Chapter 125 – Age-Related Macular Degeneration
MATTHEW T. S. TENNANT
• A common, chronic degenerative disorder of unknown pathogenesis that affects older individuals and features central visual loss as a result of geographical atrophy, serous detachment of the retinal pigment epithelium, and choroidal neovascularization.
• Age older than 50 years.
• Geographical atrophy.
• Serous retinal pigment epithelial detachment.
• Choroidal neovascularization.
• Retinal pigment epithelial clumping or loss.
• Subretinal fluid.
• Subretinal hemorrhage.
• Lipid exudation.
• Subretinal fibrosis (disciform scarring).
• Generally progressive.
Age-related macular degeneration (AMD) is the leading cause of central visual loss among individuals 65 years of age and older in developed countries.     The disease primarily affects the choriocapillaris, Bruch’s membrane, and retinal pigment epithelium (RPE). However, visual loss typically results from photoreceptor dysfunction due to underlying atrophy or choroidal neovascularization (CNV), with its corresponding fluid accumulation, hemorrhage, lipid exudation, and fibrosis.  Despite the profound clinical impact of this disorder and the extensive research regarding its prevention and treatment, the cause remains unclear, treatment is largely unsatisfactory, and prevention is usually not possible.
AMD can be classified broadly into two categories: non-neovascular (dry) and neovascular (wet). Although non-neovascular AMD accounts for approximately 80% of all diagnosed cases, neovascular AMD is responsible for nearly 80% of significant visual disability associated with this disease. Geographical atrophy, the most severe non-neovascular manifestation of AMD, causes approximately 21% of the cases of legal blindness in North America.
The average age at onset of visual loss is about 75 years. After the age of 50, the incidence steadily increases, with more than one third of people in the ninth decade of life affected. Estimates show that approximately 315,000 Americans aged 75 and older will develop AMD over a 5-year period. The visual impact is significant; the Salisbury Eye Evaluation Study reported the prevalence of blindness (visual acuity 20/200 or worse) associated with AMD as 0.38% in individuals aged 70–79 years and 1.15% in individuals aged 80–84 years.
Many studies have reported the prevalence of AMD in various populations using multiple definitions. The Framingham Eye Study cited a prevalence of approximately 2% in Americans aged 52–64 years, 11% in those 65–74 years, and 28% in those 75 years and older. In the Netherlands, severe atrophic or neovascular AMD was identified in 1.7% of the population. In a U.S. study of Chesapeake Bay watermen, 3% of the subjects older than 70 years had geographical atrophy, and 2% had neovascular AMD. The Baltimore Eye Survey reported the overall prevalence of AMD as 0.32% in individuals aged 70–79 and 2.9% in individuals aged 80 and older.
No significant gender predilection has been identified for AMD. The Framingham Eye Study showed a slightly higher incidence of moderate to severe AMD in Caucasian women compared with men. The Health and Nutrition Examination Survey (HANES), which included milder cases, found no difference.
Historically, it was believed that increased skin pigmentation decreased the risk of neovascular AMD, but recent studies are inconsistent. A study of elderly British individuals found that 3.5% had choroidal neovascularization, while a comparative, age-matched group of black African patients manifested only a 0.1% incidence. A study of an African-Caribbean population from Barbados found neovascular AMD in 0.5% of the population, a percentage possibly lower than that found in Caucasian Americans. The HANES study noted a comparable prevalence of AMD consisting primarily of cases of non-neovascular AMD in Caucasian and African-American participants.
The causes of AMD and choroidal neovascularization are currently unknown. One theory postulates that abnormalities in the enzymatic activity of aged RPE cells lead to accumulation of metabolic by-products. Engorgement of RPE cells interferes with their normal cellular metabolism, leading to extracellular excretions.   In addition, lipids are deposited in Bruch’s membrane, possibly from failure of the RPE to process cellular debris associated with outer segment turnover. The resulting hydrophobic barrier may impede the passage of fluid from the retina to the choroid, causing detachment of the RPE. Breaks in Bruch’s membrane are thought to be responsible for neovascular ingrowth from the choriocapillaris.
A more recent theory suggests that hemodynamic alteration in the choroidal circulation is an important pathophysiological mechanism. Atherosclerotic changes in the ocular vasculature lead to increased ocular rigidity and decreased vascular compliance. The resulting increased postcapillary resistance causes elevated hydrostatic pressure, with exudation of extracellular proteins and lipids; these manifest as basal deposits and drusen. Corresponding degeneration of elastin and collagen causes calcification and fragmentation of Bruch’s membrane. An angiogenic stimulus induced by relative choroidal ischemia results in increased levels of vascular endothelial growth factor (VEGF).
This, in turn, incites neovascular ingrowth from the choriocapillaris through a calcified, fractured Bruch’s membrane. In support of this theory, Doppler imaging has confirmed choroidal vascular compromise in AMD patients relative to age-matched controls in several studies.   
Regardless of the mechanism of deposition, drusen are generally accepted to be precursor lesions for AMD when they are “soft” or “indistinct” (=63?µm). Small drusen (<63?µm) are extremely common, with approximately 80% of the general population older than 30 years manifesting at least one. The number and confluence of drusen increase with age. After the age of 70 years, 26% of individuals have large or soft drusen, and 17% have confluent drusen.
Risk factors for the development of AMD have been identified despite a limited understanding of the exact pathophysiology. Various researchers have implicated atherosclerosis, oxidative damage, photic toxicity, inflammation, diet, and genetics. Systemic arterial hypertension and cigarette smoking are associated with an increased risk of neovascular AMD.  Although early studies suggested a relationship between light and AMD, more recent publications suggest that exposure to visible light is not a risk factor for AMD.  
The extent to which heredity can be implicated in the pathogenesis of AMD is not clear, but it may be substantial  ; autosomal dominant inheritance with variable penetrance has been suggested. Nearly one fourth of parents, siblings, and offspring of patients who have AMD manifest the disease concurrently. The relative roles of genetic and environmental influences need to be delineated further.    In studies of monozygotic twins with AMD and common environmental and dietary influences, the fundus appearance and degree of visual loss were strikingly similar (89–100%). Clinical concordance in dizygotic twins reared in a shared environment was markedly less but still substantial (46%).  The search for one or more AMD genes continues; AMD may ultimately prove to be a group of distinct diseases that manifest a similar clinical appearance.
Individuals affected with AMD typically report blurred vision or metamorphopsia in one or both eyes, but they may be asymptomatic. Decreased reading ability, especially in dim light, and difficulty with dark adaptation are other common complaints. The onset is subacute, except in some cases of neovascular AMD in which abrupt visual loss is noted. Neovascular AMD typically shows a more rapid progression of visual loss relative to its non-neovascular counterpart.
Non-Neovascular Age-Related Macular Degeneration
Visual loss from non-neovascular AMD is generally due to geographical atrophy involving the foveal region. This is seen clinically as one or more well-delineated areas of hypopigmentation or depigmentation due to absence or severe attenuation of the underlying RPE ( Fig. 125-1 ). The larger, deep choroidal vessels are more readily visualized through the atrophic patches. These areas are usually small (less than a disc area) and may surround the fovea in a petalloid pattern; they typically coalesce over time or manifest as one large central lesion up to 7?mm in diameter. If the foveal center is spared, good visual acuity may be preserved, although reading vision may remain poor. At times, even in the presence of severe atrophy, visual acuity is only mildly affected. Most, but not all, eyes that have geographical atrophy also exhibit drusen. In fact, most cases of geographical atrophy occur in a pattern corresponding to the regression of prior, significant drusen. Alterations in the RPE consisting of focal hyper- or hypopigmentation are also associated with AMD, distinct from geographical atrophy.
DRUSEN AND FOCAL HYPERPIGMENTATION.
Clinically, drusen appear as focal, whitish yellow excrescences deep to the
Figure 125-1 Non-neovascular age-related macular degeneration with drusen and geographical atrophy. A, Right eye. B, Left eye. Visual acuity measures 20/30 (6/9) in both eyes, with corresponding metamorphopsia
retina. Generally, they cluster in the posterior pole but can occur anywhere in the fundus. Drusen in an extramacular location are of no visual consequence. They vary widely in number, size, shape, and distribution. Most drusen are 20–100?µm in diameter. They may disappear with time, while new ones develop elsewhere in the macula. For the most part, drusen alone do not cause visual loss; mild metamorphopsia, loss of reading speed, and impaired contrast sensitivity may occur. They do represent a significant risk factor for subsequent geographical atrophy and CNV.
Drusen may be categorized into hard and soft varieties. Hard drusen are round, discrete, yellow-white deposits measuring less than 63?m. These drusen are commonly identified in many populations; they are not age related and do not carry an increased risk for the development of CNV. In contrast, soft drusen are ill defined, with nondiscrete borders, measuring 63?µm or greater. They are age related and have been associated with the development of CNV. The Macular Photocoagulation Study (MPS) reported that the 5-year risk of CNV in fellow eyes of individuals with unilateral neovascular AMD was 10% in those without large drusen and 30–46% in those with large drusen.
Focal hyperpigmentation of the RPE is another important clinical feature of non-neovascular AMD. The risk of developing soft drusen and geographical atrophy increases in its presence. The MPS showed that in patients with unilateral neovascular AMD, the 5-year risk of developing CNV in fellow eyes that manifest both soft drusen and focal hyperpigmentary changes was 58–73%.
Neovascular Age-Related Macular Degeneration
The hallmark of neovascular AMD is the ingrowth of CNV from the choriocapillaris under the macular region ( Fig. 125-2 ). The potential clinical manifestations include the following:
• Subretinal fluid.
• Macular edema.
• Retinal, subretinal, or sub-RPE hemorrhage.
• Retinal or subretinal lipid exudate.
• Plaque-like membrane or gray or yellow-green discrete discoloration.
• Retinal pigment epithelial detachment.
• RPE tear.
• Subretinal fibrosis or disciform scar.
Figure 125-2 Neovascular age-related macular degeneration. A, The patient had choroidal neovascularization followed by numerous episodes of hemorrhage, resulting in an organized scar. B, A small vessel (C, capillary) has grown through Bruch’s membrane (B) into the sub–retinal pigment epithelial space, resulting in hemorrhage and fibroplasia. C, The end stage shows a thick, fibrous scar between the choroid and the outer retinal layers (trichrome stain). Note the preservation of the retina, except for complete degeneration of the photoreceptors (B, Bruch’s membrane; C, choroid; NR, neural retina; S, sclera; ST, scar tissue). (B, Courtesy of WC Frayer. C, From Yanoff M, Fine BS. Ocular pathology, ed 5. St. Louis: Mosby, 2002.)
Associated features of non-neovascular AMD, including drusen, RPE atrophy, and focal pigmentary changes, are typically present in eyes manifesting CNV, as well as fellow eyes. However, CNV secondary to AMD may occur without any of these precursor lesions; if they are not present, other possible causes of CNV must be evaluated.
Histopathologically, patients affected by AMD may develop nonmacular peripheral CNV, especially in the temporal retina. Occasionally, such lesions result in clinically evident postequatorial subretinal hemorrhage and fluid accumulation. These peripheral disciform detachments rarely require therapy but may lead to breakthrough vitreous hemorrhage.
RETINAL PIGMENT EPITHELIAL DETACHMENT.
A retinal pigment epithelial detachment (PED) may be caused by fibrovascular tissue, hemorrhage, serous fluid, or coalescence of drusen beneath the RPE. Each has a unique clinical appearance and exhibits specific patterns of fluorescence on angiography. Fibrovascular PED represents a type of occult CNV described later. Hemorrhagic PED manifests as a dark elevation of the RPE due to underlying blood, showing blocked fluorescence throughout all phases of angiography. Serous PED appears as a dome-shaped detachment of the RPE, exhibiting bright diffuse hyperfluorescence with progressive pooling in a fixed space. Drusenoid PED, caused by coalescence of drusen, shows staining, often with fading fluorescence in the late phase and an absence of leakage.
DIAGNOSIS AND ANCILLARY TESTING
Visual loss from AMD may be diagnosed when an individual older than 50 years has geographical atrophy in the macula, a PED, or CNV. Other clinical findings, such as drusen, RPE hyperpigmentation, and RPE depigmentation help confirm the diagnosis, but their presence alone may not be associated with visual loss. Clinical examination is usually sufficient to establish a diagnosis of AMD. Subtle macular abnormalities, especially subretinal fluid, are best detected by stereoscopic slit-lamp biomicroscopic examination using a contact lens.
Fluorescein angiography is useful in any patient in whom CNV is suspected to determine the characteristics of the lesion and the patient’s potential qualification for available therapeutic modalities. It is not a useful screening test for eyes that have drusen or geographical atrophy alone, in which no new symptoms or no clinical evidence of neovascularization is present. Determination of the presence of CNV and evaluation of the extent, location, and composition of its components are critical in deciding whether treatment is indicated and, if so, which therapeutic modality is appropriate.  This is becoming increasingly important as new treatments are developed, each with its own specific criteria for effective utilization.
If a lesion is well demarcated, its location may be determined by the closest point to the center of the foveal avascular zone (FAZ). Lesion location is classified angiographically as follows:
• Extrafoveal (=200?µm and <2500?µm from the center of the FAZ).
• Juxtafoveal (1–199?µm from the center of the FAZ).
• Subfoveal (under the center of the FAZ).
Based on angiographic patterns of fluorescence, components of CNV lesions may be categorized as either classic or occult ( Fig. 125-3 ). Classic CNV is characterized by bright, uniform, early hyperfluorescence exhibiting leakage in the late phase and obscuring the boundaries. Occult CNV is recognized angiographically by one of two patterns: fibrovascular PED, or late leakage from an undetermined source.
Fibrovascular PED is characterized by an area of irregular elevation of the RPE (which is neither as bright nor as discrete as in classic CNV), often with stippled hyperfluorescence present in the midphase of the angiogram and leakage or staining by the late phase. Late leakage from an undetermined source usually appears as speckled hyperfluorescence with dye pooled in the subretinal space in the late phase; the source of leakage does not correspond to classic CNV or fibrovascular PED in the early or midphase of the angiogram. Identification of occult CNV is facilitated by late-phase images (up to 10 minutes after dye injection) and stereoscopic images, which may display the irregular elevation of the RPE. Angiograms are also evaluated for the presence of hemorrhage, blocked fluorescence that does not correspond to hemorrhage, or serous detachment of the RPE. Serous PED exhibits bright hyperfluorescence with progressive pooling of fluorescence within a fixed sub-RPE cavity (see Fig. 125-3 ). Classic or occult CNV within the area of the serous detachment may not be identifiable due to intense hyperfluorescence.
With the introduction of digital imaging systems, the use of indocyanine green (ICG) angiography in AMD has been evaluated. The dye’s characteristics enable this mode of angiography to delineate the choroidal circulation better than fluorescein angiography does. Hence, ICG angiography may be useful for the detection of areas of occult CNV. The appearance of CNV based on ICG angiography may be categorized into three types  : focal spots, plaques, and a combination of the two. Laser treatment based on ICG angiography findings has been advocated but remains unproved in a controlled, prospective study.
Figure 125-3 Neovascular age-related macular degeneration. A1–A2, Fluorescein angiography of classic choroidal neovascularization showing early, bright, uniform hyperfluorescence with leakage in the late frame. B1–B2, Fluorescein angiography of occult choroidal neovascularization (fibrovascular pigment epithelial detachment) showing stippled hyperfluorescence in the earlier frame and late leakage. C1, Fluorescein angiography of a serous pigment epithelial detachment showing pooling within a fixed sub–retinal pigment epithelial cavity. C2, Optical coherence tomography cross-section demonstrates a dome-shaped elevation of the retinal pigment epithelium by a hyporeflective (serous) fluid collection.
Rarely, ultrasonography is necessary in the diagnosis of neovascular AMD. B-scan ultrasonography may be necessary when the media is obscured by breakthrough vitreous hemorrhage from CNV, precluding a clear ophthalmoscopic view of the fundus. When a hemorrhagic macular lesion simulates a tumor, acoustic properties may assist in the diagnosis.
The differential diagnosis of non-neovascular AMD includes other conditions that affect the RPE and choriocapillaris ( Box 125-1 ). CNV has been described in a variety of different ophthalmic conditions ( Box 125-2 ), including pathological myopia, ocular histoplasmosis syndrome, and angioid streaks. Individuals affected by AMD are typically elderly and have drusen present in the involved or fellow eye. When CNV is detected, it is important to determine whether AMD is the cause, since other causes of CNV may carry different prognoses, affecting counseling and treatment decisions.
Other causes of subretinal hemorrhage must be ruled out, including retinal arterial macroaneurysm (which usually shows fluorescein or ICG dye leakage from the aneurysm centered along a retinal arteriole) or choroidal rupture (which usually shows irregular staining of the rupture site). Other causes of subretinal fluid also need to be considered, most commonly central serous chorioretinopathy.
Differential Diagnosis for Dry Age-Related Macular Degeneration
• pattern dystrophy
• Stargardt’s disease
• Best’s disease
• angioid streaks
Central serous chorioretinopathy
Bilateral idiopathic juxtafoveal telangiectasis
Acute posterior multifocal placoid pigment epitheliopathy
Histopathologically, drusen appear as focal areas of eosinophilic material between the basement membrane of the RPE and Bruch’s membrane ( Fig. 125-4 ). They stain positively with periodic acid-Schiff. Soft drusen are larger and represent detachment of the thickened inner aspect of Bruch’s membrane along with the RPE ( Fig. 125-5 ). Generally, little or no photoreceptor degeneration overlies drusen.
Partial List of Common Ophthalmic Conditions Associated With Choroidal Neovascularization
Age-related macular degeneration
Ocular histoplasmosis syndrome
Optic disc drusen
Optic nerve head pits
Pathologic (progressive) myopia
Serpiginous or geographic choroiditis
Traumatic choroidal rupture
Bruch’s membrane is a five-layered structure in which the basement membrane of the RPE represents the innermost layer. The outermost layer is a second basement membrane associated with the endothelium of the choriocapillaris. In between is a zone of elastin sandwiched on both sides by an inner and outer collagenous layer. An age-related change is the appearance of basal laminar deposits, which represent type IV collagen, between the RPE plasma and the basement membrane (see Fig. 125-5 ). Progressive thickening of this inner part of Bruch’s membrane is associated with RPE degeneration. Eosinophilic deposits that coalesce between the RPE basement membrane and the inner collagenous zone of Bruch’s membrane are called basal linear deposits. By light microscopy, it is difficult to differentiate these two types of deposits. One hypothesis suggests that the material accumulates from damaged RPE cells. Basal linear deposits are most prominent in eyes that have soft drusen and are more common in eyes affected by neovascular AMD.  Aging also results in increased lipid deposition in Bruch’s membrane. Bruch’s membrane often shows areas of calcification and fragmentation, changes found more commonly in eyes that harbor CNV due to AMD. The choriocapillaris shows thickened and hyalinized vascular walls, while larger choroidal vessels appear normal. Loss of the RPE in geographical atrophy is accompanied by attenuation of the overlying photoreceptors (see Fig. 125-5 ). In areas of geographical atrophy, the underlying choriocapillaris is also generally hyalinized.
CNV represents new blood vessel growth from the choriocapillaris through a degenerated Bruch’s membrane (see Fig. 125-2 ). The earliest form of histopathologically evident CNV consists of fine vessels within Bruch’s membrane. Occasionally, a low-grade granulomatous inflammation accompanies CNV. Even when CNV is first noted clinically, the histopathology shows a prominent fibrotic component.  The fibrotic component may be associated with hyperplasia or metaplasia of the RPE, overlying retinal atrophy, and cystoid macular edema. Hemosiderin from previous hemorrhage may be seen.
NATURAL HISTORY AND PROGNOSIS
The risk of visual loss in eyes that initially manifest drusen or RPE abnormalities varies, depending on the characteristics of the macula and the status of the fellow eye. In eyes of patients older than 65 years that have bilateral drusen but no significant visual loss initially, the risk of a new atrophic lesion or neovascular lesion that results in visual loss has been reported as 9% at 1 year, 16% at 2 years, and 24% at 3 years. Confluent drusen, focal hyperpigmentation of the RPE, and extrafoveal areas of chorioretinal atrophy are three clinical findings that increase the risk for the subsequent development of visual loss.
In individuals who already have neovascular AMD in one eye, the risk of developing CNV in the fellow eye is estimated at about 7–10% per year. If the fellow eye has no large drusen or focal RPE hyperpigmentation, the 5-year risk of developing CNV is only 10%. When both large drusen and RPE hyperpigmentation are present, however, the 5-year risk increases to approximately
Figure 125-4 Nodular (hard) drusen. Scanning (A) and gross (B) appearance of nodular drusen. Histological section (C) shows an eosinophilic nodular druse external and contiguous to the original thin basement membrane of the retinal pigment epithelium (RPE), that is, between RPE basement membrane and Bruch’s membrane. (A and B, Courtesy of Dr. R. C. Eagle Jr. C, Courtesy of Dr. M. Yanoff.)
Figure 125-5 Large (soft) drusen. A, An amorphous material is present between the retinal pigment epithelium and Bruch’s membrane. Note the presence of tiny blood vessels within the material. B, Brush-like appearance helps identify the basal laminar deposit. (A, Courtesy of M. Yanoff, MD. B, Courtesy of R.C. Eagle Jr, MD.)
60%. In one study, an individual who has subfoveal or juxtafoveal CNV in one eye, systemic arterial hypertension, and a fellow eye with large, multiple drusen with focal RPE hyperpigmentation was shown to have an 87% risk of developing CNV in the fellow eye over 5 years.
The degree of visual loss associated with CNV can be directly correlated to the most posterior extent of the neovascular complex with respect to the center of the FAZ. The vast majority of CNV lesions associated with AMD are subfoveal in location,  and most cases of untreated CNV that begin outside the fovea extend under the center of the FAZ with time. The natural history of CNV associated with AMD generally carries a poor visual prognosis.  
Occult Choroidal Neovascularization
Natural history studies of occult CNV demonstrate a poor visual outcome associated with these lesions. One retrospective study reviewed 84 eyes with occult CNV and showed a 63% rate of moderate visual loss over an average of 28 months; average visual acuity declined from 20/80 to 20/250 over this interval. The MPS observed 26 eyes with occult subfoveal CNV and reported severe visual loss in 41% of eyes at 12 months and 64% at 36 months; median visual acuity declined from 20/50 to 20/200 over 36 months. The Verteporfin in Photodynamic Therapy (VIP) Study followed 93 eyes with purely occult subfoveal CNV in a placebo control arm. At 12 months, 73% of these eyes experienced visual loss from baseline, with 32% manifesting severe visual loss. At 24 months, 79% experienced visual loss from baseline, with a 43% rate of severe visual loss. Mean loss of visual acuity from baseline was four and five lines at 12 and 24 months, respectively. 
Classic Choroidal Neovascularization
The natural history of subfoveal classic CNV can be discerned by evaluating the control arms of the MPS and the Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study.  In the MPS, visual acuity in untreated eyes harboring classic CNV decreased an average of 1.9 lines at 3 months and 4.4 lines at 24 months. Severe visual loss was noted in 11% of eyes at 3 months and 37% at 24 months. The TAP Study showed a similar trend, with a mean loss of 2 lines at 3 months, 3.5 lines at 12 months, and 3.9 lines at 24 months. Severe visual loss was identified in 36% of control eyes at 24 months.
TREATMENT AND PREVENTION
No proven treatment exists for the visual loss associated with non-neovascular AMD. Laser therapy to drusen to prevent visual loss from the development of CNV is currently under study.      Initial trials evaluated fovea-sparing laser treatment for soft drusen using low-intensity burns in a grid fashion. Results indicate that this method can speed resorption of drusen and may improve visual acuity. However, CNV may develop in treated eyes more frequently than in untreated eyes. Further study in a larger, randomized trial will attempt to define the exact role of this treatment modality in non-neovascular AMD.
Conventional laser photocoagulation and ocular photodynamic therapy (OPT) are the only proven treatments for neovascular AMD, having undergone extensive study in large, prospective, randomized trials. Other laser modalities currently under consideration include feeder vessel photocoagulation and transpupillary thermotherapy. Pharmacological inhibition of neovascularization is also being studied, targeting VEGF. Surgical approaches to the disease include submacular excision, macular translocation, macular rotation, and RPE transplantation.
As discussed earlier, the natural history of neovascular AMD carries a poor visual prognosis. Traditionally, the goal of treatment has been to reduce the risk of additional visual loss, with restoration of vision expected in only a minority of treated eyes.
Conventional Laser Photocoagulation
For many years, laser photocoagulation was the only proven treatment for CNV associated with AMD. Every controlled study that showed a benefit from laser photocoagulation in this condition included only CNV lesions with well-demarcated boundaries. Unfortunately, no more than 15–20% of neovascular AMD cases present with well-defined CNV, limiting the utility of this treatment modality.
Lesions considered eligible for photocoagulation by MPS criteria should contain some classic CNV but may manifest occult CNV. There may be associated blood, blocked fluorescence not corresponding to visible blood, or serous PED, provided the total area of these components is less than the area of any classic and occult CNV. Laser photocoagulation is performed using initial treatment settings of 200?µm spot size, 0.2–0.5 second duration, and 100–200?mW power. The lesion is treated so that the end result is a uniform, confluent, yellow-white laser burn. Photocoagulation should cover the entire lesion and extend 100?µm beyond the peripheral boundaries of all lesion components except blood. For recurrent lesions, treatment should extend 100?µm beyond the perimeter of the lesion, except at the interface of the recurrence and the previous area of photocoagulation, where the laser treatment should extend 300?µm into the area of previous laser treatment. Feeder vessels, when identified, should be treated for at least 100?µm on both sides, and 300?µm radially at the origin of the feeder vessel. Complications associated with laser photocoagulation include hemorrhage, perforation of Bruch’s membrane, RPE tear, and arteriolar narrowing.    Persistent or recurrent CNV after photocoagulation is common.
MACULAR PHOTOCOAGULATION STUDY.
The MPS consisted of eight multicenter, randomized clinical trials designed to determine whether laser photocoagulation reduces the risk of severe vision loss associated with CNV from AMD, ocular histoplasmosis syndrome, and idiopathic causes. Eligible patients were randomized to laser treatment or observation. Two randomized clinical trials studied subfoveal CNV due to AMD; one evaluated new lesions with no prior laser treatment, and the other evaluated recurrent lesions with prior laser treatment that did not involve the fovea.
Overall, for patients who had new, small (3.5 MPS disc areas), well-demarcated subfoveal lesions containing classic CNV, laser-treated eyes retained better levels of visual acuity, reading speed, and contrast sensitivity when compared with untreated eyes. These benefits were sustained for at least 4 years. However, an immediate and substantial decrease in visual acuity averaging three lines occurred after treatment. Eyes treated with photocoagulation had worse visual acuity, on average, than did untreated eyes at 3 and 6 months after enrollment. Even though both groups lost visual acuity at 4 years, the majority of treated eyes maintained visual acuity better than 20/400, whereas the majority of untreated eyes had a final visual acuity of 20/400 or worse. The treatment benefit is affected by the size of the CNV complex and by the initial visual acuity. Eyes that harbor smaller lesions typically obtain a greater treatment benefit. In contrast, a better initial visual acuity is associated with greater immediate visual loss from treatment.
After initial treatment of new subfoveal CNV, 13% of treated eyes demonstrated persistent neovascularization, and an additional 31% developed recurrent CNV within 2 years. In addition, a new, distinct area of CNV developed in 3% of treated eyes over 3 years. Mean visual acuity at 3 years after treatment was 20/400 for treated eyes that had persistent CNV, 20/250 for treated eyes that had recurrent CNV, and 20/320 (6/100) for treated eyes that had no peripheral leakage. Approximately half of all treated eyes were retreated in the study. The MPS recommended that retreatment be considered when the lesion is relatively small with well-demarcated boundaries; the size of the persistent or recurrent CNV and the previous laser-treated area was required to be equivalent to six or fewer MPS disc areas.
The MPS also demonstrated a long-term benefit of laser photocoagulation in reducing visual loss associated with extrafoveal
Figure 125-6 A, Classic choroidal neovascularization prior to ocular photodynamic therapy (OPT). B, Same lesion 2 weeks following OPT, demonstrating hypofluorescence in the area of the treatment spot and corresponding hypoperfusion of the neovascular complex; no laser scotoma is induced. Reperfusion of the choroidal circulation after several weeks will determine whether retreatment is required or the lesion has regressed to an inactive, fibrotic scar.
CNV. Approximately 46% of treated eyes, compared with 64% of untreated eyes, had severe visual loss by 5 years after study entry. Recurrence after laser treatment of extrafoveal CNV developed in 54% of eyes during the 5-year follow-up period. Most of these recurrences occurred in the first 2 years after treatment. They tended to occur on the foveal side of the original neovascular lesion, resulting in significant loss of visual acuity.
The MPS demonstrated the efficacy of laser photocoagulation for juxtafoveal CNV associated with AMD as well.  At 5 years, almost no eyes with juxtafoveal CNV showed improvement in vision over baseline levels. However, 25% of treated eyes, compared with 15% of untreated eyes, maintained their baseline visual acuity. The mean visual acuity of laser-treated eyes was 20/200, compared with 20/250 for untreated eyes. Despite this small difference in final visual acuity, more than twice as many treated eyes retained visual acuity of 20/40 or better. Similarly, 25% of treated eyes had visual acuity of 20/400 or worse, compared with 40% of untreated eyes.  Rates of severe vision loss were 52% among treated eyes and 61% among untreated eyes. Treated eyes lost 1.2 fewer lines of visual acuity on average than did untreated eyes. Disappointing long-term visual results for treated juxtafoveal lesions can be explained by the high frequency of persistent or recurrent CNV. Persistent CNV was identified in 32% of treated eyes, and recurrent CNV occurred in an additional 42% within the follow-up period.
The MPS also showed a treatment benefit for subfoveal recurrences that received prior laser photocoagulation for juxtafoveal or extrafoveal CNV.  At 3 years after randomization, laser-treated eyes had better visual acuity than did untreated eyes, although both groups had limited distance visual acuity. Twice as many treated eyes as untreated eyes had visual acuity better than 20/200 at the 3-year examination, and fewer than half as many treated eyes as untreated eyes had visual acuity of 20/400 or worse.
Laser photocoagulation is limited by restrictive eligibility criteria, immediate visual loss due to laser-induced scotoma, and high recurrence rates. These shortcomings have prompted research into alternative therapies with broader applicability and higher success in preserving or improving vision and maintaining closure of CNV.
Ocular Photodynamic Therapy
OPT is a more recent technology that uses low-energy light to activate an intravenously injected photosensitizing agent and induce closure of a choroidal neovascular complex. The goal of OPT is to specifically target neovascular tissue while sparing surrounding and overlying retinal structures. No immediate, permanent laser-induced scotoma is produced, and there is no corresponding RPE defect.  It was hoped that the narrow eligibility requirements and high recurrence rates of conventional photocoagulation would be improved with OPT ( Fig. 125-6 ).
The mechanism of action of OPT involves delivery of a photosensitizing agent to its site of action, followed by activation with wavelength-specific light. Theoretically, current photosensitizers have an affinity for proliferating neovascular tissue due to the increased expression of low-density lipoprotein (LDL) receptors on neovascular endothelium. The LDL-bound photosensitizer complex is preferentially transported across the vascular endothelium and localized within the CNV. Activation of the photosensitizer with specific nonthermal light produces a triplet state; this reacts with oxygen, ultimately producing singlet oxygen. The resulting local cytotoxicity causes an acute inflammatory response with production of cytokines. Occlusion of the vascular bed occurs from endothelial damage, platelet adhesion and aggregation, and subsequent thrombus formation.    
Benzoporphyrin derivative monoacid (Verteporfin) is the only approved photosensitizer for OPT at the time of this publication. Dosage is determined by body surface area (6?mg/m2 ). The drug is infused intravenously over 10 minutes, followed by a 5-minute accumulation phase. It is then activated with low-energy laser light for 83 seconds using a wavelength corresponding to its peak absorption at 689?nm and a fluence of 600?mW/cm2 . A treatment spot size is chosen 1000?m larger than the greatest linear dimension of the lesion to ensure complete coverage of the neovascular complex.
After treatment, individuals are advised to avoid direct sunlight or bright illumination for 5 days to prevent phototoxicity to exposed body surfaces. The treatment is generally safe, but serious adverse events have been reported, including severe vision loss and extravasation of the photosensitizer. The most common side effects include visual disturbances (blurred vision, decreased vision, visual field defect) and injection site events (extravasation, rash). Allergic reaction and back pain have also been reported. Overdosage of the drug or light may result in nonperfusion of the retinal vasculature, with subsequent severe visual loss from macular infarction.
Two large, prospective trials have evaluated Verteporfin for the treatment of subfoveal CNV due to AMD: the TAP Study and the VIP Study.
The TAP Study  enrolled 609 eyes with subfoveal CNV secondary to AMD and randomized them in a double-blind fashion to treatment with Verteporfin or a placebo control. Best-corrected visual acuity at study entry was 20/40 to 20/200 equivalent, measured on an early treatment diabetic retinopathy study (ETDRS) chart. The lesion was required to be subfoveal in location, be less than or equal to 5400?m in greatest linear dimension (nine MPS disc areas), and contain a classic component. The main outcome measure was moderate visual loss, defined as a loss of 15 letters or doubling of the visual angle (e.g., from 20/80 to 20/160).
At 24 months, outcomes were reported for 351 (87%) in the Verteporfin group and 178 (86%) in the placebo group. A statistically significant treatment benefit was identified for a specific subgroup of individuals with predominantly classic CNV. A predominantly classic lesion is defined as one that contains a classic component occupying 50% or more of the entire neovascular complex; the remainder of the lesion may consist of PED, occult CNV, or blocked fluorescence from hemorrhage or other cause. For this subgroup of patients, moderate visual loss occurred in 41% of eyes treated with Verteporfin, compared with 69% treated with placebo, at 24 months. Severe visual loss (loss
of 30 letters or quadrupling of the visual angle) occurred in 15% of treated eyes versus 36% of controls. Legal blindness resulted in 44% and 68%, respectively; mean final visual acuities were 20/160 and 20/200 in the two groups. Statistically significant benefits of Verteporfin were also demonstrated for preservation of contrast sensitivity and limitation of final lesion size, progression, and leakage.
Retreatment rates were documented for the Verteporfin and placebo groups. Lesions were eligible for retreatment at 3-month intervals if they showed any evidence of leakage on fluorescein angiography. In the first year, retreatment was performed an average of 3.4 times in the Verteporfin group, compared with 3.7 times in the placebo group. The Verteporfin group required an average of 2.1 retreatments in the second year, for a mean total of 5.5 treatments over 2 years.
The second VIP report  focused primarily on AMD patients with occult subfoveal CNV and no classic component. The study enrolled 225 eyes in the Verteporfin treatment group and 114 in the placebo control group. Eligibility required a visual acuity of at least 20/100 and a lesion size of 5400?m or less. Occult lesions were required to have associated hemorrhage or show deterioration within 3 months of enrollment. Deterioration was defined as a loss of 1 ETDRS line or a 10% increase in the greatest linear dimension of the lesion.
At 12 months, no statistically significant difference was detected between the Verteporfin and placebo groups with respect to the primary outcome measure, moderate visual loss. At 24 months, however, a statistically significant benefit was identified, with 54% in the Verteporfin group experiencing moderate visual loss, compared with 67% in the placebo group. Severe visual loss occurred in 30% of treated cases versus 46% of controls. Legal blindness resulted in 28% and 45%, respectively; mean final visual acuities were 20/126 and 20/160 in the two groups.
Four percent of Verteporfin-treated eyes experienced acute visual loss, defined as loss of 20 or more letters within 7 days of treatment. Causes included hemorrhagic PED, neurosensory detachment, and idiopathic visual loss.
OPT has generally replaced conventional laser photocoagulation for the treatment of predominantly classic subfoveal CNV due to AMD. The treatment of occult CNV is currently not universally agreed on, and results of other ongoing studies may definitively determine the treatment of choice. OPT technology in its current form is still limited by restrictive eligibility criteria and the need for multiple retreatments. Research is ongoing to evaluate newer photosensitizers in an attempt to address these issues. Other studies are combining OPT with different therapeutic modalities, such as pharmacological inhibition of VEGF, to enhance the effect. The timing of retreatment is also being altered to determine the most appropriate interval. Regardless, OPT represents a major advance in the treatment of CNV resulting from AMD.
The Age-Related Eye Disease Study is the first large, prospective trial to show a benefit of antioxidant and zinc supplementation on the progression of AMD and associated visual loss. The study enrolled 3640 participants followed for an average of 6.3 years. Individuals were randomized to receive daily oral nutritional supplementation in the following subgroups:
Antioxidants (500?mg vitamin C, 400?IU vitamin E, 15?mg beta-carotene)
Zinc (80?mg zinc oxide, 2?mg cupric oxide)
Antioxidants plus zinc
The study recommended antioxidants plus zinc for the subset of AMD patients with extensive intermediate-size drusen (=63?µm but <125?µm), at least one large druse (=125?µm), noncentral geographical atrophy in one or both eyes, or advanced AMD in one eye. Advanced AMD was defined as photocoagulation or other treatment for CNV, central geographical atrophy, nondrusenoid PED, serous or hemorrhagic retinal detachment, hemorrhage under the retina or RPE, or subretinal fibrosis.
Primary outcome measures included progression to advanced AMD and moderate visual acuity loss from baseline (loss of =15 letters or doubling of the visual angle). For the subset defined above, 28% assigned to the placebo arm progressed to advanced AMD, compared with 23% assigned to antioxidants, 22% assigned to zinc, and 20% assigned to antioxidants plus zinc. In this same subset, 29% assigned to placebo experienced moderate visual loss, compared with 26%, 25%, and 23% in the respective arms. These results were statistically significant.
Investigational and Alternative Therapies
Transpupillary thermotherapy is currently the focus of a large, randomized, prospective trial for the treatment of occult subfoveal CNV due to AMD. This technology uses subthreshold laser irradiation with a long exposure duration and a large spot size to thermally treat CNV. The induced tissue temperature rise is estimated at 10° C, well below the 42° rise encountered with laser photocoagulation. Using an 810?nm-diode laser, transmitted energy penetrates the RPE and choroid, minimizing absorption by the neurosensory retina. Proposed mechanisms of CNV closure include vascular thrombosis, apoptosis, and thermal inhibition of angiogenesis. A pilot study enrolling 16 eyes followed for 1 year showed that 16% improved by two or more Snellen lines, 56% stabilized, and 25% lost two or more lines.
Pharmacological inhibition of angiogenesis is currently being studied using anecortave acetate and other specific agents that target VEGF, a known promoter of CNV. Feeder vessel photocoagulation guided by high-speed ICG angiography has been advocated but has yet to be studied in a large, controlled trial. Radiation therapy has also been suggested, but it failed to show a benefit relative to sham treatment in the prospective, randomized Radiation Therapy for Age-Related Macular Degeneration Study; the authors suggested that an alternative radiation dosage might have yielded a significantly different outcome. Surgical approaches to subfoveal CNV have been attempted using subfoveal excision and macular translocation. The Submacular Surgery Trial compared surgical excision of recurrent subfoveal CNV to laser photocoagulation and found no benefit after 2 years of follow-up. Macular translocation involves surgical displacement of the fovea overlying subfoveal CNV to a healthier area of RPE and choroid. Results have been reported in small series, but a larger, controlled trial has yet to be organized.
Low-vision aids should be considered in any individual who experiences untreatable visual loss that affects his or her ability to perform activities of daily living. Various devices exist for different tasks, such as reading, writing, computer work, driving, and distance vision. Reading lamps and simple magnifiers may be of significant benefit. Closed-circuit television and scanning devices are available to provide electronic magnification and contrast enhancement.
Age-related macular degeneration continues to be the leading cause of visual loss in developed countries, despite extensive resources dedicated to research involving its prevention and treatment. New therapeutic strategies continue to be developed and tested. Laser-based technologies remain the mainstay of current treatment. Pharmacological approaches appear promising in thwarting angiogenesis, and refinements in advanced surgical techniques may offer better outcomes in the future. Treatment of AMD in the next decade will likely be very different from its treatment a decade ago.
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