INTRAVITREAL BEVACIZUMAB

(AVASTIN) THERAPY FOR PERSISTENT

DIFFUSE DIABETIC MACULAR EDEMA
CHRISTOS HARITOGLOU, MD, DANIEL KOOK, MD,
ALJOSCHA NEUBAUER, MD, ARMIN WOLF, MD,
SIEGFRIED PRIGLINGER, MD, RUPERT STRAUSS, MD,
ARND GANDORFER, MD, MICHAEL ULBIG, MD, ANSELM KAMPIK, MD

Purpose: To evaluate the efficacy of bevacizumab (Avastin; Genentech, Inc., South San
Francisco, CA) for the treatment of diabetic macular edema.
Methods: This prospective, consecutive, noncomparative case series included 51
consecutive patients (26 females and 25 males; mean age, 64 years) with diffuse diabetic
macular edema. Inclusion criteria were determined independently of the size of edema,
retinal thickness, visual acuity, age, metabolic control, type of diabetes, or previous
treatments beyond a 6-month period. At each visit, patients underwent complete eye
examination, including determination of best-corrected visual acuity, slit-lamp examina-
tion, intraocular pressure measurement, stereoscopic biomicroscopy of the macula, retinal
thickness measurement by optical coherence tomography, fluorescein angiography, and
fundus photography. After written informed consent was obtained, all patients were
treated with a 0.05-mL injection containing 1.25 mg of bevacizumab.
Results: All patients completed 6 weeks of follow-up; 23 (45%) completed 12 weeks of
follow-up. Sixteen patients (70%) had received at least two intravitreal injections. All
patients had undergone previous treatments, such as focal laser therapy (35%), full-scatter
panretinal laser therapy (37%), vitrectomy (12%), and intravitreal injection of triamcinolone
(33%). The mean diameter of the foveal avascular zone was 503 ␮m, with 49% with values
of ⬎500 ␮m. At baseline, mean visual acuity ⫾ SD was 25.88 ⫾ 14.43 ETDRS letters (0.86
⫾ 0.38 logMAR of Snellen letters). Mean central retinal thickness by optical coherence
tomography ⫾ SD was 501 ⫾ 163 ␮m (range, 252–1,031 ␮m). Mean visual acuity ⫾ SD
increased to 0.75 ⫾ 0.37 logMAR of Snellen letters at 6 weeks after injection (P ⫽ 0.001),
with some regression to 0.84 ⫾ 0.41 logMAR of Snellen letters after 12 weeks. Changes in
ETDRS letters were not significant throughout follow-up. Mean retinal thickness ⫾ SD
decreased to 425 ⫾ 180 ␮m at 2 weeks (P ⫽ 0.002), 416 ⫾ 180 ␮m at 6 weeks (P ⫽ 0.001),
and 377 ⫾ 117 ␮m at 12 weeks (P ⫽ 0.001). Changes of retinal thickness and visual acuity
correlated weakly (r ⫽ ⫺0.480 and P ⫽ 0.03 at 6 weeks; r ⫽ ⫺0.462 and P ⫽ 0.07 at 12
weeks). The increase of visual acuity after 6 weeks as measured by ETDRS charts could
be predicted best by baseline visual acuity. No other factors investigated, such as age,
thickness by optical coherence tomography, or previous treatments, were predictive for
the increase in visual acuity.
Conclusion: Even in cases of diffuse diabetic macular edema not responding to
previous treatments such as photocoagulation, intravitreal injection of triamcinolone, or
vitrectomy, improvement of visual acuity and decrease of retinal thickness could be
observed after intravitreal injection of bevacizumab. Although our follow-up period was too
short to provide specific treatment recommendations, the short-term results encourage
further prospective studies with different treatment groups and longer follow-up.
RETINA 26:999 –1005, 2006

999
1000 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
D iabetic retinopathy is a common ocular compli-
cation of diabetes mellitus and is the most com-
mon cause of blindness in people of working age.1 In
Germany, 6,000 to 10,000 patients are expected to
become legally blind due to diabetic microangiopathy,
and retinopathy is newly diagnosed in 60,000 diabet-
ics per year.2 Diabetic retinopathy represents a major
socioeconomic problem. Approximately 90% of patients
with type 1 diabetes become legally blind because of
proliferative diabetic retinopathy and/or development of
macular edema, despite the availability of several effec-
tive therapeutic options such as laser treatment or vitreo-
retinal surgery.3 However, especially in macular edema,
laser treatment is not always beneficial.
The development of diabetic retinopathy is a mul-
tifactorial process. Much of the retinal damage that
characterizes the disease is now understood to result
from retinal vascular leakage and nonperfusion4 me-
diated by numerous growth factors such as vascular
endothelial growth factor (VEGF).5 VEGF was first
isolated from guinea pig ascites.6 The upregulation of
VEGF is associated with breakdown of the blood–
retina barrier, with increased vascular permeability
resulting in retinal edema,7 stimulation of endothelial
cell growth, and neovascularization.8 –12 In light of this
information, the pharmacologic inhibition of VEGF
appeared to be a promising treatment strategy for
ocular diseases, in which breakdown of the blood–
retina barrier and neovascularization play an impor-
tant pathogenetic role.13,14 One such VEGF inhibitor
is bevacizumab (Avastin; Genentech, Inc., South San
Francisco, CA), a US Food and Drug Administration–
approved full-length humanized monoclonal antibody
that until recently was used for the treatment of met-
astatic colorectal cancer.15,16 Bevacizumab has
emerged as a therapeutic strategy for retinal diseases,
especially age-related macular degeneration,17–19 pro-
viding promising functional results. It seems very
reasonable to assume that VEGF inhibitors such as
bevacizumab will also be applicable in other retinal
diseases, such as retinal vein occlusion20 and diabetic
macular edema. As with other VEGF inhibitors,13,14
bevacizumab has also been reported to be suitable and
safe for intravitreal injection.
The present prospective study was performed to
evaluate the effect of intravitreal bevacizumab injec-
tion on retinal thickness and visual function in patients
with diabetic macular edema.
From the Department of Ophthalmology, Ludwig-Maximilians-
University, Munich, Germany.
The authors have no financial interests in this study.
C.H. and D.K. contributed equally.
Reprint requests: Christos Haritoglou, MD, Department of Ophthal-
mology, Ludwig-Maximilians-University, Mathildenstrasse 8, 80336
Munich, Germany; e-mail: Haritoglou@med.uni-muenchen.de
● 2006 ● VOLUME 26 ● NUMBER 9
Methods
The present study was designed as a prospective,
consecutive, noncomparative case series. Because
there are no evidence-based indications for the treat-
ment of diabetic macular edema using bevacizumab,
we included a wide range of patients with diffuse,
clinically significant diabetic macular edema21,22 who
did not respond to other treatments such as photoco-
agulation, intravitreal injection of triamcinolone, or
vitrectomy. Patients were included in the study inde-
pendently of the size of the leakage area, retinal thick-
ness (as determined by optical coherence tomography
[OCT]), visual acuity, age, metabolic control, type of
diabetes mellitus, or previous treatments such as pho-
tocoagulation, vitrectomy, or intravitreal triamcino-
lone injection performed beyond a 6-month period
previously.
At each visit, complete eye examination was per-
formed, including determination of best-corrected vi-
sual acuity using both Snellen testing and ETDRS
standard charts at a 4-m distance, slit-lamp examina-
tion, intraocular pressure measurement, stereoscopic
biomicroscopy of the retina using a 78-diopter lens,
retinal thickness measurement by OCT (Stratus OCT;
Carl Zeiss Meditec, Jena, Germany), fluorescein an-
giography, and fundus photography of the macular
area. All patients were seen by two examiners (A.W.
and R.S.). Visits occurred 1 day before injection, 2
weeks after injection, and then at 4-week intervals.
Further injections were performed for patients with
only limited response to the first injection in terms of
decreasing retinal thickness or improvement of visual
acuity or for patients with recurrent edema and asso-
ciated deterioration of visual acuity during follow-up.
The foveal avascular zone was measured in abso-
lute diameters in the early phase of fluorescein an-
giography using the instrument’s proprietary software
(Heidelberg Retina Angiograph; Heidelberg-Engi-
neering, Heidelberg, Germany) by an investigator who
was masked to the clinical data.
Injection Technique
Before injection, topical anesthesia was induced by
applying tetracaine (1%) eyedrops at least three times.
The conjunctiva bulbi and the fornices were repeat-
edly rinsed with Betadine ([povidone–iodine] Alcon,
Ft. Worth, TX). Povidone–iodine was also applied to
the eyelid margins and the lashes, avoiding expression
of the meibomian glands. After application of a sterile
drape, a lid speculum was inserted. Patients then re-
ceived a unilateral intravitreal injection of a 0.05-mL
volume containing 1.25 mg of bevacizumab using a
sharp 27-gauge needle at a distance of 3.5 mm from
 BEVACIZUMAB THERAPY FOR DIABETIC MACULAR EDEMA
the limbus or 4.0 mm in pseudophakic eyes, respec-
tively. The needle was carefully removed using a
sterile cotton applicator to prevent reflux. After injec-
tion, antibiotic eyedrops (polymyxin and neomycin)
were applied for 3 days four times per day. The drug
(0.1 mL) was drawn under sterile conditions from a
bevacizumab infusion bottle used for systemic treat-
ment of cancer patients by our pharmacy department
and was not diluted further.
All patients provided written informed consent. They
were especially informed about the off-label character of
the treatment and the potential risk of endophthalmitis
and retinal detachment as well as the likelihood that
additional treatments might be required.
Statistical Analysis
Only one eye per subject was treated. All data were
collected on a MS-Excel 2000 spreadsheet (Microsoft
Corporation, Redmond, WA) and analyzed using
SPSS 13.0 for Windows (SPSS, Inc., Chicago, IL).
For all statistical tests, P ⬍ 0.05 was considered
significant. Extended graphical analysis and methods
such as regression models and analysis of variance
models were performed where appropriate.
Results
Subjects
A total of 51 individuals (26 females and 25 males)
with nonproliferative and proliferative diabetic reti-
nopathy were enrolled in the study (Table 1). The
mean age of the patients was 64.1 years (range, 23–79
years). All patients completed 6 weeks of follow-up;
23 (45%) presented for the 12-week follow-up visit.
Changes in visual acuity measured later than 12 weeks
were not included in the analysis due to a limited
number of patients. Sixteen patients (70%) received a
second intravitreal injection of bevacizumab. Twenty-
eight right eyes (55%) and 23 left eyes were included
in the study.
All 51 eyes had received at least one alternative
therapy before intravitreal injection. Focal laser ther-
apy had been applied once on 18 eyes (35%) and twice
on 10 eyes (20%). Full-scatter panretinal laser therapy
had been performed on 19 eyes (37%), and 6 eyes
(12%) had undergone vitrectomy with internal limit-
ing membrane peeling. Previous intravitreal injection
of triamcinolone had been performed once on 17 eyes
(33%), twice on 7 eyes (14%), and three times on 1
eye (2%). The mean measured diameter of the foveal
avascular zone was 503 ␮m. For 25 patients (49%), a
value of ⬎500 ␮m was measured, indicating some
degree of macular ischemia. No injection-related ad-
● HARITOGLOU ET AL 1001
verse events (both locally and systemically such as
hypertension) were observed.
Visual Acuity
For assessing visual acuity, both Snellen test results
converted to logMAR and letters on ETDRS standard
charts were used. At baseline, mean visual acuity ⫾
SD was 0.86 ⫾ 0.38 logMAR of Snellen letters (i.e.,
20/145) and 25.88 ⫾ 14.43 ETDRS letters. After 2
weeks, mean visual acuity ⫾ SD had improved to 0.80
⫾ 0.37 logMAR on Snellen charts (not significant)
and to 28.65 ⫾ 14.78 ETDRS letters (not significant).
Six weeks after the injection, a significant improve-
ment to 0.75 ⫾ 0.37 logMAR was observed by
Snellen testing (P ⫽ 0.001) with a similar, significant
increase to 31.32 ⫾ 14.33 ETDRS letters (P ⫽ 0.024).
Twelve weeks after the injection, some regression of
the increase in mean visual acuity ⫾ SD to 0.84 ⫾
0.41 logMAR of Snellen letters (not significant) and to
27.05 ⫾ 14.83 ETDRS letters (not significant) was
noted. The visual acuity results are summarized in
Figure 1. An increase in visual acuity of at least 3 lines
was observed for 29% (15) of 51 eyes at the 6-week
follow-up and 26% (6) of 23 eyes completing 12
weeks of follow-up.
OCT
Mean central retinal thickness ⫾ SD by OCT was
501 ⫾ 163 ␮m (range, 252–1,031 ␮m) at baseline.
Two weeks postoperatively, a significant (P ⫽ 0.002)
decrease of mean retinal thickness ⫾ SD to 425 ⫾ 180
␮m was observed. Six weeks after the injection, mean
macular retinal thickness ⫾ SD had further decreased
to 416 ⫾ 180 ␮m, a highly significant difference (P ⫽
0.001) compared with baseline. After 12 weeks, mean
retinal thickness ⫾ SD further decreased to 377 ⫾ 117
␮m (P ⫽ 0.001). Figure 2 summarizes OCT-measured
retinal thickness results. Changes in retinal thickness and
visual acuity were moderately correlated after
6 weeks (r ⫽ ⫺0.480; P ⫽ 0.03) and after 12 weeks (r ⫽
⫺0.462; P ⫽ 0.07). An example is given in Figure 3.
Factors Influencing Treatment Success
In a multiple stepwise regression model, the in-
crease of visual acuity after 6 weeks as measured by
ETDRS charts could be predicted best by baseline
visual acuity (standardized ␤-0.418, total model R 2 ⫽
0.175; P ⫽ 0.002). The other factors investigated,
such as OCT-measured retinal thickness, age, previ-
ous treatments received, and degree of ischemia by
fluorescein angiography, were not predictive for the
increase in visual acuity. Very similar results were
1002 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES ● 2006 ● VOLUME 26 ● NUMBER 9

Table 1. Baseline Characteristics

VA,
No. of Previous VA, LogMAR Retinal Second
No. of Intravitreal FAZ Snellen of Thickness Bevacizumab
Age Previous Previous Previous Triamcinolone Diameter Test Snellen ETDRS by OCT Injection
Patient Sex (y) FRP PRP PPV Injections (␮m) Results Letters Letters (␮m) Received

1 M 68 1 0 0 1 350 0.30 0.52 61 614 Yes

2 F 23 1 1 0 0 430 0.50 0.30 43 421 No
3 F 67 2 0 0 0 450 0.40 0.40 36 562 No
4 M 52 0 1 0 2 630 0.30 0.52 18 444 No
5 F 67 1 1 0 0 450 0.30 0.52 20 360 No
6 F 70 1 0 0 1 425 0.20 0.70 5 466 Yes
7 F 68 0 1 0 0 350 0.07 1.17 24 487 No
8 M 63 0 1 0 1 1,150 0.40 0.40 34 361 Yes
9 F 71 0 0 0 1 300 0.05 1.30 36 594 No
10 M 71 1 0 0 1 500 0.10 1.00 16 461 No
11 M 75 0 0 0 1 0 0.03 1.55 41 609 No
12 F 74 2 0 0 0 570 0.05 1.30 12 737 No
13 F 74 2 0 0 0 0 0.10 1.00 23 473 No
14 M 65 1 0 0 0 430 0.20 0.70 38 492 No
15 F 53 2 1 0 2 390 0.03 1.55 10 414 No
16 M 71 1 0 0 2 300 0.05 1.30 18 480 Yes
17 M 60 0 1 1 1 475 0.20 0.70 32 564 Yes
18 M 66 1 0 1 1 440 0.10 1.00 13 850 Yes
19 M 55 2 0 0 0 540 0.16 0.80 27 588 No
20 F 69 1 1 0 0 600 0.20 0.70 39 252 No
21 M 40 0 1 1 1 650 0.10 1.00 8 1031 Yes
22 M 69 2 0 0 0 560 0.20 0.70 23 484 No
23 F 76 1 0 0 1 450 0.10 1.00 38 485 Yes
24 F 79 1 0 0 0 490 0.05 1.30 15 482 Yes
25 F 75 2 0 0 1 355 0.05 1.30 6 370 Yes
26 F 65 0 0 0 1 580 0.30 0.52 29 447 No
27 F 45 0 0 0 0 320 0.40 0.40 39 600 No
28 F 54 0 1 0 3 — 0.05 1.30 31 486 Yes
29 M 57 1 0 0 0 — 0.30 0.52 25 926 No
30 M 57 1 0 0 0 — 0.10 1.00 36 571 No
31 M 55 1 0 0 0 310 0.60 0.22 42 364 Yes
32 F 59 1 0 0 1 565 0.20 0.70 34 459 No
33 F 63 2 1 1 0 380 0.05 1.30 29 434 No
34 M 55 0 1 1 0 890 0.05 1.30 28 705 Yes
35 M 63 0 1 0 2 1,150 0.30 0.52 34 361 Yes
36 F 71 0 0 0 2 730 0.20 0.70 14 620 No
37 F 77 1 0 0 0 600 0.05 1.30 6 710 Yes
38 M 66 2 0 0 0 420 0.05 1.30 22 435 No
39 F 64 1 1 0 1 435 0.25 0.60 55 329 No
40 M 48 0 1 0 1 555 0.20 0.70 28 300 Yes
41 M 71 0 1 0 0 305 0.20 0.70 20 308 No
42 M 78 1 0 0 0 550 0.30 0.52 12 541 Yes
43 F 63 0 1 1 0 340 0.60 0.22 9 288 No
44 M 72 0 1 0 0 360 0.40 0.40 41 410 Yes
45 F 60 0 1 0 2 600 0.05 1.30 3 530 No
46 F 68 0 0 0 0 500 0.05 1.30 2 580 No
47 F 65 1 0 0 2 415 0.07 1.17 26 284 No
48 M 69 2 0 0 1 845 0.40 0.40 41 340 Yes
49 M 61 0 1 0 0 240 0.20 0.70 32 306 No
50 M 75 0 0 0 1 500 0.05 1.30 1 400 Yes
51 F 68 0 0 0 0 280 0.20 0.70 14 514 No

FRP, focal retinal photocoagulation; PRP, panretinal photocoagulation; PPV, pars plana vitrectomy; FAZ, foveal avascular zone; VA,
visual acuity; OCT, optical coherence tomography.

obtained for Snellen logMAR visual acuities. When amount of reduction of retinal thickness by OCT could
investigating the visual acuity results after 12 weeks, be predicted moderately by the baseline OCT-mea-
again baseline visual acuity was the only significant sured retinal thickness (standardized ␤-0.44, P ⫽
predictor (standardized ␤-0.378, P ⫽ 0.006). The 0.02; total model R 2 ⫽ 0.195, P ⫽ 0.02), again with
 BEVACIZUMAB THERAPY FOR DIABETIC MACULAR EDEMA ● HARITOGLOU ET AL 1003

Fig. 1. Development of visual acuity (logMAR of Snellen letters) evaluated after 6 weeks (A) and 12 weeks (B) of follow-up.

the other factors being nonsignificant. Similar results
were obtained for the retinal thickness at 12 weeks
(standardized ␤-0.806, P⬍0.001; total model R 2 ⫽
0.649, P ⬍ 0.001).
Discussion
Bevacizumab is a humanized monoclonal antibody
that binds to all isoforms of VEGF. Although preclin-
ical experimental data for primates suggested that the
full-length antibody might not penetrate the internal
limiting membrane of the retina,23 recent studies
showed full-thickness penetration of the retina within
24 hours.24 To our knowledge, all clinical17–20,25 and
experimental 26,27 studies presented so far did not
observe drug-related toxic effects to any retinal struc-
ture. The intravitreal injection of bevacizumab has
been met with great enthusiasm in the ophthalmic
community, especially as a new treatment option for
patients with neovascular age-related macular degen-
eration.17–19 The approach to inject bevacizumab into
the vitreous cavity, as presently done mostly for pa-
tients with age-related macular degeneration, is based
on reliable results of clinical reports clearly indicating
an increase of visual acuity and a decrease of retinal
thickness.18,19 Nevertheless, to our knowledge, there are
no prospective, randomized studies available at present.
Furthermore, a significant improvement has been re-
ported even in other conditions associated with increased

Fig. 2. Development of retinal thickness measured by optical coherence tomography after 6 weeks (A) and 12 weeks (B) of follow-up.
1004 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
Fig. 3. Retinal thickness measured by optical coherence tomography
at baseline (710 ␮m; top), after 6 weeks (middle), and after 12 weeks
(bottom) for Patient 37 in Table 1.
intravitreal levels of VEGF, such as macular edema in
association with central retinal vein occlusion.20,25 Other
VEGF inhibitors such as pegaptanib, which binds to one
VEGF isoform, have also been successfully used to treat
diabetic macular edema in a phase 2 trial28: subjects
treated with pegaptanib had better visual acuity out-
comes, were more likely to have reduction in central
retinal thickness, and were deemed less likely to need
additional therapy with photocoagulation at follow-up.
In light of this information, it seemed reasonable to us to
initiate a prospective study investigating the effect of
bevacizumab on patients with chronic diffuse diabetic
macular edema unresponsive to other therapies, a group
of patients for which no other effective treatment strategy
is currently available. Of note, other VEGF inhibitors
such as pegaptanib or ranibizumab were not available at
that time.
In the present investigation, we found that even in
patients with chronic diffuse diabetic macular edema,
which did not respond to other treatments such as laser
photocoagulation, vitrectomy, or intravitreal applica-
tion of triamcinolone, significant improvement (de-
● 2006 ● VOLUME 26 ● NUMBER 9
crease of retinal thickness and increase of visual acu-
ity) was achieved after intravitreal injection of
bevacizumab even after a short period. At the initia-
tion of the study, we were aware of the fact that the
negative selection of cases would greatly influence the
outcome of this investigation. Therefore, the positive
effects observed appear especially noteworthy, be-
cause it seems very likely that the treatment effect was
biased by the negative case selection as performed in
our study and even better results might be expected
with a different study design and a selection of patients
with less severe stages of the disease at baseline. How-
ever, at present, the intravitreal injection of bevaci-
zumab, be it for the treatment of neovascular age-related
macular degeneration or diabetic retinopathy, represents
an off-label use. This implies that the intravitreal injec-
tion of bevacizumab may be performed only in cases for
which no other treatment option seems to be available.
We observed a decrease in retinal thickness and an
increase in visual acuity throughout follow-up with at
least two injections of bevacizumab in most patients. In
one third of the patients, the increase of visual acuity was
with at least 3 lines of definite clinical significance.
However, it remains unclear whether it is necessary to
follow a strict treatment regimen as performed in the
VISION trial and the MARINA trial that evaluated the
effect of pegaptanib or ranibizumab, where injections
were performed every 6 weeks for at least 2 years or
every 4 weeks for 6 months, respectively.13,29,30 We
decided to observe the development of visual acuity and
retinal thickness during follow-up and perform further
injections only in cases of recurrent subretinal or in-
traretinal fluid shown by OCT and visual deterioration.
The observed slight reduction of the increase in visual
acuity observed at the limited 12-week follow-up may hint
that repeated bevacizumab injections may be necessary.
Another indication for intravitreal injection of bev-
acizumab might be the treatment of proliferative dia-
betic retinopathy as suggested by Spaide and Fisher,31
where marked regression of neovascularization and
rapid resolution of vitreous hemorrhage within a short
period were described. Consequently, one might sug-
gest that bevacizumab may also be helpful for patients
with proliferative diabetic retinopathy and tractive
changes in the macular area requiring vitrectomy to
relieve traction. An intravitreal injection of bevaci-
zumab a few days before vitrectomy may help to
reduce the risk of intraoperative complications such as
excessive bleeding from active neovascularization.
A limitation of the present investigation is the short
follow-up, which did not allow for any estimation of
long-term efficacy and safety of this treatment. How-
ever, the results presented herein are promising, even
though we were treating patients with very advanced
 BEVACIZUMAB THERAPY FOR DIABETIC MACULAR EDEMA
stages of the disease, and underline the need for fur-
ther investigations. Other limitations are the lack of a
control group and the broad inclusion criteria, which
were attributed to the off-label character of the treat-
ment as mentioned above. Strengths of the present
study are the prospective design, the relatively large
number of patients, and the careful follow-up. Most
studies on intravitreal injection of bevacizumab in-
cluded only very limited numbers of patients and were
designed as retrospective analyses.18 –20,25,31
The intravitreal injection of VEGF inhibitors such as
bevacizumab provides new treatment strategies for a
variety of retinal diseases and offers patients a true per-
spective of visual recovery. Further prospective and ran-
domized studies will be needed to better determine
which patients benefit the most and how often and in
which concentration the drug should be administered.
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