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Chapter 124 – Choroidal Neovascularization

Chapter 124 – Choroidal Neovascularization

 

RICHARD F. SPAIDE

 

 

 

 

 

DEFINITION

• Choroidal neovascularization is an inappropriate ingrowth of blood vessels and accompanying cellular infiltrate originating in the choroid, which extends through Bruch’s membrane to proliferate under the retina, the retinal pigment epithelium, or both. It is a common end-stage process leading to severe visual loss in a number of different diseases.

 

KEY FEATURES

• Decreased central visual acuity.

• Metamorphopsia.

• Intraretinal, subretinal, subretinal pigment epithelial hemorrhage.

• Macular edema.

• Subretinal fluid.

• Hyperfluorescence and leakage of dye during fluorescein angiography.

 

ASSOCIATED FEATURES

• Lipid exudation.

• Detachment of the retinal pigment epithelium.

• Retinal pigment epithelial tear.

• Scarring.

 

 

 

INTRODUCTION

Choroidal neovascularization (CNV) is an aberrant growth of blood vessels under the macula associated with numerous disorders ( Fig. 124-1 ). The most significant is age-related macular degeneration (AMD). [1] Several other conditions associated with CNV include intraocular inflammation, angioid streaks, choroidal rupture, pathological myopia, chorioretinal scars, or chorioretinal dystrophy. Despite the disparate causes, the techniques for diagnosis and, in most cases, treatment are common to any form of CNV. Vital in patient management is a thorough understanding of the principles of ocular angiography to establish the diagnosis, categorize the underlying disease process, and plan management strategies. The Macula Photocoagulation Study group (MPS) provided clinicians with valuable information and guidelines in order to make informed and rational decisions about laser photocoagulation by means of randomized clinical trials. More recently, photodynamic therapy (PDT) using verteporfin has been effective for a number of types of CNV in randomized clinical trials. Further investigation of treatment techniques includes pilot studies using laser photocoagulation, PDT, surgery and, more recently, pharmacological therapy. The guidelines provided by these studies are vital to optimal disease management.

EPIDEMIOLOGY AND PATHOGENESIS

CNV may occur in response to virtually any disturbance of the retinal pigment epithelium (RPE) or Bruch’s membrane, or by loci of inflammation adjacent to these structures. The incidence of specific etiologies varies with the age of the individual. Traumatic causes may lead to rupture of Bruch’s membrane and are seen frequently in younger individuals. Inflammation may lead directly to CNV or may cause scarring and disruption of the normal ocular architecture, which predisposes an individual to later vascular ingrowth. Most, but certainly not all, inflammation-related CNV occurs in young to middle-aged patients. AMD typically is seen in patients over 50 years of age. Pathological myopia is associated with fractures of Bruch’s membrane, known as lacquer cracks, and also areas of atrophy which may facilitate the growth of CNV, which can occur at any age. By definition, idiopathic CNV is found in individuals less than 50 years of age who do not have evidence of intraocular inflammation, trauma, pathological myopia, chorioretinal scars, or chorioretinal dystrophy.

Theories to explain the growth of CNV include the following pathways:

• Release of cytokines (e.g., vegetative epithelial growth factor [VEGF])

• Rupture of Bruch’s membrane

• Inflammation

• Oxidative stress of the RPE

• Abnormal accumulation of lipid by-products

• Vascular insufficiency

OCULAR MANIFESTATIONS

The invading vessels cause visually significant effects through a variety of mechanisms. The physical presence of the vessels causes direct mechanical distortion of the macular tissue. The neovascularization often can be seen as a grayish discoloration under the retina. The vessels are typically incompetent and display varying degrees of leakage. The excessive fluid released manifests as accumulation within tissue or between tissue planes. Detachments of the RPE, macula, and intraretinal edema are the result. Tensile stress from the contracting fibrovascular membrane and excessive hydrostatic pressure may lead to rips of the RPE. Chronic leakage is associated with deposition of lipid and degenerative changes within the detached retina. The newly growing vessels display a peculiar tendency to bleed, which may result in hemorrhages under the RPE or retina or, in extreme cases, may result in breakthrough hemorrhages into the vitreous cavity. Eventually proliferation of RPE, fibroblasts, and glial cells results in the deposition of scar tissue, leading to a whitish accumulation under the macula.

The source for CNV, as implied by the name, is the choroid. The choroid is not the only source of blood flow in some patients, however. Retinal vessels may dive down into the subretinal space and contribute to the neovascular process. The most obvious examples of this tendency are frank chorioretinal anastomosis, which can be seen in inflammatory conditions such as toxoplasmosis and in AMD. Hartnett and coworkers[3] were the first to identify a group of patients with subretinal proliferation of vessels derived solely from the retina; they termed this entity deep retinal vascular complexes. Although subsequent investigators have found this entity to be relatively common, the presence of

 

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Figure 124-1 A 66-year-old patient with metamorphopsia and a visual acuity of 20/40. She had a small focus of classic choroidal neovascularization that appeared early (A) and showed prominent leakage late (B) in the fluorescein angiogram. She was treated with laser photocoagulation, but 6 months later she developed recurrent neovascularization (C) that extended under the center of the fovea. She was treated with photodynamic therapy and had a resolution of her exudative manifestations. Three months after her only photodynamic therapy session, she showed staining but no leakage from the lesion (D). Two years later her acuity was 20/20.

retinal contribution to the exudative process, curiously, has not been mentioned by any large randomized trial of CNV.

DIAGNOSIS AND ANCILLARY TESTING

Patients suspected of having CNV require ancillary testing to establish the diagnosis and to plan and monitor their subsequent treatment. The principal test to diagnose CNV is fluorescein angiography, with indocyanine green (ICG) angiography useful in a limited number of cases.[1]

Angiographic Findings of Choroidal Neovascularization

Vascular ingrowth causes remarkable physiological alteration in the macular region, and this alteration can be detected and evaluated with angiography. The vessels usually grow in the inner portion of Bruch’s membrane, although they may penetrate into the subretinal space. The angiographic appearance of CNV is governed by the location, density, and maturity of the new vessels, as well as the amount and character of the intervening tissue. Relatively acute growth of vessels in the inner portion of Bruch’s membrane, or even in the subretinal space, with minimal accompanying tissue results in a vascular network that shows hyperfluorescence soon after the appearance of the dye. In this pattern of vascular ingrowth, the vessels themselves often are easily visualized during the early phases of the angiogram. These vessels show prominent leakage during the course of the angiogram, and the vessels often are obscured by the overlying fluorescein which has leaked from the vessels. This topographical and temporal pattern defines classic CNV. In classic CNV there is early hyperfluorescence with late leakage. Vessels in classic CNV can appear as a “brush” or “cartwheel” early in the angiogram. This pattern as a pure component is seen in only about 10% of patients with AMD but in a much higher proportion of patients with other causes of CNV.

 

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Obscuration of the fibrovascular ingrowth by intervening tissue alters the fluorescein appearance of the lesion. In such lesions we can observe the fluorescein characteristics of the vessels indirectly. Because we don’t see the vessels directly but, instead, infer their presence through more indirect effects, this type of CNV is called occult CNV. There are two fluorescein angiographic types of occult CNV,[2] and the differentiation depends on the relative elevation of the leaking lesion. Fibrovascular ingrowth leads to elevation of the RPE, producing a fibrovascular PED. After injection of fluorescein, the fluorescence within the fibrovascular PED slowly increases, often in a heterogeneous manner. Retention of dye within the fibrovascular PED late in the angiogram leads to the appearance of staining. Leakage from the fibrovascular PED can result in the appearance of hypofluorescence internal to the fibrovascular elevation, into the subretinal space, or even into the retina. This leakage can blur the outer margins of the fibrovascular PED. A second form of occult CNV is called late leakage of undetermined source. In this form of occult CNV, there is little or no early hyperfluorescence and leakage emanating from poorly defined areas later in the angiogram. Late leakage of undetermined source is not elevated, as is a fibrovascular PED. On occasion the term poorly defined CNV is used synonymously for occult CNV, but this is not correct terminology. Some forms of occult CNV, particularly fibrovascular PEDs, can be well defined even though they show occult characteristics.

ICG offers additional insights into characterizing CNV. Generally, CNV seen as classic during fluorescein angiography is not imaged as dramatically by ICG angiography. Classic CNV does not show prominent leakage during ICG angiography, probably because of the higher protein binding of ICG. Occult CNV, either fibrovascular PEDs or late leakage of undetermined source, shows a variety of patterns during ICG angiography. Curiously, areas of CNV which appear very poorly defined during fluorescein angiography can be well defined during ICG angiography. Most regions of occult CNV appear as relatively large plaques during ICG angiography. On occasion, there may be focal areas of intense hyperfluorescence. These may be due to a limited number of conditions, in particular polypoidal choroidal vasculopathy[22] and deep retinal vascular anomalous complexes.[3] Polypoidal choroidal vasculopathy was first described in black women but subsequently has been found in all races. Patients with polypoidal choroidal vasculopathy have a slowly progressive vascular proliferation, which has characteristic findings during ICG angiography. The lesion is composed of nodular, aneurysmal dilatations at the outer border of the lesion, with intervening vascular channels. It is not uncommon to see plaque-like changes typically seen in occult CNV in older patients with polypoidal choroidal vasculopathy.

Disciform Scar

With time, continued exudation, bleeding, proliferation of vessels, hyperplasia of REP cells, and invasion of fibroblasts and inflammatory cells, a sizable scar may form in the macular region. On occasion the scar becomes white and fibrous in appearance, being almost completely devoid of visible vessels. This typical end-stage manifestation is called a disciform scar, although certain studies have used slightly differing definitions based on fluorescein angiography. Disciform scars are a common end-stage development in AMD but may be seen in a number of different diseases causing CNV.

DIFFERENTIAL DIAGNOSIS

Only a limited number of diseases may be mistaken for typical CNV:

• Acute posterior multifocal placoid pigment epitheliopathy

• Serpiginous choroidopathy

• Unilateral acute idiopathic maculopathy

• Central serous chorioretinopathy

• Cystoid macular edema

• Epiretinal membrane

SYSTEMIC RISK FACTORS

Systemic risk factors vary with the cause of the CNV. Patients with angioid streaks usually have a predisposing cause, the most common being pseudoxanthoma elasticum. Those with inflammatory lesions in the eye may have generalized systemic conditions. The interaction among systemic risk factors and CNV has been studied most in patients with AMD. Interestingly, many of the AMD studies identified differing risk factors depending on the populations studied. One risk factor common to most studies for the development of CNV in AMD was cigarette smoking. Other risk factors identified in some studies include hypertension and hypercholesterolemia. The Eye Disease Case-Control study had only a handful of women using estrogen replacement, but these patients seemed to have had a lower risk for neovascularization than women not using estrogen.[4] Hypertension appears to be a risk factor for poor response to thermal laser among patients with juxtafoveal CNV.

PATHOLOGY

The fundamental pathological change in CNV is the invasion of blood vessels through the outer portion of Bruch’s membrane.[5] Along with the invasion of blood vessels, there are usually a varying proportion of inflammatory cells including lymphocytes and macrophages. Once Bruch’s membrane is breached, the vessels may proliferate in the inner portion of Bruch’s membrane, may proliferate in the subretinal space, or may do both. There is an unusual tendency for the proliferating fibrovascular tissue to hemorrhage. The free blood may accumulate under the RPE, in the subretinal space, or may even break through into the vitreous cavity. Organization of the blood can lead to scarring. The RPE cells in the regions surrounding the CNV may show hyperplasia and fibrous metaplasia, also. Admixture of these tissue elements produces a fibrocellular scar known as a disciform scar. The inner portion of the scar is characteristically less vascular than the outer portion. Serous, serosanguineous, or frankly hemorrhagic detachment of the retina may occur. Chronic exudation of fluid commonly is accompanied by the deposition of yellowish subretinal material referred to as lipid. This material probably is composed of lipid and lipoprotein and appears to accumulate, because the aqueous phase of the exudation is resorbed faster than lipid and lipoproteins, which are removed from the subretinal space through differing transport mechanisms.

TREATMENT

The strategies for treating CNV are constrained by the location of the proliferating tissue, the close proximity of this proliferating tissue to delicate, easily damaged structures critical for detailed vision and, chiefly, by the lack of understanding of why and how the body makes these vessels grow. Much of our conceptualization of the condition, which leads directly to terminology and ultimately to management approaches, was derived from angiography, principally fluorescein angiography. The vascular ingrowth appears to be the hallmark of the disease (and its name). It is logical that management approaches attacked the vessels with heat, light, ionizing radiation and, more recently, photodynamic effects. Newer pharmacological approaches have attempted to block cytokines or the induced effects of cytokines.

Laser Photocoagulation

The investigation of the effect of laser photocoagulation on CNV was one of the first multicenter randomized trials organized in ophthalmology. The extrafoveal study investigators examined patients aged 50 years or older, who had CNV located

 

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200–2500?µm from the center of the foveal avascular zone, with a best-corrected acuity of 20/100 or better and drusen in the study or fellow eye. The juxtafoveal study enrolled patients aged 50 years or greater with (1) CNV located 1–199?µm from the center of the foveal avascular zone or (2) more than 200?µm if there was blood or pigment extending to within 200?µm of the center of the foveal avascular zone with a best-corrected acuity of 20/400 or better and drusen in the study or fellow eye. The Subfoveal New CNV study enrolled patients with recent CNV less than 3.5 MPS standard disc areas located under the geometrical center of the fovea who had a visual acuity from 20/40 to 20/320. (An MPS standard disc area is an arcane measurement bearing only an approximate correlation with the typical size of the optic nerve head. One MPS standard disc area = 1.77?mm2 .) The Recurrent Subfoveal CNV study enrolled patients with recurrent CNV located under or within 150?µm of the geometrical center of the fovea who had an acuity of 20/40 to 20/320. For both subfoveal studies, most of the lesion had to be composed of CNV.

For extrafoveal CNV, the lesion was treated using green or blue-green argon laser, with the goal of uniform whitening of the lesion extending 100–125?µm around the lesion.[6] The enrollment for the extrafoveal study was stopped after 18 months because of a large difference between the treatment and control groups. After 18 months, 60% of untreated patients sustained a severe visual loss, which was defined as a 6-line visual acuity loss, while only 25% of treated patients did. At the end of the follow-up period of 5 years, 64% of untreated patients and 46% of treated patients had severe visual loss.[6] The main cause of decreased visual acuity was recurrent CNV, which occurred in 54% of treated patients and usually was seen on the foveal side of the treated lesion. Patients who smoked cigarettes were more likely to have recurrent neovascularization. The mean acuity of patients with recurrent neovascularization was 20/250, while patients without recurrence had a mean acuity of 20/50. In the juxtafoveal study, patients were treated with krypton red laser, which has the theoretical advantage of less damage to the overlying retina.[7] [8] After 3 years of follow-up, 58% of untreated eyes versus 49% of treated eyes had severe visual loss, which was defined as 6 lines or more of visual acuity loss. After 5 years, 65% of untreated and 55% of treated eyes sustained severe visual loss.[8] Persistent neovascularization was defined as neovascularization seen within the first 6 weeks after photocoagulation and was seen in 32% of patients. Recurrent neovascularization was seen in 47% of patients by the 5-year follow-up point. Patients with hypertension did not seem to show a treatment benefit in the juxtafoveal study. Thermal laser treatment of new and recurrent subfoveal CNV demonstrated immediate loss of visual acuity in the treatment groups, with moderate treatment benefit demonstrated with extended follow-up.

Photodynamic Therapy

RANDOMIZED STUDIES.

Large randomized trials were performed to evaluate the efficacy of PDT with verteporfin for CNV secondary to AMD. Each patient in the study received 6?mg of verteporfin per square meter of body surface area intravenously over 10 minutes.[9] [10] Fifteen minutes after the start of the infusion, a diode laser at 689?nm delivered 50?J/cm2 at an intensity of 600?mW/cm2 over 83 seconds using a spot size diameter of 1000?µm larger than the greatest linear dimension of the neovascular lesion. Patients were re-evaluated at 3-month intervals. Patients showing leakage during fluorescein angiography at the 3-month return visit were retreated. Patients in the Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group showed 1- and 2-year treatment benefit results for patients with predominantly classic CNV.[9] [10]

Patients with occult CNV who had less than 50% classic findings did not show a treatment benefit. Patients were retreated a mean of 3.3 times during the first year and 2.2 times during the second year. At the end of the first year of follow-up, the patients treated with verteporfin showed a pronounced treatment effect when their neovascular lesions comprised 50% or more of classic CNV, with 67% versus 39% (P <.001) showing fewer than 15 letters of visual acuity lost. This trend continued at the second year follow-up, when 59% of those treated and 31% of control patients lost fewer than 3 lines of acuity. Verteporfin therapy of occult subfoveal CNV in AMD was studied in the Verteporfin In Photodynamic Therapy (VIP) study.[11] The entry criteria for this study were somewhat elaborate, in that patients had to have either occult with no classic CNV and a history of recent visual acuity loss, or they had to have classic CNV with a visual acuity of 20/40 or better. Clearly, evaluation of the results of the study required extensive subgroup analysis. After 1 year of follow-up, treated patients did not fare better than untreated controls. After 2 years of follow-up, there was a statistically significant treatment benefit, with 55% of treated patients versus 68% of control patients experiencing at least 15 letters of acuity decline. Further subgroup analysis (which was already of a subgroup of the recruited patients) showed that eyes with smaller lesions (4 disc areas or less) or lower levels of visual acuity (approximately Snellen equivalent of 20/50 or worse) at baseline did better than did eyes not having these characteristics. Patients who had occult with no classic CNV required a mean of 3.1 treatments during the first year and 1.8 during the second.

PDT for pathological myopia was studied in a multicenter randomized trial.[12] After 1 year of follow-up, 72% of the verteporfin-treated patients compared with 44% of the placebo-treated patients lost fewer than 8 letters of visual acuity (which corresponds to approximately 11/2 lines). A lower threshold was chosen, because pathological myopia frequently doesn’t cause as profound a visual loss as does AMD. Among treated patients, 32% improved by 5 letters, yet a different threshold, as compared with 15% of control patients. Two-year follow-up data had a less impressive difference with a loss of statistical significance.

NON-COMPARATIVE STUDIES.

Patients with CNV 5400?m or smaller secondary to ocular histoplasmosis syndrome were treated with PDT using verteporfin.[13] Analysis of data from 25 patients followed for 1 year showed a median improvement of 7 letters, and 56% of patients gained 7 or more letters, while 16% lost 8 or more letters. No ocular or systemic side effects were noted. Additional non-comparative studies have been performed independently of pharmaceutical company support and have examined idiopathic CNV, polypoidal choroidal vasculopathy, and CNV associated with multifocal choroiditis and panuveitis. A study of PDT using verteporfin for idiopathic subfoveal CNV in eight eyes of eight patients with a mean age of 34.6 years found that the mean improvement was of 3.6 lines of Snellen acuity after a mean of 13.5 months of follow-up.[14] The difference in visual acuity at the end of the follow-up period was significantly different than the baseline acuity (P = .027). Visual acuity improvement, defined as a halving of the visual angle, was seen in five of the eight patients. Some patients had a remarkable improvement of visual acuity. The mean number of treatments was 2.9. No patient had any treatment-related side effects. The incidence of side effects in alternative methods of treatment, such as vitrectomy, would be expected to be much higher.

Patients with polypoidal choroidal vasculopathy have a slowly progressive vascular growth associated with exudative manifestations typically seen in CNV, such as leakage and hemorrhage. However, the disease process seems to progress over a period of what may be many years. Sixteen patients with subfoveal involvement were treated with PDT, and they were followed for a mean of 12 months.[15] The mean age of the patients involved was 70.5 years. The visual acuity improved (defined as a halving of the visual angle) in nine (56.3%), remained the same in five (31.3%), and decreased (defined as doubling of the visual angle) in two (12.5 %). The mean change in visual acuity was an improvement of 2.38 lines, a difference that was highly significant. The mean number of treatments given was 2.3. One patient had an exudative detachment that resolved after 5 days. No patient had any permanent ocular or systemic side effects. Although the short-term results for

 

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treatment of polypoidal choroidal vasculopathy appear to be favorable, the long-term outcome is unknown. CNV secondary to AMD often will “burn out” and leave a fibrotic scar that sometimes appears to be devoid of vessels. Polypoidal choroidal vasculopathy almost never burns out. The vessels continue to expand, albeit slowly, with the threat of exudation and hemorrhage looming larger in lockstep. Although patients with polypoidal choroidal vasculopathy have a lessening of the exudation after PDT, the vessels, particularly the larger vascular channels, persist.

Multifocal choroiditis and panuveitis causes recurrent inflammation associated with punched-out chorioretinal atrophic spots and usually occurs in myopic young to middle-aged women. Subfoveal neovascularization sometimes may respond to corticosteroids but often will not. In a study of seven patients with subfoveal CNV, the mean change in acuity after a follow-up period of 10 months was an improvement of 0.86 lines, a change that was not statistically significant from the baseline acuity.[16] However, three patients (42.8%) had an improvement in visual acuity representing at least a halving of their visual angle, while the other four patients remained stable. The patients required a mean of 1.9 treatments. Four of the seven were being treated with corticosteroids at baseline, and by the end of the follow-up period none of the patients was using corticosteroids. No patient had any ocular or systemic side effects. Although the neovascularization showed good anatomical response, many patients with MCP have underlying abnormalities of the RPE and choroid that may limit visual recovery.

A curious complication of verteporfin infusion is the incidence of pain associated with the infusion. This pain usually starts a few minutes after the infusion is begun and stops a few minutes after the infusion is stopped. The pain usually occurs in the back, chest, or groin. Its incidence has been estimated from a little more than 2% to up to 9.6% of patients receiving an infusion. [17] The pain during infusion has been linked to transient neutropenia, most likely representing massive neutrophil margination, induced by infusion of the verteporfin.[17]

Additional Treatment Modalities

RADIATION.

CNV has been treated with a variety of dosages and types of ionizing radiation. Initial reports suggested that external beam radiotherapy was a beneficial treatment for CNV secondary to AMD.[18] Subsequent case series also reported what the authors believed was a favorable treatment effect from radiation. A larger series which compared 91 patients treated with 10?Gy (2?Gy in 5 fractions) of external beam photons and an historical control group recruited with similar entry criteria found no treatment benefit.[19] A multicenter parallel, randomized, double-masked clinical trial with sham controls administered 16?Gy (2?Gy in 8 fractions) of external beam photons to treated patients.[20] After 1 year, 51.1% of treated patients and 52.6% of control subjects lost 3 or more lines (P = .88). Analysis of classic versus occult disease showed no apparent treatment benefit in either subgroup. A prospective randomized trial using 14?Gy (2?Gy × 7) found no statistically significant differences in changes in visual acuity, contrast sensitivity, or fluorescein angiographic progression from baseline between groups after any follow-up period.[21] A randomized trial using a higher dosage of radiation, 24?Gy (6?Gy in 4 fractions), found a treatment benefit.[22] At follow-up after 12 months, 52.2% of the observation group versus 32.0% of the irradiation group had lost 3 or more lines of visual acuity (Snellen acuity was used), a significant result (P = .03). No complication, particularly radiation retinopathy, was seen in the short term of the follow-up. The number of patients lost to follow-up was significant.

SURGERY.

Submacular surgery has been used as an approach for a number of types of CNV. Surgical removal did not appear to have any benefit for most cases of CNV secondary to AMD, and most researchers have focused on other forms of CNV. Surgical technique has been refined over time, with a reduction in the number of complications. Unavoidable complications are expected with any vitrectomy surgery, such as the progression of nuclear sclerosis. A particularly difficult problem with surgical excision of CNV is the high rate of recurrence, which in large series has been reported as 57% in those with pathological myopia[23] and 52% of patients with ocular histoplasmosis[24] after 24 months. The Submacular Surgery Trials have been initiated to study the efficacy of sumacular surgery. The trials have recruited patients fully, but the Data and Safety Monitoring Committee has not come out with any recommendations yet.

Macular translocation involves moving the macula and varying amounts of adjacent retina to a new location, away from the ingrowth of the new vessels. This may be accomplished by limited translocation, in which a limited retinal detachment is made and the scleral wall is shortened by imbrication or outpouching, or there may be a 360-degree retinotomy, with a rotation of the entire retina. Some patients having translocation have had large amounts of acuity improvement. The complication rate is very high. In a series of 100 eyes with AMD undergoing limited inferior translocation follow-up, information was available for 86 eyes that were followed for 1 year.[25] The mean visual acuity at baseline was 20/160 and at the end of the follow-up period was 20/150. Of these, 52 (60.4%) achieved what the authors considered effective translocation and laser photocoagulation. Of those 52, an estimated 34.6% had recurrence of their neovascularization by the 12-month follow-up visit. The main complications included retinal detachment in 11.6%, retinal breaks in 4.7%, and macular fold in 3.5%. The incidence of cataract was not listed. The results of translocation surgery will probably improve with refinement in technique, but the complication rate is very high given the modest acuity results.

Pharmacological Therapy

Intravitreal triamcinolone has been studied in case series reports and in a randomized trial involving 27 patients. In the randomized trial, patients treated with intravitreal triamcinolone had better acuity after 3 and 6 months than did untreated controls, but they still suffered an acuity loss. Increased intraocular pressure was seen in 25% of treated patients.[26] In a recent study of combination intravitreal triamcinolone with PDT using verteporfin, the mean change in acuity for newly treated patients with any type of CNV secondary to AMD was an improvement of 1.9 lines after 3 months and an improvement of 2.4 lines after 6 months.[27] The need for retreatment because of recurrent leakage was much less than would be expected from PDT alone. Patients treated with the combination therapy had a statistically significant improvement in visual acuity, as compared with the expected decline in acuity for those treated with PDT alone. Anecortave acetate is an angiostatic steroid with no corticosteroid effects, which is being investigated using a posterior sub-Tenon injection every 6 months. The results of a phase II study are awaiting publication. An aptamer directed against VEGF165 has been investigated in a phase IA trial.[28] Of 15 patients treated with intravitreal injections, four improved by 3 or more lines with no apparent complications. A phase III trial is under way. An antibody fragment that binds to all isoforms of VEGF has undergone phase I study and is expected to undergo phase III study shortly.

 

 

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9. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trial—TAP report 1. Treatment of age-related macular degeneration with photodynamic therapy (TAP) study group. Arch Ophthalmol. 1999;117:1329–45.

 

10. Bressler NM. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials—TAP report 2. Arch Ophthalmol. 2001;119:198–207.

 

11. Verteporfin In Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization—verteporfin in photodynamic therapy report 2. Am J Ophthalmol. 2001;131:541–60.

 

12. Verteporfin In Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial—VIP report no. 1. Ophthalmology. 2001;108:841–52.

 

13. Saperstein DA, Rosenfeld PJ, Bressler NM, et al. Photodynamic therapy of subfoveal choroidal neovascularization with verteporfin in the ocular histoplasmosis syndrome: one-year results of an uncontrolled, prospective case series. Ophthalmology. 2002;109:1499–50.

 

14. Spaide RF, Martin ML, Slakter J, et al. Treatment of idiopathic subfoveal choroidal neovascular lesions using photodynamic therapy with verteporfin. Am J Ophthalmol. 2002;134:62–8.

 

15. Spaide RF, Donsoff I, Lam DL, et al. Treatment of polypoidal choroidal vasculopathy with photodynamic therapy. Retina. 2002;22:529–35.

 

16. Spaide RF, Freund KB, Slakter J, et al. Treatment of subfoveal choroidal neovascularization associated with multifocal choroiditis and panuveitis with photodynamic therapy. Retina. 2002;22:545–9.

 

17. Spaide RF, Maranan L. Neutrophil margination as a possible mechanism for verteporfin infusion-associated pain. Am J Ophthalmol. 2003. In press.

 

18. Chakravarthy U, Houston RF, Archer DB. Treatment of age-related subfoveal neovascular membranes by teletherapy: a pilot study. Br J Ophthalmol. 1993;77: 265–73.

 

19. Spaide RF, Guyer DR, McCormick B, et al. External beam radiation therapy for choroidal neovascularization. Ophthalmology. 1998;105:24–30.

 

20. A prospective, randomized, double-masked trial on radiation therapy for neovascular age-related macular degeneration (RAD Study). Radiation therapy for age-related macular degeneration. Ophthalmology. 1999;106:2239–47.

 

21. Marcus DM, Sheils W, Johnson MH, et al. External beam irradiation of subfoveal choroidal neovascularization complicating age-related macular degeneration: one-year results of a prospective, double-masked, randomized clinical trial. Arch Ophthalmol. 2001;119:275–6.

 

22. Bergink GJ, Hoyng CB, van der Maazen RW, et al. A randomized controlled clinical trial on the efficacy of radiation therapy in the control of subfoveal choroidal neovascularization in age-related macular degeneration: radiation versus observation. Graefes Arch Klin Exp Ophthalmol. 1998;236:321–5.

 

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