Signs and symptoms of neovascular AMD

Patients with neovascular AMD describe a sudden onset of decreased vision, metamorphopsia, and/or paracentral scotomas. Amsler grid self-testing by patients is highly effective for early detection of neovascular AMD. Clinical signs of CNV may include subretinal or intraretinal fluid (eg, CME), exudate and/or blood, a pigment ring or gray-green membrane, irregular elevation of the RPE or a PED, an RPE tear, and/or a sea-fan pattern of subretinal vessels.

Anatomical classification of CNV

Currently, CNV is classified according to its level of origin. In type 1 neovascularization, new vessels originating from the choriocapillaris grow through a defect in Bruch membrane into the sub–RPE space (Fig 4-6). Fluid leakage and bleeding can produce a vascularized serous or fibrovascular PED. These fibrovascular PEDs typically have an irregular surface contour. In type 2 neovascularization, the CNV originates between the RPE and the neurosensory retina. On examination, it typically appears as a lacy or gray-green lesion; in AMD, this finding is less common than type 1 neovascularization. In type 3 neovascularization, the neovascularization develops from the deep capillary plexus of the retina and grows downward toward the RPE. Because of their intraretinal origin, these lesions were originally termed retinal angiomatous proliferations (RAPs). On examination, they often appear as a small area of red discoloration, associated with retinal exudate or a bleb of subretinal fluid.

Left untreated, these neovascular membranes typically evolve into a hypertrophic, fibrotic scar that is disciform in appearance. The overlying retina suffers a loss of normal outer retinal architecture, which can lead to severe, permanent central vision loss.

Fluorescein angiography of CNV FA patterns of CNV may be classified as classic, occult, or some combination of both. Classic CNV refers to a bright, lacy, and well-defined hyperfluorescent lesion that appears in the early phase and progressively leaks by the late phases (Fig 4-7). Occult CNV refers to more diffuse hyperfluorescence that takes 1 of 2 forms: (1) PED, either fibrovascular PED or vascularized serous PED, or (2) late leakage from an undetermined source.

Fibrovascular PED is an irregular elevation of the RPE with progressive, stippled leakage on FA. Alternatively, the PED may pool dye rapidly in a homogenous ground-glass pattern that is consistent with a serous PED but has a notch, or hot spot, due to a vascular component, hence the term vascularized serous PED (Fig 4-8).

Late leakage from an undetermined source describes fluorescence at the level of the RPE that is poorly defined in the early phases of FA, but better appreciated in the late phases.

The angiographic appearance of occult CNV is consistent with type 1 neovascularization, whereas the appearance of classic CNV is more often related to type 2 neovascularization; however, this is not a hard-and-fast rule.

Type 3 neovascularization, or RAPs, may appear as a spot of retinal hemorrhage in the macula. It produces a focal hot spot on FA and indocyanine green (ICG) angiography with late CME or pooling into a PED.

Thick blood, pigment, scar tissue, or a PED may block fluorescence during angiography and obscure an underlying CNV. ICG angiography, with its longer wavelength fluorescence in the infrared spectrum, may be able to penetrate deeper through heme or pigment to reveal a hot spot that identifies CNV. Because it has 90% protein-binding, it can also differentiate between scar tissue or serous RPE fluid to reveal an active vascular lesion.

SD-OCT of CNV SD-OCT is noninvasive and is the most practical visualization technique for the diagnosis and classification of CNV as well as for monitoring the response to treatment. SD-OCT reveals the elevation of the RPE and PEDs produced by type 1 CNV. Serous PEDs appear as sharply elevated, dome-shaped lesions with hollow internal reflectivity and typically no associated subretinal or intraretinal fluid. Fibrovascular PEDs may or may not be sharply elevated and typically demonstrate lacy or polyp-like hyperreflective lesions on the undersurface of the RPE, with or without signs of contraction (Fig 4-9; Activity 4-1). Chronic fibrovascular PEDs often have a multilayered appearance due to sub-RPE cholesterol crystal precipitation in an aqueous environment; this appearance has been termed the “onion” sign. The fibrotic “bridge arch–shaped” serous PED can develop following anti–vascular endothelial growth factor (anti-VEGF) treatment and is associated with poor visual outcome.

ACTIVITY 4-1 OCT Activity: OCT of subfoveal pigment epithelial detachment.

Courtesy of Colin A. McCannel, MD.

Access all Section 12 activities at www.aao.org/bcscactivity_section12.

Subretinal hyperreflective material (SHRM), which is hyperreflective on SD-OCT, is found between the retina and RPE in eyes with CNV. SHRM has an adverse effect on visual acuity, and results in scarring if it persists. Complex fibrovascular scarring may be visualized in the sub-PED compartment, with or without associated subretinal and/or intraretinal fluid.

Type 2 CNV appears as a hyperreflective band or plaque in the subneurosensory space, with associated subretinal and/or intraretinal fluid. Type 3 CNV presents on SD-OCT as hyperreflective foci emanating from the deep capillary plexus of the retina, with or without associated CME and PED. Recognition of these patterns may be helpful for differential diagnosis and predicting treatment outcomes.

• Mrejen S, Sarraf D, Mukkamala SK, Freund KB. Multimodal imaging of pigment epithelial detachment: a guide to evaluation. Retina. 2013;33(9):1735–1762.

OCT Angiography of CNV OCT angiography (OCTA) reveals the structural details of CNV. The fine details of the vascular architecture of each CNV type can be easily visualized, free of the blur caused by fluorescein leakage in fluorescein angiography (Figs 4-10, 4-11, and 4-12).

Polypoidal choroidal vasculopathy Polypoidal choroidal vasculopathy (PCV), initially called posterior uveal bleeding syndrome, is a variant of CNV (type 1) and presents with multiple, recurrent serosanguineous RPE detachments. A network of polyps is associated with feeder vessels that adhere to the RPE monolayer of the fibrovascular PED in a “string-of-pearls” configuration. Although PCV was first discovered in hypertensive middle-aged women of African American or Asian ancestry, it has since been identified in women and men of all races. In Asians, however, 20%–50% of cases of neovascular AMD are PCV type, whereas in whites the PCV type is responsible for <5% of cases of CNV. The associated serosanguineous detachments are often peripapillary and multifocal but may be peripheral, and there may be associated nodular, orange, subretinal lesions. Vitreous hemorrhage occurs more frequently in association with PCV than in non-PCV AMD. Soft drusen, typical in AMD, may or may not be present. A thickened or so-called pachychoroid is often present on EDI-OCT. Natural history and visual acuity outcomes of PCV may be better than those of CNV associated with AMD, except in cases with severe subretinal hemorrhage (Fig 4-13; see also Chapter 2, Fig 2-11 in this volume). ICG angiography, SD-OCT, and OCTA are useful for identifying the polyps. PCV is less responsive to anti-VEGF therapy than other types of CNV. The Everest Studies demonstrated that photodynamic therapy with verteporfin, with or without ranibizumab, results in better treatment response than ranibizumab alone.

• Koh A, Lee WK, Chen LJ, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina. 2012;32(8):1453–1464.

Differential diagnosis of neovascular AMD

There are many conditions associated with disruption of the Bruch membrane complex and secondary CNV that can mimic the CNV of AMD (see the section Other Causes of Choroidal Neovascularization later in this chapter).

Central serous chorioretinopathy can easily be confused with AMD. Subretinal fluid may be seen in both conditions; however, eyes with CSC typically do not have associated subretinal hemorrhage unless secondary CNV has developed. The choroidal layer, which is best visualized using EDI-OCT, is typically thick in eyes with CSC compared to the typical thin choroidal layer in eyes with AMD. CSC is further characterized by geographic patches of RPE pigment mottling that may extend to the inferior periphery in a drainage or drippage-like gravitational configuration often referred to as “guttering.” These lesions can be visualized with fluorescein angiography or autofluorescence imaging.

Management of neovascular AMD

If neovascular AMD is suspected clinically, OCT and FA studies should be obtained to help establish the diagnosis as well as for monitoring response to therapy.

Laser photocoagulation (“thermal laser”) Thermal laser treatment is now used only in very rare instances due to poor outcomes from high recurrence rates, as revealed in the Macular Photocoagulation Study Trials. Lesions sufficiently peripheral to the foveal center that present minimal risk of iatrogenic foveal laser damage and lower rate of recurrence may still benefit from laser photocoagulation treatment.

Photodynamic therapy (“cold laser”) PDT was introduced in 2000 as a less-destructive phototherapy for treating CNV. Treatment involves intravenous administration of the photo-sensitizing drug verteporfin followed by the application of light of a specific wavelength. The light incites a localized photochemical reaction in the targeted area, resulting in CNV thrombosis. Although PDT slows progression, it does not prevent significant vision loss in most eyes with CNV and has been shown to upregulate VEGF in the treatment area. Use of PDT for the management of exudative AMD is now rare, except for the most recalcitrant cases or for eyes with PCV.

Antiangiogenic therapies Angiogenesis is the formation of new blood vessels that sprout from existing vessels via a complex cascade of events. The first events in that cascade are vasodilation of existing vessels and increased vascular permeability. Next comes degradation of the surrounding extracellular matrix, facilitating migration and proliferation of endothelial cells. As endothelial cells join to create lumen, new capillaries develop and then mature, remodeling into stable vascular networks. This cascade requires a balanced interplay of growth-promoting and growth-inhibiting angiogenic factors to proceed. Activators of angiogenesis include vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor α (TGF-α) and TGF-β, angiopoietin-1, and angiopoietin-2. Inhibitors of angiogenesis include thrombospondin, angiostatin, endostatin, and pigment epithelium–derived factor (PEDF).

Most antiangiogenesis research has focused on the inhibition of VEGF, which increases in pigment epithelial cells in the early stages of AMD. High concentrations of VEGF in excised CNV and vitreous samples from patients with AMD have further suggested a causal role for VEGF in the initiation of neovascularization. VEGF is a homodimeric glycoprotein that has a heparin-binding growth factor specificity for vascular endothelial cells. It induces vascular permeability, angiogenesis, and lymphangiogenesis, and it acts as a survival factor for endothelial cells by preventing apoptosis. There are at least 4 major VEGF isoforms; VEGF165 is thought to be the most dominant in AMD.

Pegaptanib In 2004, the US Food and Drug Administration (FDA) approved the first intravitreal anti-VEGF therapy, pegaptanib, an RNA oligonucleotide ligand (or aptamer) that binds human VEGF165. Studies showed that it slowed vision loss, but it has since been supplanted by more effective agents.

Ranibizumab Ranibizumab is a recombinant humanized antibody fragment (Fab) that binds VEGF. Ranibizumab binds to and inhibits all active isoforms of VEGF-A as well as their active degradation products. Two studies, MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD) and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD), demonstrated a loss of fewer than 15 ETDRS in 95% of ranibizumab-treated patients at 12 months compared with 62% of sham-treated patients and 64% of PDT-treated patients. In addition, 30%–40% of ranibizumab-treated patients experienced visual acuity improvement of 15 letters or more compared with 5% or less in the control participants (Fig 4-14, Table 4-3). Approximately 90% of ranibizumab-treated eyes lost fewer than 15 ETDRS letters at 24 months.

Visual acuity improvements in participants of the PIER (Phase 3b, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects With Subfoveal Choroidal Neovascularization With or Without Classic Choroidal Neovascularization Secondary to AMD) and EXCITE (Efficacy and Safety of Ranibizumab in Patients With Subfoveal Choroidal Neovascularization Secondary to AMD) studies were similar to the improvements seen in the MARINA and ANCHOR studies over the first 3 months; however, treatment effects declined in participants undergoing quarterly (every 3 months) ranibizumab dosing as opposed to monthly dosing. These results suggest that quarterly treatment is suboptimal. However, accepted anti-VEGF treatment methods that deviate from the FDA-approved monthly injections include “as needed” and “treat and extend.” On the as-needed regimen, regular treatment is administered until the macula appears dry clinically and on OCT; after that, treatment is only resumed when signs of recurrent exudation appear. The treat-and-extend regimen also involves administration of regular monthly treatment until the macula is dry; after that, treatment continues at progressively increasing intervals. This more cautious second approach continues to treat inactive CNV (albeit at longer intervals between injections) to avoid sudden recurrence of exudation (see Fig 4-14).

Several clinical trials have evaluated as-needed approaches to anti-VEGF therapy: PrONTO (Prospective Optical Coherence Tomography Imaging of Patients With Neovascular AMD Treated With Intraocular Ranibizumab), SAILOR (Study to Evaluate Ranibizumab in Subjects With Choroidal Neovascularization Secondary to AMD), SUSTAIN (Study of Ranibizumab in Patients with Subfoveal Choroidal Neovascularization Secondary to AMD), and HORIZON (Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to AMD). In each of these studies, participants were administered 3 monthly injections, followed by various as-needed treatment regimens based on clinical and OCT-guided criteria. All of the studies had vision and OCT outcomes comparable to or reduced from those obtained with MARINA and ANCHOR. The HORIZON study was a continuation trial of patients enrolled in prior ranibizumab AMD trials. Eyes that had gained 10.2 letters on the ETDRS (Early Treatment Diabetic Retinopathy Study) eye chart during ANCHOR or MARINA after 2 years of monthly injections declined in visual acuity, ending with only a mean 2.0-letter gain compared with baseline (ie, they lost nearly 8 letters once the regimen was switched from monthly injections to an as-needed protocol). Experts believed the reason participants in the HORIZON study experienced a decline in visual acuity was because the study did not offer any re-treatment guidelines for investigators, resulting in a mean of 3.6 ranibizumab injections in the 12 months of the extension trial. HARBOR (A Study of Ranibizumab Administered Monthly or on an As-Needed Basis in Patients With Subfoveal Neovascular AMD) compared higher-dose (2.0 mg) with standard-dose (0.5 mg) ranibizumab therapy and failed to find any difference in visual acuity or anatomical outcomes between the 2 dosages.

Table 4-3 Selected Clinical Trials, Treatments, and Outcomes

Eyes with fibrovascular PEDs may be at increased risk for the development of an RPE tear following anti-VEGF therapy, especially for PEDs greater than 600 μm in height. The mechanism for the tear is believed to be contraction of the underlying type 1 CNV, resulting from the anti-VEGF drug action.

• Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432–1444.

Aflibercept Aflibercept (also known as VEGF Trap) is a soluble protein that acts as a VEGF receptor decoy; it combines the ligand-binding elements of the extracellular domains of VEGFR1 and VEGFR2 fused to the constant region (Fc) of immunoglobulin G (IgG). Aflibercept binds both VEGF and placental-like growth factor and fully penetrates all retinal layers.

In the studies VIEW 1 and VIEW 2 (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD 1 and 2), patients received aflibercept in monthly or every-second-month regimens, while a comparison group received monthly ranibizumab treatment. All aflibercept treatment regimens demonstrated noninferiority to ranibizumab monthly treatment. Patients receiving monthly aflibercept, 2 mg, gained 10.9 letters of visual acuity on average, whereas those receiving monthly ranibizumab, 0.5 mg, had a mean 8.1-letter gain (P < .01). Other aflibercept-dosed groups in the 2 studies had results similar to those from the patients receiving ranibizumab, and after 3 monthly doses, aflibercept administered every 2 months showed similar efficacy to ranibizumab administered monthly (see Fig 4-14, Table 4-3).

Mean letter increase at 96 weeks was 7.6 letters in the group treated every 8 weeks with 2 mg of aflibercept, compared with 7.9 letters in the monthly ranibizumab group; 3-line VA increases were seen in 30%–33% for each arm of the study. OCT-measured anatomical response was maintained through 2 years with no significant difference in central retinal thickness among the 4 groups. Safety profiles were similar for both aflibercept and ranibizumab.

• Heier JS, Brown DM, Chong V, et al; VIEW 1 and VIEW 2 Study Groups. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537–2548.

Bevacizumab In 2004, the FDA approved bevacizumab, which is a full-length monoclonal antibody against VEGF, for the treatment of metastatic colorectal cancer. It has also been used “off-label” for the treatment of AMD via intravitreal and intravenous administration. Although bevacizumab and ranibizumab are manufactured by the same pharmaceutical company, there are important differences between the drugs: bevacizumab is larger, with 2 antigen-binding domains, contrasted with the smaller ranibizumab with a single domain. In addition, bevacizumab costs substantially less, impacting its availability to some patients. Because full-length antibodies are not cleared as rapidly as fragment antibodies, intravitreal injections of bevacizumab have a longer systemic half-life than intravitreal injections of ranibizumab (~21 days for bevacizumab vs 2.2 hours for ranibizumab).

Bevacizumab’s similar efficacy compared with ranibizumab and its 40-fold lower wholesale cost has prompted several comparative efficacy studies. Table 4-4 summarizes the major studies comparing bevacizumab to ranibizumab efficacy in the management of neovascular AMD.

CATT (Comparison of Age-Related Macular Degeneration Treatments Trials) was the first and largest multicenter, randomized clinical trial to compare the relative safety and efficacy of ranibizumab with bevacizumab for the treatment of neovascular AMD. Funded by the US National Eye Institute, it studied 1208 patients. Results showed that bevacizumab was noninferior to ranibizumab therapy in monthly or as-needed delivery schedules over 2 years. Mean letters gained from baseline were 8.8 letters in the ranibizumab-monthly group, 7.8 letters in the bevacizumab-monthly group, 6.7 letters in the ranibizumab as-needed group, and 5.0 letters in the bevacizumab as-needed group. Systemic adverse events were significantly greater in the bevacizumab (39.9%) than in the ranibizumab (31.7%) group, but death and arteriothrombotic events were not statistically different between the 2 drugs. At 5 years, vision gains in the first 2 years were not sustained, but 50% of eyes maintained 20/40 or better visual acuity. Geographic atrophy development or increase appeared to be stimulated by anti-VEGF therapy, with evidence that progression was related to persistence or absence of subretinal fluid.

Table 4-4 Clinical Trials Comparing Bevacizumab to Ranibizumab

Clusters of severe vision loss due to endophthalmitis following bevacizumab injection related to a few instances of substandard and erroneous compounding practices have raised concerns about the off-label use of this drug in the United States. In response, legislative changes have led to improved regulation and increased monitoring of compounding pharmacies.

Treatment effect modifiers Vitreoretinal interface status may significantly modify the response to therapy with anti-VEGF agents. Hyaloidal separation appears to facilitate penetration of drug, so that fewer injections need to be administered, however, visual acuity is not affected. Eyes with epiretinal membrane may require more injections due to anatomic disturbance, reduced penetration, or associated inflammation.

Complications of intravitreal anti-angiogenic therapy Intravitreal injections are typically well tolerated. Minor complications such as subconjunctival hemorrhage and local irritation are common. In rare instances, serious ocular complications can occur, including inflammation, persistent ocular hypertension, retinal detachment, vitreous hemorrhage, and endophthalmitis. The rate of endophthalmitis is approximately 1 in 2000 or lower (see also Chapter 20 of this volume). Systemic administration of bevacizumab for cancer treatment has been shown to increase the risk of hypertension; thromboembolic events, especially myocardial infarctions and cerebral vascular accidents; gastrointestinal perforations; and bleeding. There is conflicting evidence whether intravitreal injections of any of these agents increase the rate of these complications.

• Solomon SD, Lindsley K, Vedula SS, Krzystolik MG, Hawkins BS. Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 2014;(8):CD005139.

Combination treatment Combinations of therapies have been explored to address the complex interaction between inflammation, angiogenesis, and fibrosis that are thought to play a role in the limited success of the single agents currently available. Trials exploring the use of combination therapies (eg, RADICAL [Reduced Fluence Visudyne-Anti-VEGF-Dexamethasone in Combination for AMD Lesions] and DENALI [Safety and Efficacy of Verteporfin PDT Administered in Conjunction With Ranibizumab Versus Ranibizumab Monotherapy in Patients With Subfoveal CNV Secondary to AMD]) found that adding PDT to ranibizumab reduced re-treatment rates compared with ranibizumab mono-therapy. However, visual outcomes were inferior to monotherapy. Combination strategy appeared beneficial in some cases of PCV recalcitrant to anti-VEGF therapy. Adding radiation to ranibizumab therapy may also reduce the injection burden, but again, visual outcomes were inferior to monotherapy.

Surgical treatments In cases of thick submacular hemorrhage, intravitreal or subretinal tissue plasminogen activator injection with pneumatic displacement may be helpful in some patients. Submacular surgery, involving the removal of the CNV from beneath the fovea, and macular translocation surgery, in which the fovea is moved over to an area of healthier RPE, are complex surgical techniques that were developed prior to anti-VEGF agents and have largely been abandoned today.

Low vision therapies Despite the success of intravitreal anti-VEGF pharmacotherapy, a significant number of patients with AMD will ultimately progress to bilateral central blindness, for which few therapeutic options exist. The implantable miniature telescope can provide magnification up to factor of 2.7; its use improved visual acuity by 2 lines in the pivotal FDA trials. However, corneal decompensation due to endothelial cell loss is projected to bring the corneal transplant rate to 5% at 5 years after the implantation surgery.

Low vision rehabilitation Vision loss of any degree can have a profound effect on a patient’s daily activities, especially reading and driving. Severe vision loss and central blindness resulting from AMD can be devastating. In addition, central scotomas may be complicated by visual release hallucinations (Charles Bonnet syndrome), which can overlay blank areas with small geometric figures or faces or any other image. Although primary efforts are focused on rescue therapies, consideration should be given to low vision rehabilitation strategies. Low vision rehabilitation and the use of optical and nonoptical devices can maintain the patient’s functional status and sustain quality of life (see BCSC Section 3, Clinical Optics). Even patients who have undergone successful anti-VEGF therapy may retain visual acuity that has been reduced to the 20/50–20/70 range and can benefit from low vision strategies such as magnification (eg, high-plus lenses, video magnifiers), optimal lighting, and contrast enhancement techniques. Training on the use of eccentric fixation outside the area of scotoma that is produced by the disciform scar or area of atrophy may also be helpful. To foster such rehabilitation, clinicians should consider referring patients for low vision evaluation at local low vision centers or to state services for the blind, available in most US states.

The American Academy of Ophthalmology’s Initiative in Vision Rehabilitation page on the ONE Network (www.aao.org/low-vision-and-vision-rehab) provides resources for low vision management, including patient handouts and information about additional vision rehabilitation opportunities beyond those provided by the ophthalmologist.

Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.