Neovascular age-related macular degeneration

Age-related macular degeneration (AMD) is a disease associated with a deterioration of central vision. As AMD is the leading cause of blindness in persons aged 75 and older in the USA and other countries worldwide, its importance cannot be underestimated.

AMD is a spectrum of disease that is diagnosed based on clinical examination. It can be divided into nonneovascular, also known as dry or nonexudative disease, and neovascular, also known as wet or exudative disease. Advanced AMD is a term used to describe the most severe forms of AMD, namely geographic atrophy involving the center of macula, the fovea, or features of choroidal neovascularization (CNV). CNV is the growth of new blood vessels from the choroid toward the retina. They breach Bruch’s membrane and proliferate under the retinal pigment epithelium (RPE) and/or the retina.

Treatment of CNV has blossomed recently with the advent of anti-vascular endothelial growth factor (VEGF) therapy, yet a cure still remains elusive. A thorough understanding of the pathogenesis of neovascular AMD is important both for treating patients with AMD and for exploring new modes of therapy.

Clinical background

AMD involves the photoreceptors responsible for central vision, thus explaining the most common clinical presentation. Patients with neovascular AMD will typically note decreased or distorted vision. However other typical complaints include scotomas, micropsia or, occasionally, the patient may be asymptomatic. Symptoms are secondary to fluid and/or blood within or under the retina that results in disruption of the retinal architecture. Clinical examination combined with ancillary testing will confirm the presence of CNV, the hallmark of neovascular AMD (see diagnostic workup , below). As the disease progresses, complications such as RPE tears, breakthrough vitreous hemorrhage, or disciform scarring may result.

Historical development

Natural history data of neovascular AMD have been evaluated in a meta-analysis providing a sound basis for treatment. Using 53 trials a comprehensive study concluded that vision loss of 0–3 lines occurred in 76% of untreated patients at 3 months. Severe visual loss ( > 6 lines) was seen in 10% of untreated patients at 3 months, 28% at 1 year, and 43% at 3 years.

Interestingly, while AMD was described as early as 1885, most of the current concepts of neovascular disease are attributed to J Donald M Gass and his work starting as early as the late 1960s. However, it was not until the early 1990s and the publication of the Macular Photocoagulation Study (MPS) that a documented effective treatment was achieved from a randomized controlled clinical trial ( Figure 69.1 ). Yet, the MPS only demonstrated a favorable treatment benefit for patients with extra- or juxtafoveal CNV due to the immediate visual loss associated with thermal laser performed to the foveal center. The next major breakthrough came in the late 1990s with the advent of photodynamic therapy (PDT). This opened the door to treating more patients using angiographic-based categories. Major clinical trials demonstrated a beneficial effect in treating subfoveal CNV in the reduction of moderate (3 or more lines) and severe (6 or more lines) visual loss in patients treated with PDT therapy versus placebo at 1 and 2 years. However, even the most efficacious subgroup analysis still demonstrated a 23% chance of moderate visual loss by 1 year despite treatment.

Figure 69.1

Timeline of discovery of therapy for neovascular age-related macular degeneration. CNV, choroidal neovascularization; VEGF, vascular endothelial growth factor; PDT, photodynamic therapy.

Basic research into understanding the pathophysiology of neovascular AMD identified angiogenic growth factors as key regulators of CNV. This, in turn, led to the development of pharmacotherapy aimed at inhibiting angiogenic factors. In 2004 pegaptanib (Macugen) emerged as the first drug selectively to block the angiogenic factor VEGF-A, specifically targeting the 165 isoform. Treatment of CNV regardless of angiographic characteristics was proven in the VEGF Inhibition Study in Ocular Neovascularization (VISION) trial. It was ascertained that 71% of treated patients lost less than 3 lines of vision versus 55% for the control groups. In 2005, off-label bevacizumab (Avastin) began to be used to treat patients with neovascular AMD, with anecdotal reports indicating excellent results. In particular, some patients noted an improvement in visual acuity.

Stabilization and improvement of visual acuity were further categorized in the clinical trials surrounding ranibizumab (Lucentis) therapy. Ranibizumab is an intravitreal injectable medication approved by the Food and Drug Administration that, like bevacizumab, binds all isoforms of VEGF-A. Compared to bevacizumab it is smaller and has a greater affinity for VEGF. Two phase III clinical trials proved the efficacy of intravitreal ranibizumab as approximately 95% of patients lost less than 3 lines of vision in the treated groups versus nearly 65% in the controls. Perhaps even more surprising was that these trials represented the first prospective, randomized, controlled clinical trials to show a gain in visual acuity in neovascular AMD, with approximately 35% of treated patients gaining 3 or more lines of vision versus 5% in the control groups.

Treatment of neovascular AMD is an area of blossoming growth. From initial treatment with thermal laser to modern approaches of VEGF blockade, the treatment of neovascular AMD is now aimed at early diagnosis and visual improvement rather than slowing the natural history. As we continue to understand more of the pathophysiology behind neovascular AMD, we will see a proliferation of new therapies and a combination of existing treatment options.


AMD is a common disease that predominantly affects the elderly white population. Epidemiologic studies have provided estimates of disease prevalence in a variety of countries across the world. A large meta-analysis was performed providing pooled data on the prevalence of neovascular AMD by age, gender, and race. Selected data are presented in Table 69.1 and the reader is referred to the original studies for further details.

Table 69.1

Prevalence rates for wet age-related macular degeneration

Modified from The Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004;122:564–572.

Age (years) White females White males Black females Black males
55–59 0.16 0.28 0.60 0.30
60–64 0.26 0.42 0.73 0.37
65–69 0.51 0.73 0.89 0.45
70–74 1.09 1.33 1.08 0.55
75–79 2.40 2.49 1.31 0.67
80 11.07 8.29 1.78 0.92

Data are presented as prevalence per 100 individuals.

Diagnostic workup

The diagnosis of neovascular AMD is ascertained based on clinical symptoms and signs. Metamorphopsia and decreased visual acuity are the most common symptoms. Clinical examination by slit-lamp biomicroscopy may show a grayish-green membrane under the retina, hemorrhage under or within the retina, and/or RPE detachments. However, ancillary testing is an important adjunct to diagnosis in many cases and serves as confirmatory evidence prior to initiating treatment ( Box 69.1 ).

Box 69.1

Diagnostic workup for neovascular age-related macular degeneration includes many ancillary testing techniques

  • Fluorescein angiography assesses leakage from incompetent neovascular vessels imaging the area of choroidal neovascularization

  • Optical coherence tomography uses reflected light to create an optical cross-section of the retina enhancing morphometric evaluation

  • Dynamic indocyanine green angiography assesses flow within the choroidal vasculature enabling visualization of the following vascular patterns:

    • Capillary-dominated lesions

    • Arteriolar-dominated lesions

    • Mixed capillary–arteriolar lesions

Traditionally, ancillary testing and diagnostic confirmation were based on fluorescein angiography ( Figure 69.2 ). With the development of optical coherence tomography (OCT), this serves as a critical adjunctive tool ( Figure 69.3 ). More recently, dynamic indocyanine green (ICG) angiography has allowed visualization of the neovascular complex and morphologic determination ( Figure 69.4 ). Finally, the role of fundus autofluorescence is being evaluated for a complementary role in determining RPE health.

Figure 69.2

Fluorescein angiogram of a classic choroidal neovascular membrane.

Figure 69.3

Optical coherence tomography of a patient with neovascular age-related macular degeneration showing evidence of both a pigment epithelial detachment and subretinal fluid.

Figure 69.4

Single frame from a dynamic indocyanine green angiography of a choroidal neovascular lesion demonstrating a mixed capillary–arteriolar lesion.

Due to the biochemical properties of fluorescein dye, 15% is nonprotein-bound in the blood stream after injection. This allows fluorescein to leak out of incompetent neovascular vessels imaging the area of CNV. Fluorescein angiographic patterns can be subdivided into classic and occult based on the pattern of leakage. OCT has further helped diagnose and follow CNV lesions. In this imaging modality, reflected light is used to create an optical cross-section of the retina. Typical findings include any combination of the following: subretinal fluid, RPE detachments, diffuse retinal thickening, cystic changes within the retina, and hyperreflectivity corresponding to the neovascular lesion. Dynamic ICG angiography has been another area of recent development in defining morphologic patterns of CNV. Due to the near-infrared range of light absorption (~805 nm) and emission spectrum (~835 nm) and protein-bound affinity (98%) of ICG dye, visualization of the choroidal vasculature is possible. Furthermore, with the advent of confocal scanning lasers and rapid computer-processing algorithms, the sequence can be viewed as a dynamic movie (16 frames per second) versus static images (maximum 1 frame per second). This allows dynamic ICG to evaluate flow within the vasculature and not merely leakage, as traditional fluorescein and static ICG angiography have done in the past. The authors have evaluated hundreds of cases and determined the following patterns of pathophysiologic significance: capillary-dominated lesions, arteriolar-dominated lesions, and mixed subtypes of the two. Ongoing research into this modality will help to define the role of dynamic ICG angiography in prognosticating therapeutic responsiveness.

Differential diagnosis

The differential diagnosis of neovascular AMD can be viewed from three separate perspectives. First, as our understanding has developed surrounding neovascular AMD, three main subtypes have been delineated: polypoidal CNV, retinal angiomatous proliferation (RAP), and traditional CNV ( Box 69.2 ).

Aug 26, 2019 | Posted by in OPHTHALMOLOGY | Comments Off on Neovascular age-related macular degeneration

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