Neovascular (Wet) Age-Related Macular Degeneration

Introduction

Age-related macular degeneration (AMD) is a leading cause of blindness worldwide and is the most common cause of blindness in developed countries. The World Health Organization estimates that 8.7% of global blindness is caused by AMD, with 14 million people worldwide rendered either blind or severely visually impaired as a result. Meta-analyses have shown that age-specific prevalence is similar in populations of Asian and Caucasian ancestry, at approximately 6.8%, though early AMD signs are less common among Asians. Factors conferring increased risk include female gender, age, and smoking. An association with cardiovascular risk factors has been identified in various studies, but may not be universal. At present, the prevalence of AMD is increasing further, with patient numbers forecast to increase from 9.1 million in 2010 to 17.8 million in 2050.

The global cost of visual impairment due to AMD is estimated to be US$343 billion, including US$255 billion of direct healthcare cost. The societal costs of AMD are also substantial, in terms of both direct vision-related medical costs (e.g., treatment of AMD and vision-related equipment), direct nonvision-related medical costs (e.g., medications), and direct nonmedical-related costs (e.g., home health care and social services). In addition, severe AMD often causes a decrease in the patient’s quality of life comparable to severe systemic disease.

AMD has traditionally been categorized into neovascular (wet) AMD and nonneovascular (dry) types or presentations. In neovascular AMD, patients manifest with subretinal exudates and hemorrhages, which most commonly originate from choroidal neovascularization (CNV): the proliferation of new capillaries from the choriocapillaris into the subretinal or subretinal pigment epithelium (RPE) space. In contrast, nonneovascular (dry) AMD generally manifests with drusen at the macula and RPE changes, which may not affect vision significantly at an early stage. However, in advanced forms of nonneovascular AMD, such as geographic atrophy of the RPE, patients may also suffer from significant visual impairment. In addition, despite successful pharmacotherapy, many patients with neovascular AMD also eventually go on to develop macular atrophy over time, suggesting that rather than being a distinct type of AMD, wet or neovascular AMD may simply be an interval event in some patients.

The majority of patients with AMD manifest with the nonneovascular form of AMD alone. However, while neovascular AMD accounts for approximately 10–20% of total cases of AMD, it is responsible for 90% of severe visual impairment among AMD patients. Hence, neovascular AMD represents a significant disease.

The current mainstay of treatment for neovascular AMD is antivascular endothelial growth factor (VEGF) agents. These drugs are injected intravitreally, typically at monthly intervals. The efficacy of anti-VEGF agents has been well documented and can result in significant gain of vision from baseline. However, these drugs are also associated with ocular and systemic side effects. Therefore, it is important to accurately diagnose AMD and to monitor its treatment response. Advances in ophthalmic imaging modalities have increased the ability of ophthalmologists to detect the presence of AMD and monitor its progress over time.

Fluorescein Angiography

Fluorescein angiography (FA) is an imaging technique that utilizes the principle of fluorescence, where a substance absorbs light of a specific wavelength (465–490 nm) and reemits it at a longer wavelength (520–530 nm) with lower energy levels. Fluorescein dye is injected intravenously, where around 70–80% of the dye is bound by plasma proteins. Fluorescein does not leak from normal retinal vessels or an intact retinal RPE. However, it does leak from choroidal neovascular membranes such as those which occur in neovascular AMD and can be used to detect the presence and extent of the lesion.

Both FA and indocyanine-green angiography (ICGA) may be performed with modified fundus cameras or confocal scanning laser ophthalmoscopes (CSLOs). With fundus cameras, the entire fundus is illuminated simultaneously by a bright light source, and the reflected light is captured by the charge-coupled device camera. This produces an angiogram in which reflections from various layers of the retina and choroid are superimposed. In contrast, CSLO technology uses a small pinhole to restrict light from a narrow focal plane, thereby enabling an image of a thin layer of the retina without interference from light originating from more superficial or deeper layers.

CNV is a characteristic feature of neovascular AMD. CNV is the result of the growth of new blood vessels from the choroidal circulation which extend into the sub-RPE and/or subretinal space. A classification for CNV was described by Gass based on the anatomical position of the CNV lesion relative to the RPE. Type 1 CNV is located beneath the RPE, in the space between the RPE and Bruch’s membrane. In contrast, Type 2 CNV has penetrated the RPE layer and proliferated in the subretinal (subneurosensory) space. More recently, it has been recognized that neovascularization in the setting of AMD can also originate from the retina (Type 3 CNV) and can grow from an intraretinal location to the subretinal and sub-RPE spaces.

Indocyanine-Green Angiography

In contrast to FA, which leaks from the choriocapillaris, indocyanine-green dye is 98% protein-bound and does not leak from the choriocapillaris. This allows better visualization of the choroidal vasculature, as well as abnormal lesions such as CNV lesions and polypoidal choroidal vasculopathy (PCV). In addition, ICGA absorbs light in the near-infrared range (790–805 nm) and has an emission spectrum ranging from 770 to 880 nm, peaking at 835 nm. Because of this longer operating wavelength, ICG is able to fluoresce better through pigment, fluid, lipid, and hemorrhage compared to fluorescein dye, which allows better visualization of the dye through hemorrhage, fluid, or pigments.

In a review by Stanga et al ., the authors recommended ICGA for (1) identification of PCV, (2) in cases of occult CNV, (3) patients with CNV associated with PED, and (4) recurrent CNV membranes. In these conditions, ICGA helped to confirm the diagnosis and identify treatable lesions or feeder vessels.

Among patients with neovascular AMD, ICGA is useful to detect CNV lesions. ICG angiography is often employed in conjunction with FA and aids to confirm the FA findings of CNV in patients with well defined CNV. It is especially useful in cases of occult CNV, where FA is unable to visualize the neovascular net or in patients where the neovascularization may be blocked by the presence of hard exudates or hemorrhages.

In a study of 51 patients with acute spontaneous submacular hemorrhage, Kim et al . reported that the cause of the hemorrhage was diagnosed in 84.3% of eyes based on ICGA findings, with 93% of the initial diagnoses being correct. In three patients, however, an initial diagnosis of AMD was revised to PCV on follow-up ICGA. In that series, the most common causes of submacular hemorrhage were neovascular AMD (52.9%) and PCV (37.3%).

ICGA in Variants of Neovascular AMD

A variant of neovascular AMD is PCV, which is characterized by an abnormal vascular network, often referred to as a branching vascular network, and terminal dilatations which form the polyps ( Fig. 7.3 ). First described as peripapillary lesions among African-American females, PCV is now known to occur more commonly among certain populations, such as Asians, where it may account for up to 55% of patients presenting with neovascular AMD.

Since the features of PCV on FA appear similar to neovascular AMD, ICGA is essential for the accurate diagnosis of PCV. Although different diagnostic criteria are used by various investigators, the standardized criteria used in the EVEREST study consisted of early, focal hyperfluorescence on ICGA, appearing within the first 5 min, together with at least one of the following criteria:

• 1.

  Nodular appearance of the polyps on stereoscopic examination,

• 2.

  Presence of a hypofluorescent halo around the nodule,

• 3.

  Presence of abnormal vascular channels supplying the polyps,

• 4.

  Pulsation of the polyp,

• 5.

  Orange-red subretinal nodule(s) which correspond to the location of the hyperfluorescence on ICGA, and

• 6.

  Massive submacular hemorrhage (defined as hemorrhage with an area of four disc areas or larger).

The use of CSLO ICGA is useful because the polyps and the branching vascular networks are shown more clearly compared to conventional flash ICGA ( Fig. 7.3E ). In addition, the presence of pulsation of the polyp can only be detected during the dynamic phase of the angiogram.

In the EVEREST study, the frequency of the various diagnostic features were nodular appearance—91.8%, abnormal vascular channels—88.5%, hypofluorescent halo—68.9%, pulsation of the polyp—6.6%, orange subretinal nodules—55.7%, and massive submacular hemorrhage—13.1%.

Some papers have described subtypes of PCV, based on differences in their appearance on ICGA. In one study, three subtypes of PCV were described based on the type of abnormal vascular channel supplying the polyps (a series of interconnecting channels or a branching vascular network) and the presence of significant leakage on FA. Type A PCV had interconnecting channels only, Type B had a branching vascular network but no significant leakage on FA, while Type C had a branching vascular network with significant leakage on FA. Over 5 years, the visual outcomes were best for those with Type A, intermediate for those with Type B, and worst for those with Type C. This classification may be useful in prognosticating patients and identifying those who may require closer follow-up and more aggressive treatment.

Fundus Autofluorescence

Autoflourescence is a phenomenon where tissues demonstrate fluorescence without the use of a dye (such as fluorescein). Fundus autofluorescence (FAF) is an imaging modality for the metabolic mapping of naturally or pathologically occurring ocular fluorophores such as lipofuscin. Lipofuscin is formed from the phagocytosis of damaged photoreceptor outer segments by the RPE cells. Over time, as RPE phagocytose more outer segments, lipofuscin accumulates in the cell. Other causes for lipofuscin accumulation include oxidative stress and disease states. Areas of hyperfluorescence indicate excess lipofuscin accumulation, while areas of hypofluorescence may indicate RPE cell death. Hence, lipofuscin accumulation may be an early marker of retinal degeneration. FAF is useful in AMD as it may show phenotypes that are not evident on color photography or other imaging modalities.

FAF can be imaged using green (532 nm) and blue (488 nm) light. A standard fundus camera such as the Topcon TRC-50DX uses flash photography with modified green light filters (Spaide AF filters), while the Heidleberg Spectralis uses CSLO with blue light filters to obtain FAF images.

In CNV, a typical FAF pattern consists of various patterns of hypoautofluorescence corresponding to hemorrhages, exudates, and atrophy. There may also be hyperautofluorescence in areas with RPE proliferation and lipofuscin accumulation. In late stages of AMD, where there is a disciform scar, FAF shows a hypoautofluorescent area corresponding to the scar. Some scars may also have some increased FAF signal at the junctional zone.

Some studies have postulated that the accumulation of lipofuscin, and thereby the presence of autofluorescence, especially at the junctional area of geographic atrophy, precedes cell death. Holz et al. reported that in patients with geographic atrophy, areas of increased autofluorescence heralded new atrophic areas with enlargement of existing atrophic areas. In particular, areas of increased autofluorescence preceded the development and enlargement of outer retinal atrophy. This may be due to a direct pathogenetic effect of lipofuscin causing RPE dysfunction, or that excessive accumulation of lipofuscin already signifies RPE cell dysfunction.