WHAT YOU SEE IS NOT ALWAYS WHAT YOU GET IN ATROPHIC MACULAR DISEASE Janet S. Sunness, MD, GBMC
Purpose: To show that the area of atrophy seen on ophthalmoscopy may not correspond with the area of scotoma in some macular diseases. Methods: Three cases are presented, one with geographic atrophy (GA) from agerelated macular degeneration, one with Stargardt disease, and one with a macular dystrophy. Nidek MP-1 microperimetry was performed and the correspondence of the dense scotoma to the visible atrophy is reported. Results: In the GA patient, the dense scotoma corresponds with the atrophy. In the patient with Stargardt disease, the dense scotoma is larger than the area of visible atrophy. In the patient with a macular dystrophy, the dense scotoma is smaller than the area of visible atrophy. Conclusions: In GA from age-related macular degeneration, the dense scotoma generally corresponds with the atrophy, so that measurement of the enlargement rate of the atrophy is a direct measure of enlargement of the scotoma. This may not be true of other macular diseases. RETINAL CASES & BRIEF REPORTS 2:205–208, 2008
From the Richard E. Hoover Services for Low Vision and Blindness and the Department of Ophthalmology, Greater Baltimore Medical Center, Maryland.
lost foveal vision, their areas of atrophy and scotoma may enlarge, with resulting reduction in reading rate,4 without significant change in visual acuity. Therefore, some measure of the area of atrophy, or the size of scotomas in the central visual field, is an important outcome variable to follow. We have previously shown that in geographic atrophy (GA) from age-related macular degeneration (AMD), the observed area of GA is essentially identical with the area of the dense scotoma measured by scanning laser ophthalmoscope (SLO) fundus perimetry.5 For GA from AMD, a measure from a photograph is sufficient for identifying and quantifying the area of dense scotoma, since this corresponds to the area of atrophy. However, for other diseases this may not be the case. For example, we have previously shown that in patients who underwent submacular surgery for choroidal neovascularization, areas that appeared to be retinal pigment epithelial (RPE) atrophy may actually have visual function.6 We demonstrate here that for other causes of atrophic macular disease besides AMD, the visible lesion may be an underestimate or an overestimate of the area of dense scotomas.
I
nterest has just recently begun to focus on possible treatments for atrophic macular disease. One important question is what to choose as an outcome measure. Visual acuity is always important, but in many types of atrophic macular disease there is preservation of the foveal center, with atrophy near or surrounding the foveal center.1,2 Single letter visual acuity is then an underestimate of the degree of visual impairment and disease progression, because the areas of atrophy, with their corresponding scotomas, may not allow the person to see a full word or a full face.3 Thus, their reading ability and their ability to recognize faces may be much worse than the single letter acuity would indicate. In addition, for patients who have already Supported in part by NIH R03 EY14148, and the John Mitchell, Jr. Trust. The author has no proprietary interest related to this manuscript. Reprint requests: Janet S. Sunness, MD, GBMC, 6569 N. Charles St., PPW #305, Baltimore, MD 21204; e-mail: [email protected]
205
RETINAL CASES & BRIEF REPORTSℜ
206
●
2008
●
VOLUME 2
●
NUMBER 3
Fig. 1. Macular perimetry for eye with geographic atrophy from age-related macular degeneration. The open squares show areas with a dense scotoma, while the filled squares are seeing areas. The small blue dots show fixation during the course of the testing. The atrophic area is outlined in black. The scotoma corresponds essentially exactly to the area with geographic atrophy.
The Nidek MP-1 Microperimeter (Nidek, Inc., Fremont, CA) was used to measure the dense scotoma present in three patients with atrophic macular disease. Static and kinetic perimetry were employed, using the semiautomatic and kinetic strategies and automated tracking provided by the MP-1 software. A Goldmann size III stimulus was used, with the stimulus intensity at its maximum (0 dB). Case Reports Area of Dense Scotoma Equal to Area of Visible Atrophy Patient 1 is a 74-year-old man with GA from AMD. Visual acuity was 20/50 in each eye. Figure 1 shows the MP-1 map of the patient’s scotoma. As can be seen, there is a dense scotoma corresponding to the area of GA (open squares) temporal to fixation on the retina. The points tested outside the atrophic area are seeing. (The patient’s fixation was unstable during the testing; nonetheless, with the automated tracking the scotoma corresponds precisely to the retinal lesion.) Area of Scotoma Larger Than Area of Visible Atrophy Patient 2 is a 25-year-old woman with Stargardt disease. Fluorescein angiography performed in the past showed a dark choroid, with hyperfluorescence
Fig. 2. Macular perimetry for eye with Stargardt disease. A, Assessment with static perimetry. The open squares show areas with a dense scotoma, while the filled squares are seeing areas. The small blue dots show fixation during the course of the testing. The atrophic area is outlined in black. The dense scotoma extends beyond the border of the atrophic area. This patient had a very small spared foveal area, and fixation was maintained in this area. B, Assessment with kinetic perimetry. Kinetic perimetry was performed with the stimuli moving from outside the atrophic lesion inward (i.e., from seeing to nonseeing). The points indicate the position of the stimulus when the patient indicated that it had disappeared; the ring connecting these points represents the isopter border for this stimulus.
centrally and some staining of the flecks. On examination, she had tiny spared foveal areas with visual acuity of 20/40 in each eye, surrounded by a ring of atrophy. Many flecks were noted. Static perimetry of the right eye (Figure 2A) showed a dense scotoma including the observed atrophy, but also extending peripheral to the observed atrophic lesion. To explore this further, kinetic perimetry was performed (Figure 2B), going from the outside seeing area inward (i.e.,
207
SCOTOMAS IN ATROPHIC MACULAR DISEASE
Fig. 3. Macular perimetry for eye with a macular dystrophy. The open squares show areas with a dense scotoma, while the filled squares are seeing areas. The small blue dots show fixation during the course of the testing. The atrophic area is outlined in black. The atrophic lesion includes seeing areas as well as nonseeing areas.
beginning 10 degrees from fixation and going toward the center, with the patient indicating when the stimulus was no longer seen). If the patient had a delayed reaction time, the measured size of the scotoma would be smaller than the true value, because the stimuli would have reached a position closer to the center when the beeper was pressed. Even in this testing paradigm, the borders of the dense scotoma are well outside the visible atrophic lesion size. Area of Scotoma Smaller Than Area of Visible Atrophy Patient 3 is a 35-year-old woman with an unclassified autosomal dominant macular dystrophy (she is light sensitive and has somewhat reduced color vision, but has normal cone function on electroretinography testing). Fundus examination showed atrophy surrounding the fovea in a horseshoe configuration, with central sparing. Fluorescein angiography showed changes associated with the atrophy, without evidence of leakage. There was not a dark choroid present. Visual acuity was 20/40 –2. Figure 3 shows the static perimetry performed for this patient. Only the superior area of the atrophic lesion has a dense scotoma, while the inferior area does not.
uated or hypopigmented. While areas of obvious geographic atrophy from AMD are associated with a dense scotoma, other atrophic lesions may not be. The enlargement of an area of atrophy is an important measure of progression, but the area of atrophy may not be identical with the area of dense scotoma. Other imaging modalities such as autofluorescence imaging may be helpful in showing a lack of autofluorescence where the RPE is absent; it appears to be almost 100% sensitive for GA from AMD.7,8 However, a lack of autofluorescence is not specific for RPE atrophy, and may be seen over drusen and over areas with normal visual function despite pigmentary alteration.8 It is possible that future ultrahigh resolution optical coherence tomography imaging will be able to define loss of photoreceptors and RPE, but thus far such quantitation is not available. Stargardt disease, in particular, does not show the expected findings of an atrophic disorder. In Stargardt disease, some patients may fixate at a distance from the edge of the dense scotoma, with intervening seeing retina between the edge of the scotoma and the eccentric fixation, thus putting fixation at a retinal site that seems more eccentric than necessary.4 The reasons for this finding, and for the finding reported in this article of the scotoma extending past the borders of the atrophic lesion, are not yet clear but may be related in part to pathology that may be visible by autofluorescence imaging, but not yet by ophthalmoscopy.8,9 The availability of fundus perimetry, in the form of the Nidek MP-1 instrument, allows for reproducible mapping of retinal sensitivity and its correlation with observed retinal pathology. This ability may be important in future clinical trials for atrophic macular disorders, to quantify the central visual field abnormalities over and above the observed retinal pathology. In patients with reduced visual acuity and poor fixation, conventional visual fields will be unable to adequately measure the location and extent of visual field defects, while fundus perimeters that can correct for eye movement associated with unstable or eccentric fixation can compensate and give true measures of field loss. Key words: macula, macular degeneration, agerelated macular degeneration, geographic atrophy, Stargardt disease, microperimetry, visual field. References 1.
Discussion An atrophic appearance is generated by a loss of RPE, but it may also be seen when the RPE is atten-
2.
Hart WM Jr, Burde RM. Three-dimensional topography of the central visual field. Sparing of foveal sensitivity in macular disease. Ophthalmology 1983;90:1028–1038. Fletcher DC, Schuchard RA. Preferred retinal loci relationship to macular scotomas in a low-vision population. Ophthalmology 1997;104:632–638.
208 3.
4.
5.
6.
RETINAL CASES & BRIEF REPORTSℜ
Sunness JS, Rubin GS, Applegate CA, et al. Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. Ophthalmology 1997;104:1677–1691. Sunness JS, Applegate CA, Haselwood D, Rubin GS. Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt’s disease. Ophthalmology 1996;103:1458–1466. Sunness JS, Schuchard RA, Shen N, Rubin GS, Dagnelie G, Haselwood D. Landmark-driven fundus perimetry using the scanning laser ophthalmoscope (SLO). Invest Ophthalmol Vis Sci 1995;36:1863–1874. Loewenstein A, Sunness JS, Bressler NM, Marsh MJ, de Juan
7.
8.
9.
●
2008
●
VOLUME 2
●
NUMBER 3
E Jr. Scanning laser ophthalmoscope fundus perimetry after surgery for choroidal neovascularization. Am J Ophthalmol 1998;125:657–665. Schmitz-Valckenberg S, Jorzik J, Unnebrink K, et al. Analysis of digital scanning laser ophthalmoscopy fundus autofluorescence images of geographic atrophy in advanced age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2002;240:73–78. Sunness JS, Ziegler MD, Applegate CA. Issues in quantifying atrophic macular disease using retinal autofluorescence. RETINA 2006;26:666–672. Sunness JS, Steiner JN. Retinal function and loss of autofluorescence in Stargardt disease. RETINA (in press).
Purpose: To show that the area of atrophy seen on ophthalmoscopy may not correspond with the area of scotoma in some macular diseases. Methods: Three cases are presented, one with geographic atrophy (GA) from agerelated macular degeneration, one with Stargardt disease, and one with a macular dystrophy. Nidek MP-1 microperimetry was performed and the correspondence of the dense scotoma to the visible atrophy is reported. Results: In the GA patient, the dense scotoma corresponds with the atrophy. In the patient with Stargardt disease, the dense scotoma is larger than the area of visible atrophy. In the patient with a macular dystrophy, the dense scotoma is smaller than the area of visible atrophy. Conclusions: In GA from age-related macular degeneration, the dense scotoma generally corresponds with the atrophy, so that measurement of the enlargement rate of the atrophy is a direct measure of enlargement of the scotoma. This may not be true of other macular diseases. RETINAL CASES & BRIEF REPORTS 2:205–208, 2008
From the Richard E. Hoover Services for Low Vision and Blindness and the Department of Ophthalmology, Greater Baltimore Medical Center, Maryland.
lost foveal vision, their areas of atrophy and scotoma may enlarge, with resulting reduction in reading rate,4 without significant change in visual acuity. Therefore, some measure of the area of atrophy, or the size of scotomas in the central visual field, is an important outcome variable to follow. We have previously shown that in geographic atrophy (GA) from age-related macular degeneration (AMD), the observed area of GA is essentially identical with the area of the dense scotoma measured by scanning laser ophthalmoscope (SLO) fundus perimetry.5 For GA from AMD, a measure from a photograph is sufficient for identifying and quantifying the area of dense scotoma, since this corresponds to the area of atrophy. However, for other diseases this may not be the case. For example, we have previously shown that in patients who underwent submacular surgery for choroidal neovascularization, areas that appeared to be retinal pigment epithelial (RPE) atrophy may actually have visual function.6 We demonstrate here that for other causes of atrophic macular disease besides AMD, the visible lesion may be an underestimate or an overestimate of the area of dense scotomas.
I
nterest has just recently begun to focus on possible treatments for atrophic macular disease. One important question is what to choose as an outcome measure. Visual acuity is always important, but in many types of atrophic macular disease there is preservation of the foveal center, with atrophy near or surrounding the foveal center.1,2 Single letter visual acuity is then an underestimate of the degree of visual impairment and disease progression, because the areas of atrophy, with their corresponding scotomas, may not allow the person to see a full word or a full face.3 Thus, their reading ability and their ability to recognize faces may be much worse than the single letter acuity would indicate. In addition, for patients who have already Supported in part by NIH R03 EY14148, and the John Mitchell, Jr. Trust. The author has no proprietary interest related to this manuscript. Reprint requests: Janet S. Sunness, MD, GBMC, 6569 N. Charles St., PPW #305, Baltimore, MD 21204; e-mail: [email protected]
205
RETINAL CASES & BRIEF REPORTSℜ
206
●
2008
●
VOLUME 2
●
NUMBER 3
Fig. 1. Macular perimetry for eye with geographic atrophy from age-related macular degeneration. The open squares show areas with a dense scotoma, while the filled squares are seeing areas. The small blue dots show fixation during the course of the testing. The atrophic area is outlined in black. The scotoma corresponds essentially exactly to the area with geographic atrophy.
The Nidek MP-1 Microperimeter (Nidek, Inc., Fremont, CA) was used to measure the dense scotoma present in three patients with atrophic macular disease. Static and kinetic perimetry were employed, using the semiautomatic and kinetic strategies and automated tracking provided by the MP-1 software. A Goldmann size III stimulus was used, with the stimulus intensity at its maximum (0 dB). Case Reports Area of Dense Scotoma Equal to Area of Visible Atrophy Patient 1 is a 74-year-old man with GA from AMD. Visual acuity was 20/50 in each eye. Figure 1 shows the MP-1 map of the patient’s scotoma. As can be seen, there is a dense scotoma corresponding to the area of GA (open squares) temporal to fixation on the retina. The points tested outside the atrophic area are seeing. (The patient’s fixation was unstable during the testing; nonetheless, with the automated tracking the scotoma corresponds precisely to the retinal lesion.) Area of Scotoma Larger Than Area of Visible Atrophy Patient 2 is a 25-year-old woman with Stargardt disease. Fluorescein angiography performed in the past showed a dark choroid, with hyperfluorescence
Fig. 2. Macular perimetry for eye with Stargardt disease. A, Assessment with static perimetry. The open squares show areas with a dense scotoma, while the filled squares are seeing areas. The small blue dots show fixation during the course of the testing. The atrophic area is outlined in black. The dense scotoma extends beyond the border of the atrophic area. This patient had a very small spared foveal area, and fixation was maintained in this area. B, Assessment with kinetic perimetry. Kinetic perimetry was performed with the stimuli moving from outside the atrophic lesion inward (i.e., from seeing to nonseeing). The points indicate the position of the stimulus when the patient indicated that it had disappeared; the ring connecting these points represents the isopter border for this stimulus.
centrally and some staining of the flecks. On examination, she had tiny spared foveal areas with visual acuity of 20/40 in each eye, surrounded by a ring of atrophy. Many flecks were noted. Static perimetry of the right eye (Figure 2A) showed a dense scotoma including the observed atrophy, but also extending peripheral to the observed atrophic lesion. To explore this further, kinetic perimetry was performed (Figure 2B), going from the outside seeing area inward (i.e.,
207
SCOTOMAS IN ATROPHIC MACULAR DISEASE
Fig. 3. Macular perimetry for eye with a macular dystrophy. The open squares show areas with a dense scotoma, while the filled squares are seeing areas. The small blue dots show fixation during the course of the testing. The atrophic area is outlined in black. The atrophic lesion includes seeing areas as well as nonseeing areas.
beginning 10 degrees from fixation and going toward the center, with the patient indicating when the stimulus was no longer seen). If the patient had a delayed reaction time, the measured size of the scotoma would be smaller than the true value, because the stimuli would have reached a position closer to the center when the beeper was pressed. Even in this testing paradigm, the borders of the dense scotoma are well outside the visible atrophic lesion size. Area of Scotoma Smaller Than Area of Visible Atrophy Patient 3 is a 35-year-old woman with an unclassified autosomal dominant macular dystrophy (she is light sensitive and has somewhat reduced color vision, but has normal cone function on electroretinography testing). Fundus examination showed atrophy surrounding the fovea in a horseshoe configuration, with central sparing. Fluorescein angiography showed changes associated with the atrophy, without evidence of leakage. There was not a dark choroid present. Visual acuity was 20/40 –2. Figure 3 shows the static perimetry performed for this patient. Only the superior area of the atrophic lesion has a dense scotoma, while the inferior area does not.
uated or hypopigmented. While areas of obvious geographic atrophy from AMD are associated with a dense scotoma, other atrophic lesions may not be. The enlargement of an area of atrophy is an important measure of progression, but the area of atrophy may not be identical with the area of dense scotoma. Other imaging modalities such as autofluorescence imaging may be helpful in showing a lack of autofluorescence where the RPE is absent; it appears to be almost 100% sensitive for GA from AMD.7,8 However, a lack of autofluorescence is not specific for RPE atrophy, and may be seen over drusen and over areas with normal visual function despite pigmentary alteration.8 It is possible that future ultrahigh resolution optical coherence tomography imaging will be able to define loss of photoreceptors and RPE, but thus far such quantitation is not available. Stargardt disease, in particular, does not show the expected findings of an atrophic disorder. In Stargardt disease, some patients may fixate at a distance from the edge of the dense scotoma, with intervening seeing retina between the edge of the scotoma and the eccentric fixation, thus putting fixation at a retinal site that seems more eccentric than necessary.4 The reasons for this finding, and for the finding reported in this article of the scotoma extending past the borders of the atrophic lesion, are not yet clear but may be related in part to pathology that may be visible by autofluorescence imaging, but not yet by ophthalmoscopy.8,9 The availability of fundus perimetry, in the form of the Nidek MP-1 instrument, allows for reproducible mapping of retinal sensitivity and its correlation with observed retinal pathology. This ability may be important in future clinical trials for atrophic macular disorders, to quantify the central visual field abnormalities over and above the observed retinal pathology. In patients with reduced visual acuity and poor fixation, conventional visual fields will be unable to adequately measure the location and extent of visual field defects, while fundus perimeters that can correct for eye movement associated with unstable or eccentric fixation can compensate and give true measures of field loss. Key words: macula, macular degeneration, agerelated macular degeneration, geographic atrophy, Stargardt disease, microperimetry, visual field. References 1.
Discussion An atrophic appearance is generated by a loss of RPE, but it may also be seen when the RPE is atten-
2.
Hart WM Jr, Burde RM. Three-dimensional topography of the central visual field. Sparing of foveal sensitivity in macular disease. Ophthalmology 1983;90:1028–1038. Fletcher DC, Schuchard RA. Preferred retinal loci relationship to macular scotomas in a low-vision population. Ophthalmology 1997;104:632–638.
208 3.
4.
5.
6.
RETINAL CASES & BRIEF REPORTSℜ
Sunness JS, Rubin GS, Applegate CA, et al. Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. Ophthalmology 1997;104:1677–1691. Sunness JS, Applegate CA, Haselwood D, Rubin GS. Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt’s disease. Ophthalmology 1996;103:1458–1466. Sunness JS, Schuchard RA, Shen N, Rubin GS, Dagnelie G, Haselwood D. Landmark-driven fundus perimetry using the scanning laser ophthalmoscope (SLO). Invest Ophthalmol Vis Sci 1995;36:1863–1874. Loewenstein A, Sunness JS, Bressler NM, Marsh MJ, de Juan
7.
8.
9.
●
2008
●
VOLUME 2
●
NUMBER 3
E Jr. Scanning laser ophthalmoscope fundus perimetry after surgery for choroidal neovascularization. Am J Ophthalmol 1998;125:657–665. Schmitz-Valckenberg S, Jorzik J, Unnebrink K, et al. Analysis of digital scanning laser ophthalmoscopy fundus autofluorescence images of geographic atrophy in advanced age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2002;240:73–78. Sunness JS, Ziegler MD, Applegate CA. Issues in quantifying atrophic macular disease using retinal autofluorescence. RETINA 2006;26:666–672. Sunness JS, Steiner JN. Retinal function and loss of autofluorescence in Stargardt disease. RETINA (in press).
