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Perspective
Anti-VEGF: the Future Treatment of Choroidal Neovascularization in
Pathologic Myopia?
ZHU Hong*1,WANG Feng-hua*2, SUN Xiao-dong1
Keywords: choroidal neovascular, Anti-VEGF treatment, pathologic Myopia
Myopia is the most common refractive disorder. High myopia affects 27% to 33% of all
［1,2］
myopic eyes in Asia
. The pathologic myopia (PM) is the most severe vision-threatening
phenotype of high myopia
［3］
. It is also the second most common cause of choroidal
neovascularization (CNV) in Asia. Unlike age-related macular degeneration (AMD) which
mostly effecting elders. PM causes severe vision loss in young adults, resulting in a
［4］
significant impairment of their working ability
. PM has become the second leading cause
of low vision and blindness particularly among those ages 40 to 49 years old in some Asia
countries
［3］
.
Definition of Pathologic Myopia
Pathologic myopia
［5,6,7］
is usually defined with eyes has -6 diopters or more with typical
fundus pathologic changes such as peripapillary chorioretinal atrophy, tigroid fundus
(choroidal vessels being visible through the retina, often with lacquer cracks in Bruch’s
membrane), geographic atrophy of the retinal pigment epithelium (RPE) and choroid
(diffuse or patchy), posterior staphyloma, lacquer cracks, choroidal neovascularization
* ZHU Hong,WANG Feng-hua contributed equally to this work
1 Department
of Ophthalmology, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiao Tong
University, 100 Haining Road, Shanghai, 200080, China.
2
Shanghai Key Laboratory of Fundus Disease, Eye Research Institute of Shanghai JiaoTong University,
Shanghai, China
1
Corresponding authors: SUN Xiao-dong Sun
Email: [email protected]
Grants: China National Basic Research Program (973 Program, 2011CB707506), and China National Natural
Science Foundation ( 81271030 and 81100678 ), Shanghai Key Basic Research Grant (11JC141601),
Shanghai Scholar Leadship Grant (12XD1404100)
1
(CNV), spontaneous subretinal haemorrhages, and Fuchs’ spot. Among these changes,
CNV is the most vision threatening complication of myopia and develops in around
5.2-10.2% of high myopic eyes［5-7］ .
In particular, PM imposes an even greater public health burden because of its vision
threatening complications such as CNV, retinal degeneration and increased risk of
［4-5］
glaucoma, cataract, and retinal detachment
. These vision threatening complications
cannot be prevented by optical or surgical correction..
Epidemiology of Pathologic Myopia
In recent years, evidences have shown that the prevalence of myopia is increasing rapidly
in populations of Northeast Asian, Southeast Asian, Caucasian and Australian Aboriginal
origin.
In Asia, Population-based studies on children and adults have been carried out in both
northern and southern India. Bourne［8］reported that the prevalence of high myopia in
Bangladeshi adults was 1.8%. The prevalence of myopia is quite low in comparison to
those reported from East Asia. Xu,et al［9］ reported that prevalence of myopia of in urban
and rural adults of northern China population of high myopia (<-6.0 D) was 4.1%. In
Singapore, Wong［10］ reported 9.1% prevalence of high myopia among adult Chinese in
Singapore. In Taiwan, a national survey revealed that the subjects between the ages of 16
to 18 years have a rate of myopia of 84%. The prevalence of high myopia is 18% among
young Taiwanese men and 24% among young Taiwanese women. In the west, a large
population-based study of people aged 4 to 74 years in the U.S. showed that 3.2% had high
myopia (-5.01 to -10.00 D), and 0.2% had extreme myopia (< -10.00 D)
［11］
. In the Israeli
population, the prevalence of high myopia significantly increased from 1.7% in 1999 to
2.05% in 2002. In the Melbourne Visual Impairment Project［12］, it was found the prevalence
of high myopia 2%, and extreme myopia 0.3%. This problems not only affected in adults,
but also in school age children. Myopic refractive error is becoming a major cause of
reduced vision in school-age children. The prevalence of myopia in young adolescent eyes
has increased substantially over recent decades. It is now approaching 10–25% and
60–80%, respectively, in industrialized societies of the West and East［13,14］.
2
Myopia is considered to be a complex disease involving familial inheritance genetic origin
and environmental factors. There is compelling evidence to suggest that myopia is a
hereditary condition. Evidence is also strongly supported that myopia may be under
environmental influences. The rapid increase in the prevalence of myopia over the last
several decades suggests that environmental factors are important. It was significantly
associated with younger age, urban region, higher education, management occupations
and socioeconomic factors.
Choroidal Neovascularization in Pathologic Myopia
PM remains one of the leading causes of CNV in people younger than 50 years and the
second commonest cause of CNV after age related macular degeneration (AMD) ［15］. Most
myopic CNV is subfoveal or juxtafoveal “classic” lesion with minimal subretinal fluid or
exudation［16］. Myopic CNV is associated with significant socioeconomic setbacks in many
countries, since it is commonly seen in younger working populations［4］. It is still unclear the
initial stimulation that produce neovascularization in PM. The development of CNV in PM is
probably a function of the attenuated blood supply to the thin choroid. Based on previous
research with CNV in other diseases, the growth of CNV is most likely the result in the
overproduction of VEGF or an imbalance of VEGF levels［17］.
Natural history studies［4,18,19］ showed that the visual prognosis of CNV secondary to PM is
generally extreme poor though it shows a self-limiting course after ten years follow up.
Yoshida and associates［4］ studied 25 consecutive patients (27 eyes) with myopic CNV who
were observed without treatment for more than 10 years. Most of the patients lost visual
acuity over the course of the study. At initial examination, 22.2% of eyes had a visual acuity
of greater than 20/40, while 29.6% of eyes had a visual acuity of less than 20/200. However,
at final examination, only one eye retained a visual acuity of greater than 20/40 and 96.3%
of eyes had a visual acuity of less than 20/200 during the follow-up of more than 10 years.
At 5 and 10 years after onset, all CNV were observed to have regressed completely,
becoming flat and sometimes unrecognizable. Hayashi et al［20］ observed 57 eyes with
myopic CNV who were followed for at least 5 years after the onset of CNV. Among 57 eyes,
14.0% patients had a final visual acuity better than 20/40. 64.9% patients had a final visual
3
acuity worse than 20/200. 91.9% patients developed chorioretinal atrophy. Most studies
showed that the finial visual acuity worse than 20/200 was between 60% and 73% with
different follow up period. Secretan et al［19］ reported the results of 50 laser treated and 50
non-treated patients with myopic CNV after 5-10 years follow-up. The difference between
the mean decrease in VA of the treated and non-treated groups was no longer significant
after 8 years and 10 years. After long term observation with 325 eyes, Ohno-Matsui［5］ also
found that the incidence was higher (34.8%) among the fellow eyes of patients with
pre-existing CNV than among eyes of patients without pre-existing CNV (6.1%). So it is
clear that treatments need to be developed to help eyes with myopic CNV avoid
progressive visual impairment.
Treatment options for myopic CNV
There are some options used for treatment of myopic CNV. These include thermal laser
photocoagulation, surgical management (surgical excision of CNV and macular
translocation), Transpupillary thermotherapy (TTT) and photodynamic therapy (PDT) with
verteporfin.
Laser photocoagulation for CNV has been associated with several potentially
vision-threatening
complications
such
as
inadvertent
foveal
ablation,
subretinal
hemorrhage, and retinal pigment epithelial (RPE) tears［21,22］. Laser scar expansion is a
well-recognized and severe long-term complication after laser treatment in eyes with PM,
even in eyes free of CNV recurrence. It was reported that expansion of laser scars occurred
in 92% to 100% of myopic eyes treated with various wavelengths. A high rate of CNV
recurrence is another major problem associated with thermal laser treatment. Lacquer
cracks arising after laser treatment are often observed and may be a risk factor for CNV
recurrence. Recurrence rates varying from 31% to 72% have been reported, with recurrent
CNV arising most commonly from the edge of laser scars.
TTT involves long-exposure, large spot size irradiation of the CNV using an 810 nm diode
laser, associated with a lower thermal output than traditional laser photocoagulation. TTT
may represent another alternative for the management of myopic CNV ［23］. Because diode
laser energy absorbed depends greatly upon the amount of melanin, the most effective
4
light absorber in the chorioretinal layers and highly attenuated RPE and choroids in PM, it is
necessary to get appropriate laser settings for patients of differing racial background case
by case. It is easier that TTT may cause damage to the neurosensory retina［24］. Ultimately,
a randomized prospective trial evaluating TTT for the treatment of CNV in PM of varying
racial backgrounds may be necessary.
Surgical methods were also developed to removal of the CNV membrane with or without
limited or 360 degree macular translocation. Different approaches of submacular surgery
for CNV in PM have been evaluated in several studies with differing outcomes［25,26］.
Machemer et al first developed macular translocation surgery for repositioning the
neurosensory retina overlying the CNV onto an area of healthier RPE and
choriocapillaris[27]. Most studies were small case series and had conflicting results. One of
the main disadvantages of macular translocation with limited or 360 degree retinotomy is
more extensive surgical manipulations. Other complications include retinal detachment,
proliferative vitreoretinopathy, postoperative diplopia, recurrent CNV, and severe hypotony.
Therefore confirmation of long term efficacy and safety of macular translocation surgery
await further assessment, though it is effective treatments for myopic CNV[28].
Verteporfin (Visudyne, QLT Inc./Novartis Ophthalmics) PDT has been widely investigated
in AMD as well as in PM ［29,30,31］. PDT involves the administration of an intravenous
photosensitive dye that is thought to accumulate preferentially in the CNV. The CNV is then
exposed to non-themal irradiation using a 689 nm diode laser. This wavelength activates
the accumulated dye and occludes the CNV. Until now, the Veteporfin PDT is the only
therapy with evidences from randomized large scale clinical trial.
PDT was first successfully used for the treatment of CNV in the Treatment of Age-Related
Macular Degeneration with Photodynamic Therapy Study Group (TAP) Trials［29］. The
subsequent Verteporfin in Photodynamic Therapy (VIP) clinical trial evaluated the use of
PDT for PM［29,31］. In the VIP trial, 120 patients with subfoveal CNV associated with PM were
randomly assigned to verteporfin therapy (81 eyes) or placebo (39 eyes). For entry, the
greatest linear dimension of the lesion had to be no more than 5,400 microns, with a
best-corrected visual acuity of approximately 20/100 or better. After one-year follow up, VIP
5
study Group reported that 58 (72%) of the PDT-treated patients compared with 17 (44%) of
the placebo-treated patients lost fewer than eight letters（P<0.01）, including 26 (32%)
versus 6 (15%) improving at least five letters (>/=1 line). Seventy (86%) of the PDT-treated
patients compared with 26 (67%) of the placebo-treated patients lost fewer than 15 letters.
The visual acuity of the verteporfin-treated group had a greater chance of remaining stable
compared with the placebo-treated group. However, by 2-years of follow up, statistical
significance of the treatment benefit was lost. Twenty-Nine of 81 PDT-treated patients (36%)
compared with 20 of 39 placebo-treated patients (51%) lost at least 8 letters (P=0.11).
Schnurrbusch , Pece et al reported similar results［32］.
In view of the possible ethnic influence on the results of the VIP study, Lam et al
［30］
conducted a prospective, noncomparative study of 31, 11 ethnic Chinese, respectively with
subfoveal and juxtafoveal CNV secondary to PM. In subfoveal group after 24 months of
follow-up, the median visual acuity improved by1.7 lines, although the mean visual acuity
remained unchanged at the baseline level; 14 (63.6%) eyes had stable or improved BCVA
while 6 (27.3%) eyes gained more than three lines of vision. The mean number of PDT
treatments required in the first 2 years, 2.3, was considerably less than the mean of 5.1
treatments required in the VIP study. These studies in Asians showed that visual outcomes
of PDT for myopic CNV achieved similar to those in Caucasian populations but with less
retreatment. Visual acuity recovery correlates with the number of PDT re-treatments and
ages.
The results of difference between the TAP study and the VIP study are possibly because
the nature history difference between neovascular AMD and PM［31］. PDT is most effect for
predominantly classic CNV in AMD, the most aggressive form of neovascular AMD.
However, only 80% of PM eyes enrolled in the VIP study contained predominantly classic
CNV and there’s a greater tendency for CNV in PM to be self-limited, so the treatment
benefit may be less apparent. In addition, PDT may not occlude the CNV in PM as well as
the CNV in AMD. A histopathologic evaluation of CNV after PDT showed only partial
vascular occlusion, and
Moshfeghi, et al concluded that PDT therapy did not appear to
lead to permanent and complete occlusion of the CNV ［33］. The complications of PDT for
CNV in PM include delay in choroidal perfusion, occlusion of large choroidal vessels,
6
［34］
lacquer crack formation and subretinal fibrosis
. Myopic eyes may be more susceptible to
PDT-induced chorioretinal damage. Myopic eyes may be predisposed to post-treatment
lacquer cracks, recurrent CNV, and RPE atrophy with subequent loss of visual acuity.
Anti-VEGF treatment and myopic CNV
Vascular endothelial growth factor A (VEGF), also known as vascular permeability factor, is
a homodimeric protein that is a potent stimulator of vascular endothelial cell growth,
functions as a survival factor for newly formed vessels, facilitates the recruitment of
leukocytes by acting as a chemotactic factor, and induces vascular permeability.
These
biological activities give it a central role in angiogenesis, both in normal and pathologic
conditions. Inappropriate over expression of VEGF has been hypothesized to play a key
role in the growth of pathologic neovascularization in AMD , diabetic retinopathy, retinal
vein occlusion and other vascular eye diseases［17,35,36］. Despite differences in pathogenesis
among the AMD and PM processes, there is evidence that the concentration of VEGF in
aqueous humor increases in PM. It suggests that VEGF may also play a key role in the
development of CNV in PM just as that in other neovascular eye diseases［17,35］.
Available vascular endothelial growth factor inhibitors, include Pegaptanib, Bevacizumab,
Ranibizumab, VEGF-trap and Conbercept, have been used for eye disease treatment. All
the agent can treat CNV via inhibit the activity of VEGF, especially VEGF-A. Although there
is no evidence from randomized clinical trials to prove the efficacy and safety of these drug
in treating neovascular PM, many finished retrospective and perspective researches
showed promising results. The visual outcome of these therapies has been reported to be
better than the natural history of the condition［36-42］
Ranibizumab (rhuFabV2, Lucentis; Novartis, Switzerland), a humanized monoclonal
antibody fragment, is designed to bind all isoforms of VEGF and block vessel permeability
and angiogenesis. It binds and inhibits VEGF165, VEGF121, and VEGF110 and has also
been shown to penetrate all layers of the rabbit retina-the first demonstration of retinal
penetration of an anti-VEGF therapy intended for AMD, diabetic macular edema and retinal
vein occlusion. Figurska et al first reported using ranibizumab treated CNV in two patients
with high myopia. After 9 months follow-up in a 25 years old woman's after three injections
7
of Lucentis, visual acuity improved of three lines on ETDRS chart (15 letters), another
patient gained 10 letters after 2 injections.[8] After then, there has been number of
publications reporting the use of intravitreal ranibizumab in the treatment of myopic CNV.
These studies are limited to case-series involving relative small number of study subjects,
and short follow-up period (3 to 36 months). In these series with limited follow-up,
intravitreal ranibizumab was a safe and effective treatment for CNV secondary to PM,
resulting in functional and anatomic improvement ［37-39,42-45］. Recently, Franqueira
［46］
reported a three-year retrospective, nonrandomized, interventional case series. They
observed forty eyes of 39 patients with myopic CNV. 15 with previous photodynamic
therapy, and 25 naive eyes. Best-corrected visual acuity (BCVA) changes, central foveal
thickness (CFT), and number of treatments were assessed, from baseline to month 36. A
mean of 4.1 injections were performed in the first year, 2.4 in the second year and 1.1 in the
third year. It was concluded that Intravitreal ranibizumab seems to be an effective and safe
therapeutic procedure to treat CNV in highly myopic eyes, with a high proportion of patients
gaining or stabilizing BCVA at a 3-year follow-up.
Bevacizumab is a full-length recombinant, humanized antibody approved for the treatment
of metastatic adenocarcinoma of the colon, appears to effectively treat choroidal
neovascular membranes associated with age-related macular degeneration［47］. Since the
initial promising results of systemic and intravitreal using bevacizumab on the treatment of
CNV in AMD, now bevacizumab is currently being used at multiple centers around the
world as an “off-label” treatment of neovascular AMD and other ocular diseases. It was
widely “off-lable” used to treat different types of CNV and macular edema because its
relative cheap cost and well tolerated and efficacy that was proved by the visual acuity and
anatomic improvements after injection. Nguyen et al［48］ reported the first two patients with
subfoveal CNV secondary to PM treated with intravenous bevacizumab. These two patients
both were presented with recurrent CNV and treated bevacizumab as a salvation therapy.
They showed significantly substantial improvement of vision with decrease in foveal
thickness and macular volume proved by OCT. There were no ocular or systemic side
effects were observed after intravenous bevacizumab. Then Yamamoto, Sakaguchi et al
［49,50］
reported intravitreal injection bevacizumab results. Yamamoto at al reported the
results of 11 eyes with the history of treated by photodynamic therapy, which 3 eyes
8
received 2 bevacizumab injections and 8 eyes received 1 injection. It was showed that
visual acuity improved by a mean of +3.5 lines with no injection complications or
drug-related side effects observed after intravitreal injection bevacizumab after a mean
follow-up of 153 (range 35-224) days. The visual improvement was also proved by OCT
evaluation that central foveal thickness improved from 340μm (range, 253 to 664 μm) to
234μm (range, 142 to 308μm). The encouraging results are similar with Sakaguchi’s results
that the BCVA improved two or more lines in six eyes (75%) and remained the same in two
eyes (25%), which is recently supported by more cases reports.
Kumari Neelam et al
［51］
reviewed 32 studies which used pegaptanib (1), bevacizumab (22)
and ranibizumab (9). In these primarily small series, although mostly with limited follow-up,
it was elementarily proved that intravitreal bevacizumab is a safe and potentially efficiency
treatment for subfoveal CNV secondary to PM. The mean number of injections per year in
PM patients are far more less than that in AMD.
Since the adverse events (AE) are still observed in anti-VEGF treatment, less injection
might means less incidence of AE. Unlike systemic administration of VEGF inhibitors
associated with potential life-threatening complications, such as thromboembolic events,
myocardial infarction, malignant hypertension, intravitreal administration of VEGF inhibitors
minimizes the risk. The ocular complications reported included the risk of developing
intraocular inflammation, glaucoma, endophthalmitis, and cataract. Also, in myopic eyes,
there is an increase likelihood of developing retinal tear and retinal detachment［52］. It was
also reported that development and gradual expansion of chorioretinal atrophy around
regressed CNV could be observed following successful treatment with VEGF inhibitors,
however, the area of chorioretinal atrophy may be smaller in these eyes than eyes treated
with PDT［53］.
Currently, there appears to be a global consensus that the treatment strategy is logical and
understandable, despite these shortcomings of present preliminary studies. We are
optimistic using VEGF inhibitors as the first line therapy for the CNV secondary to
pathologic myopia in the future. But it must be cautious until the numerous questions can
be answered by rigorously designed a large series of case-controlled, prospective,
9
randomized, multicenter, long-term follow up clinical trials.
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