Michael D. Lewen, MD and Andre J. Witkin, MD

Age-related macular degeneration (AMD) is a leading cause of vision loss among adults worldwide, and advances in its management represent one of the most successful recent achievements in medicine. AMD can cause severe central vision loss in advanced disease, which is marked by geographic atrophy in the non-neovascular or “dry” form and by the growth of abnormal choroidal neovascular membranes (CNV) in neovascular or “wet” disease. The targeted inhibition of vascular endothelial growth factor (VEGF) has revolutionized the treatment of neovascular AMD, and these medications are currently among the most frequently used in all of medicine.¹

Epidemiology

Population-based studies in the United States (US), Australia, and Europe estimate the prevalence of neovascular AMD to range between 0.41% and 1.55% in adults older than 40 years of age, with higher prevalence in Caucasian compared to African American individuals.² The incidence in predominantly Caucasian populations over a 15-year period is estimated at 2.0% to 4.4%.^3,4 Both the prevalence and incidence of neovascular AMD increase dramatically with age, particularly after the age of 70.^2–4 Although the neovascular form represents a small percentage of AMD overall, it accounts for the overwhelming degree of severe vision loss due to AMD.⁵

Significant risk factors associated with development of AMD include tobacco use, hypertension, increased body mass index, hyperopia, and certain genetic markers.^6,7 Clinical features of nonexudative AMD, including soft, indistinct drusen and pigmentary abnormalities, are considered high-risk features for the development of neovascularization. In addition, the presence of CNV in one eye increases the risk of development in the fellow eye,⁸ the incidence of which was approximately 33% at 2 years in recent landmark studies of neovascular AMD.^9,10 Over 7 years of follow-up, these patients demonstrated bilateral neovascular disease in 51% of the cohort.¹¹

The etiology and pathogenesis of AMD is multifactorial and has not been completely elucidated, though progression includes degeneration of Bruch’s membrane and the retinal pigment epithelium (RPE). This can lead to formation of abnormal capillary-like vessels that emanate from the choriocapillaris and invade into the sub-RPE space (type 1) or subneurosensory retinal space (type 2); these abnormal fibrovascular complexes are termed choroidal neovascular membranes (CNV).12,13 Less commonly, CNV may originate from abnormal vessels within the retinal circulation and grow to invade the sub-RPE space, categorized as retinal angiomatous proliferation (type 3).¹⁴ CNV are prone to leaking serous fluid, lipid, or hemorrhage that can be observed clinically as exudation or intra- or subretinal hemorrhage (Figures 7-1A and 7-2).

Depending on the anatomical location and severity of neovascularization, patients may experience abrupt changes in vision ranging from distortion of straight lines, known as metamorphopsia, to profoundly decreased central vision. Clinical examination typically demonstrates a decrease in visual acuity, and if left untreated, this visual loss can be rapidly progressive. Although fundus findings are often suggestive of neovascular AMD, subtle cases may be difficult to diagnose on examination alone. Therefore, ancillary testing is crucial in confirming the diagnosis of neovascular AMD.

Fluorescein angiography (FA) has long been considered the gold standard in diagnosis of neovascular AMD. FA classically shows leakage of dye at the site of the CNV, as the blood vessel endothelium in CNV has improperly formed tight junctions allowing for extravasation of fluorescein dye over time. The appearance of CNV can vary depending on its location. Type 2 CNV, termed classic on FA, appears early as well-defined hyperfluorescent lesions that leak in mid- to late-frames (Figure 7-1). Type 1 CNV, termed occult on FA, is ill defined, and leakage often appears only in later frames (Figures 7-2 and 7-3). In type 3 CNV, a focal “hot spot” is often visualized at the point of anastomosis between retinal and choroidal circulations. Indocyanine green angiography is another technique to image CNV and can be particularly useful in differentiating neovascularization associated with AMD from other known variants such as polypoidal choroidal vasculopathy.

Optical coherence tomography (OCT) has become the most commonly used imaging modality in managing neovascular AMD, as it allows for precise, rapid, and noninvasive cross-sectional and volumetric analysis of the retinal architecture. Intra- or subretinal fluid, signs of neovascular disease, can be detected in untreated eyes with CNV and also serve as signs of persistent disease activity once therapy has been initiated. These subtle anatomic changes might otherwise be clinically undetectable but can easily be visualized with OCT (Figures 7-1, 7-4, and 7-5).

The natural history of neovascular AMD is rapid progression to severe loss of visual acuity. In a meta-analysis of more than 4000 treatment-naïve patients with neovascular AMD, the mean change in visual acuity worsened from 1 line lost at 3 months to 2.7 lines lost at 12 months and 4 lines lost at 24 months. At 3 years, more than 40% of untreated patients experienced severe vision loss (defined as a decrease of more than 6 lines) and more than 75% of patients had visual acuity worse than 20/200.¹⁵ End-stage disease is characterized by atrophy of the neurosensory retina and RPE or fibrovascular scar tissue formation, often termed a disciform scar.

Evolution of Treatment

Prior to anti-VEGF therapy, the treatment for neovascular AMD consisted of thermal laser photocoagulation and photodynamic therapy (PDT) with verteporfin (Visudyne). A small percentage of eyes with extrafoveal CNV had improvements in visual acuity from direct laser photocoagulation;¹⁶ however, laser photocoagulation for subfoveal CNV resulted in poor visual outcomes, and its use was largely abandoned after the development of PDT. The Treatment of Age-Related Macular Degeneration with PDT (TAP) study demonstrated benefit from PDT for subfoveal CNV lesions that were “predominantly classic,” with greater than 50% of the CNV lesion being classic.17 Treatment success, however, was largely defined in terms of slowing or limiting visual loss, not visual improvement.

The discovery of VEGF and its major role in neovascular AMD dramatically changed the treatment paradigm, and PDT and thermal laser have largely become historical treatments for this disease. VEGF is a glycoprotein that is instrumental in angiogenesis, endothelial cell growth, and increased vascular permeability.¹⁸ Of the multiple VEGF genes, VEGF-A is the predominant form. There are several isoforms of VEGF-A based on the size of the protein products; VEGF₁₆₅ is the principal isoform in humans.¹⁹ The larger isoforms can be further modified by enzymes resulting in smaller proteins that have different biologic activities or properties such as the capacity to easily diffuse through retinal tissue.²⁰

Shortly after VEGF was isolated and sequenced, increased intraocular levels of VEGF were demonstrated in the setting of retinal ischemia and neovascularization.^21,22 Mouse models were shown to develop CNV in the setting of VEGF overexpression,²³ and engineered antibodies against VEGF demonstrated efficacy in decreasing leakage from and formation of CNV in animal studies,²⁴ thus ushering in the era of anti-VEGF treatment for neovascular AMD. The following 4 anti-VEGF medications have been used for treatment of neovascular AMD (Table 7-1):

1. Pegaptanib sodium
   
2. Ranibizumab
   
3. Bevacizumab
   
4. Aflibercept

Although pegaptanib sodium was the first anti-VEGF medication on the market for treatment of neovascular AMD, its use quickly declined as more effective treatments became available, and its use for treatment of neovascular AMD is now largely of historical significance.

Bevacizumab and Ranibizumab

Bevacizumab (Avastin) is a full-length recombinant humanized antibody that binds to all isoforms of VEGF^19,25 and was US Food and Drug Administration (FDA) approved in 2004 for the treatment of colon cancer in combination with chemotherapy. It was initially thought the size of bevacizumab as a full-length antibody would preclude efficient diffusion through the retina to reach its site of action within the choroid, so a similar but truncated molecule was developed, ranibizumab, specifically formulated for intravitreal injection.^19,26 Ranibizumab (Lucentis) is a recombinant humanized antibody fragment that also binds to and blocks all active forms of VEGF.

Prior to the FDA approval of ranibizumab, a small pilot study of 9 patients with neovascular AMD were treated with intravenous, systemic bevacizumab. The results were encouraging, with a mean improvement of vision and positive anatomical outcomes as evidenced by decreased central retinal thickness and reduction or complete absence of leakage of the CNV.²⁷ Soon after, another pilot study demonstrated that off-label use of bevacizumab for intravitreal injection was well tolerated and very effective,²⁸ and despite early concerns that bevacizumab would be a poor candidate for intravitreal use because of its large molecular structure, its intravitreal use became widespread.

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