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SHORT–TERM EFFECTS OF
INTRAVITREAL BEVACIZUMAB FOR
SUBFOVEAL CHOROIDAL
NEOVASCULARIZATION IN PATHOLOGIC
MYOPIA
MYRIAM L. HERNA
´
NDEZ-ROJAS, MD,* HUGO QUIROZ-MERCADO, MD,*
JOSE
´
DALMA-WEISZHAUSZ, MD,* JANS FROMOW-GUERRA, MD, MS
C,*
ANDRE
´
S AMAYA-ESPINOSA, MD,*† ADRIANA SOLI
´
S-VIVANCO, MD,*
ELIZABETH REYNA-CASTELA
´
N, MD,* MAURA ABRAHAM-MARI
´
N, MD,*
MARIA ANA MARTI
´
NEZ-CASTELLANOS, MD,*
LLOYD P. AIELLO, MD, P
HD†
Purpose: To determine short–term effects of intravitreal bevacizumab for subfoveal
choroidal neovascularization (CNV) in pathologic myopia.
Methods: In this prospective interventional case series, patients were treated with 2.5
mg of intravitreal bevacizumab and followed for 3 months. Best-corrected visual acuity
(BCVA), optical coherence tomography (OCT), and fluorescein angiography (FA) were
recorded. Indications for retreatment were active leaking CNV shown by FA and presence
of subretinal fluid by OCT in combination with visual disturbances.
Results: Fourteen patients were included, with a mean age of 53.86 ⫾ 16.26 years
(range 29– 85). Mean spherical equivalent was ⫺13.87 ⫾ 3.68 diopters (⫺7.25 to ⫺20.50).
Minimum follow-up was 3 months. There were no adverse events. The mean initial visual
acuity was 20/200 improving to 20/100 at 2 weeks, 20/80 at 4 weeks, and 20/60 at 8 and
12 weeks (P ⫽ 0.007; P ⫽ 0.001; P ⫽ 0.005; P ⫽ 0.001, respectively). Initial foveal
thickness improved from 385.43
m ⫾ 125.83
m to 257.64 ⫾ 76.6
m and 194.54 ⫾
54.35
m after the first and third month, respectively (P ⫽ 0.001).
Conclusions: Initial treatment results of patients with CNV due to pathologic myopia did
not reveal any short-term safety concerns. Intravitreal bevacizumab resulted in a significant
decrease in foveal thickness and improvement in visual acuity. These favorable initial
results support further larger and long-term studies.
RETINA 27:707–712, 2007
H
igh myopia is a major cause of legal blindness in
many developed countries.
1
It affects approxi-
mately 2% of the general population
2
and 27–33%
3
of
myopic eyes. The pathogenesis of high myopia is
associated with progressive and excessive elongation
of the anteroposterior axis of the eye.
4,5
In highly
myopic eyes, the collagen fibers are pathologically
abnormal and the smaller fibers have less cross linking
than those of emmetropic eyes.
6,7
These factors pre-
dispose to the development of various degenerative
changes involving the sclera, choroid, and retina. In
highly myopic eyes, elongation of the axial length
stretches the retinal pigment epithelium, causing atro-
From *Hospital Luis Sa´nchez Bulnes, Asociacio´n Para Evitar la
Ceguera en Me´xico I.A.P., Me´xico City, Me´xico; and †Beetham
Eye Institute, Joslin Diabetes Center, Department of Ophthalmol-
ogy, Harvard Medical School, Boston, Massachusetts.
No authors have a proprietary interest.
Reprint requests: Myriam L. Hernandez-Rojas, MD, Vicente
Garcia Torres #46 Col. San Lucas Coyoacan C.P. 04030 Mexico
D.F., Mexico; e-mail: myrianhernandez@hotmail.com
707
phy and breaks in Bruch membrane observed clini-
cally as lacquer cracks, which are thought to facilitate
the development of choroidal neovascularization
(CNV).
8
A number of studies have demonstrated that vascu-
lar endothelial growth factor (VEGF), a potent mito-
gen for endothelial cells, plays a central role in the
development of neovascularization in various chori-
oretinal diseases.
9,10
Stretching of the retinal pigment
epithelium was reported to upregulate the expression
and secretion of VEGF in retinal epithelium cells in
vitro.
11
Myopic maculopathy, consisting of chorioretinal
atrophy and macular CNV, is the most common cause
of vision loss in highly myopic patients.
12
Typically,
myopic CNV is a small, flat, grayish, subretinal mem-
brane which is less than 1 disk diameter
13
and is
located between the neurosensory retina and retinal
pigment epithelium (Type 2).
1
Different therapeutic
approaches have been employed to treat myopic
maculopathy, including the use of thermal laser pho-
tocoagulation,
14,15
radiotherapy,
16
different surgical
procedures,
17,18
photodynamic therapy (PDT),
19
and
more recently, antiangiogenic therapy.
20
Several antiangiogenic drugs are being tested for the
management of CNV. Bevacizumab (Avastin, Genen-
tech Inc., San Francisco, CA) is a monoclonal antibody
that blocks all isoforms of VEGF that has been used
clinically to treat colorectal cancer.
21
Recent reports have
suggested that bevacizumab delivered by intravitreal ad-
ministration may inhibit by neovascularization and prove
useful for treating CNV.
22,23
In this study we evaluate the effects of intravitreal
bevacizumab on CNV due to pathologic myopia.
Patients and Methods
This was a prospective, interventional, longitudinal
case series of patients with CNV due to pathologic
myopia recruited at the Retina Service of “Dr. Luis
Sa´nchez Bulnes” Hospital from the “Asociacio´n Para
Evitar la Ceguera en Me´xico” from September 2005 to
February 2006.
Inclusion criteria were refractive error of ⫺6.00 D
spherical equivalent or more, clear media, dilated pupil
size ⱖ4 mm, and presence of choroidal neovasculariza-
tion confirmed by fluorescein angiography (FA). Exclu-
sion criteria were heart disease, uncontrolled systemic
hypertension, diabetes, fluorescein allergy, pregnancy,
use of intraocular toxic drugs, and any other retinal
condition.
Initial evaluation included manifest refraction, best-
corrected visual acuity (BCVA) evaluated by ETDRS
testing (Lighthouse International, NY) under standard
conditions, slit lamp examination, tonometry, fundus
examination using indirect ophthalmoscopy and slit
lamp, FA, and optical coherence tomography (OCT).
After informed consent and discussion of therapeu-
tic options, patients were treated with intravitreal in-
jection of 0.1 mL (2.5 mg) of bevacizumab, 4 mm
posterior to the limbus, in the superotemporal quad-
rant under aseptic conditions.
Patient follow-up was at 1, 2, 4, 8, and 12 weeks after
intravitreal injection. On each evaluation BCVA, com-
plete ocular examination, and blood pressure measure-
ment was performed. Fluorescein angiography and OCT
were done at 4 and 12 weeks after treatment.
Retreatment was considered if there was persistence
of subretinal fluid on clinical evaluation or by OCT,
active leakage on FA, or decrease in visual acuity
associated with leakage at the late phases of the FA.
Results
Fourteen eyes of 14 patients were treated. Ten
(71.4%) were female. The mean age was 53.86 ⫾
16.26 (29 – 85 years). Mean spherical equivalent was
⫺13.87 ⫾ 3.68 D (⫺7.25 to ⫺20.50 D). Choroidal
neovascular membranes were classified as subfoveal
classic in 12 patients (85.7%), juxtafoveal classic in 1
(7.1%), and subfoveal occult in 1 (7.1%).
There were no adverse effects noted after the intra-
vitreal injection of bevacizumab, for the duration of
the study. The mean initial visual acuity was 20/200
(logMAR ⫺0.95) which improved to 20/100 (logMAR
⫺0.70) 2 weeks after treatment, 20/80 (logMAR ⫺0.62) at
4 weeks, 20/60 (logMAR ⫺0.56) at 8 weeks, and at 12
weeks the BCVA averaged 20/60 (logMAR ⫺0.56)
(GLM repeated measures pairwise comparisons: P ⫽
0.007; P ⫽ 0.001; P ⫽ 0.005; P ⫽ 0.001, respec-
tively) (Figure 1).
Thirteen patients (92.8%) had 12 weeks follow-up.
One patient was lost to follow-up at week 6. Benefits
from bevacizumab were seen as early as 2 weeks after
injection. At this time, visual acuity in 2 patients
(14.2%) was unchanged, improved 5 to 15 letters in 10
patients (71.4%), and improved more than 15 letters in
2 patients (14.2%). After 4 weeks of follow-up one
patient (7.1%) lost less than 5 letters, 9 patients
(64.2%) gained 5 to 15 letters, and 4 patients (28.5%)
gained more than 15 letters acuity. At the 12-week
follow-up visit all patients had gained more than 5
letters: 7 (50%) gained 5 to 15 letters and 6 (42.8%)
gained more than 15 letters (Table 1).
Mean foveal thickness by OCT was 385.43
m ⫾
125.83
m which decreased to 257.64 ⫾ 76.6
m and
194.54 ⫾ 54.35
m at the first and third month respec-
tively (Wilcoxon signed rank test P ⫽ 0.001) (Figure 2).
708 RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES
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The amount of reduced thickness was 33.1 and 50
m,
respectively (Figures 3 and 4).
Four eyes (28.6%) had persistent leakage on FA
and OCT associated with decreased visual acuity and
required retreatment after 5 ⫾ 1.09 weeks.
Discussion
In pathologic myopia, CNV causes visual loss in
5–10% of patients.
13
Choroidal neovascularization in
high myopia is often considered self-limited; how-
ever, long-term follow-up has demonstrated poor
prognosis due to RPE atrophy.
14
Direct laser photocoagulation is no longer an indica-
tion for subfoveal CNV since it causes a full thickness
burn lesion in the retina which results in an irreversible
scotoma
2
and a high incidence of recurrences.
12,14,15,24
Surgical removal of the CNV, though achieving good
anatomical results, often causes loss in retinal pigment
epithelium cells and poor final visual acuity.
17,25
Sub-
macular surgery has been evaluated for myopic CNV in
several studies with conflicting outcomes.
26
The VIP study is the largest study addressing the
efficacy and safety of PDT with verteporfin in the treat-
ment of subfoveal CNV associated with myopia.
19
At 12
months, 72% of verteporfin-treated eyes compared with
44% of placebo-treated eyes had a visual loss of less than
eight letters, which was the primary outcome measure.
Moreover, 14% of the verteporfin treated group com-
pared with 33% of the placebo group developed moder-
ate visual loss of 15 letters or more. In this study, after 24
months follow-up, visual improvement of 5 letters (1
line) was noted in treated patients with PDT of 40%
versus 13% of placebo group.
27
Prospective, randomized, multicenter, double-masked
Fig. 1. Mean values ⫾ SDs
of visual acuity over time (in
weeks) in choroidal neovas-
cularization in pathologic my-
opia that was treated with in-
travitreal bevacizumab. An
improvement of visual acuity
is observed.
Table 1. Frequency Distribution of Changes in Visual Acuity From Baseline in Choroidal Neovascularization in
Pathologic Myopia Treated With Intravitreal Bevacizumab
Change From Baseline in Visual Acuity
Patients, n (%)
2wk 4wk 8wk 12wk
ⱕ⫺1 Line (loss ⬍5 letters) 0 (0) 1 (7.1) 1 (7.1) 0 (0)
0 Lines (maintenance or gain ⬎0 letters) 2 (14.3) 0 (0) 0 (0) 0 (0)
1 to 3 lines (gain 5 to 15 letters) 10 (71.4) 9 (64.3) 4 (26.6) 7 (50)
ⱖ3 Lines (gain ⬎15 letters) 2 (14.3) 4 (26.6) 7 (50) 6 (42.9)
709INTRAVITREAL BEVACIZUMAB FOR CNV
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studies reported the 2-year safety profile of pegaptanib
sodium (Macugen, Eyetech Pharmaceuticals, New York,
NY) in patients with exudative AMD
28,29
and multidose
studies
30,31
using ranibizumab for treatment of neovas-
cular age-related macular degeneration (AMD) had a
good safety profile and were well tolerated and biologi-
cally active in eyes with neovascular AMD.
Michels et al
32
evaluated the short-term safety of
Fig. 2. Mean values ⫾ SDs
of retinal thickness (measured
by optical coherence tomog-
raphy) over time (in months)
in choroidal neovasculariza-
tion in pathologic myopia that
was treated with intravitreal
bevacizumab. A significant
decrease in thickness over
time (P ⫽ 0.001) is observed.
Fig. 3. Fundus photograph
of a patient with myopic
choroidal neovascularization
(CNV). A CNV with subreti-
nal hemorrhage is noted at
baseline. At 4 weeks resolu-
tion of the subretinal hemor-
rhage is noted with a decrease
in foveal thickness by optical
coherence tomography. A
small residual subretinal fi-
brotic lesion is seen at 12
weeks with no subretinal
fluid.
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systemic bevacizumab for CNV AMD and it was well
tolerated, with an improvement in VA, OCT, and
angiographic outcomes.
Nguyen et al
20
treated two patients with intravenous
infusions of bevacizumab (5 mg/kg) to CNV caused
by pathologic myopia and reported anatomical and
visual improvement.
Our initial results show that intravitreal bevaci-
zumab produces a statically significant and clinical
meaningful benefit in visual acuity and retinal thick-
ness in patients with CNV associated with pathologic
myopia. This effect is observed as early as 2 weeks
after treatment and becomes increasingly evident over
the course of the 3-month follow-up.
Although eyes with hyperfluorescence with well-
defined borders but increasing hyperfluorescence at
late phases of the FA might be considered to be
leaking actively and in need of retreatment, these eyes
were only treated in presence of activity measured by
OCT. Although 4 patients (28%) required retreatment
after 5 ⫾ 1.09 weeks, all of them were considered
inactive after 12 weeks of follow-up.
Reports of intravenous use of bevacizumab have
mentioned complications including gastrointestinal
bleeding and systemic hypertension.
21
We found no
short-term side effects, either local or systemic,
associated with intravitreal bevacizumab. Limiting
factors of our study include the few participants,
short–term follow-up, and the absence of a control
group.
The potential clinical benefit of intravitreal bevaci-
zumab will only be known after careful long-term
studies specifically evaluating the safety profile and
efficacy of this therapeutic approach. However, the
current study demonstrated short-term benefit without
observed side effects and thus supports future evalu-
ation of this promising pharmacologic approach for
treating CNV from pathologic myopia.
Key words: antiangiogenic therapy, subfoveal
choroidal neovascularization, pathologic myopia,
bevacizumab.
References
1. Hatchkiss ML, Fine SL. Pathological myopia and choroidal
neovascularization. Am J Ophthalmol 1981;91:177–183.
2. Curtin B. The myopias: basic science and clinical manage-
ment. Philadelphia: Harper and Row; 1985:7–10.
3. Mondon H. Physiopathologie de la myopie forte. In: Mondon H,
Metge P, eds. La myopie forte. Paris: Masson; 1994:29–57.
4. Curtin BJ, Karlin DB. Axial length measurement and fundus
changes of the myopic eyes. Am J Ophthalmol 1971;71:42–50.
5. Noble KG, Carr RE. Pathologic myopia. Ophthalmology
1982;89:1099–1100.
6. Curtin BJ, Iwamoto T, Renaldo DP. Normal and staphylo-
matous sclera in high myopia: an electron microscopic study.
Arch Ophthalmol 1979;97:912–915.
7. McBrien NA, Norton TT. Prevention of collagen crosslinking
increases form deprivation myopia in tree shrew. Exp Eyes
Res 1994;59:475–486.
8. Adamis AP, Shima DT, Tolentino MJ, et al. Inhibition of
vascular endothelial growth factor prevents retinal ischemia-
associated iris neovascularization in a nonhuman primate.
Arch Ophthalmol 1996;114:66–71.
9. Lopez PF, Sippy BD, Lambert HM, et al. Transdifferentiated
retinal pigment epithelial cells are immunoreactive for vas-
cular endothelial growth factor in surgically excised age
related macular degeneration-related choroidal neovascular
Fig. 4. Fluorescein angiog-
raphy of the same patient in
Figure 3. A, B, C, Early, mid,
and late phase images of a
subfoveal choroidal neovas-
cularization with fluorescence
blockage by the subretinal
hemorrhage. D, E, F, Resolu-
tion of the subretinal hemor-
rhage with a decrease in flu-
orescein leakage. At the
fluorescein angiography at 12
weeks (G, H, I), no leakage is
noted.
711INTRAVITREAL BEVACIZUMAB FOR CNV
●
HERNA
´
NDEZ-ROJAS ET AL
membranes. Invest Ophthalmol Vis Sci 1996;37:855–868.
10. Armstrong D, Augustin AJ, Spengler R, et al. Detection of
vascular endothelial growth factor and tumor necrosis factor
alpha in epiretinal membrane of proliferative diabetic reti-
nopathy, proliferative vitreoretinopathy and macular pucker.
Ophthalmologica 1998;212:410–414.
11. Seko Y, Seko Y, Fujikura H, et al. Induction of vascular
endothelial growth factor after application of mechanical
stress to retinal pigment epithelium of the rat in vitro. Invest
Ophthalmol Vis Sci 1999;40:3287–3291.
12. Avila MP, Weiter JJ, Jalkh AE, et al. Natural history of
choroidal neovascularization in degenerative myopia. Oph-
thalmology 1984;91:1573–1581.
13. Hampton GR, Kohen D, Bird AC. Visual prognosis of dis-
ciform degeneration in myopia. Ophthalmology 1983;90:
923–926.
14. Ruiz-Moreno JM, Montero JA. Visual acuity results after
argon green laser photocoagulation of juxtafoveal choroidal
neovascularization in highly myopic eyes: long term results.
Eur J Ophthalmol 2002;12:117–122.
15. Secretan M, Kuhn D, Soubreane G, et al. Long-term visual
outcome of choroidal neovascularization in pathologic myo-
pia: natural history and laser treatment. Eur J Ophthalmol
1997;7:307–316.
16. Kobayashi H, Kobayashi K. Radiotherapy for subfoveal neo-
vascularization associated with pathological myopia: a pilot
study. Br J Ophthalmol 2000;84:761–766.
17. Adelberg DA, del Priore IV, Kaplan HJ. Surgery for subfo-
veal membranes in myopia, angioid streaks and other disor-
ders. Retina 1995;15:198–205.
18. Fujikado T, Ohji M, Hayashi A, et al. Anatomic and functional
recovery of the fovea after foveal translocation surgery without
large retinotomy and simultaneous excision of a neovascular
membrane. Am J Ophthalmol 1998;126:839–842.
19. Verteporfin in photodynamic therapy (VIP) study group. Pho-
todynamic therapy of subfoveal choroidal neovascularization
in pathologic myopia with verteporfin, 1 year results of a
randomized clinical trial-VIP report No. 1. Ophthalmology
2001;108:841–852.
20. Nguyen QD, Shah S, Tatlipinar S, et al. Bevacizumab sup-
presses choroidal neovascularization caused by pathological
myopia. Br J Ophthalmol 2005;89:1368–1370.
21. Hurtwiz H. Bevacizumab plus irinotecan, fluorouracil and
leucovorin for metastatic colorectal cancer. N Engl J Med
2004;350:2335–2342.
22. Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal
bevacizumab (Avastin) for neovascular age-related macular
degeneration. Ophthalmology 2006;113:363–372.
23. Rosenfeld PJ, Moshfeghi AA, Puliafito CA. Optical coherence
tomography findings after an intravitreal injection of bevaci-
zumab (Avastin) for neovascular age-related macular degener-
ation. Ophthalmic Surg Lasers Imaging 2005;36:331–335.
24. Hotchkiss M, Fine S. Pathologic myopia and choroidal neo-
vascularization. Am J Ophthalmol 1981;91:177–183.
25. Ruiz-Moreno JM, de la Vega CS. Surgical removal of sub-
foveal choroidal neovascularization in highly myopic pa-
tients. Br J Ophthalmol 85:1041–1043.
26. Thomas MA, Dickinson JD, Melberg NS, et al. Visual results
after surgical removal of subfoveal choroidal neovascular
membranes. Ophthalmology 1994;101:1384–1396.
27. Blinder KJ, Blumenkranz MS, Bressler NM, et al. Vertepor-
fin therapy of subfoveal choroidal neovascularization in
pathologic myopia: 2-year results of a randomized clinical
trial–VIP report no 3. Ophthalmology 2003;110:667–673.
28. VEGF Inhibition Study in Ocular Neovascularization
(V.I.S.I.O.N.) Clinical Trial Group, D’Amico DJ, Masonson
HN, et al. Pegaptanib sodium for neovascular age-related
macular degeneration: two-year safety results of the two
prospective, multicenter, controlled clinical trials. Ophthal-
mology 2006;113:992–1001.
29. Gragoudas ES, Adamis AP, Cunningham ET, et al. Pe-
gaptanib for neovascular age-related macular degeneration.
N Engl J Med 2004:351;2805–2826.
30. Heier JS, Antoszyk AN, Pavan PR, et al. Ranibizumab for
treatment of neovascular age-related macular degeneration: a
phase I/II multicenter, controlled, multidose study. Ophthal-
mology 2006;113:642.
31. Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N. Tolerabil-
ity and efficacy of multiple escalating doses of ranibizumab
(Lucentis) for neovascular age-related macular degeneration.
Ophthalmology 2006;113:632.
32. Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN,
Venkatraman AS. Systemic bevacizumab (Avastin) therapy
for neovascular age-related macular degeneration twelve-
week results of an uncontrolled open-label clinical study.
Ophthalmology 2005;112:1035–1047.
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