|Year : 2019 | Volume
| Issue : 2 | Page : 72-92
Polypoidal choroidal vasculopathy: An update on current management and review of literature
Amit Harishchandra Palkar, Vikas Khetan
Department of Vitreoretinal Services, Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, Chennai, Tamil Nadu, India
|Date of Submission||14-Mar-2018|
|Date of Acceptance||29-Jun-2018|
|Date of Web Publication||31-May-2019|
Dr. Vikas Khetan
Department of Vitreoretina, Shri Bhagwan Mahavir Vitreoretinal Services, Sankara Nethralaya, 18, College Road, Chennai - 600 006, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Polypoidal choroidal vasculopathy (PCV) is a subtype of neovascular age-related macular degeneration (nAMD), commonly seen in the Asian population. It is dissimilar in epidemiology, genetic heterogeneity, pathogenesis, natural history, and response to treatment in comparison to nAMD. Confocal scanning laser ophthalmoscopy-based simultaneous fluorescein angiography and indocyanine green angiography, spectral-domain optical coherence tomography (OCT) with enhanced depth imaging, swept-source OCT, and OCT angiography have improved the ability to detect PCV, understand its pathology, and monitor treatment response. A plethora of literature has discussed the efficacy of photodynamic therapy, anti-vascular endothelial growth factor (VEGF) monotherapy, and combination of both, but only a few studies with higher level of evidence and limited follow-up duration are available. This review discusses the understanding of PCV with respect to epidemiology, pathogenesis, clinical features, natural history, imaging techniques, and various treatment options. Recent clinical trials (EVEREST-II and PLANET study) have emphasized that either anti-VEGF monotherapy or combination treatment is equally capable to strike a balance between polyp regression and stabilization of visual acuity. The recurrent nature of the disease, the development of macular atrophy, and the long-term poor visual prognosis despite treatment are concerns that open avenues for further research.
Keywords: Epidemiology, imaging, natural history, pathogenesis, polypoidal choroidal vasculopathy, treatment
|How to cite this article:|
Palkar AH, Khetan V. Polypoidal choroidal vasculopathy: An update on current management and review of literature. Taiwan J Ophthalmol 2019;9:72-92
|How to cite this URL:|
Palkar AH, Khetan V. Polypoidal choroidal vasculopathy: An update on current management and review of literature. Taiwan J Ophthalmol [serial online] 2019 [cited 2019 Jul 23];9:72-92. Available from: http://www.e-tjo.org/text.asp?2019/9/2/72/244531
| Introduction|| |
Polypoidal choroidal vasculopathy (PCV) is a distinct abnormality of the choroidal vasculature with characteristic branching vascular network (BVN) of choroidal vessels and surrounding polypoidal dilatation of the vessels on indocyanine green angiography (ICGA). It was thought to be a peculiar phenotype of neovascular age-related macular degeneration (nAMD) for some time., It is now known that PCV shows distinct characteristics that can be distinguished from typical nAMD.,
The clinical value and relevance of ICGA were underestimated for nearly a decade since its clinical use in ophthalmology. The use of ICGA was recommended to identify PCV and demonstrated an ability to differentiate the disease from other chorioretinal diseases. The development of swept-source optical coherence tomography (SS-OCT) has enabled definition of chorioretinal anatomy with enhanced resolution. Multimodal imaging allows an integrated evaluation of the choroidal abnormalities in PCV. So far that, it is now considered within a group of thickened choroidal entities termed pachychoroid spectrum.
Photodynamic therapy (PDT) has been the mainstay in the treatment of PCV, following better visualization of the lesion on ICGA. With the experience of anti-vascular endothelial growth factor (anti-VEGF) agents in new vessel diseases, they have been promising in PCV as well. They have widened the armamentarium in the treatment of PCV. The efficacy of these agents as monotherapy or combination therapy with PDT has been demonstrated in the recent clinical studies.
The review summarizes the recent literature regarding the natural course of disease, imaging features, and treatment options with treatment trials, to study the transition in the understanding of PCV.
| Historical Perspective|| |
PCV was first described as polypoidal subretinal lesions causing serous retinal detachment (SRD) and hemorrhagic retinal detachment by Yannuzzi. He proposed the term “idiopathic polypoidal choroidal vasculopathy” at the Annual Meeting of the American Academy of Ophthalmology in 1982. Kleiner andJohnson in 1984 described a peculiar hemorrhagic disorder of the macula with recurrent subretinal and sub-retinal pigment epithelium (RPE) bleeding and termed it as posterior uveal bleeding syndrome. Later, Yannuzzi et al. expanded the description of the entity as a distinct choroidal abnormality, peripapillary in location, characterized by dilated and branching inner choroidal vessels with terminal reddish-orange, spheroid “polyp-like” lesions. They considered it as a subtype of choroidal neovascular (CNV) membrane causing recurrent serosanguinous detachments of the RPE and neurosensory retina. The lesions were not identified unless large enough to be clinically visible or imaged with fluorescein angiography (FA). Later, the nomenclature was revised to omit “idiopathic” to polypoidal choroidal vasculopathy or PCV. The utility of ICGA and OCT imaging was realized, and early descriptions of PCV lesions were made., The disease can clinically resemble AMD with hemorrhagic or serous pigment epithelial detachment, and it can be difficult to distinguish PCV from nAMD.
| Epidemiology|| |
Obtaining accurate estimate of the prevalence of PCV is limited often because its presentation is disguised as presumed exudative AMD. PCV is more prevalent in Black population and predominantly Japanese, including other Asians (22%–62%), than in White population (8%–13%) with a tentative diagnosis of nAMD.,,,,,,,,,, Asian patients with PCV are younger when compared to patients with exudative AMD without PCV. PCV is more prevalent in Asian men and Caucasian women.,,,, A comparative epidemiological study is needed to investigate these demographic differences between Asian and White populations.
PCV lesions are often located in the central macula in Asians, whereas the location seems more extrafoveal and peripapillary in White patients. Moreover, PCV lesions may be located beyond the posterior pole causing peripheral exudative hemorrhagic chorioretinopathy or found together with macular lesion.,,, Bilaterality is present in 6%–24% of the Asian patients with PCV. Large soft drusen frequently seen with nAMD without PCV is less prevalent in patients with PCV.
Smoking is found to increase four-fold risk of PCV and nAMD. Diabetes mellitus and end-stage renal disease show a higher prevalence in nAMD than PCV. Central serous chorioretinopathy (CSCR) has been reported as a risk factor for PCV. Both entities though phenotypically different were found to have increased choroidal thickness (CT) and choroidal hyperpermeability in the affected as well as the fellow eye. Both conditions may be complicated by the development of CNV. The similarities found between CSCR and PCV suggest that they may be disease of the same spectrum.,,, Polypoidal lesions are also associated with tilted disc syndrome in myopic Asians eyes, angioid streak secondary to pseudoxanthoma elasticum, and radiation retinopathy.,,,
Cytokine analysis of the serum found C-reactive protein to be inconsistently associated with PCV. On the contrary, an increase of plasma homocysteine by 1 μmol/L conferred a 1.5-fold increased risk of PCV. Homocysteine is responsible for the endothelial injury, increased oxidative stress, promotion of thrombosis, and arteriosclerotic changes., These arteriosclerotic changes predispose to the development of aneurysmal-like dilations seen in the polypoidal lesions. Arteriosclerotic and aneurysmal changes seen in PCV strongly suggest derangements in remodeling of extracellular matrix (ECM). Increased serum levels of matrix metalloproteinases (MMP-2 and MMP-9) in PCV eyes cause breakdown of the ECM. Interleukin-1 β, a pro-inflammatory cytokine, was found in higher concentration in the vitreous aspirates of eyes with vitreous hemorrhage in PCV. Aqueous levels of VEGF were found higher in PCV compared to controls though significantly lower than aqueous levels in nAMD. On the contrary, pigment epithelium-derived growth factor (PEDF), which is a potent natural angiogenesis inhibitor, was also found to be higher in these eyes.,
| Genetics|| |
The differences in age, gender, ethnicity, and cytokines expression indicate variable gene susceptibilities of PCV in different cohorts of population. PCV was considered a variant of nAMD because they have similar phenotypes. However, PCV differs in the natural course of the disease and treatment response than nAMD. Genetic studies have identified susceptibility single-nucleotide polymorphisms (SNPs) in multiple genes in both PCV and nAMD. An updated meta-analysis identified 31 SNPs in 10 genes/loci that are associated with PCV susceptibility, including ARMS2, HTRA1, CFH, C2, CFB, RDBP, SKIV2L, CETP, 4q12, and 8p21. These genes are related to ECM, basement membrane, complement cascade, lipid metabolism, cellular apoptosis, and inflammation. In contrast, variants in ELN, LIPC, LPL, ABCA1, VEGF-A, TLR3, LOXL1, SERPING1, and PEDF have no significant association with PCV. Furthermore, 12 polymorphisms at the ARMS2-HTRA1 locus were found to have different effects in PCV and nAMD. The different molecular mechanisms leading to the pathophysiologic differences of PCV and nAMD remain unknown. The meta-analysis represented cohorts of Asian population, especially Japanese and Chinese, and the polymorphisms yet remain unknown in non-Asians.
| Pathogenesis|| |
PCV lesions have been described earlier based on studying human specimens obtained during vitreoretinal surgery or enucleation. MacCumber et al. were the first to report a thick fibrovascular membrane (FVM) within the Bruch's membrane with many vascular ingrowths from the choroid into the Bruch's membrane. Lafaut et al. also described an intra-Bruch's FVM seen with saccular, thin-walled aneurysmal vessels that appeared to be of venular rather than arteriolar origin. In the PCV tissues collected during macular translocation surgery, Terasaki et al. found a polypoidal vascular complex within the Bruch's space below the RPE. It contained dilated, thin-walled vessels without pericytes, which corresponded with the orange-colored polyp. These vessels were surrounded by macrophages and fibrin material. A similar fibrovascular complex with dilated vessels, which were not choroidal vessels, was found in the subretinal space. A positive immunohistochemical stain to anti-VEGF in the RPE and vascular endothelial cells confirmed it to be subretinal neovascularization. Conversely, Shiraga et al. only found an FVM under the sensory retina and above the RPE without a polypoidal vascular complex in a surgically excised membrane in submacular hemorrhage (SMH).
Okubo et al. characterized the thin-walled dilated aneurysmal vessels to have hyaline-like appearance in the vessel walls, similar to vessels in the branch retinal vein occlusion. They were identified as large choroidal arterioles with an inner elastic layer by Kuroiwa et al. The walls of these arterioles were thick and showed sclerotic change associated with an increase in basement membrane-like materials together with collagen fibers. This is referred to as “hyalinization” which involves extensive replacement of the smooth muscle component by amorphous pseudocollagenous tissue of a poorly defined nature. Hyalinized vessels are characterized by extravasation of plasma protein and deposition of basement membrane-like material. This arteriosclerotic change seen in the choroid is similar to the change seen in other organs such as brain, kidneys, and pancreas. Ross et al. found PCV with retinal artery macroaneurym with similar arteriosclerotic changes and epidemiological profile of Black, hypertensive elderly women. The dilated hyalinized choroidal vessels allow massive exudation of fibrin and blood plasma to raise choroidal tissue pressure sufficient to produce protrusion of choroidal tissues through the weakened or disrupted RPE and Bruch's membrane. The hyalinized choroidal vessels are negative for α-smooth muscle actin (SMA) expression compared to immunoreactive for α-SMA in pericytes of CNV vessels. This indicates disappearance of smooth muscles cells of choroidal vessels due to the increased intraluminal pressure resulting from systemic hypertension. However, no association was found between diastolic blood pressure and PCV. VEGF positivity was recognized in macrophages, fibroblast-like cells, and RPE cells, but not in vascular endothelial cells, unlike CNV. With significant lower aqueous levels of VEGF in PCV eyes, VEGF may hardly contribute to the occurrence of PCV. These findings point out the inconsistency in the pathogenic processes of CNV in nAMD and PCV. Nevertheless, the possibility that PCV and CNV can occasionally exist in the same eye simultaneously cannot be ruled out. They may either coexist incidentally, or CNV can grow secondarily as a result of a wound repair reaction to a collapse of the RPE or Bruch's membrane in advanced PCV.
CNV is a granulation tissue proliferation that later undergoes fibrosis, typically representing a wound repair response. The polypoidal complex of PCV predominantly lacks this granulation or fibrosis. Yet, fibrotic scars develop in PCV secondary to RPE tears or sequelae of subretinal hemorrhage (SRH).,,, Following SMH, an irreversible injury sets into the sensory retinal tissue. This is attributed to the limitation of the passage of nutrients to the retina, shrinkage of the outer retinal layers due to clot formation, and release of toxic substances, such as fibrin, iron, and hemosiderin. Toxic effects of subretinal blood can be demonstrated 24 h after hemorrhage. As the SMH resolves, there is often a subsequent subretinal scar formation.
| Clinical Features|| |
The characteristic lesions of PCV are protruding orange-red nodular lesions., They are usually located at the posterior pole, in the macular or peripapillary region, but peripheral PCV lesions are reported [Figure 1].,, The nodular lesions are usually accompanied with serous exudation and hemorrhage that may lead to pigment epithelial detachments (PEDs), SRD, SRH, subretinal fibrin, intraretinal lipids, hard exudates, and drusens., Polyp lesions are mostly present at the margin and inside the serosanguinous PED, which may appear as a “notch sign.” A notch in the margin of a large PED frequently indicates the site of polypoidal lesions. Microrips of the RPE and RPE tears could be found at the margins of the PEDs., When associated with hemorrhage, the SRH may block the view of the nodular lesions. In such cases, they are observed on ICGA and easily visible with OCT. Furthermore, the view of the fundus is sometimes obscured by vitreous hemorrhage.
|Figure 1: (a) Peripapillary polypoidal choroidal vasculopathy with subretinal pigment epithelium hemorrhage (gray-green) and hard exudates (top left); fluorescein angiography featuring classic choroidal neovascular membrane (top middle) and indocyanine green angiography detecting the polypoidal lesion within the blocked cyanescence due to hemorrhage below the retinal pigment epithelium (top right). (b) A well-circumscribed hemorrhagic pigment epithelial detachment with orange-red nodular lesions at the temporal edge of the pigment epithelial detachment and subretinal hemorrhage (bottom left); stippled hyperfluorescence on fluorescein angiography (bottom middle) and a small branching vascular network with single polypoidal lesion identified on indocyanine green angiography (bottom right)|
Click here to view
The funduscopic findings and visual acuity (VA) vary depending on the time of initial presentation of the patient. VA depends on the degree of exudation and is usually good in the absence or minimal subretinal fluid or hemorrhage at the fovea. SRH or SMH may occur because of the rupture of the abnormal areas of vascular dilation or aneurysmal venules. SMH in the subfoveal region, particularly when massive (>4 disc diameter area or thick hemorrhage beyond the temporal arcades), induces an abrupt decrease in the VA and can lead to RPE and outer retinal degeneration.
| Imaging|| |
PCV appears as occult CNV or minimally classic AMD on fluorescein angiography (FA) because BVN in PCV is located in Bruch's membrane. They may sometimes appear as “classic” CNV because of an increased hyperfluorescence due to the atrophy of overlying RPE or subretinal fibrin deposition or presence of type 2 CNV., The RPE in FA hampers visualization of the BVN beneath it unless in case of overlying RPE atrophy or less pigmented fundus. Serosanguinous complications of PCV further block the underlying polypoidal abnormalities. These drawbacks of FA are superseded by ICGA.
Indocyanine green angiography
Indocyanine green absorbs and emits near-infrared light, which readily penetrates the RPE. In addition, the dye has a higher binding affinity to plasma proteins and does not leak rapidly from the choriocapillaris as against fluorescein. PCV primarily involves the inner choroidal vasculature, and so, ICGA remains the gold standard to diagnose PCV. The indications of performing an ICGA are clinical findings of serosanguinous maculopathy with one of the following: clinically visible orange-red subretinal nodules; spontaneous massive SRH; notched or hemorrhagic PED; a lack of response to anti-VEGF therapy. ICGA characteristics of PCV include the presence of single or multiple focal areas of hyperfluorescence arising from the choroidal circulation within the first 6 min after injection of the dye, with or without an associated BVN. The orange-red subretinal nodules correspond to the ICGA hyperfluorescence that are polypoidal aneurysms or dilations at the edge of the BVN. Pulsations in polyps can be observed only in video ICGA. Active polyps are those having a hypofluorescent halo around it, indicating fluid surrounding the polyp. ICGA enables viewing the total lesion area (all polyps and the BVN), making it amenable to plan treatment with laser or PDT. Kawamura et al. classified PCV based on ICGA into two types: Type 1, both feeder and draining vessels are visible on ICGA and numerous network vessels; Type 2, neither feeder nor draining vessels are detectable and the number of network vessels is small. ICGA is now considered gold standard in differentiating PCV from classic or occult CNV associated with typical nAMD. However, ICGA is invasive, time-consuming, and not widely available in many clinics.
Optical coherence tomography
Spectral-domain OCT (SD-OCT) allows high-resolution cross-sectional images to study the retinochoroidal morphologic changes. It can localize the lesions and define their extent more precisely. Several reports have described characteristic features as follows [Figure 2]:
|Figure 2: (a) A “V” depression between two pigment epithelial detachments – “notch” sign (red arrowhead) with moderate hyperreflectivity below the smaller pigment epithelial detachment representing polypoidal lesion beneath. (b) Thumb-shaped pigment epithelial detachment with an abutting moderate hyperreflective ring with surrounding hyporeflective area (yellow dot) demonstrating the lumen of the polypoid lesion. Two hyperreflective membranes (green line with arrows), a double membrane sign, correlating with the branching vascular network|
Click here to view
- A sharp peak-like or thumb-like PED with underlying moderate reflectivity within the peak, most likely representing the polyp itself,
- Tomographic notch: “V”-shaped depression between two PEDs or at the margin of a large PED,,
- A moderate hyperreflective ring surrounding an area of hyporeflectivity located underneath the PEDs probably represents the lumen of the polypoidal lesions. They are attached to the posterior surface of the RPE and correspond in location with polypoidal lesions seen by ICGA,
- The double-layer sign, consisting of two hyperreflective lines, is believed to represent the separation of the RPE from Bruch's membrane by the BVN and corresponds to the extent of late geographic hyperfluorescence on ICGA.
Lui et al. reported a high sensitivity and specificity of OCT over ICGA with these features. Its ability as a screening modality can be harnessed when ICGA is not available and may be able to differentiate PCV from CNV in nAMD.
Enhanced depth imaging mode of the SD-OCT and SS-OCT provides clearer images of sub-RPE structures and shows agreeable efficacy to study the PCV lesions and choroidal features. Subfoveal CT is an important and objective parameter in the clinical diagnosis of PCV and nAMD.,,,,, However, CT measurement may not entirely reflect the detailed structural and functional alterations within the choroid in different exudative maculopathy. Choroidal vascular characteristics were used to subclassify PCV into two subtypes – typical PCV with thick choroid and PCV without thick choroid (polypoidal CNV). The former has significantly higher vascular area, which is consistent with the pachychoroid spectrum in which choroidal vessel dilatation plays a key role in the pathogenesis. The later subtype of polypoidal CNV has similar choroidal vascular characteristics to eyes with AMD and may be similar treatment response.,, ICGA and OCT correlate well at baseline findings of polypoidal lesions in PCV. However, discrepancy may be seen during treatment to monitor efficacy. Polypoidal lesions persisted more often on OCT after treatment despite improvement evident on ICGA and OCT.
Optical coherence tomography angiography
OCT angiography (OCTA) uses a split-spectrum amplitude-decorrelation algorithm, to noninvasively detect the blood flow in the retina and structural changes simultaneously. The flow patterns of PCV has confirmed the location of the polyps and BVNs in the compartment space between the RPE and Bruch's membrane rather than in the choroid.,,, BVNs are better delineated on OCTA than on ICGA but do not show the polyps as clearly as ICGA. This may be attributed to the slower flow velocity resulting either from an abrupt dilatation or from an partial obstruction of the lumen of the polyp or turbulent flow in it., However, a recent study using layer-by-layer OCTA analysis revealed that the BVN may be located in a range from inner side to outer side of Bruch's membrane. Besides, the PCV seems to have a three-dimensional structure, with the polyps located at the inner-most part, the BVN outer to the polyps, and a feeding vessel stalk even outer and at the choroidal layer. However, the presence of hemorrhage, fluid, fibrosis, or exudates may mask the images below the RPE. In addition, artifacts and auto-segmentation are the limitations of OCTA that cautions interpretation of the images.
| Natural History (Why to Treat?)|| |
The natural history of PCV has been studied after long-term observation of cases since its description.,,,, It indicates that PCV is a chronic persistent disease of the choroid that undergoes recurrences and spontaneous resolution of leakage and hemorrhage at macula. In the process, it culminates into degeneration of the RPE and sensory retina at the macula and severe visual loss.
Uyama et al. described the natural history of PCV. Two distinct patterns were observed: (1) exudative characterized by serous PED and SRD and (2) hemorrhagic characterized by hemorrhagic PED and SRH at the macula. Polypoidal CNV in the form of small aneurysmal dilations of vessels resembling cluster of grapes has a high risk of bleeding and leakage. These recurring aneurysmal dilations arise from postcapillary venules or capillaries. They disappear on occlusion by a thrombus only to grow into dilations at other areas. These dilations can either leak to give rise to exudative pattern or rupture to develop hemorrhages. When small dilations rupture, small hemorrhages develop; however, venules rupture to develop massive hemorrhage.
The underlying process as to why spontaneous hemorrhage occurs is still unknown. The accelerated infiltration from the polyp lesions into the sub-RPE space increases the tension on the PED flap. It is followed by PED microrips that lead to an acute decompression of the PED, increased blood flow in the polyp, and eventually rupture of the polyp.
The main cause of severe visual loss is due to macular manifestation in PCV. Persistent serous detachment of the macula leads to atrophy of the RPE and sensory retina. Subretinal fibrovascular proliferation markedly damages the macula function. Moreover, finally, persistent massive SMH damages the RPE and photoreceptors, leading to degeneration.
A good VA at initial examination has a favorable outcome. Cluster of grapes on ICGA indicates a high risk for poor visual outcome. The progression of PCV is slow and visual outcome is favorable than in nAMD. An important difference between eyes with CNV in nAMD and PCV is the relative paucity of subretinal fibrosis and disciform scarring in the later., However, the overall visual outcome of PCV is relatively poor over the natural course of the disease if untreated.
| Management|| |
Categorization and activity of polypoidal choroidal vasculopathy (when to treat?)
PCV is clinically classified as follows:
- Quiescent: Polyps in the absence of subretinal or intraretinal fluid or hemorrhage
- Exudative: Exudation without hemorrhage, which includes sensory retinal thickening, neurosensory retinal detachment, PED, and subretinal lipid exudation
- Hemorrhagic: Any SRH or sub-RPE hemorrhage with or without other exudative characteristics.
The PCV lesion, whether active or inactive, decides the impact of any treatment intervention. There are currently no universally recognized criteria for defining the disease activity. PCV is considered as active if there is clinical, OCT, or FA/ICGA evidence of any one of the following: vision loss of 5 or more letters (ETDRS chart) or equivalent; subretinal fluid or intraretinal fluid; PED; SRH or sub-RPE hemorrhage; or fluorescein leakage. An active, symptomatic PCV lesion is one which causes the loss of central VA and needs treatment initiation. The circumstance of active, asymptomatic can be considered for treatment at the physician's discretion.
What to treat?
In treatment-naïve patients, the entire PCV lesions (polyps plus BVN) as identified on ICGA require to be treated. The initial goal of treatment is angiographic regression of polyps on ICGA. The efficacy of the treatment is usually measured in terms of change in best-corrected VA (BCVA) and central retinal thickness (CRT) along with complete regression of polyps.
How to treat?
There is currently a wide spectrum of treatment options available for PCV, including thermal laser photocoagulation (TLP), verteporfin PDT (vPDT), anti-VEGF therapy, and various combinations of these therapies.
Thermal laser photocoagulation
ICGA-guided direct TLP of the polyps can be considered at extrafoveal location of the lesion. However, photocoagulation of the whole lesion compared to the polyps appears to be more efficacious. Stabilization or improvement in the vision was observed in 78% cases, after TLP of extrafoveal lesion along with clinical and angiographic resolution of maculopathy. However, 10.7% of cases reported recurrence of polyps and subsequent CNV. TLP for subfoveal leads to decrease in VA in 54%, ascribed to recurrent exudation or hemorrhage and atrophy at the fovea. Certainly, in effect to this risk, direct TLP is not recommended for the initial therapy of active juxtafoveal or subfoveal PCV. Feeder vessel TLP achieved resolution of neurosensory detachment in 60% and improvement in VA in half of the cases.
Verteporfin photodynamic therapy
PDT uses a photosensitizing agent verteporfin that preferentially accumulates in the abnormal neovascular endothelial cells through their increased expression of low-density lipoprotein receptors. Verteporfin produces a photochemical reaction when activated by nonthermal laser in the far-red spectrum and produces selective vascular occlusion by thrombosis. The far-red wavelength allows good penetration through melanin, blood, fibrotic tissue, enabling effective treatment of pigmented or hemorrhagic lesions located within the choroid. Laser spot size is determined by the greatest linear dimension (GLD) of the lesion based on ICGA. Verteporfin is infused intravenously at a dose of 6 mg/m2 of body surface area over 10 min, followed by application of 689 nm laser 15 min after initiation of infusion with a light dose of 50 J/cm2 over 83 s.,,
In a systematic review and meta-analysis on the longer-term visual outcome of PCV eyes treated with PDT monotherapy, visual outcome was stable until 2 years but worsened at 3 years and 5 years [Table 1].
|Table 1: Photodynamic therapy monotherapy: Summary of studies from systematic review and meta-analysis|
Click here to view
Younger, smaller GLD (<3600 um), better baseline VA, less hemorrhaging, and presence of a serous macular detachment at baseline were independent predictive factors associated with visual improvement.,
Akaza et al., reported recurrence rate in PCV eyes treated with PDT as 64% at 2 years and 77% at 3 years. Kang et al. reported recurrence rate of 78.6% and Saito et al. with 44% at 5 years. Recurrences are responsible for deterioration in VA in the long term. Although cumulative number of PDT session in the 1st year was ≤2, damage to the normal choroidal vasculature and the RPE remains a concern for repeated PDT.
Post-PDT SRH, massive suprachoroidal hemorrhage, RPE tears, and microrips at the margin of the PED are the reported complications of PDT for PCV.,,, Hirami et al. found SRH in 28 (30.8%) of 91 eyes post-PDT, developing within 1 month of treatment and vitreous hemorrhage in 6 (6.6%) eyes. However, 82% of them maintained or improved VA. Large laser spot size may or may not be associated with increased risk of vitreous hemorrhage., However, standard fluence PDT was reported with increased risk of hemorrhagic complications by Rishi et al. However, there has been no direct comparison between reduced fluence and full fluence PDT in PCV. Regardless of the factors, visual outcome after PDT in eyes with PCV does not appear to be affected by the presence or absence of hemorrhagic complications.
PDT has demonstrated its ability to cause the regression of polyp-like dilations in spite of the relative lack of visual improvement within 2 years. In the EVEREST study, polypoidal lesion closure rate was significantly higher in the PDT monotherapy arm (71.4%) and PDT combined with ranibizumab arm (77.8%) compared to ranibizumab monotherapy arm (28.6%). However, the PDT arm achieved less visual gain (+7.5 letters) compared to ranibizumab arm (+9.2 letters). In addition, PDT alone is ineffective in causing regression of the BVN or in resolving exudative activity arising from the BVN.
Anti-vascular endothelial growth factor therapy
The rationale of intravitreal anti-VEGF therapy in PCV was based on the reports of Tong et al. and Matsuoka et al. that showed a strong expression in PCV specimens and upregulation of VEGF in the aqueous., Several case series and reports demonstrated the ability of bevacizumab (a full-length anti-VEGF antibody) to decrease the exudation and improve or stabilize VA but minimal to no change in polyp regression.,,,,, Whether the size of the drug hampers penetration into the sub-RPE space remains elusive. A weak RPE after previous treatment such as PDT may allow penetration through the RPE.
Ranibizumab, an antibody fragment with smaller size, was speculated to overcome this barrier. Early studies with intravitreal ranibizumab (IVR) reported temporary stabilization of vision and reduction in exudation in PCV.,,,, Subsequent studies with more patients and longer follow-up reported 17%–40% of patients achieved ≥0.3 logMAR (15 letters or more) improvement in BCVA. The studies followed a regimen of monthly injections for 3 months, followed by as needed retreatments or continuous monthly injections and the mean number of injections 4.5 (4.2–5.2) over 12 months [Table 2].
The EVEREST study compared the use of IVR and PDT for the treatment of PCV and concluded that PDT is more effective than IVR in achieving regression of polyps; however, the visual outcome was better in the ranibizumab monotherapy arm than in the PDT arm despite the lack of statistical power. The LAPTOP study is a prospective multicenter randomized trial that compared the vision-improving effect of IVR and PDT in PCV. At month 12, more patients in the ranibizumab arm had a VA gain of at least 0.2 logMAR compared with the PDT arm (31% vs. 17%; P = 0.039). At month 24, it was confirmed that IVR achieved better visual outcomes than PDT (P = 0.004). In addition, although several patients in the PDT arm showed improvement in vision, approximately 15% of patients showed more than six lines of vision loss. Polyp closure rate was not assessed. A high-dose ranibizumab monotherapy (2 mg/0.05 ml) was tolerated well with good efficacy and safety profile but lacked long-term follow-up.,
Few studies with 24–36 months follow-up demonstrated significant improvement in VA at 12-month interval but stabilized subsequently.,,, With longest follow-up of 6 years as yet, Hikichi reported a mean improvement of −0.10 logMAR unit (P = 0.008) after 3 months of IVR, from baseline BCVA (0.34 ± 0.37) logMAR unit and sustained until 2.5 years (P = 0.034). However, it returned to a baseline level at 3 years (0.32 ± 0.39) and maintained at the end of 6 years (0.36 ± 0.37). The study found an improvement in the mean foveal thickness of −115 um (P = 0.014) at 3 years and −123 um (P = 0.005) at 6 years, but exudative changes persisted despite mean of 21.5 ± 10.1 injections over 6 years. This was attributed to the limited effect of anti-VEGF monotherapy to cause regression of the polypoidal lesion and BVN. Moreover, progressing RPE atrophy and significant macular atrophy contributed to the poor visual gain in these patients.
PCV is a chronic disorder and warrants a continuous long-term follow-up, with or without retreatments, and yet, the visual outcome would fail to improve at a point. It adds to poor patient compliance, economic burden, and safety concerns. This emphasized individualized treatment strategies based on the response to IVR in the first 12–24 months, to ensure uninterrupted follow-up and maintain improved VA. The treat-and-extend (TAE) regimen effectively improved VA in PCV eyes responding to IVR while reducing the number of injections.,
Pigment epithelial tears, post-injection SRH and vitreous hemorrhage, and RPE atrophy are few complications reported.,, A favorable response to anti-VEGF therapy was found in young patients, with better baseline VA, smaller lesion size, smaller size of the largest polyp, single polyp, absence of cluster of grapes on ICGA.,,, The subfoveal CT decreases with ranibizumab and may be associated with PCV activity., On the contrary, PCV eyes with thick choroids were associated with poor anatomical outcomes in comparison to thin choroids that showed the greatest extent of anatomical improvement but lacked significance in terms of visual outcomes. PCV with choroidal hyperpermeability on ICGA may also show poor response to anti-VEGF monotherapy. Furthermore, VEGF levels were lower in eyes affected by PCV with thick choroid, and anti-VEGF treatment response was correlated with baseline VEGF level.
Nonresponders to ranibizumab are refractory to repeated treatments with poor visual gains. A retrospective study reported that eyes refractory to ranibizumab had significant improvement after switching to aflibercept. A prospective study comparing bevacizumab and ranibizumab found no difference in the number of injections, improvement in vision, or decrease in mean central foveal thickness. Similar results were reported on comparing ranibizumab and aflibercept. However, in addition, aflibercept-treated eyes had more frequent polyp regression (34%–75%) than ranibizumab-treated eyes (22%). Ranibizumab “nonresponders” who were switched to aflibercept treatment demonstrated reduced exudation, resolution of PEDs and polyp closure, reduced CT, and stable or improved vision.,,,,
Vascular endothelial growth factor- Trap monotherapy
Aflibercept (Eylea, Regeneron, Tarrytown, NY, USA) is a soluble decoy receptor fusion protein consisting of the binding domains of VEGF receptors 1 and 2 fused to the Fc portion of human immunoglobulin G-1, allowing for binding to all isoforms of VEGF-A, VEGF-B, and placental growth factor. Intravitreal aflibercept (IVA) injections dosed every 2 months after 3 initial monthly doses, either in pro-re-nata (PRN) regimen, fixed-dose (FD) regimen, or TAE regimen, demonstrated improvement in both visual and anatomical outcome achieving statistical significance. In addition, regression of polypoidal lesion was observed as well with variable response to the BVN. It remains the safest option in peripapillary PCV, in which PDT is precluded [Table 3].
Inoue et al. in a comparison of FD to PRN regimens showed a trend toward better visual outcomes in FD group at the end of 1 year although the difference did not reach statistical significance. Although the number of injections administered was less in the PRN group, the polypoidal lesion closure rates were similar and BVN persisted in all cases [Figure 3]. A retrospective analysis of 3-year follow-up with aflibercept monotherapy consistently showed VA to be significantly better in the FD group than in the PRN group (P = 0.031), for at least 1 year. Young age and better baseline VA were associated with better VA at long-term follow-up. Furthermore, aflibercept in TAE regimen effectively maintains the macula in a dry state and achieves good visual outcomes in 2 years, along with regression of polypoidal lesions in 55.2% cases.
|Figure 3: A 51-year-old woman with diminution of vision (OD-20/30) had (a) hemorrhages both in the subretinal pigment epithelium and subretinal space extending to the arcades with massive exudation. (c) Fluorescein angiography shows blocked fluorescence due to subretinal and sub-retinal pigment epithelium hemorrhage with stippled hyperfluorescence inferotemporal to fovea, which is identified as branching vascular network with polypoidal lesions at the temporal edge of the lesion in indocyanine green angiography (e). (g) The spectral-domain optical coherence tomography B-scan shows a subfoveal hemorrhagic pigment epithelial detachment, with minimal subretinal fluid and hyperreflective hard exudates. She received intravitreal aflibercept monotherapy and status post five injections, (b) exudation, subretinal and sub-retinal pigment epithelium hemorrhage reduced clinically, with persistent stippled fluorescence in fluorescein angiography (d), better delineation of branching vascular network with indocyanine green angiography (f). (h) Spectral-domain optical coherence tomography B-scan demonstrates subretinal fluid, pigment epithelial detachment with serous conversion and reduction in size and branching vascular network abutting the retinal pigment epithelium (blue asterisk)|
Click here to view
Aflibercept monotherapy consistently reduced the CT in PCV eyes. This suggests that aflibercept penetrates into the choroid and makes it thinner, which is consistent with previous in vivo and human study., It is known that IVA inhibits choroidal vascular hyperpermeability and has a possible vasoconstrictor effect on the choroidal vasculature., This may affect the choroidal circulation, influence of which explains outer retinal atrophy. CT tended to decrease more in the FD group than in the PRN group. However, it does not result in deleterious visual changes in the short-term though it might cause visual decline in the long term. Better visual outcomes and decreased monitoring burden favor the FD regimen although treatment costs are likely to be much higher compared to a PRN dosing regimen. To reduce the treatment burden, studies comparing IVA combined with PDT and FD IVA monotherapy are warranted. Although a lack of long-term outcomes yet, TAE regimen can be a potential option.
The PLANET study, a randomized, double-masked, sham-controlled prospective study, evaluated aflibercept monotherapy compared to combination aflibercept and deferred rescue PDT in PCV patients. After 3 initial monthly aflibercept injections, all patients were treated with FD regimen to month 12. In addition, patients were evaluated for rescue criteria, which included (1) BCVA less than or equal to 73 ETDRS letters; (2) presence of new or persistent fluid on OCT; (3) evidence of active polyps on ICGA; and either (4) BCVA loss, no change, or insufficient gain (<5 letters gain); or (5) BCVA gain more than 5 letters but less than 10 letters and PDT was determined to be of rescue. A large proportion (87.9% and 85.7% in the aflibercept monotherapy arm and combination arm, respectively; P = 0.84) did not meet the rescue criteria. Both treatment arms achieved similar BCVA gain (10.7 vs. 10.9 letters) and polyp regression rates (38.9% vs. 44.8%, respectively; P = 0.32). Over 80% of patients had no signs of polyp activity at week 52. Rescue PDT could not achieve visual significant visual gain. Polyp closure rate was similar, irrespective of receiving active rescue PDT or not. The PLANET study thus concluded that no significant additional benefit was demonstrated by adding rescue PDT in patients receiving FD aflibercept at week 52. However, no evidence exists of the benefit of PDT if combined with aflibercept at baseline.
| Combination Therapy|| |
vPDT causes thrombosis of the polypoidal lesions, and anti-VEGF therapy reduces the exudation arising from the BVN. In addition, anti-VEGF may also counteract the upregulation of VEGF following PDT, responsible for the development of secondary CNV membrane and recurrence of PCV. Theoretically, a combination of the two therapies is an attractive option as it potentially targets both components of the PCV complex, i.e., the polypoidal lesions and the BVN.,,,,,
Intravitreal anti-vascular endothelial growth factor monotherapy versus photodynamic monotherapy
[Table 4] summarizes the efficacy in mean change in BCVA and CRT with polypoidal regression rate compiled from two meta-analyses comparing the monotherapies. Anti-VEGF agents compared to PDT induce more CRT reduction although at a variable follow-up point. Moreover, both monotherapies are equivalent in terms of BCVA change. This confirms the notion that reduction of CRT does not necessarily indicate a good visual outcome. Further, PDT is more effective than anti-VEGF therapy in regressing polypoidal lesions.,, The interpretation of these findings is limited by the substantial heterogeneity in the studies included in the meta-analysis. Nevertheless, these findings suggest that neither PDT monotherapy nor anti-VEGF monotherapy is the best option for the treatment of PCV although each possesses distinct advantages over the other. Considering the shortcomings of the two monotherapies, combination therapy may allow for more comprehensive treatment.
|Table 4: Summary of comparison of monotherapies and combination treatment|
Click here to view
Combination treatment versus photodynamic monotherapy
Two systematic reviews and meta-analysis, suggested that combination of PDT and anti-VEGF therapy had more potential in achieving early and maintaining better long-term visual outcomes than PDT monotherapy. Additional PDT sessions induce SRH and ischemic damage to choroidal tissue, explaining the loss of improvement in VA in the PDT monotherapy. Combining anti-VEGF agent reduces leakage, resolves fluid, and decreases the risk of development of SRH, post-PDT application. However, the reduction in CRT is maintained over a short period.
Combination treatment versus intravitreal anti-vascular endothelial growth factor monotherapy
The meta-analysis, indicates that combination treatment is more effective in improving BCVA and polypoidal regression with no significant difference in CRT reduction. Hence, polypoidal regression is as important as reduction in CRT to achieve a good visual outcome, which in turn is brought into effect by PDT in the combination therapy.
Combination treatment versus photodynamic monotherapy versus intravitreal anti-vascular endothelial growth factor monotherapy
The EVEREST study was a landmark phase 3, double-blind, multicenter, randomized control clinical trial that compared the efficacy of PDT with or without ranibizumab 0.5 mg and ranibizumab monotherapy. At month 6, the polyp closure rate was significantly lower in the ranibizumab monotherapy group (28.6%) compared with the PDT monotherapy group (71.4%; P < 0.01) and the PDT with ranibizumab group (77.8%; P < 0.01). The study was not powered to detect the differences in VA, but there were more letters gained in the combination arm (10.9 ± 10.9 letters) and the ranibizumab monotherapy arm (9.2 ± 12.4 letters) than the PDT monotherapy arm (7.5 ± 10.7 letters).
Recently, the EVEREST II study revealed that the combination arm achieved superior BCVA gain (8.3 vs. 5.1 letters; P = 0.013), along with superior anatomical outcome, including higher polyp closure rate (69.3% vs. 34.7%; P < 0.01) and higher proportion with absence of disease activity (79.5% vs. 50.0%) at month 12 compared with ranibizumab monotherapy. The combination arm also required fewer injections (mean 5.2 vs. 7.3 injections over 12 months), with 50.6% of patients in the combination arm requiring only 3-4 injections over 12 months, which was significantly lower than that in the monotherapy arm (26.2%).
The meta-analysis demonstrates the efficacy of combination therapy over monotherapies in improving anatomical and functional outcome in PCV eyes.,,, A systematic review of retrospective studies analyzing the cohorts of combination treatment showed overall improvement in the VA at every year until 3 years of follow-up. At 1 year, the significant polyp regression rate was observed at 64.6% (anti-VEGF before PDT) and 76% (anti-VEGF after PDT) of eyes. However, it is unclear whether PDT should have been administered at the beginning of treatment or during follow-up of anti-VEGF therapy. The Fujisan study compared the outcome of initial or deferred PDT combined with IVR. Both initial PDT (within 1 week following first IVR injection) and deferred PDT (PRN PDT after 3 monthly IVR injections) combined with IVR to treat PCV show the similar visual and anatomical improvements at 12 months. Initial PDT combination leads to significantly fewer additional treatments and suggests early introduction of PDT.
Ranibizumab monotherapy versus aflibercept monotherapy
Subgroup comparison of anti-VEGF monotherapy, in two recent large randomized controlled trials (EVEREST II and PLANET), has been reported., At 1 year, signi fi cant VA improvement was seen in eyes treated with ranibizumab monotherapy (+5.1 letters in EVEREST) and afl ibercept monotherapy (+10.8 letters in PLANET). This was accompanied by polyp closure rates of 34.7% and 38.9% (ranibizumab monotherapy arm in EVEREST II and a fl ibercept monotherapy arm in P LANET, respectively). The mean number of injections in the monotherapy arms was 7.3 (EVEREST II, PRN after 3 initial monthly doses) and 8.1 (PLANET, fi xed bimonthly dosing after 3 initial monthly doses). A head-to-head randomized controlled comparison is warranted to study the effectiveness of the two anti-VEGF agents.
| Treatment of Submacular Hemorrhage|| |
The incidence of massive SMH with PCV is 2.5% in the 1st year, and this proportion increased to approximately 30% within 10 years. PCV has been found to be the cause of SMH in 20%–63.3% of cases.,,, The visual outcome depends on presenting BCVA, the duration, thickness, extent of hemorrhage, thinner neurosensory retinal thickness at presentation, and disruption of ellipsoid zone.,,,,, The aim of treatment is to displace the hemorrhage before irreversible damage to photoreceptors occurs. SMH secondary to PCV is treated with pneumatic displacement or vitrectomy with pneumatic displacement. For pneumatic displacement, an expansile gas (undiluted volume of 0.3 mL of perfluoropropane or 0.5 mL sulfur hexafluoride) is injected through the pars plana. This is followed by an anterior chamber paracentesis to reduce the intraocular pressure and prone positioning for 24 h to 2 weeks.
However, pneumatic displacement of SMH alone does not address the underlying disease; the procedure should be combined with either PDT or intravitreal anti-VEGF.,,,, PDT penetration is limited by the presence of blood and is facilitated with pneumatic displacement to treat the lesion. In cases of thin SMH, anti-VEGF monotherapy alone may be effective and save from rhegmatogenous retinal detachment or choroidal hemorrhage with pneumatic displacement.,,,, In thicker SMH (>450 um), combination of pneumatic displacement with anti-VEGF therapy helps achieve rapid improvement in VA and reduction in foveal thickness although the effect equalizes with monotherapy.
To hasten displacement of subretinal blood away from the center of fovea, enzyme-induced lysis of the clot by tissue plasminogen activator (rt-PA) was demonstrated. It can be either injected into the vitreous cavity with pneumatic displacement or injected into the subretinal space together with air following vitrectomy or into the subretinal space after vitrectomy followed by direct evacuation of the liquefied clot. rt-PA has a short half-life and a favorable safety profile at a dose ranging from 25 to 100 ug in 0.1 ml., The choice of anti-VEGF agent for coapplication with rt-PA should be considered before any intervention. Klettner et al. found, in vitro studies, that aflibercept was cleaved by rt-PA-induced plasmin while ranibizumab was functionally unaltered and concluded that coapplication of aflibercept with rt-PA may reduce its antiangiogenic activity. The management of SMH is dependent on several factors, including timing, visual prognosis, general health of the patient, and compliance to face down positioning.
nAMD-associated SMH exhibited poor visual outcome in the long term. PCV-associated SMH exhibits a superior short-term visual outcome compared to nAMD-associated SMH, due to less fibrovascular proliferation and less rapid subretinal scaring. However, the long-term visual prognosis becomes gradually similar to nAMD associated SMH, given the underlying chronic nature of recurrent hemorrhage leading to RPE atrophy in PCV.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
The authors declare that there are no conflicts of interests of this paper.
| References|| |
Yannuzzi LA, Sorenson J, Spaide RF, Lipson B. Idiopathic polypoidal choroidal vasculopathy (IPCV). Retina 1990;10:1-8.
Spaide RF, Yannuzzi LA, Slakter JS, Sorenson J, Orlach DA. Indocyanine green videoangiography of idiopathic polypoidal choroidal vasculopathy. Retina 1995;15:100-10.
Laude A, Cackett PD, Vithana EN, Yeo IY, Wong D, Koh AH, et al.
Polypoidal choroidal vasculopathy and neovascular age-related macular degeneration: Same or different disease? Prog Retin Eye Res 2010;29:19-29.
Nowak-Sliwinska P, van den Bergh H, Sickenberg M, Koh AH. Photodynamic therapy for polypoidal choroidal vasculopathy. Prog Retin Eye Res 2013;37:182-99.
Stanga PE, Lim JI, Hamilton P. Indocyanine green angiography in chorioretinal diseases: Indications and interpretation: An evidence-based update. Ophthalmology 2003;110:15-21.
Dansingani KK, Balaratnasingam C, Naysan J, Freund KB. En face
imaging of pachychoroid spectrum disorders with swept-source optical coherence tomography. Retina 2016;36:499-516.
Imamura Y, Engelbert M, Iida T, Freund KB, Yannuzzi LA. Polypoidal choroidal vasculopathy: A review. Surv Ophthalmol 2010;55:501-15.
Yannuzzi LA. Idiopathic Polypoidal Choroidal Vasculopathy. Miami, Florida: Macula Society Meeting; 1982.
Kleiner RC, Brucker AJ, Johnston RL. The posterior uveal bleeding syndrome. Retina (Philadelphia, Pa.) 1990;10:9-17.
Yannuzzi LA, Ciardella A, Spaide RF, Rabb M, Freund KB, Orlock DA, et al.
The expanding clinical spectrum of idiopathic polypoidal choroidal vasculopathy. Arch Ophthalmol 1997;115:478-85.
Iijima H, Imai M, Gohdo T, Tsukahara S. Optical coherence tomography of idiopathic polypoidal choroidal vasculopathy. Am J Ophthalmol 1999;127:301-5.
Wong CW, Wong TY, Cheung CM. Polypoidal choroidal vasculopathy in Asians. J Clin Med 2015;4:782-821.
Yannuzzi LA, Wong DW, Sforzolini BS, Goldbaum M, Tang KC, Spaide RF, et al.
Polypoidal choroidal vasculopathy and neovascularized age-related macular degeneration. Arch Ophthalmol 1999;117:1503-10.
Lafaut BA, Leys AM, Snyers B, Rasquin F, De Laey JJ. Polypoidal choroidal vasculopathy in Caucasians. Graefes Arch Clin Exp Ophthalmol 2000;238:752-9.
Scassellati-Sforzolini B, Mariotti C, Bryan R, Yannuzzi LA, Giuliani M, Giovannini A, et al.
Polypoidal choroidal vasculopathy in Italy. Retina 2001;21:121-5.
Ladas ID, Rouvas AA, Moschos MM, Synodinos EE, Karagiannis DA, Koutsandrea CN, et al.
Polypoidal choroidal vasculopathy and exudative age-related macular degeneration in Greek population. Eye (Lond) 2004;18:455-9.
Ilginis T, Ottosen S, Harbo Bundsgaard K, Uggerhøj Andersen C, Vorum H. Polypoidal choroidal vasculopathy in patients diagnosed with neovascular age-related macular degeneration in Denmark. Acta Ophthalmol 2012;90:e487-8.
Coscas G, Yamashiro K, Coscas F, De Benedetto U, Tsujikawa A, Miyake M, et al.
Comparison of exudative age-related macular degeneration subtypes in Japanese and French patients: Multicenter diagnosis with multimodal imaging. Am J Ophthalmol 2014;158:309-1800.
Hatz K, Prünte C. Polypoidal choroidal vasculopathy in Caucasian patients with presumed neovascular age-related macular degeneration and poor ranibizumab response. Br J Ophthalmol 2014;98:188-94.
Pereira FB, Veloso CE, Kokame GT, Nehemy MB. Characteristics of neovascular age-related macular degeneration in Brazilian patients. Ophthalmologica 2015;234:233-42.
Guymer R, Macfadden W, Lacey S. Baseline characteristics and 1-year outcomes of patients with neovascular age related macular degeneration (NAMD) from the real world luminous study: Global results vs. Australian cohort. Clin Exp Ophthalmol 2016;1:29.
Yadav S, Parry DG, Beare NA, Pearce IA. Polypoidal choroidal vasculopathy: A common type of neovascular age-related macular degeneration in Caucasians. Br J Ophthalmol 2017;101:1377-80.
Maruko I, Iida T, Saito M, Nagayama D, Saito K. Clinical characteristics of exudative age-related macular degeneration in Japanese patients. Am J Ophthalmol 2007;144:15-22.
Liu Y, Wen F, Huang S, Luo G, Yan H, Sun Z, et al.
Subtype lesions of neovascular age-related macular degeneration in Chinese patients. Graefes Arch Clin Exp Ophthalmol 2007;245:1441-5.
Mori K, Horie-Inoue K, Gehlbach PL, Takita H, Kabasawa S, Kawasaki I, et al.
Phenotype and genotype characteristics of age-related macular degeneration in a Japanese population. Ophthalmology 2010;117:928-38.
Cheung CM, Li X, Mathur R, Lee SY, Chan CM, Yeo I, et al.
Aprospective study of treatment patterns and 1-year outcome of Asian age-related macular degeneration and polypoidal choroidal vasculopathy. PLoS One 2014;9:e101057.
Davis SJ, Lauer AK, Flaxel CJ. Polypoidal choroidal vasculopathy in White patients. Retina 2014;34:2185-91.
Goldman DR, Freund KB, McCannel CA, Sarraf D. Peripheral polypoidal choroidal vasculopathy as a cause of peripheral exudative hemorrhagic chorioretinopathy: A report of 10 eyes. Retina 2013;33:48-55.
Mantel I, Schalenbourg A, Zografos L. Peripheral exudative hemorrhagic chorioretinopathy: Polypoidal choroidal vasculopathy and hemodynamic modifications. Am J Ophthalmol 2012;153:910-22.
Rishi P, Das A, Sarate P, Rishi E. Management of peripheral polypoidal choroidal vasculopathy with intravitreal bevacizumab and indocyanine green angiography-guided laser photocoagulation. Indian J Ophthalmol 2012;60:60-3.
] [Full text]
Tsujikawa A, Nakanishi H, Ojima Y, Iwama D, Tamura H, Otani A, et al.
Macular polypoidal choroidal vasculopathy with a remote lesion. Clin Exp Ophthalmol 2008;36:817-23.
Cackett P, Yeo I, Cheung CM, Vithana EN, Wong D, Tay WT, et al.
Relationship of smoking and cardiovascular risk factors with polypoidal choroidal vasculopathy and age-related macular degeneration in Chinese persons. Ophthalmology 2011;118:846-52.
Sakurada Y, Yoneyama S, Imasawa M, Iijima H. Systemic risk factors associated with polypoidal choroidal vasculopathy and neovascular age-related macular degeneration. Retina 2013;33:841-5.
Ahuja RM, Downes SM, Stanga PE, Koh AH, Vingerling JR, Bird AC, et al.
Polypoidal choroidal vasculopathy and central serous chorioretinopathy. Ophthalmology 2001;108:1009-10.
Kim SW, Oh J, Kwon SS, Yoo J, Huh K. Comparison of choroidal thickness among patients with healthy eyes, early age-related maculopathy, neovascular age-related macular degeneration, central serous chorioretinopathy, and polypoidal choroidal vasculopathy. Retina 2011;31:1904-11.
Park HS, Kim IT. Clinical characteristics of polypoidal choroidal vasculopathy associated with chronic central serous chorioretinopathy. Korean J Ophthalmol 2012;26:15-20.
Fung AT, Yannuzzi LA, Freund KB. Type 1 (sub-retinal pigment epithelial) neovascularization in central serous chorioretinopathy masquerading as neovascular age-related macular degeneration. Retina 2012;32:1829-37.
Mauget-Faÿsse M, Cornut PL, Quaranta El-Maftouhi M, Leys A. Polypoidal choroidal vasculopathy in tilted disk syndrome and high myopia with staphyloma. Am J Ophthalmol 2006;142:970-5.
Furuta M, Iida T, Maruko I, Kishi S, Sekiryu T. Submacular choroidal neovascularization at the margin of staphyloma in tilted disk syndrome. Retina 2013;33:71-6.
Baillif-Gostoli S, Quaranta-El Maftouhi M, Mauget-Faÿsse M. Polypoidal choroidal vasculopathy in a patient with angioid streaks secondary to pseudoxanthoma elasticum. Graefes Arch Clin Exp Ophthalmol 2010;248:1845-8.
Pang CE, Freund KB. Intravitreal polypoidal choroidal vasculopathy in radiation retinopathy. Ophthalmic Surg Lasers Imaging Retina 2014;45:585-8.
Kikuchi M, Nakamura M, Ishikawa K, Suzuki T, Nishihara H, Yamakoshi T, et al.
Elevated C-reactive protein levels in patients with polypoidal choroidal vasculopathy and patients with neovascular age-related macular degeneration. Ophthalmology 2007;114:1722-7.
Cheng HC, Liu JH, Lee SM, Lin PK. Hyperhomocysteinemia in patients with polypoidal choroidal vasculopathy: A case control study. PLoS One 2014;9:e110818.
Nakashizuka H, Mitsumata M, Okisaka S, Shimada H, Kawamura A, Mori R, et al.
Clinicopathologic findings in polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2008;49:4729-37.
Zhao M, Bai Y, Xie W, Shi X, Li F, Yang F, et al.
Interleukin-1β level is increased in vitreous of patients with neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV). PLoS One 2015;10:e0125150.
Tong JP, Chan WM, Liu DT, Lai TY, Choy KW, Pang CP, et al.
Aqueous humor levels of vascular endothelial growth factor and pigment epithelium-derived factor in polypoidal choroidal vasculopathy and choroidal neovascularization. Am J Ophthalmol 2006;141:456-62.
Matsuoka M, Ogata N, Otsuji T, Nishimura T, Takahashi K, Matsumura M, et al.
Expression of pigment epithelium derived factor and vascular endothelial growth factor in choroidal neovascular membranes and polypoidal choroidal vasculopathy. Br J Ophthalmol 2004;88:809-15.
Ma L, Li Z, Liu K, Rong SS, Brelen ME, Young AL, et al.
Association of genetic variants with polypoidal choroidal vasculopathy: A systematic review and updated meta-analysis. Ophthalmology 2015;122:1854-65.
MacCumber MW, Dastgheib K, Bressler NM, Chan CC, Harris M, Fine S, et al.
Clinicopathologic correlation of the multiple recurrent serosanguineous retinal pigment epithelial detachments syndrome. Retina 1994;14:143-52.
Lafaut BA, Aisenbrey S, Van den Broecke C, Bartz-Schmidt KU, Heimann K. Polypoidal choroidal vasculopathy pattern in age-related macular degeneration: A clinicopathologic correlation. Retina 2000;20:650-4.
Terasaki H, Miyake Y, Suzuki T, Nakamura M, Nagasaka T. Polypoidal choroidal vasculopathy treated with macular translocation: Clinical pathological correlation. Br J Ophthalmol 2002;86:321-7.
Shiraga F, Matsuo T, Yokoe S, Takasu I, Okanouchi T, Ohtsuki H, et al.
Surgical treatment of submacular hemorrhage associated with idiopathic polypoidal choroidal vasculopathy. Am J Ophthalmol 1999;128:147-54.
Okubo A, Sameshima M, Uemura A, Kanda S, Ohba N. Clinicopathological correlation of polypoidal choroidal vasculopathy revealed by ultrastructural study. Br J Ophthalmol 2002;86:1093-8.
Kuroiwa S, Tateiwa H, Hisatomi T, Ishibashi T, Yoshimura N. Pathological features of surgically excised polypoidal choroidal vasculopathy membranes. Clin Exp Ophthalmol 2004;32:297-302.
Ross RD, Gitter KA, Cohen G, Schomaker KS. Idiopathic polypoidal choroidal vasculopathy associated with retinal arterial macroaneurysm and hypertensive retinopathy. Retina 1996;16:105-11.
Spraul CW, Lang GE, Grossniklaus HE, Lang GK. Histologic and morphometric analysis of the choroid, Bruch's membrane, and retinal pigment epithelium in postmortem eyes with age-related macular degeneration and histologic examination of surgically excised choroidal neovascular membranes. Surv Ophthalmol 1999;44 Suppl 1:S10-32.
Uyama M, Matsubara T, Fukushima I, Matsunaga H, Iwashita K, Nagai Y, et al.
Idiopathic polypoidal choroidal vasculopathy in Japanese patients. Arch Ophthalmol 1999;117:1035-42.
Cheung CM, Yang E, Lee WK, Lee GK, Mathur R, Cheng J, et al.
The natural history of polypoidal choroidal vasculopathy: A multi-center series of untreated Asian patients. Graefes Arch Clin Exp Ophthalmol 2015;253:2075-85.
Mukai R, Sato T, Kishi S. Repair mechanism of retinal pigment epithelial tears in age-related macular degeneration. Retina 2015;35:473-80.
Uyama M, Wada M, Nagai Y, Matsubara T, Matsunaga H, Fukushima I, et al.
Polypoidal choroidal vasculopathy: Natural history. Am J Ophthalmol 2002;133:639-48.
Hochman MA, Seery CM, Zarbin MA. Pathophysiology and management of subretinal hemorrhage. Surv Ophthalmol 1997;42:195-213.
Sho K, Takahashi K, Yamada H, Wada M, Nagai Y, Otsuji T, et al.
Polypoidal choroidal vasculopathy: Incidence, demographic features, and clinical characteristics. Arch Ophthalmol 2003;121:1392-6.
Honda S, Matsumiya W, Negi A. Polypoidal choroidal vasculopathy: Clinical features and genetic predisposition. Ophthalmologica 2014;231:59-74.
Bessho H, Honda S, Imai H, Negi A. Natural course and funduscopic findings of polypoidal choroidal vasculopathy in a Japanese population over 1 year of follow-up. Retina 2011;31:1598-602.
Tsujikawa A, Sasahara M, Otani A, Gotoh N, Kameda T, Iwama D, et al.
Pigment epithelial detachment in polypoidal choroidal vasculopathy. Am J Ophthalmol 2007;143:102-11.
Otsuji T, Tsumura A, Takahashi K, Sho K, Nagai Y, Fukuchi T, et al.
Evaluation of cases of polypoidal choroidal vasculopathy showing classic choroidal neovascularization in their natural course. Nippon Ganka Gakkai Zasshi 2006;110:454-61.
Maruko I, Iida T, Saito M, Nagayama D. Combined cases of polypoidal choroidal vasculopathy and typical age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2010;248:361-8.
Koh AH; Expert PCV Panel, Chen LJ, Chen SJ, Chen Y, Giridhar A, et al.
Polypoidal choroidal vasculopathy: Evidence-based guidelines for clinical diagnosis and treatment. Retina 2013;33:686-716.
Kawamura A, Yuzawa M, Mori R, Haruyama M, Tanaka K. Indocyanine green angiographic and optical coherence tomographic findings support classification of polypoidal choroidal vasculopathy into two types. Acta Ophthalmol 2013;91:e474-81.
Iijima H, Iida T, Imai M, Gohdo T, Tsukahara S. Optical coherence tomography of orange-red subretinal lesions in eyes with idiopathic polypoidal choroidal vasculopathy. Am J Ophthalmol 2000;129:21-6.
Saito M, Iida T, Nagayama D. Cross-sectional and en face
optical coherence tomographic features of polypoidal choroidal vasculopathy. Retina 2008;28:459-64.
Sato T, Kishi S, Watanabe G, Matsumoto H, Mukai R. Tomographic features of branching vascular networks in polypoidal choroidal vasculopathy. Retina 2007;27:589-94.
De Salvo G, Vaz-Pereira S, Keane PA, Tufail A, Liew G. Sensitivity and specificity of spectral-domain optical coherence tomography in detecting idiopathic polypoidal choroidal vasculopathy. Am J Ophthalmol 2014;158:1228-380.
Liu R, Li J, Li Z, Yu S, Yang Y, Yan H, et al.
Distinguishing polypoidal choroidal vasculopathy from typical neovascular age-related macular degeneration based on spectral domain optical coherence tomography. Retina 2016;36:778-86.
Ting DS, Cheung GC, Lim LS, Yeo IY. Comparison of swept source optical coherence tomography and spectral domain optical coherence tomography in polypoidal choroidal vasculopathy. Clin Exp Ophthalmol 2015;43:815-9.
Coscas G, Lupidi M, Coscas F, Benjelloun F, Zerbib J, Dirani A, et al.
Toward a specific classification of polypoidal choroidal vasculopathy: Idiopathic disease or subtype of age-related macular degeneration. Invest Ophthalmol Vis Sci 2015;56:3187-95.
Jirarattanasopa P, Ooto S, Nakata I, Tsujikawa A, Yamashiro K, Oishi A, et al.
Choroidal thickness, vascular hyperpermeability, and complement factor H in age-related macular degeneration and polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2012;53:3663-72.
Koizumi H, Yamagishi T, Yamazaki T, Kawasaki R, Kinoshita S. Subfoveal choroidal thickness in typical age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2011;249:1123-8.
Rishi P, Rishi E, Mathur G, Raval V. Ocular perfusion pressure and choroidal thickness in eyes with polypoidal choroidal vasculopathy, wet-age-related macular degeneration, and normals. Eye (Lond) 2013;27:1038-43.
Li Y, You QS, Wei WB, Xu J, Chen CX, Wang YX, et al.
Polypoidal choroidal vasculopathy in adult Chinese: The Beijing eye study. Ophthalmology 2014;121:2290-1.
Gupta P, Ting DS, Thakku SG, Wong TY, Cheng CY, Wong E, et al.
Detailed characterization of choroidal morphologic and vascular features in age-related macular degeneration and polypoidal choroidal vasculopathy. Retina 2017;37:2269-80.
Balaratnasingam C, Lee WK, Koizumi H, Dansingani K, Inoue M, Freund KB, et al.
Polypoidal choroidal vasculopathy: A Distinct disease or manifestation of many? Retina 2016;36:1-8.
Ueno C, Gomi F, Sawa M, Nishida K. Correlation of indocyanine green angiography and optical coherence tomography findings after intravitreal ranibizumab for polypoidal choroidal vasculopathy. Retina 2012;32:2006-13.
Inoue M, Balaratnasingam C, Freund KB. Optical coherence tomography angiography of polypoidal choroidal vasculopathy and polypoidal choroidal neovascularization. Retina 2015;35:2265-74.
Srour M, Querques G, Semoun O, El Ameen A, Miere A, Sikorav A, et al.
Optical coherence tomography angiography characteristics of polypoidal choroidal vasculopathy. Br J Ophthalmol 2016;100:1489-93.
Tomiyasu T, Nozaki M, Yoshida M, Ogura Y. Characteristics of polypoidal choroidal vasculopathy evaluated by optical coherence tomography angiography. Invest Ophthalmol Vis Sci 2016;57:OCT324-30.
Wang M, Zhou Y, Gao SS, Liu W, Huang Y, Huang D, et al.
Evaluating polypoidal choroidal vasculopathy with optical coherence tomography angiography. Invest Ophthalmol Vis Sci 2016;57:OCT526-32.
Chi YT, Yang CH, Cheng CK. Optical coherence tomography angiography for assessment of the 3-dimensional structures of polypoidal choroidal vasculopathy. JAMA Ophthalmol 2017;135:1310-6.
Stern RM, Zakov ZN, Zegarra H, Gutman FA. Multiple recurrent serosanguineous retinal pigment epithelial detachments in black women. Am J Ophthalmol 1985;100:560-9.
Perkovich BT, Zakov ZN, Berlin LA, Weidenthal D, Avins LR. An update on multiple recurrent serosanguineous retinal pigment epithelial detachments in black women. Retina 1990;10:18-26.
Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med 2008;358:2606-17.
Yuzawa M, Mori R, Haruyama M. A study of laser photocoagulation for polypoidal choroidal vasculopathy. Jpn J Ophthalmol 2003;47:379-84.
Lee MW, Yeo I, Wong D, Ang CL. Argon laser photocoagulation for the treatment of polypoidal choroidal vasculopathy. Eye (Lond) 2009;23:145-8.
Nishijima K, Takahashi M, Akita J, Katsuta H, Tanemura M, Aikawa H, et al.
Laser photocoagulation of indocyanine green angiographically identified feeder vessels to idiopathic polypoidal choroidal vasculopathy. Am J Ophthalmol 2004;137:770-3.
Lee WK, Lee PY, Lee SK. Photodynamic therapy for polypoidal choroidal vasculopathy: Vaso-occlusive effect on the branching vascular network and origin of recurrence. Jpn J Ophthalmol 2008;52:108-15.
Schmidt-Erfurth U, Hasan T. Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age-related macular degeneration. Surv Ophthalmol 2000;45:195-214.
Lai TY, Chan WM. An update in laser and pharmaceutical treatment for polypoidal choroidal vasculopathy. Asia Pac J Ophthalmol (Phila) 2012;1:97-104.
Gomi F, Ohji M, Sayanagi K, Sawa M, Sakaguchi H, Oshima Y, et al.
One-year outcomes of photodynamic therapy in age-related macular degeneration and polypoidal choroidal vasculopathy in Japanese patients. Ophthalmology 2008;115:141-6.
Tomita K, Tsujikawa A, Yamashiro K, Ooto S, Tamura H, Otani A, et al.
Treatment of polypoidal choroidal vasculopathy with photodynamic therapy combined with intravitreal injections of ranibizumab. Am J Ophthalmol 2012;153:68-800.
Park DH, Kim IT. LOC387715/HTRA1 variants and the response to combined photodynamic therapy with intravitreal bevacizumab for polypoidal choroidal vasculopathy. Retina 2012;32:299-307.
Kim SJ, Yu HG. Efficacy of combined photodynamic therapy and intravitreal bevacizumab injection versus photodynamic therapy alone in polypoidal choroidal vasculopathy. Retina 2011;31:1827-34.
Hikichi T, Ohtsuka H, Higuchi M, Matsushita T, Ariga H, Kosaka S, et al.
Factors predictive of visual acuity outcomes 1 year after photodynamic therapy in Japanese patients with polypoidal choroidal vasculopathy. Retina 2011;31:857-65.
Sakurada Y, Kubota T, Imasawa M, Mabuchi F, Tanabe N, Iijima H, et al.
Association of LOC387715 A69S genotype with visual prognosis after photodynamic therapy for polypoidal choroidal vasculopathy. Retina 2010;30:1616-21.
Gomi F, Sawa M, Wakabayashi T, Sasamoto Y, Suzuki M, Tsujikawa M, et al.
Efficacy of intravitreal bevacizumab combined with photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2010;150:48-540.
Mori K, Horie-Inoue K, Gehlbach PL, Takita H, Kabasawa S, Kawasaki I, et al.
Phenotype and genotype characteristics of age-related macular degeneration in a Japanese population. Ophthalmology 2010;117:928-38.
Saito K, Yamamoto T, Tsuchiya D, Kawasaki R, Haneda S, Yamashita H, et al.
Effect of combined treatment with sub-tenon injection of triamcinolone acetonide and photodynamic therapy in Japanese patients with age-related macular degeneration. Jpn J Ophthalmol 2009;53:512-8.
Honda S, Kurimoto Y, Kagotani Y, Yamamoto H, Takagi H, Uenishi M, et al.
Photodynamic therapy for typical age-related macular degeneration and polypoidal choroidal vasculopathy: A 30-month multicenter study in Hyogo, Japan. Jpn J Ophthalmol 2009;53:593-7.
Imasawa M, Tsumura T, Sekine A, Kikuchi T, Iijima H. Photodynamic therapy for polypoidal choroidal vasculopathy: Baseline perimetric results and visual outcomes. Jpn J Ophthalmol 2009;53:588-92.
Honda S, Imai H, Yamashiro K, Kurimoto Y, Kanamori-Matsui N, Kagotani Y, et al.
Comparative assessment of photodynamic therapy for typical age-related macular degeneration and polypoidal choroidal vasculopathy: A multicenter study in Hyogo Prefecture, Japan. Ophthalmologica 2009;223:333-8.
Lee MW, Yeo I, Wong D, Ang CL. Photodynamic therapy with verteporfin for polypoidal choroidal vasculopathy. Eye (Lond) 2009;23:1417-22.
Eandi CM, Ober MD, Freund KB, Slakter JS, Yannuzzi LA. Selective photodynamic therapy for neovascular age-related macular degeneration with polypoidal choroidal neovascularization. Retina 2007;27:825-31.
Akaza E, Yuzawa M, Matsumoto Y, Kashiwakura S, Fujita K, Mori R, et al.
Role of photodynamic therapy in polypoidal choroidal vasculopathy. Jpn J Ophthalmol 2007;51:270-7.
Otani A, Sasahara M, Yodoi Y, Aikawa H, Tamura H, Tsujikawa A, et al.
Indocyanine green angiography: Guided photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2007;144:7-14.
Mauget-Faÿsse M, Quaranta-El Maftouhi M, De La Marnièrre E, Leys A. Photodynamic therapy with verteporfin in the treatment of exudative idiopathic polypoidal choroidal vasculopathy. Eur J Ophthalmol 2006;16:695-704.
Chang YC, Wu WC. Polypoidal choroidal vasculopathy in Taiwanese patients. Ophthalmic Surg Lasers Imaging 2009;40:576-81.
Sato T, Kishi S, Matsumoto H, Mukai R. Comparisons of outcomes with different intervals between adjunctive ranibizumab and photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2013;156:95-1050.
Honda S, Miki A, Yanagisawa S, Matsumiya W, Nagai T, Tsukahara Y, et al.
Comparison of the outcomes of photodynamic therapy between two angiographic subtypes of polypoidal choroidal vasculopathy. Ophthalmologica 2014;232:92-6.
Yoshida Y, Kohno T, Yamamoto M, Yoneda T, Iwami H, Shiraki K, et al.
Two-year results of reduced-fluence photodynamic therapy combined with intravitreal ranibizumab for typical age-related macular degeneration and polypoidal choroidal vasculopathy. Jpn J Ophthalmol 2013;57:283-93.
Nemoto R, Miura M, Iwasaki T, Goto H. Two-year follow-up of ranibizumab combined with photodynamic therapy for polypoidal choroidal vasculopathy. Clin Ophthalmol 2012;6:1633-8.
Yamashita A, Shiraga F, Shiragami C, Shirakata Y, Fujiwara A. Two-year results of reduced-fluence photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2013;155:96-1020.
Nakata I, Tsujikawa A, Yamashiro K, Otani A, Ooto S, Akagi-Kurashige Y, et al.
Two-year outcome of photodynamic therapy combined with intravitreal injection of bevacizumab and triamcinolone acetonide for polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2013;251:1073-80.
Lee YA, Yang CH, Yang CM, Ho TC, Lin CP, Huang JS, et al.
Photodynamic therapy with or without intravitreal bevacizumab for polypoidal choroidal vasculopathy: Two years of follow-up. Am J Ophthalmol 2012;154:872-8000.
Lee WK, Kim KS, Kim W, Lee SB, Jeon S. Responses to photodynamic therapy in patients with polypoidal choroidal vasculopathy consisting of polyps resembling grape clusters. Am J Ophthalmol 2012;154:355-650.
Lai TY, Lam CP, Luk FO, Chan RP, Chan WM, Liu DT, et al.
Photodynamic therapy with or without intravitreal triamcinolone acetonide for symptomatic polypoidal choroidal vasculopathy. J Ocul Pharmacol Ther 2010;26:91-5.
Tsuchiya D, Yamamoto T, Kawasaki R, Yamashita H. Two-year visual outcomes after photodynamic therapy in age-related macular degeneration patients with or without polypoidal choroidal vasculopathy lesions. Retina 2009;29:960-5.
Yanagidaira T, Arai J, Yoshida N, Arai S, Fukui E, Imai H, et al
. Two-year results following photodynamic therapy for age-related macular degeneration. Nippon Ganka Gakkai Zasshi 2008;112:1068-75.
Kurashige Y, Otani A, Sasahara M, Yodoi Y, Tamura H, Tsujikawa A, et al.
Two-year results of photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2008;146:513-9.
Akaza E, Mori R, Yuzawa M. Long-term results of photodynamic therapy of polypoidal choroidal vasculopathy. Retina 2008;28:717-22.
Silva RM, Figueira J, Cachulo ML, Duarte L, Faria de Abreu JR, Cunha-Vaz JG, et al.
Polypoidal choroidal vasculopathy and photodynamic therapy with verteporfin. Graefes Arch Clin Exp Ophthalmol 2005;243:973-9.
Hata M, Tsujikawa A, Miyake M, Yamashiro K, Ooto S, Oishi A, et al.
Two-year visual outcome of polypoidal choroidal vasculopathy treated with photodynamic therapy combined with intravitreal injections of ranibizumab. Graefes Arch Clin Exp Ophthalmol 2015;253:189-97.
Saito M, Iida T, Kano M, Itagaki K. Two-year results of combined intravitreal ranibizumab and photodynamic therapy for polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2013;251:2099-110.
Inoue M, Arakawa A, Yamane S, Kadonosono K. Long-term outcome of intravitreal ranibizumab treatment, compared with photodynamic therapy, in patients with polypoidal choroidal vasculopathy. Eye (Lond) 2013;27:1013-20.
Sakurada Y, Iijima H. Two-year results of photodynamic therapy with or without intravitreal ranibizumab for polypoidal choroidal vasculopathy. J Ocul Pharmacol Ther 2013;29:832-6.
Oishi A, Miyamoto N, Mandai M, Honda S, Matsuoka T, Oh H, et al.
LAPTOP study: A 24-month trial of verteporfin versus ranibizumab for polypoidal choroidal vasculopathy. Ophthalmology 2014;121:1151-2.
Kang HM, Koh HJ. Two-year outcome after combination therapy for polypoidal choroidal vasculopathy: Comparison with photodynamic monotherapy and anti-vascular endothelial growth factor monotherapy. Ophthalmologica 2014;231:86-93.
Akaza E, Yuzawa M, Mori R. Three-year follow-up results of photodynamic therapy for polypoidal choroidal vasculopathy. Jpn J Ophthalmol 2011;55:39-44.
Miki A, Honda S, Kojima H, Nishizaki M, Nagai T, Fujihara M, et al.
Visual outcome of photodynamic therapy for typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy over 5 years of follow-up. Jpn J Ophthalmol 2013;57:301-7.
Leal S, Silva R, Figueira J, Cachulo ML, Pires I, de Abreu JR, et al.
Photodynamic therapy with verteporfin in polypoidal choroidal vasculopathy: Results after 3 years of follow-up. Retina 2010;30:1197-205.
Jeon S, Lee WK, Kim KS. Adjusted retreatment of polypoidal choroidal vasculopathy after combination therapy: Results at 3 years. Retina 2013;33:1193-200.
Hata M, Mandai M, Kojima H, Kameda T, Miyamoto N, Kurimoto Y, et al
. Five-year visual outcomes of typical age-related macular degeneration and/or polypoidal choroidal vasculopathy patients who received photodynamic therapy (PDT) as initial treatment in comparison with patients prior to the PDT era. Nippon Ganka Gakkai Zasshi 2012;116:937-45.
Wong CW, Cheung CM, Mathur R, Li X, Chan CM, Yeo I, et al.
Three-year results of polypoidal choroidal vasculopathy treated with photodynamic therapy: Retrospective study and systematic review. Retina 2015;35:1577-93.
Kang HM, Kim YM, Koh HJ. Five-year follow-up results of photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol 2013;155:438-470.
Sakai T, Ohkuma Y, Kohno H, Hayashi T, Watanabe A, Tsuneoka H, et al.
Three-year visual outcome of photodynamic therapy plus intravitreal bevacizumab with or without subtenon triamcinolone acetonide injections for polypoidal choroidal vasculopathy. Br J Ophthalmol 2014;98:1642-8.
Kang HM, Koh HJ, Lee CS, Lee SC. Combined photodynamic therapy with intravitreal bevacizumab injections for polypoidal choroidal vasculopathy: Long-term visual outcome. Am J Ophthalmol 2014;157:598-6060.
Saito M, Iida T, Kano M, Itagaki K. Five-year results of photodynamic therapy with and without supplementary antivascular endothelial growth factor treatment for polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2014;252:227-35.
Hirami Y, Tsujikawa A, Otani A, Yodoi Y, Aikawa H, Mandai M, et al.
Hemorrhagic complications after photodynamic therapy for polypoidal choroidal vasculopathy. Retina 2007;27:335-41.
Rishi P, Rishi E, Sharma M, Maitray A, Bhende M, Gopal L, et al.
Incidence, outcomes, and risk factors for hemorrhagic complications in eyes with polypoidal choroidal vasculopathy following photodynamic therapy in Indian subjects. Indian J Ophthalmol 2017;65:712-8.
] [Full text]
Ojima Y, Tsujikawa A, Otani A, Hirami Y, Aikawa H, Yoshimura N, et al.
Recurrent bleeding after photodynamic therapy in polypoidal choroidal vasculopathy. Am J Ophthalmol 2006;141:958-60.
Musashi K, Tsujikawa A, Hirami Y, Otani A, Yodoi Y, Tamura H, et al.
Microrips of the retinal pigment epithelium in polypoidal choroidal vasculopathy. Am J Ophthalmol 2007;143:883-5.
Koh A, Lee WK, Chen LJ, Chen SJ, Hashad Y, Kim H, et al.
EVEREST study: Efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina 2012;32:1453-64.
Gomi F, Sawa M, Sakaguchi H, Tsujikawa M, Oshima Y, Kamei M, et al.
Efficacy of intravitreal bevacizumab for polypoidal choroidal vasculopathy. Br J Ophthalmol 2008;92:70-3.
Song JH, Byeon SH, Lee SC, Koh HJ, Kwon OW. Short-term safety and efficacy of a single intravitreal bevacizumab injection for the management of polypoidal choroidal vasculopathy. Ophthalmologica 2009;223:85-92.
Tsujikawa A, Ooto S, Yamashiro K, Tamura H, Otani A, Yoshimura N, et al.
Treatment of polypoidal choroidal vasculopathy by intravitreal injection of bevacizumab. Jpn J Ophthalmol 2010;54:310-9.
Cheng CK, Peng CH, Chang CK, Hu CC, Chen LJ. One-year outcomes of intravitreal bevacizumab (Avastin) therapy for polypoidal choroidal vasculopathy. Retina 2011;31:846-56.
Chhablani JK, Narula R, Narayanan R. Intravitreal bevacizumab monotherapy for treatment-naïve polypoidal choroidal vasculopathy. Indian J Ophthalmol 2013;61:136-8.
] [Full text]
Ghajarnia M, Kurup S, Eller A. The therapeutic effects of intravitreal bevacizumab in a patient with recalcitrant idiopathic polypoidal choroidal vasculopathy. Semin Ophthalmol 2007;22:127-31.
Reche-Frutos J, Calvo-Gonzalez C, Donate-Lopez J, Garcia-Feijoo J, Leila M, Garcia-Sanchez J, et al.
Short-term anatomic effect of ranibizumab for polypoidal choroidal vasculopathy. Eur J Ophthalmol 2008;18:645-8.
Kokame GT, Yeung L, Lai JC. Continuous anti-VEGF treatment with ranibizumab for polypoidal choroidal vasculopathy: 6-month results. Br J Ophthalmol 2010;94:297-301.
Hikichi T, Ohtsuka H, Higuchi M, Matsushita T, Ariga H, Kosaka S, et al.
Improvement of angiographic findings of polypoidal choroidal vasculopathy after intravitreal injection of ranibizumab monthly for 3 months. Am J Ophthalmol 2010;150:674-820.
Park YG, Kang S, Roh YJ. Effects of three consecutive monthly intravitreal injection of ranibizumab for polypoidal choroidal vasculopathy in Korea. Int J Ophthalmol 2015;8:315-20.
Matsumiya W, Honda S, Bessho H, Kusuhara S, Tsukahara Y, Negi A, et al.
Early responses to intravitreal ranibizumab in typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. J Ophthalmol 2011;2011:742020.
Hikichi T, Higuchi M, Matsushita T, Kosaka S, Matsushita R, Takami K, et al.
One-year results of three monthly ranibizumab injections and as-needed reinjections for polypoidal choroidal vasculopathy in Japanese patients. Am J Ophthalmol 2012;154:117-240.
Matsumiya W, Honda S, Kusuhara S, Tsukahara Y, Negi A. Effectiveness of intravitreal ranibizumab in exudative age-related macular degeneration (AMD): Comparison between typical neovascular AMD and polypoidal choroidal vasculopathy over a 1 year follow-up. BMC Ophthalmol 2013;13:10.
Ogino K, Tsujikawa A, Yamashiro K, Ooto S, Oishi A, Nakata I, et al.
Intravitreal injection of ranibizumab for recovery of macular function in eyes with subfoveal polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci 2013;54:3771-9.
Mori R, Yuzawa M, Akaza E, Haruyama M. Treatment results at 1 year of ranibizumab therapy for polypoidal choroidal vasculopathy in eyes with good visual acuity. Jpn J Ophthalmol 2013;57:365-71.
Kokame GT, Yeung L, Teramoto K, Lai JC, Wee R. Polypoidal choroidal vasculopathy exudation and hemorrhage: Results of monthly ranibizumab therapy at one year. Ophthalmologica 2014;231:94-102.
Oishi A, Kojima H, Mandai M, Honda S, Matsuoka T, Oh H, et al.
Comparison of the effect of ranibizumab and verteporfin for polypoidal choroidal vasculopathy: 12-month LAPTOP study results. Am J Ophthalmol 2013;156:644-51.
Hata M, Tsujikawa A, Miyake M, Yamashiro K, Ooto S, Oishi A, et al.
Two-year visual outcome of ranibizumab in typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2015;253:221-7.
Matsumiya W, Honda S, Otsuka K, Miki A, Nagai T, Imai H, et al.
Comparison of the effectiveness and prognostic factors of intravitreal ranibizumab between typical neovascular age-related macular degeneration and polypoidal choroidal vasculopathy over 24 months of follow-up. Ophthalmologica 2015;234:33-9.
Kang HM, Koh HJ. Long-term visual outcome and prognostic factors after intravitreal ranibizumab injections for polypoidal choroidal vasculopathy. Am J Ophthalmol 2013;156:652-60.
Kokame GT. Prospective evaluation of subretinal vessel location in polypoidal choroidal vasculopathy (PCV) and response of hemorrhagic and exudative PCV to high-dose antiangiogenic therapy (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 2014;112:74-93.
Marcus DM, Singh H, Fechter CM, Chamberlain DP. High-dose ranibizumab monotherapy for neovascular polypoidal choroidal vasculopathy in a predominantly non-Asian population. Eye (Lond) 2015;29:1427-37.
Hikichi T, Higuchi M, Matsushita T, Kosaka S, Matsushita R, Takami K, et al.
Results of 2 years of treatment with as-needed ranibizumab reinjection for polypoidal choroidal vasculopathy. Br J Ophthalmol 2013;97:617-21.
Hikichi T. Six-year outcomes of antivascular endothelial growth factor monotherapy for polypoidal choroidal vasculopathy. Br J Ophthalmol 2018;102:97-101.
Hikichi T, Kitamei H, Shioya S. Retinal pigment epithelial atrophy over polypoidal choroidal vasculopathy lesions during ranibizumab monotherapy. BMC Ophthalmol 2016;16:55.
Hikichi T. Individualized ranibizumab therapy strategies in year 3 after as-needed treatment for polypoidal choroidal vasculopathy. BMC Ophthalmol 2015;15:37.
Pak KY, Park SW, Byon IS, Lee JE. Treat-and-extend regimen using ranibizumab for polypoidal choroidal vasculopathy: One-year results. Retina 2017;37:561-7.
Shin JY, Choi M, Chung B, Byeon SH. Pigment epithelial tears after ranibizumab injection in polypoidal choroidal vasculopathy and typical age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2015;253:2151-60.
Cho HJ, Lee DW, Cho SW, Kim CG, Kim JW. Hemorrhagic complications after intravitreal ranibizumab injection for polypoidal choroidal vasculopathy. Can J Ophthalmol 2012;47:170-5.
Koizumi H, Yamagishi T, Yamazaki T, Kinoshita S. Predictive factors of resolved retinal fluid after intravitreal ranibizumab for polypoidal choroidal vasculopathy. Br J Ophthalmol 2011;95:1555-9.
Cho HJ, Han SY, Kim HS, Lee TG, Kim JW. Factors associated with polyp regression after intravitreal ranibizumab injections for polypoidal choroidal vasculopathy. Jpn J Ophthalmol 2015;59:29-35.
Hikichi T, Kitamei H, Shioya S. Prognostic factors of 2-year outcomes of ranibizumab therapy for polypoidal choroidal vasculopathy. Br J Ophthalmol 2015;99:817-22.
Suzuki M, Nagai N, Shinoda H, Uchida A, Kurihara T, Tomita Y, et al.
Distinct responsiveness to intravitreal ranibizumab therapy in polypoidal choroidal vasculopathy with single or multiple polyps. Am J Ophthalmol 2016;166:52-9.
Nishide T, Hayakawa N, Nakanishi M, Ishii M, Okazaki S, Kimura I, et al.
Reduction in choroidal thickness of macular area in polypoidal choroidal vasculopathy patients after intravitreal ranibizumab therapy. Graefes Arch Clin Exp Ophthalmol 2013;251:2415-20.
Hikichi T, Kitamei H, Shioya S, Higuchi M, Matsushita T, Kosaka S, et al.
Relation between changes in foveal choroidal thickness and 1-year results of ranibizumab therapy for polypoidal choroidal vasculopathy. Br J Ophthalmol 2014;98:1201-4.
Shin JY, Kwon KY, Byeon SH. Association between choroidal thickness and the response to intravitreal ranibizumab injection in age-related macular degeneration. Acta Ophthalmol 2015;93:524-32.
Sonoda S, Sakamoto T, Otsuka H, Yoshinaga N, Yamashita T, Ki-I Y, et al.
Responsiveness of eyes with polypoidal choroidal vasculopathy with choroidal hyperpermeability to intravitreal ranibizumab. BMC Ophthalmol 2013;13:43.
Baek J, Lee JH, Lee WK. Clinical relevance of aqueous vascular endothelial growth factor levels in polypoidal choroidal vasculopathy. Retina 2017;37:943-50.
Saito M, Kano M, Itagaki K, Ise S, Imaizumi K, Sekiryu T, et al.
Subfoveal choroidal thickness in polypoidal choroidal vasculopathy after switching to intravitreal aflibercept injection. Jpn J Ophthalmol 2016;60:35-41.
Cho HJ, Kim JW, Lee DW, Cho SW, Kim CG. Intravitreal bevacizumab and ranibizumab injections for patients with polypoidal choroidal vasculopathy. Eye (Lond) 2012;26:426-33.
Cho HJ, Kim KM, Kim HS, Han JI, Kim CG, Lee TG, et al.
Intravitreal aflibercept and ranibizumab injections for polypoidal choroidal vasculopathy. Am J Ophthalmol 2016;165:1-6.
Yamamoto A, Okada AA, Kano M, Koizumi H, Saito M, Maruko I, et al.
One-year results of intravitreal aflibercept for polypoidal choroidal vasculopathy. Ophthalmology 2015;122:1866-72.
Kokame GT, Lai JC, Wee R, Yanagihara R, Shantha JG, Ayabe J, et al.
Prospective clinical trial of intravitreal aflibercept treatment for polypoIdal choroidal vasculopathy with hemorrhage or exudation (EPIC study): 6 month results. BMC Ophthalmol 2016;16:127.
Oishi A, Tsujikawa A, Yamashiro K, Ooto S, Tamura H, Nakanishi H, et al.
One-year result of aflibercept treatment on age-related macular degeneration and predictive factors for visual outcome. Am J Ophthalmol 2015;159:853-600.
Hara C, Sawa M, Sayanagi K, Nishida K. One-year results of intravitreal aflibercept for polypoidal choroidal vasculopathy. Retina 2016;36:37-45.
Lee JE, Shin JP, Kim HW, Chang W, Kim YC, Lee SJ, et al.
Efficacy of fixed-dosing aflibercept for treating polypoidal choroidal vasculopathy: 1-year results of the VAULT study. Graefes Arch Clin Exp Ophthalmol 2017;255:493-502.
Hosokawa M, Morizane Y, Hirano M, Kimura S, Kumase F, Shiode Y, et al.
One-year outcomes of a treat-and-extend regimen of intravitreal aflibercept for polypoidal choroidal vasculopathy. Jpn J Ophthalmol 2017;61:150-8.
Oshima Y, Kimoto K, Yoshida N, Fujisawa K, Sonoda S, Kubota T, et al.
One-year outcomes following intravitreal aflibercept for polypoidal choroidal vasculopathy in Japanese patients: The APOLLO study. Ophthalmologica 2017;238:163-71.
Inoue M, Yamane S, Taoka R, Arakawa A, Kadonosono K. Aflibercept for polypoidal choroidal vasculopathy: As needed versus fixed interval dosing. Retina 2016;36:1527-34.
Maruyama-Inoue M, Sato S, Yamane S, Kadonosono K. Intravitreal injection of aflibercept in patients with polypoidal choroidal vasculopathy: A 3-year follow-up. Retina 2017:1–9.
Morimoto M, Matsumoto H, Mimura K, Akiyama H. Two-year results of a treat-and-extend regimen with aflibercept for polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2017;255:1891-7.
Julien S, Biesemeier A, Taubitz T, Schraermeyer U. Different effects of intravitreally injected ranibizumab and aflibercept on retinal and choroidal tissues of monkey eyes. Br J Ophthalmol 2014;98:813-25.
Koizumi H, Kano M, Yamamoto A, Saito M, Maruko I, Kawasaki R, et al.
Short-term changes in choroidal thickness after aflibercept therapy for neovascular age-related macular degeneration. Am J Ophthalmol 2015;159:627-33.
Ferrara N. Vascular endothelial growth factor: Basic science and clinical progress. Endocr Rev 2004;25:581-611.
Hood JD, Meininger CJ, Ziche M, Granger HJ. VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells. Am J Physiol 1998;274:H1054-8.
Morimoto M, Matsumoto H, Mimura K, Akiyama H. Reply to the letter to the editor: Two-year results of treat-and-extend regimen with aflibercept for polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2018;256:225-6.
Lee WK, Iida T, Ogura Y, Chen SJ, Wong TY, Mitchell P, et al.
Efficacy and safety of intravitreal aflibercept for polypoidal choroidal vasculopathy in the PLANET study: A Randomized clinical trial. JAMA Ophthalmol 2018;136:786-93.
Wong RL, Lai TY. Polypoidal choroidal vasculopathy: An update on therapeutic approaches. J Ophthalmic Vis Res 2013;8:359-71. [Full text]
Tatar O, Shinoda K, Adam A, Eckert T, Eckardt C, Lucke K, et al.
Effect of verteporfin photodynamic therapy on endostatin and angiogenesis in human choroidal neovascular membranes. Br J Ophthalmol 2007;91:166-73.
Tatar O, Kaiserling E, Adam A, Gelisken F, Shinoda K, Völker M, et al.
Consequences of verteporfin photodynamic therapy on choroidal neovascular membranes. Arch Ophthalmol 2006;124:815-23.
Tatar O, Adam A, Shinoda K, Stalmans P, Eckardt C, Lüke M, et al.
Expression of VEGF and PEDF in choroidal neovascular membranes following verteporfin photodynamic therapy. Am J Ophthalmol 2006;142:95-104.
Schmidt-Erfurth U, Schlötzer-Schrehard U, Cursiefen C, Michels S, Beckendorf A, Naumann GO, et al.
Influence of photodynamic therapy on expression of vascular endothelial growth factor (VEGF), VEGF receptor 3, and pigment epithelium-derived factor. Invest Ophthalmol Vis Sci 2003;44:4473-80.
Yong M, Zhou M, Deng G. Photodynamic therapy versus anti-vascular endothelial growth factor agents for polypoidal choroidal vasculopathy: A meta-analysis. BMC Ophthalmol 2015;15:82.
Qian T, Li X, Zhao M, Xu X. Polypoidal choroidal vasculopathy treatment options: A meta-analysis. Eur J Clin Invest 2018;48:e12840.
Wang W, He M, Zhang X. Combined intravitreal anti-VEGF and photodynamic therapy versus photodynamic monotherapy for polypoidal choroidal vasculopathy: A systematic review and meta-analysis of comparative studies. PLoS One 2014;9:e110667.
Liu L, Tham YC, Wu J, Yue S, Cheng CY. Photodynamic therapy in combination with ranibizumab versus ranibizumab monotherapy for polypoidal choroidal vasculopathy: A systematic review and meta-analysis. Photodiagnosis Photodyn Ther 2017;20:215-20.
Tang K, Si JK, Guo DD, Cui Y, Du YX, Pan XM, et al.
Ranibizumab alone or in combination with photodynamic therapy vs photodynamic therapy for polypoidal choroidal vasculopathy: A systematic review and meta-analysis. Int J Ophthalmol 2015;8:1056-66.
Koh A, Lai TYY, Takahashi K, Wong TY, Chen LJ, Ruamviboonsuk P, et al.
Efficacy and safety of ranibizumab with or without verteporfin photodynamic therapy for polypoidal choroidal vasculopathy: A randomized clinical trial. JAMA Ophthalmol 2017;135:1206-13.
Zhao M, Zhou HY, Xu J, Zhang F, Wei WB, Liu NP, et al.
Combined photodynamic therapy and ranibizumab for polypoidal choroidal vasculopathy: A 2-year result and systematic review. Int J Ophthalmol 2017;10:413-22.
Gomi F, Oshima Y, Mori R, Kano M, Saito M, Yamashita A, et al.
Initial versus delayed photodynamic therapy in combination with ranibizumab for treatment of polypoidal choroidal vasculopathy: The Fujisan study. Retina 2015;35:1569-76.
Cho JH, Ryoo NK, Cho KH, Park SJ, Park KH, Woo SJ, et al.
Incidence rate of massive submacular hemorrhage and its risk factors in polypoidal choroidal vasculopathy. Am J Ophthalmol 2016;169:79-88.
Kim H, Lee SC, Kim SM, Lee JH, Koh HJ, Kim SS, et al.
Identification of underlying causes of spontaneous submacular hemorrhage by indocyanine green angiography. Ophthalmologica 2015;233:146-54.
Kim KH, Kim JH, Chang YS, Lee TG, Kim JW, Lew YJ, et al.
Clinical outcomes of eyes with submacular hemorrhage secondary to age-related macular degeneration treated with anti-vascular endothelial growth factor. Korean J Ophthalmol 2015;29:315-24.
Papavasileiou E, Steel DH, Liazos E, McHugh D, Jackson TL. Intravitreal tissue plasminogen activator, perfluoropropane (C3F8), and ranibizumab or photodynamic therapy for submacular hemorrhage secondary to wet age-related macular degeneration. Retina 2013;33:846-53.
Shin JY, Lee JM, Byeon SH. Anti-vascular endothelial growth factor with or without pneumatic displacement for submacular hemorrhage. Am J Ophthalmol 2015;159:904-140.
Haupert CL, McCuen BW 2nd
, Jaffe GJ, Steuer ER, Cox TA, Toth CA, et al.
Pars plana vitrectomy, subretinal injection of tissue plasminogen activator, and fluid-gas exchange for displacement of thick submacular hemorrhage in age-related macular degeneration. Am J Ophthalmol 2001;131:208-15.
Hattenbach LO, Klais C, Koch FH, Gümbel HO. Intravitreous injection of tissue plasminogen activator and gas in the treatment of submacular hemorrhage under various conditions. Ophthalmology 2001;108:1485-92.
Hirashima T, Moriya T, Bun T, Utsumi T, Hirose M, Oh H, et al.
Optical coherence tomography findings and surgical outcomes of tissue plasminogen activator-assisted vitrectomy for submacular hemorrhage secondary to age-related macular degeneration. Retina 2015;35:1969-78.
Olivier S, Chow DR, Packo KH, MacCumber MW, Awh CC. Subretinal recombinant tissue plasminogen activator injection and pneumatic displacement of thick submacular hemorrhage in age-related macular degeneration. Ophthalmology 2004;111:1201-8.
Schulze SD, Hesse L. Tissue plasminogen activator plus gas injection in patients with subretinal hemorrhage caused by age-related macular degeneration: Predictive variables for visual outcome. Graefes Arch Clin Exp Ophthalmol 2002;240:717-20.
Cheung CM, Bhargava M, Xiang L, Mathur R, Mun CC, Wong D, et al.
Six-month visual prognosis in eyes with submacular hemorrhage secondary to age-related macular degeneration or polypoidal choroidal vasculopathy. Graefes Arch Clin Exp Ophthalmol 2013;251:19-25.
Stanescu-Segall D, Balta F, Jackson TL. Submacular hemorrhage in neovascular age-related macular degeneration: A synthesis of the literature. Surv Ophthalmol 2016;61:18-32.
Kim JB, Nirwan RS, Kuriyan AE. Polypoidal choroidal vasculopathy. Curr Ophthalmol Rep 2017;5:176-86.
Chan WM, Liu DT, Lai TY, Li H, Tong JP, Lam DS, et al.
Extensive submacular haemorrhage in polypoidal choroidal vasculopathy managed by sequential gas displacement and photodynamic therapy: A pilot study of one-year follow up. Clin Exp Ophthalmol 2005;33:611-8.
Kitahashi M, Baba T, Sakurai M, Yokouchi H, Kubota-Taniai M, Mitamura Y, et al.
Pneumatic displacement with intravitreal bevacizumab for massive submacular hemorrhage due to polypoidal choroidal vasculopathy. Clin Ophthalmol 2014;8:485-92.
Kimura S, Morizane Y, Hosokawa M, Shiode Y, Kawata T, Doi S, et al.
Submacular hemorrhage in polypoidal choroidal vasculopathy treated by vitrectomy and subretinal tissue plasminogen activator. Am J Ophthalmol 2015;159:683-9.
Jung JH, Lee JK, Lee JE, Oum BS. Results of vitrectomy for breakthrough vitreous hemorrhage associated with age-related macular degeneration and polypoidal choroidal vasculopathy. Retina 2010;30:865-73.
Chang MA, Do DV, Bressler SB, Cassard SD, Gower EW, Bressler NM, et al.
Prospective one-year study of ranibizumab for predominantly hemorrhagic choroidal neovascular lesions in age-related macular degeneration. Retina 2010;30:1171-6.
Cho HJ, Koh KM, Kim HS, Lee TG, Kim CG, Kim JW, et al.
Anti-vascular endothelial growth factor monotherapy in the treatment of submacular hemorrhage secondary to polypoidal choroidal vasculopathy. Am J Ophthalmol 2013;156:524-31.
Kim JH, Chang YS, Kim JW, Kim CG, Yoo SJ, Cho HJ, et al.
Intravitreal anti-vascular endothelial growth factor for submacular hemorrhage from choroidal neovascularization. Ophthalmology 2014;121:926-35.
Steel DH, Sandhu SS. Submacular haemorrhages associated with neovascular age-related macular degeneration. Br J Ophthalmol 2011;95:1051-7.
Stifter E, Michels S, Prager F, Georgopoulos M, Polak K, Hirn C, et al.
Intravitreal bevacizumab therapy for neovascular age-related macular degeneration with large submacular hemorrhage. Am J Ophthalmol 2007;144:886-92.
Kadonosono K, Arakawa A, Yamane S, Inoue M, Yamakawa T, Uchio E, et al.
Displacement of submacular hemorrhages in age-related macular degeneration with subretinal tissue plasminogen activator and air. Ophthalmology 2015;122:123-8.
Klettner A, Grotelüschen S, Treumer F, Roider J, Hillenkamp J. Compatibility of recombinant tissue plasminogen activator (rtPA) and aflibercept or ranibizumab coapplied for neovascular age-related macular degeneration with submacular haemorrhage. Br J Ophthalmol 2015;99:864-9.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4]