Polypoidal Choroidal Vasculopathy

Etiology

The cause of PCV is considered to result from inner choroidal vessel abnormalities. These vessels have multiple, small, polyp-shaped aneurysms that form as a result of a defective vascular lining. These vessels have thinned out endothelial cells and reduced pericytes compared to normal vasculature.[3] Hypertension, raised plasma viscosity, and thrombocytopenia are associated with PCV.[4][5]

One suggested mechanism for developing these polypoidal lesions is that venules form polypoidal protrusions when compressed by a sclerosed arteriole at an arterio-venous crossing site. The resulting venous stasis leads to the degeneration of tissue and fragility.[6] The polypoidal configurations that develop from this degeneration tend to leak and rupture.

Epidemiology

PCV is a relatively uncommon disease in the general population, with one study estimating that its prevalence in Europe is 0.04% of the entire population.[7] The prevalence is higher in Asians compared to white individuals. Another study found that the prevalence of PCV was 7.8% in white individuals, 23% to 54% in Japanese, 22.3% in Chinese, and 24.6% in Korean populations with the clinical appearance of neovascular age-related macular degeneration (nAMD). Previous reports suggested that PCV was more prevalent in middle-aged women and typically presents one or two decades earlier than nAMD. It is most commonly diagnosed in the age group of 50 to 65 years. The age at presentation is higher in Caucasians than in Asians. It has now been established that it affects both genders, although the female-to-male ratio is 4.7 to 1.[8] 

The association of PCV with other diseases is debatable. PCV has been reported with thrombocytopenia, sickle cell anemia, irradiation, and hypertension. However, to establish such an association, further studies are warranted.

History and Physical

Most patients with PCV  present with a diminution of vision. Other symptoms at presentation include metamorphopsia, central scotoma, and floaters. Patients presenting within three months of onset have better visual acuity and clinically have signs of subretinal exudation or hemorrhage. The presence of lipid exudation or intraretinal cysts are signs of chronicity.[9] PCV cases tend to have better visual acuity at presentation compared to typical AMD cases.[10] Better visual acuity in PCV could be due to extrafoveal location and minimal intraretinal changes. Long-standing cases show signs of subretinal fibrosis, pigment epithelial hyperplasia, or atrophic retinal changes.

PCV is usually bilateral. In most cases, one eye's involvement would eventually develop a similar presentation in the other eye. Clinically, it is characterized by orange-red elevated lesions, which can be small, medium, or large. The larger polyps can be seen clinically on a routine fundus examination. The polypoidal lesions are most commonly located in the macular region. A study reported macular involvement in 69.5% of cases and peripapillary involvement in 4.5% of cases. Mid-peripheral polyps have also been reported.[11]

Other clinical signs are serous or serosanguineous pigment epithelial detachments, subretinal hemorrhage, lipid exudation, and the affected area's neurosensory detachment. 

Clinical Classification of PCV

1. Quiescent: Presence of polyps without clinical signs of subretinal detachment or hemorrhage. 
2. Active: PCV is considered active if there is evidence of any of the following: vision loss of 5 or more letters, OCT/FFA/ICGA evidence of activity- subretinal or intraretinal fluid, pigment epithelial detachment, subretinal hemorrhage, or fluorescein leakage. Active lesions are further classified as:
   1. Exudative
   2. Hemorrhagic
   3. Mixed

Evaluation

Indocyanine green angiography (ICGA) is a preferred imaging modality compared to fundus fluorescein angiography (FFA) for PCV because indocyanine green dye absorbs and emits near-infrared light that penetrates RPE, leading to a better imaging of choroidal structures. Moreover, unlike fluorescein dye, ICG doesn't leak from choriocapillaris, so choroidal lesions are less obscured. ICGA is the gold standard for diagnosing PCV and differentiating it from retinal angiomatous proliferation and typical AMD.

The ICGA characteristics of PCV are abnormal vascular network (AVN) of inner choroidal vessels, nodular dilatations at the edge of AVN, and the presence of hyperfluorescent halo around polyps, arising within the first six minutes. Pulsation of polyps can be observed using video ICGA.

Typically, the early phase of ICGA reveals the filling of an abnormal choroidal branching vascular network. Hyperfluorescent polyps fill up soon after the delineation of AVN. The hyperfluorescent polyps leak and obscure the hyperfluorescent halo around the polyps.

OCT shows certain distinctive features that help a clinician suspect PCV. It is not diagnostic alone but should be used as an adjuvant to ICGA and must be used for disease monitoring and assessing response to treatment. Distinctive OCT features that are suggestive of PCV include: sharp-peaked PED, notched PED, hyporeflective lumen surrounded by hyperreflective ring under the surface of RPE, and Double-layer Sign (DLS). A Double-layer sign implies when RPE is seen distinct from Bruch's membrane in spectral-domain OCT and represents the presence of AVN. Sharp peaked PED denotes polyp. The presence of thickened choroid (pachychoroid) on enhanced depth imaging- OCT (EDI-OCT) supports the diagnosis of PCV and rules out typical AMD where the underlying choroid is usually thin.

FFA must be performed at the initial presentation to identify leakage from the abnormal vascular network. Leakage on FFA is a sign of disease activity. Fluorescein angiography has a limited role in diagnosing polyps. Moreover, it overestimates the lesion size, compared to ICGA, if a PED is present along the edge of the lesion because, in FFA, PED appears hyperfluorescent.

Treatment / Management

Treatment of PCV is based on the location of the disease and disease activity. As mentioned above, the presence of intraretinal/subretinal fluid, sub-RPE/subretinal hemorrhage, or vision loss of > 5 letters are the signs of active disease. Inactive disease must be observed and closely monitored. In clinically active but asymptomatic cases such as peripheral or peripapillary PCV, the decision to treat is based on the treating physician's discretion.

Different treatment modalities that can be used in the treatment of PCV are:

1. Photodynamic therapy
2. Anti-VEGF drugs
3. Thermal laser
4. Combination therapy

Photodynamic Therapy (PDT)

PDT is indicated in subfoveal or extrafoveal polyps and extension of AVN subfoveal. Isolated extrafoveal polyps and extrafoveal polyps may be treated with a thermal laser. The thermal laser can result in scotoma and hemorrhage. Hence, PDT is a safer option for large extrafoveal lesions. TL for extrafoveal lesions should be reserved for smaller polyps without AVN. 

 PDT uses verteporfin dye, which acts as a photosensitizer. When injected intravenously, dye accumulates within endothelial cells of abnormal choroidal vessels. Diode laser causes photo thrombosis within these abnormal blood vessels resulting in occlusion and resolution of exudation. The spot size for PDT is best determined using ICGA. The drawing tool on the software is used to draw the best-fit circle around the polyp and AVN, and the corresponding spot size on the diode laser should be used. The maximum lesion size can be best estimated in early-phase ICGA in 90% of cases. 

In most cases, polyp and AVN can be covered by the largest spot size available on PDT. In lesions larger than this, the current recommendation is to pretreat with three loading doses of anti-vascular endothelial growth factor (VEGF) agents and PDT over the lesion using the largest spot size. ICGA should be repeated after three months to determine disease activity. PDT can be repeated if polyps are still active. 

The most common complication reported after full fluence PDT is subretinal hemorrhage, which is most commonly reported within one month of PDT. The common risk factors for subretinal bleeding are larger lesion size, large spot size, and leaking polyps.[12] Other complications of PDT include suprachoroidal hemorrhage, RPE tears, choroidal ischemia, RPE atrophy, secondary choroidal neovascular membranes (CNVM), and fibrotic scarring.[13](B2)

Other treatment protocols are half-dose PDT or reduced fluence PDT, which may have lesser side effects compared to full fluence PDT. In reduced fluence PDT, light energy of 25 J/cm2 instead of 50 J/cm^2) with a full dose of 6 mg/m2 of verteporfin dye. In half-dose PDT, 3mg/m2 dye is used. Although the risk of subretinal bleeding is lesser with these two protocols, incomplete resolution of polyps and AVN are reported.[14]

Anti-VEGF Drugs

Anti-VEGF drugs reduce the permeability of abnormal vascular networks and polyps, thereby reducing exudation and preserving vision. Most studies suggested induction with three monthly injections, followed by as-needed intravitreal injections. Anti-VEGF agents reduce subretinal hemorrhage, macular edema, and stabilization of vision in 80% to 100% of cases.[15]

Polyps and AVN persistence have been noted in short-term and long-term studies using anti-VEGF monotherapy. The current recommendation is to rule out polyps using ICGA if a suboptimal response with anti-VEGF drugs is seen in a case of presumed neovascular AMD. No studies have proven the superiority of one drug or the other. However, aflibercept has certain advantages over bevacizumab and ranibizumab, including a longer half-life, greater affinity to VEGF, and potency against the placental growth factor. Few studies suggested switching to aflibercept in case tachyphylaxis is noted to ranibizumab.

Combination Therapy

Combination therapy combines the prothrombotic effect of PDT with the anti-permeability effect of anti-VEGF and has been shown to have better results. The landmark EVEREST trial reported polyp regression in 77.8% of cases with combination therapy, while ranibizumab monotherapy resulted in polyp regression in only 28.6% of cases.[16] However, this benefit was not replicated by the PLANET trial, using aflibercept. In summary, PDT can efficiently cause polyp regression, but the same may not be implied for visual gain. (A1)

Thermal Laser

Thermal laser (TL) has been used for extrafoveal polyps. It is an effective and relatively inexpensive treatment modality compared to PDT. TL can result in chorioretinal scar, scotoma, and secondary CNVM. Hence it is indicated for lesions located greater than 1000 microns from the center of the fovea. For lesions located within 500 to 1000 microns from the center of the fovea, TL can be considered if the lesion size is less than 1000 microns. Complete ablation of AVN must be avoided with TL due to the above-mentioned complications. However, if the feeder can be recognized using video ICGA, selective ablation of the feeder vessel must be done.

Differential Diagnosis

Neovascular AMD: PCV shares many similarities with nAMD. It has similar clinical features, increased VEGF expression, similar histology, and expression of growth factors and receptor antibodies. However, PCV has now been accepted as a distinct entity. The VEGF levels in PCV are less than nAMD or myopic CNVM. The clinical signs of PCV are also different from nAMD. The polyps project under the surface of RPE from the plane of the inner choroid. RPE invariably remains intact, unlike nAMD, where neovascular tufts arising from choroid breach Bruch's membrane and grow in sub-RPE or subretinal space. OCT findings of sharp-peaked/ notched PED or the presence of double-layer sign distinguish PCV from nAMD.

Central serous chorioretinopathy (CSC): CSC is characterized by subretinal fluid and neurosensory detachment of the macula. It has been hypothesized due to an underlying disturbance in choroidal microcirculation. Choroidal hyperpermeability with impaired RPE function leads to the pooling of fluid in sub-RPE space with eventual leakage into subretinal space. Multifocal choroidal hyperfluorescent patches suggestive of choroidal hyperpermeability are seen on ICGA. PCV masquerading as CSC has been reported. In many cases, differentiating between CSC and PCV can be difficult as both show signs of subretinal exudation and RPE changes. ICGA findings play a crucial role in clinching the diagnosis.

Prognosis

Generally, small polypoidal lesions with less than one disc diameter have a very good prognosis, with minimal vision loss and vision-threatening complications.[17] Poor prognostic factors that often lead to vision loss include large lesions, PED, cluster polyps, macular location, Caucasian race, and lesion recurrence.[8][18][19] Long-term follow-up is necessary for eyes with PCV since a significant number of eyes with inactive lesions can worsen in the future, even if stable for years.[20] Severe visual loss can be seen in around one-third of eyes with PCV.[21]

Complications

PCV may induce choroidal ischemia, inflammation, RPE damage, and breaks in Bruch's membrane. These changes can contribute to the formation of CNVM, fibrosis, and subsequent scarring. The ultimate consequence of this sequela is irreversible vision loss.