Yaşa bağlı makula dejeneresansının (YBMD) (The Age-related Eye Disease Study) Research Group tarafından tarif edilen sisteme9 göre) evrelendirilmesi
Evre I Maximum druzen büyüklüğü <63 mikron ve total alanı <125 mikron
Evre II Aşağıdakilerin bir ya da daha fazlası:
a. Maksimum druzen büyüklüğü >63 ve <125 mikron
b. Total druzen alanı >125 mikron
c. Santral yada iç alanlarda aşağıda tarif edilen SMD ile
uyumlubretina pigment epitelyum değişikliklerinin olması:
1. Depigmentasyon varlığı
2. 125 mikrondan geniş artmış pigmentasyon
3. Artmış pigment varlığı ve en azından şüpheli
Evre III Aşağıdakilerden bir ya da daha fazlasının varlığı:
d. Maksimum druzen büyüklüğünün 125 mikronun üzerinde
e. Maksimum druzen büyüklüğünün 63 mikronun üzerinde
olması ve total alanın 125-250 mikronun üzerinde olması ve
tipinin yumuşak, sınırları belirsiz olması
f. Maksimum druzen büyüklüğünün 63 mikronun üzerinde
olması ve total alanın 0.439 disk çapının üzerinde olması ve
tipinin yumuşak düzgün sınırlı olması.
g. Makula merkezinden 3000 mikron uzaklıktaki alan içinde
ancak santral 500 mikronluk alanı tutmayan jeografik atrofi
Evre IV (ileri)
Aşağıdakilerden bir yada daha fazlasının bulunması:
h. Şüpheli bile olsa santral 500 mikronluk makula alanında
jeografik atrofi bulunması
i. Neovasküler YMD bulguları
1. Fibrovasküler/seröz pigment epitel dekolmanı
2. Seröz (ya da hemorajik ) sensöryel retina
3. Subretinal/subretina pigment epiteli hemoraji
4. Subretinal fibröz doku (ya da fibrin)
5. YMD için fotokoagülasyon uygulanılmış olması
The Relation Between Bevacizumab Injection and
the Formation of Subretinal Fibrosis in Diabetic
Patients With Panretinal Photocoagulation
Cosar Batman, MD; Yasemin Ozdamar, MD
n BACKGROUND AND OBJECTIVE: To report
the development of subretinal fibrosis after the injection
of intravitreal bevacizumab in eyes with proliferative
diabetic retinopathy (PDR) refractory to panretinal
laser photocoagulation (PRP).
n PATIENTS AND METHODS: Twenty-one eyes of
15 patients treated with PRP and intravitreal injection
of bevacizumab were included in this study. The clinical
outcomes of 21 eyes having subretinal fibrosis after
intravitreal bevacizumab injection were reviewed.
n RESULTS: There were 9 men and 6 women with a
mean age of 51.3 ± 8.9 years. All eyes had PDR refractory
to panretinal photocoagulation and were treated
with at least one intravitreal injection of 1.25 mg of
bevacizumab (mean number of injections: 1.8). Before
injection, there was subretinal fibrosis in 5 eyes and vitreoretinal
traction in 19 eyes. After a mean follow-up
period of 7 months, the development or progression of
subretinal fibrosis was detected in all eyes.
n CONCLUSION: Intravitreal injection of bevacizumab
may cause formation or progression of subretinal
fibrosis in patients with PDR refractory to PRP.
[Ophthalmic Surg Lasers Imaging 2010;41:190-
From the Ministry of Health Ulucanlar Eye Research Hospital, Ankara, Turkey.
Accepted for publication August 10, 2009.
The authors have no proprietary or financial interest in the materials presented herein.
Address correspondence to Yasemin Ozdamar, MD, Ulucanlar cad. No: 59 Altindag, 06100 Ankara, Turkey.
Proliferative diabetic retinopathy (PDR) is characterized
by neovascularization of the retina, optic disc,
or both and retinal fibrovascular membranes in patients
with diabetes mellitus. Panretinal photocoagulation
has become the mainstay for the management of
PDR. In fact, successful laser treatment of PDR may
reduce the risk of severe visual loss and prevent diabetic
Vascular endothelial growth factor (VEGF) appears
to be primarily responsible for the pathogenesis of PDR
and is a potent angiogenic stimulator.1,6,7 Recently,
intravitreal anti-VEGF agents have been increasingly
used for the treatment of diabetic complications, especially
in patients with PDR not amenable to photocoagulation.8-14 Bevacizumab (Avastin; Genentech, San
Francisco, CA), an anti-VEGF agent, is a humanized
monoclonal antibody to VEGF. Anti-VEGF agents
also produce short-term stabilization or regression of
the iris, retinal neovascularization, or both, and may be
useful for cleaning early vitreous hemorrhage in PDR.
In addition, the preoperative use of bevacizumab may
facilitate vitrectomy and reduce the risk of intraoperative
In this study, we reported the development or
progression of subretinal fibrosis after the injection of
intravitreal bevacizumab in patients with diabetes mellitus
who had PDR refractory to panretinal photocoagulation.
PATIENTS AND METHODS
Twenty-one eyes of 15 patients who developed
subretinal fibrosis after bevacizumab injection were reviewed
in this study. The eyes with PDR were treated
with panretinal photocoagulation, intravitreal bevacizumab
injection, or both. The study followed the tenets
of the Declaration of Helsinki and was approved by the
institutional ethics committee. Written informed consent
was obtained from all participants prior to their
enrollment in the study after a clear explanation of the
nature of the intervention.
After detailed medical histories were obtained, the
patients underwent pre-injection examination, including
corrected visual acuity measurements with Snellen
chart, the measurement of intraocular pressure with
applanation tonometer, and biomicroscopic anterior
chamber and dilated fundus examinations.
Exclusion criteria were tractional retinal detachment
or tractional retinal detachment complicated with a history
of vitreous hemorrhage, thromboembolic events
(including myocardial infarction or cerebral vascular
events), major surgery within the previous 3 months,
uncontrolled hypertension, and known coagulation abnormalities.
Previous focal or grid macular laser treatments
were not considered as exclusion criteria.
All eyes previously underwent a full scatter laser
treatment with a 532-nm argon solid state laser. The
number of applications ranged between 1,000 and
1,600 shots (500 µm spot) at a power that caused
blanching of the retina. Despite panretinal photocoagulation,
neovascularization, macular edema, cloudy
vitreous fluid, and small vitreous bleeding spots were
considered signs of PDR refractory to panretinal photocoagulation
within 3 months and treated with bevacizumab
after panretinal photocoagulation. Intravitreal
injection of bevacizumab was applied for either stabilization
or regression of retinal neovascularization after
panretinal photocoagulation performed at two or three
All intravitreal injections of 1.25 mg of bevacizumab
were performed using proparacaine (Alcaine;
Alcon Laboratories Inc., Fort Worth, TX) under sterile
conditions (eyelid speculum, eye drapes, and povidone-
iodine). Bevacizumab 1.25 mg was injected into
the vitreous cavity using a 30-gauge needle inserted
through the inferotemporal pars plana and 3.0 to 3.5
mm posterior to the limbus. After the injection, central
retinal artery perfusion was confirmed with indirect
ophthalmoscopy. The patients received topical 0.3%
ciprofloxacin four times daily after the procedure.
Postinjection follow-up examinations were performed
weekly for the first month and monthly thereafter.
Postinjection evaluations including detailed anterior
segment and dilated fundus examinations were
recorded. Retinal findings such as neovascularization
of the disc or elsewhere, subretinal fibrosis, and vitreoretinal
traction were evaluated as negative (-), mild (+),
moderate (++), and severe (+++) according to the fundus
Twenty-one eyes of 15 patients were evaluated.
Of the patients, 9 (60%) were men and 6 (30%) were
women. The mean age of the patients was 51.3 ± 8.9
years (range: 27 to 67 years). The mean follow-up was
7 months (range: 4 to 10 months). The mean disease
duration was 9 years (range: 7 to 10 years). None of the
patients had previous vitreoretinal surgery. Five eyes
were pseudophakic and 16 eyes were phakic. The mean
intraocular pressure and anterior segment examination
findings were normal in all eyes.
All eyes had proliferative diabetic retinopathy refractory
to panretinal photocoagulation. At least 3
months after panretinal photocoagulation was completed,
bevacizumab was injected. All eyes were treated
with one or two intravitreal injections of 1.25 mg of
bevacizumab (the mean number of injections was 1.8).
Before injection, there was subretinal fibrosis in 5 eyes
and vitreoretinal traction in 19 eyes (tangential trac
tion in 12 eyes and anteroposterior traction in 7 eyes).
After a mean follow-up period of 7 months, either subretinal
fibrosis developed or existing subretinal fibrosis
progressed in all eyes. Subretinal fibrosis extended
from the inferotemporal to the superior quadrant of
the macula in almost all patients (Figs. 1 and 2).
The mean visual acuity (before intravitreal bevacizumab)
was 0.12 ± 0.16 on admission and 0.07 ± 0.12
on the last examination. No other significant ocular
or systemic adverse effects were observed. None of the
eyes underwent vitrectomy. The clinical findings of all
participants are shown in the table.
The main treatment of proliferative diabetic retinopathy
is panretinal photocoagulation. It often prevents
further retinal neovascularization and clinical
trials have demonstrated that panretinal photocoagulation
is associated with reduced visual loss and retinal
neovascularization.1-4 Approximately 60% of the
patients with PDR respond to panretinal photocoagulation
with regression of neovascularization within 3
months of treatment according to the Early Treatment
Diabetic Retinopathy Study.20,21 On the other hand,
proliferative activity may persist in diabetic eyes after
Recently, intravitreal anti-VEGF agents have been
used for the treatment of eyes refractory to panretinal
photocoagulation, the stabilization of neovascularization
and simplifying of vitrectomy as an adjuvant treatment
method in PDR.8-19 VEGF plays a key role in the
development of both PDR and diabetic macular edema.
It is upregulated in diabetic retinopathy and promotes
various steps of angiogenesis. Increased VEGF
levels have also been found in the aqueous and vitreous
humor of patients with PDR.1,6,7,22 Bevacizumab,
a recombinant antibody against VEGF, has been approved
for intravenous administration in patients with
advanced colorectal cancer. However, its use for the
treatment of ocular neovascularization remains “off label.”
Nevertheless, intravitreal bevacizumab is becoming
increasingly adopted by ophthalmologists. It binds
to and inhibits all VEGF isoforms.23,24
More recently, regression of retinal neovascularization
has been demonstrated after intravitreal injection
of bevacizumab for the treatment of diabetic retinopathy
in clinical studies.9,17-19 In addition, there have
been several reports regarding the potential efficacy of
combined treatment with intravitreal injection of bevacizumab
and panretinal photocoagulation.8,9,13,14 The
ability of bevacizumab to cause regression of neovascularization
in PDR is well defined. It is also known that
bevacizumab may lead to increased fibrosis of the fibrovascular
membrane and may facilitate removal of the
fibrovascular membrane during vitreoretinal surgery.
Therefore, it has been increasingly used as an adjunct
before vitrectomy surgery.9,15,16
With an increase in the use of bevacizumab during
the past few years, complications have been noted
in several studies.25,26 Arevalo et al.25 reported that 11
eyes developed or had progression of tractional retinal
detachment after injection of 1.25 mg of bevacizumab
intravitreally. In their study, all eyes had PDR resistant
to panretinal photocoagulation and time from injection
to tractional retinal detachment was a mean of
13 days. They suggested that several factors might be
responsible for deterioration of tractional retinal detachment,
including extensive panretinal photocoagulation,
poorly controlled diabetes mellitus, and larger
doses of bevacizumab. The development or progression
of tractional retinal detachment is believed to be due to
a rapid neovascular involution with accelerated fibrosis
and posterior hyaloid contraction.25
Similar results have been shown in advanced retinopathy
of prematurity. Honda et al.26 reported a complication
of bevacizumab injection to the eye with stage
4A plus disease. They observed regression of the vascular
component of the fibrovascular membrane and
acute contraction of the proliferative membrane and
deterioration of tractional retinal detachment.
In the current study, we applied bevacizumab
when patients failed to respond to treatment with
panretinal photocoagulation 3 months after its administration.
Although a considerable stabilization in
neovascularization appeared 6 months after panretinal
photocoagulation, 3 months of follow-up guided us in
treatment with bevacizumab in patients whose blood
glucose was not regulated well, whose vision gradually
decreased, and who did not comply with treatment.
However, it is better to wait for 6 months to administer
bevacizumab when neovascularization and macular
edema considerably decrease 3 months after panretinal
photocoagulation. In this study, either subretinal
fibrosis developed or already existing subretinal fibrosis
progressed in patients with PDR refractory to panretinal
photocoagulation after bevacizumab injection. It
can be suggested that as the injection of bevacizumab
causes neovascular regression and accelerated fibrosis,
subretinal fibrosis becomes more marked and retinal
pigment epithelium that is dispersed during panretinal
photocoagulation, especially in patients with diabetic
macular edema, might increase or initiate the activity
of subretinal fibrosis.
Intravitreal bevacizumab is commonly used as an
adjunctive agent in eyes with PDR, but it should be
kept in mind that intravitreal injection of bevacizumab
may lead to development or progression of subretinal
fibrosis, especially in patients with PDR refractory to
1. Davis MD, Blodi BA. Retinal vascular diseases: proliferative diabetic
retinopathy. In: Ryan SJ, ed. Retina, vol. 2, 4th ed. Philadelphia: Elsevier;
2. Kaufman SC, Ferris FL 3rd, Seigel DG, Davis MD, DeMets DL.
Factors associated with visual outcome after photocoagulation for
diabetic retinopathy. Diabetic Retinopathy Study Report #13. Invest
Ophthalmol Vis Sci. 1989;30:23-28.
3. Fong DS, Ferris FL 3rd, Davis MD, Chew EY. Causes of severe visual
loss in the early treatment diabetic retinopathy study: ETDRS Report
No. 24. Early Treatment Diabetic Retinopathy Study Research
Group. Am J Ophthalmol. 1999;127:137-141.
4. Early Treatment Diabetic Retinopathy Study Research Group. Early
photocoagulation for diabetic retinopathy. ETDRS Report Number
9. Ophthalmology. 1991;98:766-785.
5. The Diabetic Retinopathy Study Research Group. Photocoagulation
treatment of proliferative diabetic retinopathy: clinical application of
Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8.
6. Kroll P, Rodrigues EB, Hoerle S. Pathogenesis and classification of proliferative
diabetic vitreoretinopathy. Ophthalmologica. 2007;221:78-
7. Adamis AP, Miller JW, Bernal MT, et al. Increased vascular endothelial
growth factor levels in the vitreous of eyes with proliferative
diabetic retinopathy. Am J Ophthalmol. 1994;118:445-450.
8. Tonello M, Costa RA, Almeida FP, Barbosa JC, Scott IU, Jorge R.
Panretinal photocoagulation versus PRP plus intravitreal bevacizumab
for high-risk proliferative diabetic retinopathy (IBeHi study). Acta
9. Mason JO 3rd, Nixon PA, White MF. Intravitreal injection of bevacizumab
(Avastin) as adjunctive treatment of proliferative diabetic
retinopathy. Am J Ophthalmol. 2006;142:685-688.
10. Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment
of proliferative diabetic retinopathy complicated by vitreous hemorrhage.
11. Adamis AP, Altaweel M, Bressler NM, et al. Macugen Diabetic Retinopathy
Study Group. Changes in retinal neovascularization after
pegaptanib (Macugen) therapy in diabetic individuals. Ophthalmology.
12. Chun DW, Heier JS, Topping TM, Duker JS, Bankert JM. A pilot
study of multiple intravitreal injections of ranibizumab in patients
with center-involving clinically significant diabetic macular edema.
13. Mirshahi A, Roohipoor R, Lashay A, Mohammadi SF, Abdoallahi A,
Faghihi H. Bevacizumab-augmented retinal laser photocoagulation in
proliferative diabetic retinopathy: a randomized double-masked clinical
trial. Eur J Ophthalmol. 2008;18:263-269.
14. Arevalo JF, Wu L, Sanchez JG, et al. Intravitreal bevacizumab (Avastin)
for proliferative diabetic retinopathy: 6-months follow-up. Eye.
15. Rizzo S, Genovesi-Ebert F, Di Bartolo E, et al. Injection of intravitreal
bevacizumab (Avastin) as a preoperative adjunct before vitrectomy
surgery in the treatment of severe proliferative diabetic retinopathy
(PDR). Graefes Arch Clin Exp Ophthalmol. 2008;246:837-842.
16. Chen E, Park CH. Use of intravitreal bevacizumab as a preoperative
adjunct for tractional retinal detachment repair in severe proliferative
diabetic retinopathy. Retina. 2006;26:699-700.
17. Avery RL, Pearlman J, Pieramici DJ, Rabena MD, Castellarin AA,
Nasir MA, Giust MJ, Wendel R, Patel A. Intravitreal bevacizumab
(Avastin) in the treatment of proliferative diabetic retinopathy. Ophthalmology.
18. Oshima Y, Sakaguchi H, Gomi F, Tano Y. Regression of iris neovascularization
after intravitreal injection of bevacizumab in patients with
proliferative diabetic retinopathy. Am J Ophthalmol. 2006;142:155-
19. Minnella AM, Savastano CM, Ziccardi L, et al. Intravitreal bevacizumab
(Avastin) in proliferative diabetic retinopathy. Acta Ophthalmol.
20. Vander JF, Duker JS, Benson WE, Brown GC, McNamara JA, Rosenstein
RB. Long-term stability and visual outcome after favorable initial
response of proliferative diabetic retinopathy to panretinal photocoagulation.
21. The Early Treatment Diabetic Retinopathy Study Research Group.
Techniques for scatter and local photocoagulation treatment of diabetic
retinopathy: Early Treatment Diabetic Retinopathy Study Report
No. 3. Int Ophthalmol Clin. 1987;27:254-264.
22. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth
factor in ocular fluid of patients with diabetic retinopathy and other
retinal disorders. N Engl J Med. 1994;331:1480-1487.
23. Ferrara N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized
anti-VEGF monoclonal antibody for cancer therapy. Biochem
Biophys Res Commun. 2005;333:328-335.
24. Lynch SS, Cheng CM. Bevacizumab for neovascular ocular diseases.
Ann Pharmacother. 2007;41:614-625.
25. Arevalo JF, Maia M, Flynn HW Jr, et al. Tractional retinal detachment
following intravitreal bevacizumab (Avastin) in patients with severe
proliferative diabetic retinopathy. Br J Ophthalmol. 2008;92:213-
26. Honda S, Hirabayashi H, Tsukahara Y, Negi A. Acute contraction of
the proliferative membrane after an intravitreal injection of bevacizumab
for advanced retinopathy of prematurity. Graefes Arch Clin Exp