fistula between the
anterior chamber and subconjunctival space was reformed. A
viscoelastic material was injected subconjunctivally around
the bleb area to avoid the entrance of 5-FU or bevacizumab
into the anterior chamber before exiting the wound. The
entry site was closed with a single 8-0 Vicryl suture when
necessary. At the end of the procedure, a single sub-
conjunctival injection of 5-FU at a dose of 5 mg/0.2 mL or
bevacizumab at a dose of 1.25 mg/0.1 mL were administered
outside the viscoelastic material. Patients were examined
daily for the first week, and weekly for the first month or as
necessary, depending on the IOP and the appearance of the
filtration bleb. Topical prednisolone acetate (1%) was ad-
ministered every 2 h while awake for the first month. The
dose was then tapered according to the clinical signs of
conjunctival inflammation and bleb function. Topical oflox-
acin (2%) eye drops were administered 5 times per day for 1
week. The patients were followed for 11–26 (median, 17)
months. In control examinations, the IOP, bleb appearance,
and complications were noted. Absolute success was defined
as an IOP 21 mmHg or less without antiglaucomatous
medications measured at the last visit. A qualified success
was defined as an IOP 21 mmHg or less with topical anti-
glaucomatous medications.
The study followed the tenets of the declaration of Hel-
sinki. Written informed consent was provided by each pa-
tient after an explanation of the nature and possible
consequences of the study. The protocol was approved by
the Institutional Ethics Committee.
Statistical analyses were performed using the SPSS soft-
ware (ver. 15.0). The normality of data was evaluated using a
Shapiro–Wilk test. Descriptive statistics were used to evalu-
ate the demographic characteristics of the patients. Differ-
ences in success rates among the groups were compared
using the chi-squared test. A statistically significant differ-
ence was defined as one with a P value < 0.05.
Results
Patients with failed filtration blebs were included (n = 27).
Table 1 shows the demographic and clinical characteristics of
the patients. No statistically significant difference between
demographic characteristics was observed (P > 0.05). No di-
agnostic difference between the groups was evident. The
baseline IOP was between 27 and 42 (mean, 32.0 – 4.6) mmHg
in the 5-FU group and 26–35 (mean, 31.2 – 3.2) mmHg in the
bevacizumab group. No statistical difference was observed
between the groups (P = 0.638). Needling and subconjunctival
5-FU or bevacizumab were applied between 4 and 12 (me-
dian, 5) weeks following trabeculectomy.
The IOP was found to be 12–19 (mean, 15.8 – 1.9) mmHg
following the procedure in the bevacizumab group. The mean
IOP after the procedure was 12.4 – 2.3 (range, 8–18) mmHg in
the 5-FU group. Through an analysis with an independent
sample t-test, the difference between the preprocedure and
after-procedure IOP was statistically significant in both
groups (P = 0.001). There was also a significant difference in
terms of after-procedure IOP between groups (P = 0.00). In 8
(53.3%) eyes, the IOP remained below 21 mmHg with no
medication (complete success), while in 4 (26.7%) eyes, it was
controlled with topical antiglaucomatous agents (qualified
544 SIMSEK, CANKAYA, AND ELGIN

Table 1. Demographic and Clınıcal Table 2. Complıcatıons after Needling Revısıon

Characterıstıcs of the Patıents
Bevacizumab 5-FU
Bevacizumab group group Total
group 5-FU group Complications n (%) n (%) n (%)

Age (year) 61 – 11.3 58 – 16.9 Choroidal detachment — 1 (6.6) 1 (3.7)

Gender (F/M) 6/6 8/7 Shallow anterior chamber 1 (8.3) 1 (6.6) 2 (7.4)
Baseline IOP (mmHg 31.2 – 3.2 32.0 – 4.6 Hypotony 1 (8.3) — 1 (3.7)
mean – SD) Corneal punctate — 2 (13.3) 2 (7.4)
Previous surgeries 3/25 5/33 epitheliopathy
(patient n/%) Hyphema 1 (8.3) 1 (6.6) 2 (7.4)
Time from trabeculectomy 5 (4–12) 5 (4–12) Anterior chamber reaction 1 (8.3) — 1 (3.7)
to needle revision Subconjunctival hemorrhage 2 (16.6) 3 (20) 5 (18.5)
[week, median (min–max)]
Antimetabolite usage during 7 (58) 9 (60)
trabeculectomy n (%)
Diagnosis n (%) Discussion
Uveitic glaucoma 3 (25) 3 (20)
PEX glaucoma 3 (25) 4 (26.6) The success rate of filtration surgery has been reported as
POAG 6 (50) 8 (53.4) 67%–94% in different studies, and bleb failure remains a
common problem.1 A functional bleb is characterized by a
5-FU, 5-fluorouracil; F, female; M, male; IOP, intraocular pressure;
filtering fistula between the anterior chamber and the sub-
min, minimum; max, maximum; PEX, pseudoexfoliative; POAG,
primary open angle glaucoma. conjunctival space. A steady flow of aqueous humor is re-
quired to maintain a passageway at the outer edge of the
scleral fistula and to distend the interstitial space within the
bleb.2,6 Bleb failure in the early postoperative period may be
success) in the 5-FU group. Thus, the total success rate was
due to the obstruction of the internal filtering ostium by
80%. In the remaining 3 (20%) eyes, the IOP was above
blood clots, uveal tissue, or the vitreous, or sutures in the
21 mmHg despite topical antiglaucomatous agents. In the
scleral flap being too tight.6 In the management of immediate
bevacizumab group, the IOP was within normal limits in 1
bleb failure following trabeculectomy, numerous techniques
(8.3%) eye with no medication, and controlled with topical
have been described, including digital ocular compression,
antiglaucomatous drops in 2 (16.7%) eyes. The total success
argon laser suture-lysis, releasable sutures, tissue plasmino-
rate was 25% at the time of the last visit. Success was not
gen activator application to the anterior chamber, sub-
achieved in 9 (75%) eyes. Figure 1 shows distribution of the
conjunctival 5-FU application, and Nd-YAG laser fistula
success rate among groups. A statistically significant differ-
revision.2,6
ence in terms of the success rates between the 2 groups was
Bleb failure in the late postoperative period may be due to
observed (P = 0.007).
the proliferation of the connective tissue cells in the episclera,
Transient complications were encountered in 14/27
which fill the interstitial space within the bleb, or bridging of
(51.8%) eyes. The distribution of complications according to
the Tenon’s capsule over the bleb. These conditions are
the groups is shown in Table 2. No statistically significant
predominantly observed due to an inadequate aqueous hu-
difference between the groups in terms of the occurrence of
mor flow through the bleb.6 The adjuvant intraoperative use
complications was observed (P > 0.05). The anterior chamber
of antifibrotic agents has been shown to increase the success
reaction was thought to be due to the injection of bev-
of filtration surgery.3,5,17
acizumab, and corneal punctate epitheliopathy was thought
Subconjuctival 5-FU application in the early and late
to be due to the injection of 5-FU. Healon GV was injected
postoperative period has been shown to increase the success
into the eye with hypotony. The other complications were
rate of trabeculectomy.5,17–19 Despite the use of adjuvant
resolved without surgical intervention.
intraoperative or postoperative antimetabolites, bleb failure
is still common in high-risk glaucoma patients.1,2 Needle
revision is an alternative technique in postoperative bleb
failure cases. Needle revision has been reported to be effec-
tive in improving bleb function in bleb failure cases due to
fibrosis at the episcleral level and within the bleb or encap-
sulation by the Tenon’s capsule.4,7,8 In these studies, adju-
vant subconjunctival 5-FU application increases the success
of the needle revision technique. The success rate of needle
revision in bleb failure has been reported as 17%–91.6% in
different studies.7–9,20,21
Adjuvant subconjunctival 5-FU or MMC application during
bleb needle revision has been used in several studies.7–9,20,21
MMC has advantages over 5-FU, including higher potency, a
lower risk of bleb encapsulation, and improved control of
IOP after trabeculectomy.7 However, MMC displays several
FIG. 1. Distribution of success and failure rates among dangerous complications, including thin avascular leaking
groups. blebs, hypotony, and blebitis.9 Application of MMC at a
NEEDLING AND BEVACIZUMAB OR 5-FLUOROURACIL APPLICATION FOR FAILED BLEBS
lower concentration may reduce the occurrence of hypotony
and other complications.
It has been shown that hydrocortisone-21-phosphate and
AGM-1470 are angiogenesis inhibitors that display signifi-
cant effects on Tenon’s fibroblast proliferation and migration.
Researchers have thus suggested that angiogenesis inhibitors
may be used for wound modulation in glaucoma filtration
surgery.22,23 The use of subconjunctival bevacizumab for
bleb failure following trabeculectomy has been reported.16
The wound-healing process is carried out with both fibro-
blastic activity and angiogenesis.22 For this reason, anti-VEGF
agents would be expected to decrease the new vascular growth
and inhibit the fibroblastic activity. However, the antifibrotic
effects of bevacizumab have not been experimentally demon-
strated. Yoeruek et al. found that bevacizumab did not display
toxic effects on human corneal fibroblast cells even at high
concentrations.24 Unpublished data have shown that the in-
hibition of the neovascular cascade by anti-VEGF agents de-
creases fibroblast proliferation through cytokines, including
fibroblast growth factors.
We found that 5-FU was more effective than bevacizumab
for this procedure. The total success rates were 25% in the
bevacizumab group and 80% in the 5-FU group. The differ-
ences in the success rates may be due to the different anti-
fibroblastic activity of the adjuvant agents. Grewal et al., in a
pilot study with a small number of subjects and 6 months
follow-up, suggested that subconjunctival bevacizumab is a
potential adjunctive treatment for reducing the incidence of
bleb failure after trabeculectomy.15 The limited sample size,
short-term follow-up, and the lack of a control group were
the limitations of this study. These prevent us from making
firm conclusions regarding the efficacy of bevacizumab in-
jections in reducing bleb failure.
Memarzadeh et al. studied the usefulness of the sub-
conjunctival injection of bevacizumab on bleb morphology in
rabbits.13 They found that bevacizumab created a more favor-
able bleb morphology compared with 5-FU and control groups.
However, unlike our study, bevacizumab was injected after
trabeculectomy in this study. Therefore, the early injection of
bevacizumab after trabeculectomy would be more effective
for bleb survival than postneedling injection. Kahook et al.
reported a case in which a significant decrease in IOP was ob-
served after needling and subconjunctival injection of bev-
acizumab. In this case, the IOP decrease was transient.16 For this
reason, it may be that the IOP reduction resulted from bev-
acizumab injection or solely from the effects of the needling
procedure. It is obviously difficult to answer this question with
1 case report; further controlled clinical and experimental
studies are required to understand the effectiveness of anti-
VEGF agents in glaucoma surgery and needling procedures. In
the present study, bevacizumab injection was performed at
different stages of the wound-healing response in each patient.
This may be a reason of the failure of needling and bev-
acizumab injection. If needling and bevacizumab injection were
performed on the new vessel formation stage of the wound-
healing response, the success rate would be expected to in-
crease. In addition, repeat injection of the bevacizumab would
be more effective than a single injection in reducing angiogen-
esis and fibrosis. Li et al. demonstrated that 1 injection of a high
dosage of bevacizumab (25 mg/mL) during the surgery re-
duced the angiogenesis and fibrosis in a rabbit model of glau-
coma filtration surgery. They stated that bevacizumab was only
effective in increasing the bleb area and did not affect the IOP.25
545
The wound-healing response is a complex process; con-
sequently, more than 1 agent may be needed to inhibit scar
formation in the bleb area. Recently, How et al. found that
bevacizumab in combination with 5-FU offers greater anti-
fibrotic effect over monotherapy in a rabbit model of glau-
coma filtration surgery.26 They concluded that bevacizumab
and 5-FU have synergistic effect in reducing the fibroblastic
activity of the wound-healing process. Combined treatment
with 5-FU and bevacizumab may also be effective in the
treatment of failed filtration blebs. This treatment modality
might be advantageous to lessen corneal complications of 5-
FU. Kahook reported that the combination of intravitreal
ranibizumab and MMC at the time of trabeculectomy re-
sulted in more diffuse blebs with less vascularity compared
to the use of MMC alone.27
Several complications such as wound leak, choroidal effu-
sion, a shallow anterior chamber, bleb-related endophthalmitis,
hypotony maculopathy, suprachoroidal hemorrhage, corneal
epitheliopathy, and subconjunctival hemorrhage have been
reported to be associated with needle revision and sub-
conjunctival 5-FU application.2,6,28,29 In this study, no signifi-
cant difference was observed between the groups in terms of
complications. However, the anterior chamber reaction was
thought to be due to the injection of bevacizumab, and the
corneal punctuate epitheliopathy due to 5-FU injection. The
intravitreal injection of bevacizumab may cause IOP spikes,
particularly in suspected or confirmed cases of glaucoma.
Kahook and coworkers30 found that bevacizumab displayed a
toxic effect on trabecular meshwork cells. Other reports have
stated that bevacizumab may physically accumulate in the
trabecular meshwork and block aqueous outflow, leading to an
increased IOP. It is not yet known whether IOP elevation oc-
curs after the subconjunctival injection of bevacizumab.
In conclusion, needle revision and subconjunctival 5-FU
application was a more effective procedure than needling
and subconjunctival bevacizumab injection for bleb failure
following trabeculectomy. Further controlled clinical studies
are required to determine the time and route of administra-
tion of bevacizumab in the glaucoma surgical procedure.
Author Disclosure Statement
None of the authors have a conflict of interest with the
submission.
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Received: February 16, 2012
Accepted: May 22, 2012
Address correspondence to:
Dr. Tulay Simsek
SB Ulucanlar Göz Eğitim Aras
xtırma Hastanesi
Ulucanlar Caddesi
No: 59 Altındağ
Ankara
Turkey
E-mail: tulaysimsek@hotmail.com