96 Solomon et al months later There is a higher incidence of CNV in eyes with GA at baseline that have fellow eyes with CNV GA is bilateral in more than half of the people with this condition The size and rate of progression of atrophy are highly correlated between the two eyes of patients with bilateral GA, but the acuities may differ due to central sparing Among eyes with GA with visual acuity better than 20/50, there is a 40% rate of three-line visual loss at 2 years Maximum reading rate can be significantly affected by encroachment of GA on the fovea, even while there may still be little change in visual acuity Eyes with GA have marked loss of vision in dim environments and benefit greatly from increased lighting The development of a preferred retinal locus (PRL) can aid in the effective utilization of the remaining functional retina ACKNOWLEDGMENTS This work was supported in part by a fellowship from the Heed Foundation (SDS), by NEI R01 EY 08552 (JSS), the James S Adams RPB 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Murphy RP Retinal pigment epithelial tears: patterns and progression Ophthalmology 1988;95:8–13 61 Marmor MF, McNamara JA Pattern dystrophy of the retinal pigment epithelium and geographic atrophy Am J Ophthalmol 1996;122:382–39 62 Krill AE, Archer D Classification of the choroidal atrophies Am J Ophthalmol 1917;72:562 63 Weisz JM, deJuan E, Humayun MS Sunness JS, Dagnelie G, Soylu M, Rizzo L, Nussenblatt RB Allogenic fetal retinal pigment epithelial cell transplant in a patient with geographic atrophy Retina 1999;19:540–545 6 Exudative Age-Related Macular Degeneration Jennifer I Lim Doheny Eye Institute, University of Southern California Keck School of Medicine, Los Angeles, California I INTRODUCTION Exudative age-related macular degeneration was first described and illustrated in the literature in 1875 by Pagenstecher and Genth (1) They termed the condition chorioidioretinitis in regione maculae luteae Oeller in 1905 first used the name “diskiform” degeneration (degeneratio maculae luteae disciformis) (2) Later, Junius and Kuhnt in 1926 further elaborated on this condition and established it as a disease (3) Holloway and Verhoeff in 1928 described eight eyes with disk-like degeneration of the retina (4), histopathology in some of these eyes was performed and showed choroidal neovascularization (CNV) In 1937, Verhoeff and Grossman also demonstrated and emphasized that blood vessels had erupted through Bruch’s membrane in their cases of macular degeneration (5) In 1951 Ashton and Sorsby demonstrated in clinicopathological correlations that CNV with breaks in Bruch’s membrane resulted in subretinal fluid (6) It was not until 1967 that Gass implicated CNV as having a primary role in senile diskiform macular degeneration (7,8) In 1971, Blair and Aaberg showed the clinical and fluorescein angiographic characteristics of CNV in senile macular degeneration (9) In 1976, Small et al published a clinicopathological correlation of the evolution of CNV with a serous pigment epithelial detachment (PED) to a diskiform scar (10) In 1977, Green and Key (11) studied the histopathological features of 176 eyes from 115 patients with age-related macular degeneration (AMD) They correlated the presence of drusen with CNV Their results supported the view that drusen predispose to development of exudative AMD Since the earliest description of AMD, numerous refinements in the categorization of the types of AMD have developed In fact, even the name AMD is relatively recent in history Prior to 1990, the term “senile macular degeneration” had been in common usage The two main types of AMD are nonexudative AMD and exudative AMD, referred to colloquially as dry AMD and wet AMD, respectively Nonexudative AMD is typically associated with less severe visual disturbances than exudative AMD Nonexudative AMD includes the broad spectrum of drusen with no visual disturbance to geographic atrophy, with severe visual loss In contrast, eyes with exudative AMD typically have some visual disturbance 101 102 Lim The nomenclature of exudative AMD was developed through the concerted efforts of the Macular Photocoagulation Group members and other investigators The exudative or neovascular form of AMD has the most serious prognosis in terms of visual acuity outcomes Exudative AMD includes eyes with pigment epithelial detachment (serous and hemorrhagic) and those with the presence of abnormal vessels in the subretinal or subretinal pigment epithelial space (sub- RPE) These abnormal vessels are known as CNV This chapter will focus upon exudative AMD An overview of the risk factors associated with development of exudative AMD, fundus characteristics in exudative AMD, fluorescein and indocyanine green (ICG) findings, and treatment options for the various types of exudative AMD will be presented Exudative AMD, although the less common form of AMD, is the leading cause of new blindness in the older-age population in the United States, accounting for 16% of all new cases of blindness over the age of 65 years Indeed, the majority of patients with severe visual loss have CNV (12) In fact, 79% of eyes legally blind in the Framingham Study and 90% of legally blind eyes in a large case-control study had neovascular AMD (13,14) With the aging of the U.S population, AMD is reaching epidemic proportions In the United States alone, there are 50,000 new cases of CNV due to AMD each year II RISK FACTORS Numerous candidate risk factors are associated with the development of CNV in AMD These risk factors are discussed in great depth within this book in another chapter Of the nonocular risk factors, it appears that the strongest epidemiological associations are age, race, and smoking There are also ocular risk factors with strong associations for development of CNV as discussed below Increased age is associated with increasing risk of neovascular AMD Patients with exudative AMD have a mean age of 70.5 years versus 56.8 years for non-exudative AMD (15) Gender is not consistently associated with neovascular AMD Racial differences in the prevalence of exudative AMD (and also early AMD) exist Gregor and Joffe (16) reported that diskiform AMD was found in 3.5% of the white patients compared to 0.1% of the black South African patients (p < 0.001) The Baltimore Eye Survey found a prevalence ratio of white:black of 8.8 for neovascular AMD (17) The Barbados Eye Study found neovascular AMD in 0.6%, which is comparable to that found in the Maryland Waterman Study but lower than the 1.2% in the Beaver Dam Eye Study (18) In NHANES-III, the odds ratio for late AMD was 0.34 for non-Hispanic blacks compared to non-Hispanic whites and 0.25 for Mexican-Americans compared to nonHispanic whites (19) Thus, the prevalence is higher in Caucasians Family history is a risk factor for the development of AMD, including the exudative form The Blue Mountain Eye Study showed an odds ratio of 4.30 for neovascular AMD in patients with a family history (20) Klaver and colleagues noted a lifetime risk estimate of late AMD to be 50% for relatives of patients versus 12% for relatives of controls (21) Smoking is correlated with exudative AMD in most studies, although it was not linked to AMD in the Framingham Study (13) and the NHANES-III Study (22) The Beaver Dam Eye Study (23) linked smoking to exudative AMD with a relative risk of 3.29 for current smokers and a relative risk of 2.50 for former smokers compared to those who had never smoked In the Blue Mountain Eye Study (24), the odds ratio for exudative AMD was 4.46 when comparing current smokers to those who never smoked and 1.83 when com- Exudative AMD 103 paring former smokers to those who never smoked The POLA study showed an increasing odds ratio for exudative AMD when examining the number of pack-years smoked This higher risk of exudative AMD remained even until 20 years after cessation of smoking The association between sunlight exposure and late AMD is not clear at this time The Chesapeake Bay Waterman Study found an association between late AMD and sunlight (25) as did the Beaver Dam Eye Study (26) Yet, the EDCCS (27) and the Australian casecontrol study on sun exposure and AMD (28) did not show this same association Since the use of sunglasses (ultraviolet blocking) is relatively inexpensive and also protective against cataract formation, it is reasonable to recommend sunglass protection for older patients There have been reports of progression of early to late AMD following cataract surgery The Beaver Dam Eye Study showed an odds ratio of 2.80 for progression of AMD to late AMD after cataract surgery (and after controlling for age) (29) Pollack and colleagues also noted that progression to exudative AMD occurred in 19.1% of eyes operated on for cataracts versus 4.3% of the fellow eye (30, 31) The risk of CNV developing in patients has been linked to the presence of several fundus characteristics, among which are the presence of soft drusen Lanchoney and associates calculated the risk of CNV developing in patients with bilateral soft drusen to range from 8.6% to 15.9% within 10 years, depending upon the age and sex of the patient (32) These projections were based upon natural history studies of Smiddy and Fine (15) and Holz et al (33) The MPS group has determined the ocular risk factors for development of CNV in the fellow eye (when the opposite eye already has CNV) to include the presence of (5) or more drusen, focal hyperpigmentation, one or more large drusen (>63 microns), and systemic hypertension (34) The 5-year incidence rate for development of CNV ranged from 7% if none of these risk factors was present to 87% if all four risk factors were present This was based upon follow-up of patients with juxtafoveal CNV The role of antioxidants and vitamins in the prevention of AMD is being actively researched in multicenter clinical trials The role of nutritional supplementation with zinc, beta-carotene, and vitamin E and vitamin C was studied in the AREDS study The Physicians’ Health Study II is also evaluating the role of vitamin E, vitamin C, betacarotene, and a daily multivitamin The Vitamin E, Cataract and Age-Related Macular Degeneration Trial (VECAT) and the Women’s Health Study (WHS) are two other randomized trials assessing the risk and benefits of antioxidant vitamins for AMD The role of zinc and vitamins A, C, E supplementation for prevention of exudative AMD has been shown to be beneficial in the AREDS study Until the risk factors and genetics are determined, prevention of exudative AMD remains an enigma It is a difficult area for counseling patients At this time; modifiable risk factors (such as smoking, hypertension) should be addressed Whether prophylactic therapy such as laser to drusen is determined to be of benefit for prevention of CNV remains to be determined Future application of genetic therapy and targeted antiangiogenesis treatments will most likely play a role in the prevention of exudative AMD and attendant visual acuity loss III CLINICAL FEATURES OF EXUDATIVE AMD Patients with exudative AMD may present with complaints of sudden onset of diminished vision, metamorphopsia, central scotoma, or paracentral sootoma (35) Others may present 104 Lim with loss of vision in their previously “good eye” and may not have even recognized any visual symptoms in the fellow eye with a scar (36) Yet others may present with no ocular symptoms and be noted to have ophthalmoscopic evidence of CNV in the second eye despite a prior CNV in the fellow eye (37) Thus, patients who have risk factors for CNV should be periodically examined for development of CNV and should be encouraged to monitor their vision daily, such as by the use of an Amsler grid Other patients with cataracts may attribute their visual blurring to the cataract and the treating ophthalmologist may not detect the underlying PED or CNV These patients may undergo cataract extraction and complain of persistent poor vision postoperatively Postoperatively, the macular lesion can now be detected A careful preoperative examination for exudative AMD or advanced nonexudative AMD is therefore of utmost importance in patients with known AMD Fluorescein angiography preoperatively may help detect CNV Alternatively, if the cataract totally obscures the view of the fundus, an ultrasound may be useful in detecting macular fluid or subretinal scar formation (38) A useful test for detecting the early visual symptoms in patients with AMD is the Amsler grid (39) Each box on the grid represents one degree of visual field Thus, it tests the central 10 degrees straddling fixation The patient should look at the Amsler grid daily The patient may note that the Amsler grid is distorted, missing areas, or has black spots If these findings are present, the patient should be instructed to see an ophthalmologist immediately for an examination for exudative AMD A newly developed, computerautomated, three-dimensional threshold Amsler grid visual field test is currently being tested and may also show promise in the earlier detection of exudative AMD (personal communication, Alfredo A Sadun, M.D., Ph.D., and Wolfgang Fink, Ph.D., Los Angeles) Another useful test is to have the patient look at the thin slit lamp beam during biomicroscopy The patient is asked if the beam is distorted Frequently elevation of the RPE or retina (due to underlying CNV) causes distortion of the beam The major clinical features of active exudative AMD include subretinal fluid, subretinal hemorrhage, sub-RPE fluid, sub-RPE hemorrhage, RPE pigment alterations, and hard exudates These features may appear clinically as any one or any combination of the following: a serous or a hemorrhagic PED, grayish subretinal membrane (Fig 1, Fig 2) area of RPE alteration (Fig 3), subretinal hemorrhage (Fig 4), or hard exudates (Fig 3) The late manifestation of exudative AMD is a diskiform scar (Fig 5) or geographic atrophy (Fig 6), with or without subretinal fluid or subretinal blood It is best to examine a patient with suspected CNV and AMD using the best stereo- imaging possible A fundus contact or non-contact lens in conjunction with slit lamp biomicroscopy should be utilized for the examination For those less comfortable with the noncontact fundus macular lenses, a fundus contact lens is easiest to use The fundus contact lens or the 78-diopter lens offers more magnification than the 90-diopter lens Using biomicroscopy with a macular lens, the separation of the retina from the underlying RPE, due to underlying subretinal fluid, can be seen The overlying retina may have cystic changes and may show cystoid macular edema Sub-RPE fluid appears as a PED and typically has more sharply demarcated borders in comparison to subretinal fluid (Fig 7) Often, a combination of sub-RPE and subretinal fluid is associated with the CNV (Fig 8) The CNV itself may be visible as an area of discoloration (Fig 9) Other times, overlying subretinal blood or lipid may be the only clinical clue to the presence of an acute CNV The definitive test for the presence of CNV has been fluorescein angiography This is further discussed below Exudative AMD 105 Figure 1 Subfoveal gray pigmented CNV Soft large drusen surround CNV See also color insert, Fig 6.1 Figure 2 (A) Upper left: Color photo of the left eye shows an atrophic extrafoveal laser scar surrounded by a grayish subretinal lesion There is overlying subretinal fluid (B) Upper right: Fluorescein angiogram shows early lacy hyperfluorescence in the subfoveal area surrounding the laser scar Note the ring of blocked fluorescence around the lacy CNV There is some extrafoveal occult CNV beyond the blocked fluorescence (C) Lower left: Occult CNV is present and surrounds the blocked fluorescence around the classic CNV (D) Lower right: The occult and the classic components show late leakage See also color insert, Fig 6.2 Indocyanine Green 137 A C B D Figure 3 Occult CNV with PED (V-PED) (A) Clinical photograph demonstrating an irregularly shaped PED with turbid yellowish sub-RPE fluid (B) Late-phase FA study demonstrating hyperfluorescence of the serous PED Note the inferior notch (C) Early-phase ICG study demonstrating a well-defined hypofluorescent serous PED Because of the turbidity of the fluid, the underlying choroidal vessel cannot be visualized (D) Late-phase ICG study demonstrating a persistent hypofluorescent serous PED A focal area of hyperfluorescence (hot spot) within the notch of the PED is seen, consistent with active CNV See also color insert, Fig 7.3A Hot Spot (Focal CNV) Focal CNV or a “hot spot” is an area of occult CNV that is both welldelineated and no more than 1 disc diameter in size on ICG angiography (Figs 3–5) Also, a hot spot represents an area of actively proliferating and more highly permeable areas of neovascularization (active occult CNV) (Fig 6) Chorioretnal anastomosis (CRA) and polypoidal-type CNV may represent two subgroups of hot spots (see below) Plaque A plaque is an area of occult CNV larger than 1 disk diameter in size A plaque often is formed by late-staining vessels, which are more likely to be quiescent areas of neovascularization that are not associated with appreciable leakage (inactive occult CNV) (Fig 7) Plaques of occult CNV seems to slowly grow in dimension with time (Fig 8) Well-defined and ill-defined plaques are recognized on ICG study A well-defined plaque 138 Ciardella et al A C B D Figure 4 Occult CNV with PED (A) Late-phase fluorescein study in a patient with AMD demonstrating hyperfluorescence of a serous PED No classic CNV was identified (B) Highmagnification, early ICG study demonstrating a well-defined area of CNV along the nasal margin of the serous PED (C) Late-phase fluorescein study demonstrating hyperfluorescence of a serous PED, with irregular mottled hyperfluorescence along its nasal margin No classic CNV is seen (D) Early ICG study demonstrating a hot spot of active CNV at the inferior margin of the PED The PED itself appears hypofluorescent has distinct borders throughout the study and the full extent of the lesion can be assessed An ill-defined plaque has indistinct margins or may be one in which any part of the neovascularization is blocked by blood In a review of our first 1000 patients with occult CNV by FA that were imaged by ICG angiography, three morphological types of occult CNV were noted: focal CNV or hot spots, plaques (well defined and ill defined), and combination lesions in which both hot spots and plaques were noted The relative frequency of these lesions was: hot spots 29%, plaques 61%, combined lesions 8% Combination lesions were further subdivided into marginal spots (hot spots at the edge of plaques of neovascularization); overlying spots (hot spots on top of plaques of neovascularization); and remote spots (hot spots not in contiguity with plaques of neovascularization) (36) Two other forms of occult CNV are identified by ICG angiography: retinal-choroidal anastomosis (RCA) and polypoidal-type CNV Indocyanine Green A 139 B Figure 5 Occult CNV with sub-RPE hemorrhage and focal spot (A) Clinical photograph demonstrating a subretinal hemorrhage in the central macula in a patient with AMD (B) Late-phase fluorescein study demonstrating blocked fluorescence from the hemorrhage No CNV could be identified (C) Earlyphase ICG study demonstrating good visualization of choroidal circulation beneath the thin layer of hemorrhage A focal spot of CNV is seen See also color insert, Fig 7.5A C A B Figure 6 Active occult CNV (A) Clinical photograph demonstrating a serous PED in the central macula (B) Early-phase ICG study demonstrating intense hyperfluorescence of the CNV along the inferonasal margin of the PED (C) Late-phase ICG study revealing increased hyperfluorescence and leakage of ICG dye along the active CNV See also color insert, Fig 7.6A C 140 Ciardella et al A B Figure 7 Inactive occult CNV (A) Clinical photograph demonstrating thickening of the RPE and chronic exudative changes in the central macula (B) Early-phase ICG study demonstrating hyperfluorescence of a large, well-defined neovascular vessel located in the central macula (C) Late-phase ICG study demonstrating the full extent of the CNV The larger vessels of the plaque, which filled early in the study, are now hypofluorescent, appearing in relief against the background of the neovascular lesion See also color insert, Fig 7.7A C Retinal-Choroidal Anastomosis RCA are present in 20–93% of cases of focal hot spots of CNV noted on ICG study (37,38) (Figs 9–12) Clinical characteristics helpful in the identification of RCAs are: 1 Presence of intraretinal hemorrhages at the site of the hot spot identified on ICG study 2 Intraretinal leakage of ICG dye in a cystoid macular edema pattern overlying the area of neovascularization 3 Presence of a V-PED on ICG study 4 Highlighting of the RCA with laser treatment (the RCA remains reddish in color and is surrounded by the whitening of the retina after laser treatment) Stereoscopic view of the ICG study allows direct recognition of the network of vessels that form the RCA The identification of any of these clinical findings associated with focal hyperfluorescence on the ICG study in association with a PED bodes poorly for successful laser treatment and control of the exudative process (37) Lafaut et al recently reported on the clinicopathological correlation of RCA in AMD They found that RCA represents histologically neovascularization growing out of the neuroretina, into the subretinal space, which mimics choroidal neovascularization (39) Polypoidal-Type Occult CNV A recent observation is the recognition of hot spots of focal CNV with a polypoidal-like appearance on ICG angiography These areas of focal CNV are more often found near the optic disk, may be associated with a serosanguineous PED, and seem to better respond to direct laser photocoagulation (Figs 13, 14) Indocyanine Green 141 A C B D Figure 8 Natural history of occult CNV with plaques (A) Late-phase ICG study demonstrating a plaque of CNV in the central macula No laser treatment was performed (B) Late-phase ICG study obtained 18 months later demonstrates enlargement of the plaque of CNV (C) Late-phase ICG study of the fellow eye of the same patient on initial presentation demonstrating only minimal irregular hyperfluorescence in the macula (D) Late-phase ICG study 18 months later demonstrating a larger, well-defined area of plaque of CNV IX CLINICAL APPLICATION OF ICG ANGIOGRAPHY TO THE STUDY OF AMD Patz and associates (23) were the first to study CNV by ICG videoangiography They could resolve only two of 25 CNVs with their early model Bischoff and Flower (16) studied 100 ICG angiograms of patients with age-related macular degeneration They found “delayed and/or irregular choroidal filling” in some patients The significance of this finding is unclear, however, because these authors did not include an age-matched control group Tortuous choroidal vessels and marked dilation of macular choroidal arteries, often with loop formation, were also observed Hayashi and associates (17,18,20) found that ICG videoangiography was useful in the detection of CNV ICG videoangiography was able to confirm the fluorescein angiographic appearance of CNV in patients with well-defined.CNV It revealed a more well-defined neovascularization in 27 eyes with occult CNV by FA In a subgroup of patients with poorly defined occult CNV, the ICG angiogram, but not the FA, imaged a well-defined 142 A C E Ciardella et al B D F Figure 9 Occult CNV with serous PED and RCA (A) Clinical photograph demonstrating exudation in the central macula with subretinal hemorrhage, lipid, and a serous PED (B) Late-phase FA demonstrating occult CNV There is hyperfluorescence of the PED and blockage by the hemorrhage No well-defined CNV is seen (C) Midphase ICG study demonstrating a hot spot in the superonasal portion of the PED On stereoscopic examination, a RCA was identified in this region Focal laser treatment of the hot spot was performed (D) Clinical photograph 3 months following treatment demonstrating persistent turbid detachment of the PED and subretinal hemorrhage (E) Early-phase ICG study demonstrating multifocal hyperfluorescence at the site of prior laser treatment, indicative of recurrent CNV (F) Late-phase ICG demonstrating persistent hyperfluorescence and leakage at the site of the RCA See also color insert, Fig 7.9A, D Indocyanine Green A 143 B Figure 10 Occult CNV with serous PED and RCA (A) Red-free clinical photograph demonstrating a serous PED, submacular exudation, lipid deposition, and intraretinal hemorrhage (B) Mid-phase ICG study reveals the presence of an anastomosis between two retinal vessels and the underlying neovascular complex A B Figure 11 Occult CNV with serous PED and RCA (A) Midphase ICG study demonstrating a RCA and an associated serous PED (B) Late-phase ICG study reveals the presence of intraretinal leakage of ICG dye in a “cystoid macular edema” configuration CNV in nine of 12(75%) cases ICG videoangiography of the other three eyes revealed suspicious areas of neovascularization Hayashi and co-workers (17, 18, 20) were also the first to show that leakage from CNV with ICG was slow compared to the rapid leakage of sodium fluorescein While the results of these investigators concerning ICG videoangiographic imaging of occult CNV were promising, the spatial resolution that they could obtain was limited by the 512-line video monitor and analog tape of their ICG system Destro and Puliafito (21) reported that ICG videoangiography was particularly useful in studying occult CNV with overlying hemorrhage and recurrent CNV Guyer and coworkers (3) used a 1024-line digital imaging system to study patients with occult CNV These authors reported that ICG videoangiography was useful in imaging occult CNV and that this technique could allow photocoagulation of otherwise untreatable lesions Scheider and co-investigators (40) have reported enhanced imaging of CNV in a study of 80 patients using the scanning laser ophthalmoscope with ICG videoangiography 144 Ciardella et al A B C D Figure 12 Occult CNV with serous PED and RCA (A) Clinical photograph demonstrating hemorrhage, subretinal lipid exudates, and a PED in the macula (B) Red-free photograph reveals the presence of two RCAs in the superior macula (C) Midphase ICG study shows the presence of a serous PED and two hot spots corresponding to the RCAs (D) Clinical photograph obtained immediately following laser treatment of the two sites of CNV The reddish lesion now highlighted within the treatment site represents a network of vessels rather than hemorrhage See also color insert, Fig 7.12A Yannuzzi and associates (4) have shown that ICG videoangiography is extremely useful in converting occult CNV into classic well-defined CNV In their study, 39% of 129 patients with occult CNV were converted to well-defined CNV based on information added by ICG videoangiography These authors reported that ICG videoangiography was especially useful in identifying occult CNV in patients with serous pigment epithelial detachment (SPED) or with recurrent CNV Lim et al found that ICG angiography added useful clinical information to FA by demonstrating well-demarcated areas of hyperfluorescence in 50% of eyes selected because of diagnosis of occult CNV and in 82% of eyes selected because of PED (41) Yannuzzi et al studied the ICG atigiograms of 235 consecutive AMD patients with occult CNV and associated vascularized PED These eyes were divided into two groups, depending on the size and delineation of the CNV Of the 235 eyes, 89 (38%) had a solitary area of neovascularization that was well delineated, no more than 1 disk diameter in size, and defined as “hot spots” of focal CNV The other 146 eyes (62%) had a larger area of neovascularization, with variable delineation defined as a plaque CNV (42) Indocyanine Green 145 A C E B D F Figure 13 Polypoidal-type occult CNV with subretinal hemorrhage (A) Clinical photograph demonstrating subretinal hemorrhage secondary to CNV (B) Late-phase FA study demonstrating blocked fluorescence by the hemorrhage and an area of hyperfluorescence in the nasal juxtafoveal area (C) Early-phase ICG study demonstrating localized hyperfluorescence in the peripapillary region This area does not correspond to the hyperfluorescence seen on FA study (D) Highmagnification image of the localized CNV Note the polypoidal-like appearance of the neovascular complex This lesion was photocoagulated (E) Clinical photograph 3 months after laser treatment demonstrating resolution of the subretinal hemorrhage (F) FA study demonstrating hypofluorescence at the site of treatment The hyperfluorescence noted on the original fluorescein corresponds to an area of RPE atrophy See also color insert, Fig 7.13A, E 146 Ciardella et al A C B D Figure 14 Polypoidal-type occult CNV with subretinal hemorrhage (A) Color photograph demonstrating hemorrhagic detachment of the macula Note the absence of drusen at the posterior pole (B) Late-phase FA study demonstrating blocked fluorescence by the subretinal hemorrhage and intense hyperfluorescence in the papillomacular bundle (C) Late-phase ICG study demonstrating a hot spot in the papillomacular bundle On higher magnification the hot spot presented a polypoidal-like appearance (D) Clinical photograph 1 year after ICG-guide laser treatment demonstrating resolution of the subretinal hemorrhage Visual acuity improved from 20/200 to 20/25 See also color insert, Fig 7.14A, D In a further report, 657 consecutive eyes with occult CNV by fluorescein angiography were studied with ICG angiography Of 413 eyes with occult CNV without pigment epithelium detachments, focal areas of neovascularization were noted in 89(22%) Overall, 142 eyes (34.3%) had lesions that were potentially treatable by laser photocoagulation based on additional information provided by ICG angiography Of the 235 eyes with occult CNV and vascularized PEDs, 98 (42%) were eligible for laser therapy based on ICG angiography findings The authors calculated that ICG angiography enhances the treatment eligibility by approximately one-third (43) In an expanded series the same authors reported their results on ICG angiography study of 1000 consecutive eyes with occult CNV by fluorescein angiography (44) They recognized three morphological types of CNV, which included focal spots, plaques (well defined and poorly defined), and combination lesions (in which both focal spots and plaques are noted) Combination lesions were further subdivided into marginal spots (fo- Indocyanine Green 147 cal spots at the edge of plaque of neovascularization), overlying spots (hot spots overlying plaques of neovascularization), or remote spots (a focal spot remote from a plaque of neovascularization) The relative frequency of these lesions was as follows: focal spots 29%; plaques 61%, consisting 27% of well-defined plaques and 34% of poorly defined plaques; and combination lesions 8%, consisting of 3% of marginal spots, 4% of overlying spots, and 1% of remote spots (44) A follow-up study from the same authors of patients with newly diagnosed unilateral occult CNV secondary to AMD showed that the patients tended to develop the same morphological type of CNV in the fellow eye (45) Finally, Lee et al reported on 15 eyes with surgically excised subfoveal CNV that underwent preoperative and postoperative ICG angiography All excised membranes were examined by light microscopy, and all surgically excised ICG-imaged membranes corresponded to sub-RPE and subneurosensory retinal CNV (46) Chang et al (47) reported on the clinicopathological correlation of AMD with CNV detected by ICG angiography Histopathological examination of the lesion revealed a thick subretinal pigment epithelium CNV corresponding to the plaque-like lesion seen with ICG angiography The above studies demonstrate that ICG videoangiography is an important adjunctive study to FA in the detection of CNV FA appears to be more sensitive than ICG videoangiography in imaging fine capillaries that connect larger vessels and capillaries at the proliferating edge of well-defined CNV While FA may image well-defined CNV better than ICG videoangiography in some cases, ICG videoangiography can enable treatment of about 30% of occult CNV by the detection of well-defined CNV eligible for ICG-guided laser treatment in about 30% of cases (36,48) Thus, the best imaging strategy to detect CNV is to perform FA and ICG videoangiography X ICG-GUIDED LASER TREATMENT OF CNV IN AMD Patients potentially eligible for laser photocoagulafion therapy by ICG guidance are the ones with clinical and FA evidence of occult CNV The technique for ICG-guided laser photocoagulation has been previously described and is illustrated in Figure 15 Of the two types of occult CNV that can be identified by ICG study, hot spots and plaques, we recommend direct laser photocoagulation only of hot spots In fact, as mentioned above, hot spots represent areas of actively leaking neovascularization that can be obliterated by laser photocoagulation in an attempt to eliminate the associated serosanguineous complications, and stabilize or improve the vision On the contrary, plaques seem to represent a thin layer of neovascularization that is not actively leaking and may not require laser photocoagulation (Figs 16–19) This approach has practical considerations In the case of a lesion with both a hot spot and a plaque, and in which the hot spot is at the margin of the plaque (which may extend under the fovea), one applies laser photocoagulation to the extrafoveal hot spot and spares the foveal area This treatment approach was successful in obliterating the CNV and stabilizing the vision in 56% of a consecutive series of AMD patients (48) On the contrary, we have had poor success with direct laser treatment of hot spots overlying plaques, and confluent treatment of the entire plaque Two subtypes of hot spots are RCA and polypoidal-type CNV When a RCA is present, the success of laser photocoagulation is negatively influenced by the presence of an 148 Ciardella et al A B C D E F Figure 15 Occult CNV treatment technique (A) Clinical photograph demonstrating a subretinal hemorrhage in the macular area (B) Midphase fluorescein study demonstrating blocked fluorescence by the hemorrhage There is mild staining in the papillomacular bundle and peripapillary region (C) Late-phase ICG study demonstrating less blocked fluorescence centrally, with a triangular area of faint hyperfluorescence nasal to fixation (D) Red-free photograph with overlying tracing of the lesion noted on ICG study, used as guide for laser treatment (E) Red-free photograph immediately after laser treatment demonstrating the extent of the photocoagulation application (F) Clinical photograph obtained 6 months after treatment demonstrating mottling of the RPE at the site of laser treatment and complete resolution of the subretinal hemorrhage See also color insert, Fig 7.15A, D Indocyanine Green 149 A B C D E F Figure 16 ICG-guided laser treatment of occult CNV with serous PED (A) Clinical photograph demonstrating a large, lobular serous PED in the temporal macula (B) Late-phase FA study revealing hyperfluorescence of the serous component of the PED Nasally there is an area of irregular hyperfluorescence suggesting occult CNV (C) Early-phase ICG study demonstrating hyperfluorescence of the serous PED, with focal hyperfluorescence corresponding to CNV along the nasal margin of the PED (D) Clinical photograph immediately after ICG-guided laser treatment of the CNV (E) Clinical photograph 1 month later demonstrating partial resolution of the PED and a chorioretinal scar at the site of the treatment (F) Four years later there is flattening of the PED Fibrous metaplasia is seen temporally at the site of prior exudation See also color insert, Fig 7.16A, D, E, F 150 A C Ciardella et al B D Figure 17 ICG-guided laser treatment of occult CNV (A) Clinical photograph revealing an exudative macula detachment, with multiple confluent drusen beneath the neurosensory elevation (B) Late-phase FA study revealing diffuse leakage under the neurosensory retina Hyperfluorescent drusen are seen nasally (C) Late-phase ICG study demonstrating a hot spot of focal, active CNV in the juxtafoveal region (D) Clinical photograph 1 month after ICG-guided laser photocoagulation of the hot spot of focal CNV There is complete resolution of the neurosensory detachment of the macula See also color insert, Fig 7.17A, D associated serous PED In a small series of patients with RCA and associated PED, laser photocoagulation was successful in closing the CNV in only 14% of cases (37) Slakter and associates (49) performed ICG-guided laser photocoagulation in 79 eyes with occult CNV The occult CNV was successfully eliminated Visual acuity was stabilized or improved in 29 (66%) of 44 eyes with occult CNV associated with neurosensory retinal elevations, and in 15 (43%) of 35 eyes with occult CNV associated with PED This study demonstrated that in some cases ICG videoangiography imaging can successfully guide laser photocoagulation of occult CNV In another pilot study of ICG-guided laser treatment of occult CNV, Regillo et al had similar results (50) Guyer and co-workers reported on a pilot study of ICG-guided laser photocoagulation of 23 eyes that had untreatable occult CNV secondary to AMD with focal spots at the edge of a plaque of neovascularization on the ICG study ICG-guided laser photocoagulation was applied solely to the focal spot at the edge of the plaque At 24 months of follow- Indocyanine Green 151 A B C D Figure 18 Peripapillary occult CNV with subretinal hemorrhage (A) Clinical photograph demonstrating subretinal hemorrhage surrounding the optic nerve (B) Midphase ICG study demonstrating a small hot spot of CNV in the peripapillary area A large, irregular area of faint hyperfluorescence is seen in the central macula, suggestive of a quiescent plaque of CNV (C) Posttreatment clinical photograph demonstrating resolution of the subretinal hemorrhage (D) Posttreatment late-phase ICG study demonstrating an hypofluorescent scar at the site of laser treatment (Case courtesy of Dr Kurt Gitter.) up anatomical success with resolution of the exudative findings was obtained in 6 (37.5%) of 16 eyes (48) Importantly, these studies set the foundation for future prospective studies of ICG-guided laser treatment In addition, they proved that the presence of a PED is a poor prognostic factor in the treatment of exudative AMD A recent study prospectively evaluated 185 consecutive eyes with exudative AMD and a well-delineated area (hot spot or focal area) of hyperfluorescence by ICG angiography All the patients were divided into two groups (with PED and without PED) Of the 185 eyes, 99 eyes without PED achieved a 71% rate of obliteration at 6 months and 48% rate of obliteration at 12 months Eyes with PED did significantly worse with an obliteration rate of the CNV of 23% at 12 months The overall success rate was 36% at 12 months (36) A possible explanation for the high recurrence rate after laser photocoagulation of occult CNV, particularly when a vascularized PED is present, may be found in the peculiar anatomy of the CNV in such cases It has recently been observed that there is a variant of CNV where the neovascularization is fed both by a choroidal and by a retinal component to create a retinochoroidal anastomosis ... alleles with age-related macular degeneration Am J Hum Genet 2000;67:487–491 32 Yates JR, Moore AT Genetic susceptibility to age-related macular degeneration J Med Genet Feb 2000 ;37 (2): 83? ??87 33 Gass... advanced age-related macular degeneration Ophthalmology 1989;96 :37 5? ?38 1 44 Macular Photocoagulation Study Group Five-year follow-up of fellow eyes of patients with age-related macular degeneration. .. 1996;114:1518–15 23 27 Age-Related Eye Disease Study Research Group Risk factors associated with age-related macular degeneration: a case-control study in the Age-Related Eye Disease Study: Age-Related