Introduction et al dropped the word ”idiopathic,” introduced the

Introduction

Polypoidal choroidal vasculopathy (PCV)
characterized by recurrent, multiple, bilateral, asymmetric, sero-sanguineous
retinal pigment epithelial detachments was first described by Stern et al(1) in the early 1980s and was originally thought to be a
distinct abnormality of the choroidal vasculature found in the peripapillary
area.(2–4) The retinal manifestations of PCV resemble
neovascular age-related macular degeneration (AMD)(3), however, the clinical course and visual outcome of
PCV are more stable, more favourable and different from those of AMD.(2,5–13)

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In recent years, the spectrum of PCV has been expanded
further, allowing us to describe the pathogenesis, clinical manifestations,
demographic profile, fluorescein and indocyanine green (ICG) angiographic
findings, natural course, modalities of treatment, and prognosis with greater
detail and precision.

History

It has been nearly three decades since Yannuzzi and
co-workers first recognized a variant of choroidal neovascularization in the
peripapillary area and described polypoidal, subretinal, vascular lesions
associated with serous and hemorrhagic detachments of the retinal pigment
epithelium in a series of patients and proposed the term ”idiopathic
polypoidal choroidal vasculopathy” at the 1982 meeting of The Macula Society.(2) They described a series of patients with strikingly
similar choroidal vascular abnormalities within the posterior pole. Two years
later in 1984, at the American Academy of Ophthalmology meeting, Kleiner et al
described a similar group of patients in a presentation entitled ”Posterior
Uveal Bleeding Syndrome.(3) Soon after, Stern et al described a group of black
women with hemorrhagic detachments of the pigment epithelium and neurosensory
retina.(1) Later, a study from the same group of
authors showed an expanded clinical spectrum for PCV, affecting various ages,
both genders, and several racial populations.  

Yannuzzi et al described these vessels as a distinct
abnormality of the choroidal vasculature with two demonstrable components: (1)
dilated and branching inner choroidal vessels, and (2) terminal reddish-orange,
spheroid aneurismal-like definitions which were called ”polyp-like”.(2) They presumed that this choroidal vasculopathy was a
distinct clinical entity associated with multiple, recurrent serosan- guineous
detachments of the retinal pigment epithelium (RPE) and neurosensory retina
with leakage and bleeding specifically coming from the polypoidal components of
the vascular abnormality. Their early descriptions relied on clinical and
fluorescein angiographic features to make a definitive diagnosis. Only eyes
with large aneurysmal or polypoidal lesions beneath atrophic pigment epithelium
could be recognized clinically with slit-lamp biomicroscopy and imaged with
fluorescein angiography.

Later, Yannuzzi et al dropped the word ”idiopathic,”
introduced the term polypoidal choroidal vasculopathy or PCV, and reported on
an expanded clinical spectrum in a larger group of patients.(5,6) They confirmed the clinical features, such as the
demographic predilection for pigmentary races and a peripapillary location in
the fundus. They also, however, described PCV in white patients with and
without concomitant drusen in the macula, concluding ultimately that the
vasculopathy represented a distinct form of neovascularization with
characteristics including a predilection for patients of pigmented races,
clinical features such as small to large or bullous pigment epithelial detachment
(PED) with variable degrees of sero-sanguineous complications, and a natural
course tendency for recurrent neovascularization and secondary sero-sanguineous
detachments. PCV was now viewed as a form of distinct form of choroidal
neovascularization (type 1 under the RPE).

With the advent and utilization of indocyanine green
(ICG) angiography, the full spectrum of the vasculopathy was better appreciated
as the choroidal circulation was better imaged by the longer wavelengths used
to excite the indocyanine molecule through the pigment epithelium and the
serosanguineous fluid.

Pathogenesis

PCV is regarded as a primary abnormality of the
choroidal vessels, characterized by an inner choroidal vascular network of
vessels ending in an aneurysmal bulge or outward projection, often visible as a
reddish-orange, spheroid, polyp-like structure. PCV primarily involves the
inner choroidal vasculature that is well differentiated from the middle and
larger choroid vessels by histology.(14) These abnormal vessels are lined by a thin
endothelium with occasional pericytes. The lesion may sometimes be associated
with islands of lymphocytic infiltration.(12) Biomicroscopy and
ophthalmoscopy indicated PCV vascular abnormalities to lie between the RPE and
Bruch’s membrane.

Uyama et al described lesions termed polypoidal CNV.(11) Okubo et al used light and electron microscopy, on a surgically
excised macular PCV lesion, to identify a degenerated RPE-Bruch’s membrane
choriocapillaris complex.(15) An unusually dilated, tortuous
venule adjacent to a sclerotic arteriole and two native inner choroid vessels
appearing to form an arteriovenous crossing suggested hyperpermeability,
haemorrhage, and sclerosis, at the crossing site, to promote oedema and tissue
degeneration. Histopathological similarities with branched vein retinal
occlusion were noted. A venule with stasis might become fragile, leading to the
beaded or polypoidal configurations of PCV. Pulsation suggests branching
network vessels arising from the inner choroidal vasculature. Vessels
persisting in networks showed focal dilatation, constriction, and tortuousity.
Slow filling in early and dye leakage in late IGA indicated stasis and
exudation from branching network vessels.

Iijima et al, using OCT on two PCV eyes, observed
polypoidal structures protruding from the inner choroid and speculated that
these lesions cause serosanguineous RPE detachments via damage to the overlying
Bruch’s membrane and/or RPE, and even adhesion between the two.(16) Yanuzzi et al
reported the portion of the choroidal vasculature evolving into PCV networks to
vary among patients, indicating network vessels to lie at various levels within
the choroid.(5)

In a histopathologic
report, by Nakashizuka et al., who examined specimens surgically extracted from
five eyes of five PCV patients, the pathologic findings revealed little
granulation tissue formation in any of the specimens; on the other hand, all
the specimens exhibited a massive exudative change and leaking, all the vessels
exhibited hyalinization, and choriocapillaris had disappeared, even in the
cases in which RPE had been preserved.(17) This group also demonstrated by
immunohistochemistry that PCV is not the same as choroidal neovascularization
(CNV). CD-34 is a marker of vascular endothelial expression, and CD-34 staining
revealed discontinuity in the vascular endothelium, smooth muscle actin (SMA)
was negative in hyalinized vessels, and there was disruption and injury of
smooth-muscle cells causing dilation of vessels. VEGF antibody was negative in
vascular endothelial cells. These histopathologic findings indicated that
hyalinization of choroidal vessels, like arteriosclerosis, was characteristic
of PCV.(17)

Studying two macular translocation
specimens using a light microscope, Terasaki et al identified a fibrovascular
membrane within Bruch’s membrane.(18) Clusters of thin walled dilated vessels correlated
with polypoidal structures on ophthalmoscopy and IGA, indicating that the
fibrovascular complex was subretinal CNV. However, this eye had previously
undergone radiation for a subretinal neovascular membrane, making radiation
associated choroidal neovasculopathy a possibility.(19)

A fibrovascular sub-RPE lesion described
by Lafaut et al was also within Bruch’s membrane but beneath the diffuse
drusen, contained inflammatory cells and dilated, thin walled vessels, some
with very large lumens, suggesting PCV to represent an AMD variant.(20) The reliability of surgical specimen studies is often
limited by disease severity and/or coexisting disorders.(20,21) Secondary histopathological changes cannot be ruled
out.

                According to Yuzawa et al study, PCV is classifiable into three groups.(22) The most common type involves
choroidal vasculature abnormalities, in the present narrow sense. A second type
is polypoidal CNV, expanding rapidly under the RPE, ultimately with polypoidal
lesions developing at vessel terminal. Radiation associated choroidal
neovasculopathy is the third type.

When the lesion is increasing in size,
it usually does so by three proposed mechanisms. The lesion may enlarge by
simple vessel hypertrophy, by conversion of the lesion into the advancing edge
of a vascular channel, and by unfolding of a cluster of aneurysmal elements and
subsequent transformation into enlarging, vascular, tubular components. The
latter mechanism is usually apparent on clinical examination as a large,
reddish-orange subretinal mass that corresponds to a cluster of aneurysmal
elements. On ICG imaging, this same process is noted to be composed of
multiple, polypoidal elements that project anteriorly from the inner choroid
toward outer retina. With time, these mass like vascular lesions flatten out
and expand tangentially in its plane.

Genetics

The genetic studies with CNV and PCV
have been controversial in published papers.(23,24) Recently, a series of meta anlysis
was done to investigate the relationship between CNV of AMD and PCV.(25) It was found that many genes have
common associations with PCV and CNV – polymorphisms at LOC387715, HTRA1, Complement factor H (CFH) variants rs3753394
and rs 800292 , and C2 were found to be significantly associated with both
PCV and AMD, which demonstrates major genetic evidence to support the
similarity between neovascular AMD and PCV. LOC387715 rs10490924 was
the only variant showing a significant difference between PCV and AMD.(25) This variant was also correlated
with lesion size, vitreous hemorrhage, and therapeutic response in PCV. The
elastin gene identified by Kondo et al. in 2008 was shown to disrupt the
elastic area of the Bruch’s membrane. He found that a common elastin gene (ELN)
variant was significantly associated with susceptibility to PCV.(26)

CETP genetic variants to be associated with a high
risk of PCV and is concordant with reports of elevated HDL as a risk factor for
AMD, suggesting possible involvement of the high-density lipoprotein pathway.(27) Recent meta-analysis (2015) showed genes associated
with PCV implicated in Complement cascade (CFH Y402H SNP rs1061170, CFH I62V
SNP rs800292, C2 SNP rs547154, CFB SNP rs4151657, RDBP SNP rs3880457, and
SKIV2L SNPs rs2075702 and rs429608), Inflammatory pathway
(TNFRSF10A-LOC389641SNP rs13278062 and BEST- C4orf14-POLR2B-IGFBP7 SNP rs1713985),
Extracellular matrix/basement membrane regulation pathway (ARMS2 A69S SNP
rs10490924 and HTRA1 promoter SNP rs11200638) and lipid metabolism pathway
(CETP SNP rs3764261).(28)

Genotype associated with retreatment response:

·        
ARMS2 LOC387715
rs10490924 variant:  usually associated
with larger lesion size, higher likelihood of vitreous hemorrhage, and worse
visual outcome after PDT or combination therapy.

·        
ARMS2 A69S risk
genotype: higher risk for second eye involvement.

·        
CFH I62V
polymorphism: associated with choroidal thickness.

·        
ARMS2 A69S
(rs10490924), HTRA1-rs11200638, PEDF gene polymorphism (SERPINF1 rs12603825):
poor outcome after PDT.

Risk
Factors

Systemic Risk factors

Several studies have determined the systemic risk
factors of PCV. It has been reported that 41– 45% of PCV patients had systemic
hypertension.(29,30) Another report demonstrated that C-reactive protein
levels were increased in patients with PCV.(31) Cigarette smoking is a potent risk factor for PCV(32), and a history of central serous chorioretinopathy
was a significant risk factor for PCV.(33) One other interesting systemic association is blood
abnormality: raised plasma viscosity level and thrombocytopenia. Increased
plasma viscosity leads to impairment of the microcirculation, induces high
coagulability and therefore increased fibrin deposition which in turn leads to
the development of atherosclerotic disease which may cause choroidal vascular
histological damage with hyaline degeneration, adventitial thickening, and
subsequent tortuosity with focal arterial constrictions and dilatations, predisposing
to thrombus formation.(34,35) The presence of coexisting systemic cardiovascular
disease and blood abnormality may predispose to frequent haemorrhagic tendency
in IPCV. In a study by
Ueta et al., the prevalence of DM was also found to be higher in
CNV-AMD than in PCV (24.7% vs. 13.0%; p =
0.027)(29), while other systemic risk
factors including BMI, hypertension, stroke, ischemic heart disease,
hyperlipidemia, smoking and alcohol consumption were similar. Serum levels of
vascular endothelial growth factor (VEGF) have been shown to be higher in
patients with CKD(36), and in uncontrolled diabetic
patients with associated micro-vascular complications(37,38), suggesting that VEGF related
mechanisms might be more important in the pathogenesis of CNV-AMD than PCV.
This theory is supported by previous findings that aqueous levels of VEGF are
lower in PCV than in CNV-AMD.(39)

Ocular Risk
Factors

Several studies
have demonstrated a markedly thicker choroid in patients with PCV compared to
CNV-AMD. Eyes with PCV showed increased
(285.9 mm; subfoveal) choroidal thickness, whereas eyes with wet-AMD (119.4 mm;
subfoveal) showed reduced choroidal thickness in comparison with normal eyes.(40)

Based on our
recent experience, we have observed a significant association existing between central serous chorioretinopathy (CSC) and PCV. Several studies
have reported that a history of CSC is a risk factor for PCV development.(41–43) Further, studies have
demonstrated increased choroidal thickening in both diseases. Patients with sleep apnea have increased levels of
circulating epinephrine and norepinephrine. With elevated levels of
catecholamines, OSA has been hypothesized to be a direct risk factor for CSC which in turn is related to PCV.(44) Increased
hydrostatic pressure has been proposed as a possible mechanism for
the choroidal thickening and hyperpermeability seen in both diseases, but the
exact mechanisms leading to the differential development of each phenotype
require further elucidation.(45) Vascular endothelial growth factor (VEGF)
and pigment epithelium– derived factor (PEDF) were co-expressed and increased
with positive correlation in aqueous humor of eyes with active PCV.(39)

Serum Biomarkers

C-Reactive
Protein (CRP): Raised serum
levels of CRP, an acute phase protein that rises in response to inflammation,
have been associated with an increased risk for PCV. Kikuchi et al.,
showed that high CRP levels (>0.95 mg/dL) were associated with a three-fold
risk of PCV.(31)

Homocysteine: High serum levels of
homocysteine can cause endothelial injury, increase oxidative stress and
promote thrombosis, and has been identified as an independent risk factor for
vascular diseases.(46) In a recent study, Cheng et
al., found that each 1 µmol/L increase of plasma homocysteine conferred a
1.5-fold increased odds of PCV. Based on histopathological observation, the
authors proposed that homocysteine-mediated arteriosclerosis might lead to the
development of aneurysmal-like dilations seen in polypoidal lesions.(17)

Matrix Metalloproteinases: The
arteriosclerotic and aneurysmal changes seen in PCV strongly suggest
derangements in Extracellular matrix (ECM) remodelling.(17,47) ECM metabolism is regulated by
matrix metalloproteinases (MMPs) and tissue metalloproteinase inhibitors
(TIMPs) which is a crucial element of vascular remodeling and an imbalance
between the MMP/TIMP ratio can result in angiogenesis and pathological changes
in vessel wall structure, leading to vascular diseases. Zeng et
al., further demonstrated, in his pilot study, increased serum levels of
MMP-2 and MMP-9 in PCV eyes.(48)

Demographics

The prevalence of PCV in presumed
neovascular AMD was reported as 7.8% in US(6), 4.0% in Belgian(12),  9.8% in Italian(49), 8.2% in Greek(50), 23.0–54.7% in Japanese(51), 22.3–49% in Chinese(52), and 24.6% in Korean populations.(53) The prevalence varies with age.(54) In summary, PCV is more
prevalent in blacks, Japanese, Chinese, and other Asians than in whites, while
the incidence of AMD is very high in whites and low in blacks. The incidence of
both diseases is high in Asians.

In a study done in an Indian
population by Anantharaman et al, it was found that the disease was more prevalent in
males and was unilateral; mean age at presentation was 61.06 years. Timely intervention in cases with symptomatic polyps
could achieve stabilization of visual acuity.(55) PCV
is known to be a bilateral disease with the majority of patients with PCV in
one eye developing similar lesions in the fellow eye.(6) The bilateral
involvement of 4.5% in an Indian study series(55) is less than that reported in other
Asian ethnic groups 24% in Koreans(53), 10% in Japanese cohorts(51). Polypoidal choroidal vascularization was originally reported in women
of pigmented races; more recent cases included patients of Caucasian descent as
well as men.(12)

 Age

Polypoidal choroidal vascularization is most commonly
diagnosed in patients between the ages of 50 and 65 years; however, the age of
diagnosis can range from 20s to 80s. The average age of onset for all the
affected patients from the literature is 60.1 years,  which is comparable to other studies of Asian
PCV patients, including Korean (mean age 64.6 years) (53), Chinese (mean age 65.4 years)(52), Japanese (mean age 72.8 years)(51) and Indian (mean age 61.06 years).(55) Caucasian patients usually present the disease at an
older age.

Sex

It was thought that polypoidal choroidal vascularization
affects exclusively women; recently, it has been shown that although women are
involved predomi- nantly over men by a ratio of approximately 4.7:1 (53 to 12),
men could still have manifestations of the disorder. In an Indian study, the disease was more prevalent in males (M:F = 1.4:1).(55)  PCV
is more prevalent in men than women in Asian populations (22–37% female), but
the opposite is observed in Caucasians (52–65% female).(35)

Race

Individuals of African-American and Asian descents are
at risk for developing PCV(16), as the disorder seems to preferentially affect
pigmented individuals by a ratio of 4.2:1; however, it has been shown that
patients of other racial backgrounds may be afflicted.

Size

Polypoidal lesions are classified as small, medium,
and large. The width of the lesion varies, depending on the vascular channels
affected. Polypoidal lesions usually appear larger when the outer choroidal
vessels are involved. Such lesions are easily diagnosed on biomicroscopy,
especially when they are located beneath the atrophic RPE and on ICG.
Polypoidal lesions appear smaller when the disease affects the middle choroidal
vasculature. In this case, the lesions are more challenging to diagnose on
clinical examina- tion, and the preferential method of diagnosis is fluorescein
angiography.

Location

The choroidal vascular lesions of PCV are most
commonly found in the peripapillary area, although recent evidence suggests
that the lesions could also be found in the central macula(10) and in the mid periphery.(9)  Polypoidal
vascular abnormalities are located in the macula in 85% cases, in peripapillary
area in 7% cases, and in both macula and peripapillary areas in 3% cases. The high incidence of macular polyps (74.5%) in an
Indian study series is  consistent with
the observations made in other Asian ethnic groups.(55)

In a study from our centre (unpublished data), we
found that the mean age of PCV cases was 66+6 years with 57% of them
being males. There was no significant association with reference to diet,
smoking, alcoholism, exercise, diabetes mellitus, ischemic heart disease and
plasma homocysteine in cases of PCV. On Multivariate analysis, stress, lack of
sleep, obesity and higher socioeconomic status (p

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