Neovascular AMD With Active CNV: Subtypes and Key Insights

Age-related macular degeneration (AMD) is a leading cause of vision loss, with neovascular AMD (nAMD) being the more severe form due to abnormal blood vessel growth beneath the retina. Active choroidal neovascularization (CNV) can lead to rapid disease progression and significant visual impairment if untreated.

Understanding CNV subtypes and their characteristics is essential for accurate diagnosis and effective management.

Mechanisms Of Active CNV

Choroidal neovascularization (CNV) in nAMD results from a complex interplay of molecular and cellular processes that disrupt the normal balance of angiogenesis. The pathological formation of new blood vessels originates from the choroid and extends through Bruch’s membrane into the subretinal space, driven primarily by dysregulated vascular endothelial growth factor (VEGF) signaling. Under normal conditions, VEGF supports endothelial cell survival and vascular integrity. However, in active CNV, excessive VEGF expression leads to uncontrolled vessel proliferation, increased permeability, and fluid leakage into retinal layers, contributing to vision loss.

Hypoxia triggers VEGF upregulation as retinal pigment epithelial (RPE) cells respond to ischemic stress by releasing pro-angiogenic factors. Oxidative damage, accumulating with age, weakens Bruch’s membrane, making it more susceptible to neovascular invasion. The immature vessels formed lack proper pericyte coverage, making them prone to leakage and hemorrhage. The breakdown of the blood-retinal barrier further accelerates disease progression by allowing plasma proteins and inflammatory mediators to infiltrate retinal tissue.

The extracellular matrix (ECM) also plays a role, with matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, degrading Bruch’s membrane, facilitating neovascular growth. Dysregulated ECM remodeling promotes vessel invasion and fibrosis, a late-stage complication leading to irreversible scarring and permanent vision impairment. Chronic CNV, driven by persistent VEGF stimulation and inflammatory signaling, exacerbates both vascular proliferation and extracellular matrix deposition.

Angiographic Subtypes: Classic, Occult, And Polypoidal

Classifying CNV into classic, occult, and polypoidal subtypes provides critical insights into disease behavior, prognosis, and treatment response. These subtypes are distinguished through imaging techniques such as fluorescein angiography (FA) and indocyanine green angiography (ICGA), which reveal differences in vascular morphology, leakage patterns, and progression. Recognizing these distinctions allows clinicians to tailor treatment strategies effectively.

Classic CNV appears as well-defined hyperfluorescent lesions on FA, with early-phase leakage that intensifies over time. This subtype represents highly active neovascular proliferation, often beneath the RPE or extending into the subretinal space. The rapid and aggressive course frequently results in significant exudation, hemorrhage, and photoreceptor damage, leading to swift visual decline if untreated. Classic CNV generally responds well to anti-VEGF therapy, particularly in early stages, though recurrence remains a concern, necessitating long-term monitoring.

Occult CNV presents with poorly defined hyperfluorescence on FA, often with a stippled pattern and late-phase leakage. This subtype features a more diffuse, less organized vascular network, typically beneath the RPE, progressing more slowly than classic CNV. Chronic fluid accumulation and persistent retinal edema contribute to gradual visual decline. Unlike classic CNV, which shows rapid leakage, occult lesions exhibit subtle, fluctuating exudation, complicating treatment decisions. Anti-VEGF therapy remains the primary approach, though some cases require combination treatments such as photodynamic therapy (PDT) for optimal control.

Polypoidal choroidal vasculopathy (PCV) is a distinct angiographic entity characterized by aneurysmal vascular dilations—polyps—typically identified using ICGA. These lesions are often accompanied by branching vascular networks and episodic hemorrhagic or serous RPE detachments. Unlike classic and occult CNV, which involve capillary-level neovascularization, PCV features larger vascular structures that may be less dependent on VEGF-driven angiogenesis. This distinction influences treatment response, as PCV lesions often require adjunctive PDT alongside anti-VEGF therapy. PCV generally carries a better visual prognosis than classic CNV, particularly in cases with limited hemorrhagic complications, though persistent or recurrent activity remains a challenge.

Common Signs And Symptoms

Patients with nAMD and active CNV often experience progressive central vision loss, which may begin subtly before advancing to severe impairment. Early symptoms include mild blurriness or distortion, making straight lines appear wavy or bent (metamorphopsia). This distortion is particularly noticeable when reading or viewing objects with defined edges, prompting medical attention once visual disruption becomes persistent. Unlike dry AMD, nAMD with active CNV can progress rapidly, sometimes within weeks to months.

As CNV activity intensifies, fluid leakage from abnormal vessels leads to retinal thickening and subretinal or intraretinal fluid accumulation, worsening visual disturbances. Patients may report dark or gray patches in their central vision (scotomas), which can enlarge as retinal damage progresses. Hemorrhages within the macula can accelerate vision deterioration, leading to sudden declines in acuity. Some individuals experience photopsias (flashes of light) due to retinal irritation from leaking vessels.

Chronic CNV activity can result in fibrotic scarring, permanently altering retinal architecture and reducing the potential for visual recovery. As scar tissue forms, central vision loss becomes more profound and irreversible, underscoring the importance of early intervention. Some patients develop a perception of missing or distorted portions of their vision, significantly impacting daily activities.

Imaging Techniques

Accurate diagnosis and monitoring of nAMD with active CNV rely on advanced imaging modalities that visualize abnormal blood vessels, fluid accumulation, and disease progression. These techniques help differentiate CNV subtypes, assess treatment response, and guide clinical decisions.

Fluorescein Angiography

Fluorescein angiography (FA) remains a cornerstone in CNV evaluation, providing high-resolution imaging of retinal vasculature and leakage patterns. This technique involves intravenous injection of fluorescein dye, which circulates through retinal and choroidal vessels, allowing dynamic visualization of blood flow. In classic CNV, FA reveals well-demarcated hyperfluorescence in the early phase, with progressive leakage in later frames, indicating active neovascular proliferation. Occult CNV presents with more diffuse hyperfluorescence and late-phase pooling. FA is particularly useful in assessing lesion activity, though it cannot visualize deeper choroidal structures and carries a small risk of adverse reactions to the dye.

Indocyanine Green Angiography

Indocyanine green angiography (ICGA) provides enhanced visualization of choroidal vasculature, making it particularly valuable for detecting PCV. This technique involves the injection of indocyanine green dye, which binds to plasma proteins and emits infrared fluorescence, allowing deeper penetration into choroidal layers. ICGA is especially effective in identifying branching vascular networks and polyp-like dilations not clearly visible on FA. In PCV, ICGA reveals nodular hyperfluorescence corresponding to aneurysmal dilations, influencing treatment selection. ICGA also helps differentiate CNV from other macular pathologies, such as central serous chorioretinopathy.

Optical Coherence Tomography

Optical coherence tomography (OCT) is a non-invasive imaging technique that provides high-resolution cross-sectional views of retinal and subretinal structures, making it essential for detecting fluid accumulation and monitoring treatment response. OCT reveals intraretinal, subretinal, or sub-RPE fluid—hallmarks of active CNV—and structural changes such as pigment epithelial detachments, retinal thickening, and fibrosis. OCT angiography (OCTA) further enhances diagnostics by enabling non-invasive visualization of neovascular networks without dye injection. While OCT does not directly assess vascular leakage, its ability to track fluid dynamics and morphological changes makes it a critical tool for guiding anti-VEGF treatment regimens.

Genetic And Environmental Factors

The development of nAMD with active CNV is influenced by genetic predisposition and environmental exposures. Genome-wide association studies (GWAS) have identified genetic variants that contribute to disease risk, particularly polymorphisms in complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2). CFH mutations impair complement system regulation, promoting chronic inflammation that facilitates neovascularization. ARMS2 is implicated in extracellular matrix dysfunction, allowing abnormal vessel invasion through Bruch’s membrane. These genetic factors influence disease severity and treatment response.

Environmental factors also play a role. Smoking significantly increases the risk of nAMD by accelerating RPE damage and disrupting vascular homeostasis. Dietary habits affect susceptibility, with high saturated fat intake increasing risk, while omega-3 fatty acids, lutein, and zeaxanthin offer protective benefits. Systemic conditions like hypertension and cardiovascular disease further exacerbate choroidal circulation abnormalities.

Differential Features In Clinical Evaluation

Distinguishing nAMD with active CNV from other retinal disorders requires a thorough clinical evaluation integrating patient history, symptoms, and multimodal imaging. Conditions such as central serous chorioretinopathy (CSCR) and diabetic macular edema (DME) share overlapping features but differ in lesion morphology and fluid distribution. Persistent subretinal or intraretinal fluid despite anti-inflammatory treatments suggests active CNV, while CSCR typically presents with serous retinal detachment without significant exudation.

Response to anti-VEGF therapy also aids diagnosis, as nAMD lesions typically show rapid fluid reduction. Functional assessments, including visual acuity tests and Amsler grid evaluations, provide additional insights, with persistent central distortion or scotomas characteristic of active CNV. Clinicians must integrate these findings to ensure accurate diagnosis and personalized treatment planning.