VISUAL FIELD IN AREOLAR ATROPHY OF THE RETINAL PIGMENT EPITHELIUM ASSOCIATED WITH AGE-RELATED MACULAR DEGENERATION

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1 Visual field in areolar atrophy of the retinal pigment epithelium 483 VISUAL FIELD IN AREOLAR ATROPHY OF THE RETINAL PIGMENT EPITHELIUM ASSOCIATED WITH AGE-RELATED MACULAR DEGENERATION ALESSANDRO MAGNASCO 1, PAOLO CAPRIS 1, MARIO ZINGIRIAN 1 and ENRICO GANDOLFO 2 1 Department of Neurological Sciences and Vision, Ophthalmology B, University of Genoa, Genoa; 2 Department of Ophthalmology, University of Brescia, Brescia; Italy Abstract Areolar atrophy of the retinal pigment epithelium (RPE) is an important stage in age-related macular degeneration (AMD). Areolar atrophy of the RPE is the progression of tiny areas of reticulated hypo- and hyperpigmentation in the central macula. These atrophic areas are more likely to cause visual field disturbances than drusen, which do not typically cause visual field dysfunction. The aim of this study was to compare the visual field defects with the angiographic findings in areolar atrophy of the RPE associated with AMD. Twenty-four eyes of 14 patients with AMD, aged from 52 to 83 years, were tested with the Central 10-2 and Macula Programs of the Humphrey Visual Field Analyzer. Fluorescein and indocyanine green videoangiography by Topcon IMAGEnet H1024 Digital Imaging System (Paramus, NJ) were performed in all patients. The Macula Program was able to detect macular RPE atrophy areas with a diameter of at least 750 µm. The Central 10-2 Program revealed reduction of macular sensitivity, but was not able to detect the small RPE atrophy areas. The study showed good correspondence of the areas of macular RPE atrophy with the visual field defects. Introduction Age-related macular degeneration (AMD) is the leading cause of severe visual loss in the western world 1 in people over 50 years of age. AMD is considered an alteration of the retinal pigment epithelium, Bruch s membrane and choriocapillaris. Areolar atrophy is an area of well-demarcated atrophy of the retinal pigment epithelium (RPE) in which the overlying retina appears to be thin or where there are tiny areas of reticulated hypo- and hyperpigmentation of the RPE in the central macula. The characteristic well-defined areolar atrophy of macular RPE generally occurs in patients over 70 years of age. In younger patients, tiny areas of reticulated hypo-hyperpigmentation or focal hyperpigmentation are more common. Fluorescein angiography shows varying degrees of loss of the choriocapillaris within the areolar area of atrophy, Address for correspondence: Alessandro Magnasco, MD, Department of Neurological Sciences and Vision, Ophthalmology B, University of Genoa, S. Martino Hospital, Pad.9, Largo R. Benzi, 10, Genoa, Italy Perimetry Update 1998/1999, pp Proceedings of the XIIIth International Perimetric Society Meeting, Gardone Riviera (BS), Italy, September 6 9, 1998 edited by M. Wall and J.M. Wild 1999 Kugler Publications, The Hague, The Netherlands

2 484 A. Magnasco et al. presumably resulting from increased transmission of choroidal fluorescence due to hypopigmentation, attenuation, or lack of RPE. In the late frames of the angiogram, persistent staining of the areas of areolar atrophy will be noted, probably due to increased visibility of fluorescein staining of the choroidal and scleral tissue through the atrophic RPE. The focal areas of hyperpigmentation are at the level of the outer retina 2. Clinical studies have shown that focal clumps of hyperpigmentation are associated with an increased risk of the development of choroidal neovascularization (CNV). Non-areolar atrophy refers to tiny mottled areas of hypo- and hyperpigmentation that may show some thinning of the overlying sensory retina. Indocyanine green (ICG) videoangiography with an efficient and sensitive system provides an enhanced image of the choroidal circulation and helps to detect occult choroidal neovascularization 3. In our study, ICG videoangiography was helpful in detecting areolar atrophy, hypoand hyperpigmentation of the RPE with underlying or adjacent occult choroidal neovascularization. Perimetry represents a non-invasive and easy technique to evaluate modifications of macular light sensitivity in AMD. The Central 10-2 and Macula Programs of the Humphrey Visual Field Analyzer (VFA) II 750 can help to define the full extent of a small localized defect in the macular area 4,5. The purpose of this study was to evaluate how conventional computerized automated perimetry was able to detect small defects in the macular area and to correlate the areas of visual sensitivity loss with areolar atrophy and focal hypo-and hyperpigmentation of the RPE associated with AMD. Subjects and methods Twenty-four eyes of 14 patients with non-exudative AMD, aged from 52 to 83 years (average age 72 years), with a visual acuity ranging from 0.5 to 1.0 (average acuity 0.65), were studied. Patients with exudative AMD, diabetes mellitus and other ocular or systemic disease which may affect macular function were excluded. Inclusion and exclusion criteria are summarized in Table 1. The macula was defined anatomically as that part of the retina centered on the foveola in which the ganglion cell layer is more than one cell in thickness, measuring 5500 µm in total diameter and subtending an angle of 18, which corresponds to a central visual field of 9. The macula may be subdivided into portions. The fovea measures about 2000 µm across, subtends an angle of 5 (visual field: 2.5 ), and also includes the capillary free zone which measures 500 µm in diameter and 1.5 in angle. The parafoveal central retina is an annular zone 500 µm in width which, together with the fovea, measures 2500 µm in diameter and subtends an angle of about 8 (visual field: 4 ). The perifoveal central retina is 1500 µm in width beyond the parafoveal retina 6-8. Other authors define the inner macula as the area within a circle centered on the foveola, 3000 µm in diameter, and the outer macula as the area between the inner macula and a circle with a diameter of 6000 µm 10,11. Subjects were tested with the Central 10-2 and Macula Programs of the Humphrey VFA II 750. The macula threshold test examines 16 points with a resolution of 2.7 in an area of 4, and the Central 10-2 Program examines 68 points, with a grid having the same resolution, in an area of 10 ; both programs also measure the foveal threshold 11. In the Macula Program, the threshold measurement is repeated twice for each test point location. In the Central 10-2 Program, only ten points are retested for short-term fluctuation measurement. Fluorescein and ICG videoangiography by Topcon IMAGEnet H1024 Digital Imaging System (Paramus,

3 Visual field in areolar atrophy of the retinal pigment epithelium 485 Table 1. Inclusion and exclusion criteria Inclusion criteria Exclusion criteria Age 50 years Macular areolar atrophy of RPE or hypoand hyperpigmentation of RPE in the macula Clear ocular media Visual acuity 0.5 Refraction ±3.00D Good reliability in performing perimetric tests Good fixation stability in performing perimetric tests Age <50 years Exudative AMD Diabetes mellitus Ocular or systemic disease which may affect macular function Drug use which could affect visual function History of retinal surgery NJ) with the fundus camera on 50, were performed in all patients. This system is composed of several integrated units, and the images are recorded by a high-sensitivity camera (Videk Mega plus Kodak, model 1.4; Eastman-Kodak, Rochester, NY) that can convey highresolution digital images ( ) to a computer processing unit. Selected images from each examination can be downloaded to optical discs and made available for later study. For fluorescein angiography, 4 ml of 20% fluorescein solution was injected intravenously, while ICG angiography required 1/3 of a solution containing 50 mg of ICG in 10 ml of aqueous solvent. Fluorescein angiography included a standard sequence of photographs; ICG images were obtained at one- or two-second intervals until the choroid was completely filled. Thereafter, images were obtained at intervals of increasing length over a span of 30 minutes 12. The fundus camera was positioned as straight as possible in order to eliminate oblique angles that might induce distortion in the angiograms. The size of the lesions and their retinal topographic coordinates were calculated by the line image measuring upon the Littmann Correctional values, a tool of the Topcon IMAGEnet software that permits a precise and real measure of the retina in millimeters on the angiographic image hard copies. Each subject underwent a visual field examination with the Central 10-2 and Macula Programs with a time interval of at least 30 minutes between one examination and the other. In order to reduce the learning effect phenomenon, perimetric training was carried out with the Macula Program for at least two minutes. The foveal fixation target was utilized for all subjects. Any test point in the Central 10-2 Program with a p value of <1% in the pattern deviation plot was considered abnormal, and any test point in the Macula Program with 4dB less than the expected value was considered abnormal. The inverted pattern of the test points of the two programs was superimposed over the angiographic image hard copies and corrected for magnification by an appropriate algorithm. In each angiogram, size and retinal position of the three types of retinal alterations (areolar atrophy and hypoand hyperpigmentation of the RPE) were measured 13. Then, the point-to-point sensitivity data of each quadrant of the visual field were compared with the macular alteration on the angiogram hard copies to verify the topographic correspondence between the computerized automated perimetry and angiography 14,15. In each visual field of the study, the defect depth plot of the Macula Program and the pattern deviation plot of the Central 10-2 Program were considered in order to distinguish between the normal and the defective points. The sensitivity and specificity of all visual fields were calculated on 16-point grid pattern of the Macula Program, on the 16-point and 52-point grid patterns of the foveal and parafoveal Central 10-2 Program, and on the 68-point grid pattern of the Central 10-2

4 486 A. Magnasco et al. Table 2. Patient data Case Eye/age, year/sex Visual acuity Areolar atrophy Hypo- hyperpigmentation 1 OD/78/F 5/10 X 2 OD/52/F 6/10 X 2 OS/52/F 5/10 X 3 OD/58/F 5/10 X 3 OS/58/F 10/10 X 4 OD/77/M 7/10 X 5 OD/79/M 5/10 X 5 OS/79/M 6/10 X 6 OS/60/F 10/10 X 7 OD/75/M 9/10 X 7 OS/75/M 7/10 X 8 OD/83/F 5/10 X 8 OS/83/F 5/10 X 9 OS/62/F 9/10 X 10 OD/75/M 6/10 X 10 OD/75/M 7/10 X 11 OD/81/F 6/10 X 11 OS/81/F 5/10 X 12 OD/78/M 7/10 X 12 OS/78/M 5/10 X 13 OD/79/F 5/10 X 13 OS/79/F 6/10 X 14 OD/73/M 7/10 X 14 OS/73/M 8/10 X Program Age, sex, visual acuity, and kind of age-related retinal alterations in the macular area of each case are summarized in Table 2. Results Analysis of the data showed good correlation between focal visual field defects and retinal alterations. The number of false positive, false negative, positive responses, negative responses, and average sensitivity and specificity of each examination are shown in Table 3. The statistical comparison with Student s t test (p=0.05) in the Macula Program showed a sensitivity of 69 ± 12.4% and a specificity of 95 ± 5.4%. The foveal Central 10-2 Program showed a sensitivity of 45 ± 15.9% and a specificity of 99 ± 2%. The parafoveal Central 10-2 Program showed a sensitivity of 54 ± 22% and a specificity of 99 ± 2%. The Central 10-2 Program showed a sensitivity of 48% and a specificity of 99 ± 1.9%. The sensitivity of all tests with p=0.01 presented a wider error margin, as shown in Table 4. The false positive defects of the visual field were probably due to angioscotomas, and the false negative may be attributed to retinal alterations that produce a minimal sensitivity loss 19. The two programs defined the full extent of small localized defects in central retinal area up to 750 µm as the average diameter of areolar atrophy and hypo- and hyperpigmentation of the RPE. The Macula Program was able to detect macular lesions with a higher sensitivity that the fovea Central 10-2 Program or the parafovea Central 10-2

5 Visual field in areolar atrophy of the retinal pigment epithelium 487 Table 3. Sensitivity and specificity of visual fields compared with angiograms Macula Central 10-2 Central 10-2 Central 10-2 fovea parafovea 16-point grid 16-point grid 52-point grid 68-point grid False positive False negative Positive responses Negative responses Average sensitivity 69% 45% 54% 48% Average specificity 95% 99% 99% 99% Table 4. Statistical comparison of visual field points with angiograms in percentage (%) Macula Central 10-2 Central 10-2 Central 10-2 fovea parafovea (n=384) (n=384) (n=1248) (n=1632) Sensitivity 69 ± ± ± ± 16.1 (p=0.05)* Sensitivity 69 ± ± ± ± 21.2 (p=0.01)* Specificity 95 ± ± 2 99 ± 2 99 ± 1.9 (p=0.05)* Specificity 95 ± ± ± ± 2.5 (p=0.01)* *Student s t test Program. There was a linear relationship between visual field sensitivity and macular alterations. The areolar atrophy of the RPE showed greater sensitivity loss compared to hypoand hyperpigmentation, probably due to greater reduction of overlying photoreceptors. Discussion Conventional computerized automated perimetry is able to identify the small perimetric defects caused by areolar atrophy or hypo- and hyperpigmentation of macular RPE. The technique of superimposing quantitative static light threshold values on fluorescein and ICG angiograms may provide important information on the evolution of retinal areas in non-exudative AMD 20. Matching angiograms or color slides to the central visual field is difficult because of possible unsteady fixation, coarse alignment of the optic disc, and the different optical properties and distortions of the perimeter and imaging systems; this is especially true when small fundus lesions are studied 21,22. Certainly, microperimetry with the scanning laser ophthalmoscope is more exact than conventional computerized automated perimetry in distinguishing small RPE alterations in the macular area, but conventional perimetry is more widespread in clinical practice. Conventional automated perimetry is often used to examine patients over the age of 50 years with RPE macular alterations due to early stages of AMD. Moreover, we did not find that the Macula and Central 10-2 Programs

6 488 A. Magnasco et al. had particular significance to the perceptual completion phenomenon in the evaluation of absolute or relative central scotomas 23. Sometimes, conventional computerized automated perimetry was unable to detect small macular defects because they were too small or because, despite the retinal appearance, the photoreceptor loss was insufficient to cause a significant visual field defect. In summary, the Macula Program is more sensitive than the Central 10-2 Program, but it only examines the foveal area. The Central 10-2 Program, however, examines the parafoveal area, which is 4.25 times larger than the foveal area, and in which age-related macular alterations are frequently observed. Therefore, in AMD it is better to use the Central 10-2 Program, even though it is less sensitive than the Macula Program. References 1. Bressler N, Bressler S, Fine S. Age-related macular degeneration. Surv Ophthalmol 32: , Bressler SB, Bressler NM, Gragoudas E: Age-related macular degeneration: drusen and geographic atrophy. In: Albert DM, Jacobiek FA (eds) Principles and Practice of Ophthalmology, Vol 2, pp Philadelphia, PA: WB Saunders Yannuzzi LA, Slakter JS, Sorenson JA, Guyer DR, Orlock DA: Digital indocyanine green videoangiography and choroidal neovascularization. Retina 12: , King D, Drance SM, Douglas GR, Wijsman K: The detection of paracentral scotomas with varying grids in computed perimetry. Arch Ophthalmol 104:524, Zingirian M: Périmétrie automatisée et pathologie maculaire. J Fr Ophtalmol 12: , Hogan MJ, Alvarado J, Wendell JE: Histology of the Human Eye: An Atlas and Textbook. Philadelphia, PA: WB Saunders Yannuzzi LA, Flower RW, Slakter JS: Indocyanine Green Angiography. St Louis, MO: CV Mosby Duane s Clinical Ophthalmology. Philadelphia, PA: Lippincott-Raven Publ Safran AB, Almeida L, Mermoud C, Desangles D, Weiss C, Lang R: Intraocular and interocular variability of blind spot surface measurements by means of automated perimetry. In: Mills RP, Heijl A (eds): Perimetry Update 1990/1991, pp Amsterdam/New York/Milano: Kugler & Ghedini Publ Klein R, Davis MD, Magli YL, Segal P, Klein BE, Hubbard L: The Wisconsin age-related maculopathy grading system. Ophthalmology 98: , The International ARM Epidemiological Study Group: An international classification and grading system for age-related maculopathy and age-related macular degeneration. Surv Ophthalmol 39: , Cardillo Piccolino F, Borgia L: Central serous chorioretinopathy and indocyanine green angiography. Retina 14: , Bressler N, Bressler S, West S, Fine S, Taylor H: The grading and prevalence of macular degeneration in Chesapeake Bay watermen. Arch Ophthalmol 107: , Bell JA, Feldon SE: Retinal microangiopathy: correlation of Octopus perimetry with fluorescein angiography. Arch Ophthalmol 102: , Tolentino MJ, Miller S, Gaudio AR, Sandberg MA: Visual field deficits in early age-related macular degeneration. Am J Ophthalmol 117: , Midena E, Segato T, Blarzino MC, Degli Angeli C: Macular drusen and the sensitivity of the central visual field. Doc Ophthalmol 88: , Atchison DA, Lovie-Kitchin JE, Swann PG: Investigation of central visual fields in patients with agerelated macular changes. Optom Vis Sci 67(3): , Lachenmayr BJ, Vivell PMO: Perimetry and Its Clinical Correlation, pp Stuttgart/New York: G Thieme Zingirian M, Gandolfo E, Capris P: Perimetria: Stato Attuale. Monografie della Società Oftalmologica Italiana, n 1, 1990, pp Rome: Esam Futura Budenz DL: Atlas of Visual Field. Philadelphia, PA: Lippincott-Raven Publ 1997

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