Choroidal neovascularization (CNV) is a disease in which new blood vessels originating from the choroid preferentially occur in the macula. The new vessels proliferate beneath the retinal pigment epithelium (RPE) (type 1/classic) or above the RPE (type 2/occult). In cases of choroiditis or idiopathic CNV, inflammation plays a major role, and CNV is considered a reactive change or wound healing process in response to damage to the RPE-Bruch’s membrane-choriocapillaris complex.
Inflammatory choroidal neovascularization (I-CNV) is a severe complication of posterior uveitis caused by chorioretinal inflammation. It can occur in both infectious and non-infectious uveitis1). I-CNV is considered the third most common cause of CNV after AMD and pathologic myopia1).
In patients with posterior uveitis, CNV occurs in 2.7%, and in patients with panuveitis, 0.8%, which is more frequent than in anterior or intermediate uveitis (0.1%)1). In idiopathic uveitis, CNV occurs as a complication in 13–20% of cases3). Most I-CNV presents as type 2 (classic) CNV, forming beneath the RPE (type 1) or above the RPE (type 2) after breaking through Bruch’s membrane1).
Diseases that cause frequent I-CNV
Punctate inner choroidopathy (PIC): 17–40%
Multifocal choroiditis (MFC): 32–50%
Serpiginous choroiditis: 10–25%
Vogt-Koyanagi-Harada disease (VKH): 9–15%
Ocular histoplasmosis syndrome: 5–17.4%
Birdshot chorioretinitis: 5%
I-CNV in infectious diseases
Toxoplasma chorioretinitis: 0.3–19%
Ocular histoplasmosis: 5–17.4%
Ocular tuberculosis: rare case reports
Candida chorioretinitis: rare (prevalence unknown)
Rubella retinopathy: rare case reports
Toxocariasis: rare case reports
The typical initial symptom of I-CNV is a sudden worsening of visual acuity and the appearance of metamorphopsia 1).
Active lesions located outside the fovea may be asymptomatic and can be missed due to inflammatory lesions, scars, pigmentation, or accumulation of intraretinal or subretinal fluid1).
Fundus examination reveals yellowish-white subretinal lesions around the macula.
After CNV involutes, atrophic lesions of the retinal pigment epithelium-choriocapillaris complex may form. In sub-RPE CNV, fibrous tissue forms under the retina, which may lead to permanent vision loss, central scotoma, and metamorphopsia.
Pathophysiology: Two mechanisms 1)
Activated inflammatory cells secrete cytotoxic enzymes that degrade Bruch’s membrane. Released pro-angiogenic cytokines (IL-6, IL-8, TNF-α) promote VEGF expression and CNV growth 2). In uveitis, cytokines such as TNF-α, IL-6, and IL-1 damage RPE, further amplifying VEGF expression and promoting I-CNV formation 3).
According to the Uveitis Clinical Practice Guidelines (2019), caution is needed for CNV complications in posterior uveitis such as PIC, multifocal choroiditis, sarcoidosis, Harada disease, and serpiginous choroiditis, and a combination of inflammation control and anti-VEGF therapy is recommended 3).
Risk factors5):
| Risk factor | Details |
|---|---|
| Presence of subretinal neovascularization | Risk of I-CNV development increases by 3 times or more |
| Active inflammation | Significantly higher CNV risk compared to inactive phase |
| Anterior chamber inflammation grade 2+ | Significant association with I-CNV |
| History of CNV in the fellow eye | Several-fold increased risk of CNV development |
| Unilateral uveitis | Higher CNV risk than bilateral |
Diagnosis of I-CNV is challenging, and multimodal imaging is recommended1).
Fluorescein angiography (FA): Most I-CNVs appear as classic (type 2) CNV. CNV lesions show early isofluorescence to hyperfluorescence with late leakage. However, active inflammatory lesions also show similar FA findings, so FA alone has limitations in diagnosis 1). Characteristic features include well-defined hyperfluorescence in the early phase (classic type) or diffuse pigment leakage in the late phase (occult type).
Indocyanine green angiography (ICGA): Allows more detailed evaluation of choroidal vascular structures than FA. I-CNV shows early hyperfluorescence, enabling differentiation from active inflammatory foci (early hypofluorescence) 1). ICGA is essential for differentiating sub-RPE CNV, and in multifocal choroiditis, it is useful for assessing non-perfusion areas of the choriocapillaris and evaluating CNV risk 1).
Optical coherence tomography (OCT): Non-invasively and quickly examines cross-sections of the macula, allowing assessment of the positional relationship between CNV and the fovea, whether CNV is above or below the RPE, and associated retinal detachment, RPE detachment, and cystoid macular edema.
OCT angiography (OCTA): Non-invasively visualizes the vascular structure of CNV. It has higher accuracy than FA alone in differentiating CNV from inflammatory lesions and is particularly useful for identifying type 1 neovascular networks8).
Fundus autofluorescence (FAF): Active I-CNV shows normal fluorescence or hyperautofluorescence. Hypoautofluorescent areas correlate with photoreceptor and RPE loss and are useful for detecting peripheral I-CNV1).
OCT is very useful for evaluating I-CNV, but definitive diagnosis alone is often difficult. OCT findings characteristic of I-CNV, such as the “pitchfork sign,” have ancillary value, but multimodal imaging combining FA, ICGA, OCTA, and FAF is essential for accurate diagnosis and differentiation from inflammatory lesions1).
Prompt treatment of I-CNV prevents irreversible vision loss. Treatment requires a combination of two approaches.
First, rule out infectious diseases (e.g., toxoplasmosis, tuberculosis, Bartonella henselae) and provide appropriate anti-infective therapy. For underlying uveitis after exclusion:
Regardless of the underlying disease, intravitreal injection of VEGF inhibitors is performed for foveal CNV. Since VEGF is closely involved in the development and growth of CNV, drugs that inhibit it are useful for inducing CNV regression and preventing hemorrhage and exudation.
| Drug | Overview | Application to inflammatory CNV |
|---|---|---|
| Aflibercept (Eylea) | VEGF-A/VEGF-B/PlGF inhibition | Not covered by insurance (covered for AMD and myopic maculopathy) |
| Ranibizumab (Lucentis) | Anti-VEGF-A monoclonal antibody fragment | Not covered by insurance (covered for AMD and myopic maculopathy) |
| Bevacizumab (Avastin) | Anti-VEGF-A full-length monoclonal antibody | Not covered by insurance (off-label), used for inflammatory CNV |
Aflibercept and ranibizumab are covered by insurance only for age-related macular degeneration and myopic maculopathy. For inflammatory CNV, bevacizumab (1.25 mg/0.05 mL intravitreal injection) is used off-label 3).
Combination of anti-inflammatory therapy and anti-VEGF drugs results in improvement in 80% of patients and stabilization in 15% 4). Anti-VEGF monotherapy in PIC patients has a reported recurrence rate of 50%, indicating the need for systemic treatment of underlying uveitis 7).
Comparison between an induction phase (monthly injections for 3 months) and pro re nata (PRN) dosing shows that an induction phase does not lead to superior outcomes 1). Randomized controlled trials have confirmed that anti-VEGF drugs (ranibizumab 0.5 mg intravitreal injection) are effective in improving visual acuity and regressing neovascularization in I-CNV 6).
Aflibercept (Eylea) and ranibizumab (Lucentis) are only covered by insurance for age-related macular degeneration and myopic maculopathy. For inflammatory CNV, bevacizumab (Avastin, off-label) may be used at some ophthalmology facilities. Treatment choice should be decided after thorough consultation with the attending physician.
For extrafoveal CNV, photocoagulation with a thermal laser is performed. Photocoagulation directly occludes the CNV, but the irradiated area results in permanent retinal damage, so the distance from the fovea must be carefully evaluated to determine the indication.
The pathophysiology of I-CNV is similar to that of CNV in AMD and pathologic myopia, but is characterized by the addition of inflammatory factors 1).
Chronic inflammation, oxidative stress, and ischemia are involved, and CNV occurs as a reactive change or wound healing process in response to damage to the RPE-Bruch membrane-choriocapillaris complex.
Molecular mechanisms:
In uveitis, cytokines such as TNF-α, IL-6, and IL-1 are secreted by inflammatory cells, damaging the RPE and further amplifying VEGF expression 3). The interaction between these cytokines and VEGF promotes I-CNV formation.
Differences between I-CNV and AMD-related CNV: Immunohistochemical studies have reported that the CXCR4 staining pattern of the vascular mesh in I-CNV differs from that in AMD-related CNV, suggesting that capillaries may play different roles in membrane formation 9).
Some “idiopathic” CNV may appear as a preceding symptom of posterior uveitis 1). New blood vessels often grow from the edge of the inflammatory lesion (the edge of post-inflammatory atrophic chorioretinal scar).
Improved diagnostic accuracy with OCTA:
OCTA plays an important role in the diagnosis and follow-up of I-CNV. Evidence of the superiority of OCTA over FA/ICGA alone is accumulating, and it has been shown to be essential for identifying type 1 neovascular networks even when FA/ICGA results are inconclusive8). OCTA is also useful as a monitoring indicator for active CNV, allowing quantitative assessment of neovascular regression after treatment8).
Clinical significance of the “sponge sign”:
Increased choroidal thickness under I-CNV on OCT (the “sponge sign,” which decreases after treatment) is attracting attention as a new auxiliary indicator for monitoring I-CNV activity. It may also be applicable for differentiating inflammatory CNV from myopic CNV1).
Long-term outcomes of anti-VEGF therapy:
Medium- to long-term data have accumulated showing an improvement of approximately 0.3 logMAR units in visual acuity after anti-VEGF therapy (1–5 injections) for posterior uveitis of various causes4). A recurrence rate of 50% has been reported with anti-VEGF monotherapy in PIC patients, and management of the underlying disease determines long-term prognosis7).
Treat and Extend (T&E) regimen:
The T&E regimen (gradually extending treatment intervals), established for AMD and myopic CNV, is being investigated for application to I-CNV. It may reduce treatment burden while maintaining vision, but evidence specific to inflammatory CNV is awaited.
Faricimab (anti-VEGF-A/Ang-2 dual inhibitor):
Faricimab, which simultaneously inhibits VEGF-A and angiopoietin-2 (Ang-2), is approved for AMD and diabetic macular edema, and its application to inflammatory CNV is under research. Since Ang-2 is involved in both angiogenesis and inflammation, a specific effect on I-CNV is expected.
Standardization of multimodal approach:
A multimodal approach including FAF, OCTA, and near-infrared autofluorescence imaging is promising for diagnosing I-CNV, and FAF is particularly useful for detecting and monitoring peripheral I-CNV 1).
Control of underlying uveitis and early treatment with anti-VEGF agents can help maintain or improve visual acuity. However, a 50% recurrence rate with anti-VEGF monotherapy has been reported in PIC, and management of the underlying disease determines long-term prognosis 7). Regular OCT and OCTA monitoring is useful for early detection of recurrence.
