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Characteristics of visual loss by scanning laser ophthalmoscope microperimetry in eyes with subfoveal choroidal neovascularization secondary to age-related macular degeneration
Characteristics of Visual Loss by Scanning Laser Ophthalmoscope Microperimetry in Eyes With Subfoveal Choroidal Neovascularization Secondary to Age-related Macular Degeneration GILDO Y. FUJII, MD, EUGENE DE JUAN, JR., MD, MARK S. HUMAYUN, MD, PHD, JANET S. SUNNESS, MD, TOM S. CHANG, MD, AND JULIANA V. ROSSI, MD
● PURPOSE:
To evaluate the effects of subfoveal choroidal neovascularization secondary to age-related macular degeneration on functional parameters obtained by scanning laser ophthalmoscope microperimetry. ● DESIGN: Retrospective observational case series and cross-sectional study. ● METHODS: At the Doheny Retina Institute and Wilmer Eye Institute a consecutive series of 179 eyes of 175 patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration was studied. The onset of visual symptoms, best-corrected visual acuity, fluorescein angiography, evaluation of fundus microperimetry and fixation pattern using the Rodenstock scanning laser ophthalmoscope were obtained for each patient. The main outcome measures were central retinal sensitivity and fixation pattern (fixation location and fixation stability) in eyes with subfoveal choroidal neovascularization and their relationship to the length of disease, type and characteristics of choroidal neovascularization, and visual acuity. ● RESULTS: Of 179 eyes, 135 (75%) had central fixation, 27 (15%) had poor central fixation, and 17 (9%)
Accepted for publication June 3, 2003. InternetAdvance publication at ajo.com Oct 8, 2003. From the Doheny Retina Institute, Doheny Eye Institute, University of Southern California, Keck School of Medicine, Los Angeles, California (G.Y.F., E.D.J., M.S.H., T.S.C., J.V.R.), and the Lions Vision Center, Wilmer Ophthalmological Institute, The Johns Hopkins Hospital, Baltimore, Maryland (J.S.S.). This work was supported in part by National Eye Institute Grant EY08552 (J.S.S.), Research to Prevent Blindness James S. Adams Special Scholar 1999 –2000 (J.S.S.), and the Panitch Fund to Stop AMD. Inquiries to Eugene de Juan, Jr, MD, Doheny Eye Institute, University of Southern California, Keck School of Medicine, 1450 San Pablo St, Room 3620, Los Angeles, CA 90033; fax: (323) 442-6519; e-mail: [email protected] 0002-9394/03/$30.00 doi:10.1016/S0002-9394(03)00663-9
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2003 BY
had predominantly eccentric fixation. Seventy-six eyes (42%) had stable fixation, 70 eyes (39%) had relatively unstable fixation, and 33 eyes (18%) had unstable fixation. In 50 eyes (28%) a dense central scotoma was noted. Eighty-nine of 100 eyes (89%) with length of symptoms of less than 3 months had predominantly central fixation and 58 (58%) had stable fixation; 14 of 34 eyes (41%) with length of symptoms of more than 6 months had predominantly central fixation, and 5 eyes (15%) had stable fixation. In 15 eyes of patients who elected not to receive treatment, successive scanning laser ophthalmoscope microperimetry were obtained over time (follow-up of 18 months after onset of symptoms). Three months or less after the onset of symptoms, 13 eyes (87.7%) had predominantly central fixation and 9 eyes (60%) had stable fixation. More than 3 months and 6 months or less after the onset of symptoms, 10 eyes (66.7%) had predominantly central fixation and 7 eyes (46.7%) had stable fixation. This trend was further demonstrated in eyes more than 6 months after the onset of symptoms. ● CONCLUSIONS: We conclude that the sequence of events leading to visual function deterioration appears to involve an initial mild decrease in central retinal sensitivity and visual acuity followed by progressive fixation instability and, ultimately, development of an absolute central scotoma with totally eccentric fixation. Increased length of disease is associated with worse fixation pattern and retinal sensitivity deterioration as assessed by scanning laser ophthalmoscope microperimetry. A better understanding of the characteristics of visual loss assessed by fixation pattern evaluation and microperimetry in age-related macular degeneration may help optimize timing, patient selection, and treatment options in eyes with this condition. (Am J Ophthalmol 2003;136: 1067–1078. © 2003 by Elsevier Inc. All rights reserved.)
ELSEVIER INC. ALL
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of Age-related Macular Degeneration with Photodynamic Therapy (TAP) study.16 Static fundus perimetry was performed on all patients using the Rodenstock scanning laser ophthalmoscope (G. Rodenstock Instrument GmbH, Munich, Germany). The infrared laser was used for imaging, and the helium-neon red laser was used for stimulus presentation. A stimulus size equivalent to a Goldmann III test spot was used. With SLO microperimetry, the stimulus intensity can vary in 0.1-logarithmic steps from 0 to 35 dB. We used the following stimulus intensity: 0 dB, 6 dB, 11 dB, 16 dB, and 21 dB. We defined a dense scotoma as one in which the stimulated area could not be detected with a 0-dB spot of Goldmann III size and a relative scotoma as one in which the stimulated area could be detected by a 0-dB spot but not by a 21-dB spot. (Normal sensitivity is approximately 24 dB in the macular region.) A fixation cross of 1 degree in size on the retina was used. The Rodenstock scotometry software used allowed for acquiring a fundus image at the time of stimulus presentation, and placing a cursor on a retinal landmark on the frozen image to allow for correction for eye movements when the results are displayed. At the conclusion of testing, the results of perimetry are displayed on the retinal image, with stimulus placement adjusted for changes in retinal landmark location at the time of each stimulus presentation. The SLO represents a dynamic assessment of retinal microperimetry. To accurately determine the location and stability of fixation, eye movements during testing must be measured and accounted for. This is carried out in the following manner. At each point of stimulus presentation, the position of a distinct retinal landmark (that is, arteriovenous crossing) was identified by cursor placement in the method described above. Eye movements (as measured by the changes in the landmark position) reflect the changes in the location of fixation. The amplitude of these eye movements is a reflection of fixation stability. At the conclusion of testing, a scattergraph depiction of fixation is displayed. This was used to quantify fixation pattern. The fixation pattern was graded based on two variables: fixation location (defined as the position of fixation with respect to the center of the foveal avascular zone) and fixation stability (defined as the ability of the eye to maintain fixation in the preferred retinal locus). In assessing the fixation location we defined a standard of central fixation to approximate a 2-degree diameter (approximately 700-m) circle centered on the fovea. Patients with more than 50% of the preferred fixation points located within central fixation were classified as L1, predominantly central fixation. Eyes with more than 25% but less than 50% of the preferred fixation points located within central fixation were classified as L2, poor central fixation. Eyes with less than 25% of the preferred fixation points located within central fixation were classified as L3, predominantly eccentric fixation. For eyes with both predominantly central and poor central fixation, the patients
HE NATURAL HISTORY OF EYES WITH SUBFOVEAL
choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) is poor. Patients with this condition typically experience a significant decrease in visual acuity in a relatively short time.1 In one series, 70% of eyes with subfoveal CNV related to AMD were noted to have a visual acuity of 20/200 or worse within 2 years of the onset of visual symptoms.1 Several clinical trials have provided additional information regarding visual acuity loss in eyes with untreated neovascular AMD.2–7 In many respects, visual acuity is not a complete measure of the visual function. One test of visual function that may help to better understand the characteristics of visual loss in these patients is scanning laser ophthalmoscope (SLO) microperimetry. This instrument can provide accurate determination of preferential fixation location and fixation stability.8 –13 The SLO is also useful in measuring focal areas of retinal sensitivity with correction for eye movements that are common in patients with central visual loss.11 The information given by this functional test provides valuable information about the location of the retinal sensitivity loss, its magnitude and its potential impact on central fixation. The knowledge of fixation and sensitivity parameters in eyes with subfoveal CNV and their relationship to the length of disease may help to understand the mechanisms of visual loss in this disease. In a previous study, we have found that by evaluating the fixation and retinal sensitivity pattern it was possible to assess the retinal cell viability of the macular region in terms of likelihood of improvement in acuity following macular translocation.14 The main purpose of this study was to evaluate the effects of subfoveal CNV secondary to AMD on functional parameters obtained by SLO microperimetry.
METHODS WE RETROSPECTIVELY STUDIED 179 EYES OF 175 CONSECU-
tive patients with subfoveal CNV secondary to AMD at the Wilmer Ophthalmologic Institute and Doheny Retina Institute with appropriate institutional review board approval. Inclusion criteria for this study were (1) fluorescein angiographic evidence of CNV extending under the center of the foveal avascular zone, (2) evidence of age-related macular degeneration, and (3) absence of coexisting ocular disease. The onset of visual symptoms and best-corrected visual acuity on the standard Snellen chart were obtained in each patient. Slit-lamp and fundus biomicroscopic examination, stereo color fundus photography, and Macular Photocoagulation Study (MPS) protocol fluorescein angiography were performed on each patient.15 The CNV size was evaluated using the MPS guidelines15 and the CNV type was classified according to the guidelines of the Treatment 1068
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FIGURE 1. Classification of location of fixation. Fixation points in green indicate the fixation location during each perceived stimulus presentation. Fixation points in red indicate the fixation location during nonperceived stimulus presentation. The fixation cross seen in each picture indicates only the last fixation point recorded at the end of the testing. (Top) The location of fixation was defined as predominantly central fixation when more than 50% of the preferred fixation points were located within a predetermined limit area of variation of 2-degree diameter circle centered in the fovea. (Middle) The location of fixation was classified as poor central fixation when less than 50% but more than 25% of the preferred fixation points were located within the 2-degree diameter circle. (Bottom) The location of fixation was classified as predominantly eccentric fixation when less than 25% of the preferred fixation points located within the 2-degree diameter circle.
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FIGURE 2. Classification of fixation stability. (Top) The location of fixation was defined as stable fixation when more than 75% of the fixation points were located within a predetermined limit area of variation of a 2-degree diameter circle centered in the gravitational center of all fixation points, regardless of the position of the foveal center. (Middle) The location of fixation was classified as relatively unstable fixation when less than 75% of the fixation points were located within a 2-degree diameter circle but more than 75% of the fixation points were located within a 4-degree diameter circle. (Bottom) The location of fixation was classified as unstable fixation when less than 75% of the fixation points were located within a 4-degree circle.
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were required to confirm their ability to see the fixation target while looking straight at it. In situations where patients were unable to maintain foveal fixation even for a short duration, they would be automatically classified as having predominantly eccentric fixation (Figure 1). For the purpose of evaluating the stability of fixation we suggest two new terms: target fixation and extra-target fixation. Target fixation is defined as a 2-degree diameter circle positioned with respect to the gravitational center of all fixation points. Likewise, extra-target fixation is defined as a 4-degree diameter circle positioned with respect to the gravitational center of all fixation points. Eyes with more than 75% of the fixation points located within the target fixation were classified as S1, or stable. If less than 75% of the fixation points were located within the target fixation but more than 75% of the fixation points within extratarget fixation the eye was classified as having S2, or relatively unstable fixation. If less than 75% of fixation points were located within the extra-target fixation, the pattern was described as being S3, or unstable fixation. The stability of fixation was classified separately from the fixation location because some eyes can present with predominantly eccentric and relatively stable fixation (Figure 2). Eyes were classified as having a dense central scotoma when more than three 0-dB-stimuli were not perceived by the patient in a 3-degree diameter circle centered in the fovea. The microperimetric findings and visual acuity were grouped for each specific SLO evaluation according to length of symptoms and visual acuity. In 15 eyes of patients who elected not to receive treatment, successive SLO microperimetry were obtained over time with one visit each 3 months. All 15 eyes included in this series had onset of symptoms within 3 months of presentation and were followed up to 18 months after initial visual symptoms. The statistical analysis for all tests of association was performed using the 2 test. All P values .05 or less were considered significant.
RESULTS THE BASELINE DESCRIPTIVE DATA OF THE PATIENTS IN-
cluded in this study is shown in Table 1. Patient ages ranged from 54 to 91 years with a mean of 74.5 years. The median and mean lengths of symptoms respectively were 3 and 4.8 months, ranging from 1 week to 96 months. The lesion and choroidal neovascularization characteristics were identified with fluorescein angiography and are also described in Table 1. Choroidal neovascular lesions varied in size, ranging from 1 to 16 MPS disk areas with a median size of 3 MPS disk areas (mean, 3.3 MPS disk areas; range, 1–9 MPS disk areas). One hundred and twenty-six eyes in this study (70%) had classic or predominantly classic VOL. 136, NO. 6
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TABLE 1. Preoperative Data for Study Group (175 Patients, 179 Eyes) Characteristic
Age, years ⬍50 50–59 60–69 70–79 ⱖ80 Sex Male Female Study eye Right Left Duration ⬎1 week and ⱕ3 months ⬎3 months and ⱕ6 months ⬎6 months and ⱕ9 months ⬎9 months and ⱕ12 months CNV Character Predominantly classic Predominantly occult Size of CNV ⱕ1 ⬎1 and ⱕ3 ⱖ3.5 and ⱕ4 ⱖ5 Baseline visual acuity 20/30–20/80 20/100–20/160 20/200–20/320 20/400–20/640 20/800 or worse
N
%
0 10 34 79 52
0 5.7 19.4 45.1 29.7
94 81
53.7 46.3
100 79
55.9 44.1
100 45 22 12
55.9 25.1 12.3 6.7
126 53
70.4 29.6
24 77 30 48
13.4 43 16.7 26.8
40 83 35 17 4
22.3 46.4 19.5 9.5 2.2
CNV ⫽ choroidal neovascularization.
patterns of CNV leakage; 53 eyes (30%) had occult or minimally classic CNV. The median visual acuity was 20/150, ranging from 20/30 to counting fingers. The distribution of lesion characteristics by length of symptoms is described in Table 2. As anticipated, lesion size increased with the length of symptoms. In the study group, the percentage of predominantly classic vs minimally classic CNV was essentially the same for all duration of symptoms. The distribution of visual acuity by length of symptoms is described in Table 3. In general, visual acuity worsened with duration of symptoms (P ⫽ .05). Using the SLO, determination of the macular retinal sensitivity, fixation location, and fixation stability was achieved during fundus perimetry. Of all 179 eyes with CNV, 135 (75%) had predominantly central fixation, 27 (15%) had poor central fixation, and 17 (9%) had predominantly eccentric fixation. Seventy-six eyes (42%) had stable fixation, 70 eyes (39%) had relatively unstable AGE-RELATED MACULAR DEGENERATION
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TABLE 2. Lesion Characteristics by Duration of Symptoms Lesion Size (MPS Disk Areas) (179 Eyes)
CNV Type (179 Eyes)
Duration of Symptoms (Months)
ⱕ1 N (%)
⬎1 and ⱕ3.5 N (%)
ⱖ3.5 and ⱕ5 N (%)
⬎5 N (%)
Predominantly Classic N (%)
Predominantly Occult N (%)
0–3 (least) ⬎3–6 (short) ⬎6–9 (medium) ⬎9 (long)
17 (17) 6 (13) 1 (4) 0 (0)
47 (47) 17 (38) 9 (41) 4 (33)
15 (15) 9 (20) 3 (14) 3 (25)
21 (21) 13 (29) 9 (41) 5 (42)
70 (70) 33 (73) 15 (68) 8 (67)
30 (30) 12 (27) 7 (32) 4 (33)
CNV ⫽ choroidal neovascularization; MPS ⫽ Macular Photocoagulation Study.
were obtained over time. At presentation, 12 eyes (80%) had predominantly classic lesion whereas 3 eyes (20%) had minimally classic lesions. Median lesion size at baseline was 3 MPS disk areas (range, 1– 6 MPS disk areas). After 18 months of follow-up, the composition of the CNV type did not change significantly. Only one eye that was classified as minimally classic lesion at baseline converted to predominantly classic. However, the mean lesion size increased to 4.8 MPS disk areas (range, 2–9 MPS disk areas). Figures 4 and 5 illustrate the line of deterioration of the fixation pattern over time. There was significant association between fixation location and length of symptoms, with more eyes with predominantly eccentric fixation overtime (P ⫽ .003). Similarly, there was significant association between fixation stability and length of symptoms, with more eyes with unstable fixation overtime (P ⫽ .01; Figure 5).
TABLE 3. Visual Acuity by Duration of Symptoms (179 Eyes)
Duration of Symptoms (Months)
ⱖ20/100 (Good VA) N (%)
⬍20/100 and ⬎20/200 (Medium VA) N (%)
ⱕ20/200 (Worst VA) N (%)
0–3 (least) ⬎3–6 (short) ⬎6–9 (medium) ⬎9 (long)
42 (42) 17 (38) 3 (14) 2 (17)
35 (35) 12 (27) 8 (36) 4 (33)
23 (23) 16 (35) 11 (50) 6 (50)
VA ⫽ visual acuity.
fixation, and 33 eyes (18%) had unstable fixation. In 50 eyes (28%) a dense central scotoma was noted. The distribution of SLO findings by length of symptoms and visual acuity are summarized in Table 4 and Figure 3. In general, fixation pattern (fixation location and fixation stability) worsened with increased length of symptoms and with decreased visual acuity. (P ⬍ .0001 and P ⬍ .0001, respectively). The development of retinal sensitivity loss was not always homogeneous and varied significantly in location, size, and intensity throughout the lesion. When located within the fovea, retinal sensitivity loss resulted in further loss of fixation stability and a secondary loss of central fixation. Some eyes with subfoveal CNV presented a profound loss of parafoveal retinal sensitivity to the level of absolute dense scotoma but preserved a small island of foveal sensitivity that accounted for preservation of central fixation. Alternatively, some eyes presented with relatively good parafoveal sensitivity and an absolute foveal scotoma resulting in predominantly eccentric and unstable fixation. However, some eyes with predominantly eccentric fixation location presented with relatively stable fixation. Dense central scotoma was present in four of 64 eyes (6%) in the good acuity group and in 33 of 56 eyes (59%) of eyes in the worst acuity group. In general, dense central scotoma was associated with increased length of symptoms (P ⫽ .0002). In 15 eyes of patients who elected not to receive treatment, successive SLO microperimetry measurements 1072
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DISCUSSION WE FOUND THAT VISUAL IMPAIRMENT IN EYES WITH SUB-
foveal CNV secondary to AMD is associated with progressive visual function deterioration expressed by decreased fixation stability, loss of central fixation, and impaired retinal sensitivity as measured by SLO microperimetry. In eyes with progressive deterioration, the inability to maintain the preferential fixation location within the fovea progresses until complete absence of foveal visual perception is established and the preferential fixation location becomes totally eccentric. This reflects a profound loss of central retinal sensitivity and functionality. By drawing a progression line of visual function deterioration across time, we observed that eyes with subfoveal CNV secondary to AMD initially experience metamorphopsia and blurred vision that is usually associated with progressive loss of central retinal sensitivity, visual acuity, and fixation stability. The early morphologic changes associated with those symptoms are probably related to impaired photoreceptor function secondary to abnormal retinal pigment epithelium function (retinal metabolism); impaired nutrient/waste exchange across the retinal pigment epithelium OF
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FIGURE 3. Distribution of scanning laser ophthalmoscope microperimetry findings by length of symptoms. (Top) Fixation location by length of symptoms. (Middle) Fixation stability by length of symptoms. (Bottom) Presence of dense central scotoma by duration of symptoms.
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FIGURE 4. A sequence of scanning laser ophthalmoscope (SLO) microperimetry shows the progressive functional deterioration in one eye with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The SLO testing demonstrated that eyes with subfoveal CNV secondary to AMD resulted in a predictable and progressive loss of fixation stability, decreased central retinal sensitivity, and loss of central fixation location. A 65-year-old man presented with 20/150 vision and a 1-month history of decreased vision due to a predominantly classic subfoveal CNV secondary to AMD. (A) The SLO testing done at presentation disclosed a pattern of predominantly central and stable fixation. The balls indicate the areas where the patient could perceive the stimulus; the triangles indicate the areas where the patient could not perceive the stimulus. Each ball and triangle is color-coded to indicate the intensity of the stimulus. (B) The SLO microperimetry also showed a mild decrease in central retinal sensitivity. The patient elected not to receive any treatment and had a follow-up visit 4 months after initial visual symptoms. (C) A SLO test was performed and demonstrated that the fixation pattern became poor central and relatively unstable.
FIGURE 4. (Continued) (D) The microperimetry also showed that retinal sensitivity was marked affected with some central areas of dense scotoma. Best-corrected visual acuity at this visit was 20/200. Twelve months after onset of initial visual symptoms and no treatment, SLO microperimetry was performed and disclosed further functional deterioration. (E) The fixation became predominantly eccentric and unstable. (F) During the retinal sensitivity testing it demonstrated a large central area of dense central scotoma.
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TABLE 4. Scanning Laser Ophthalmoscope Findings by Visual Acuity Fixation Stability (179 Eyes)
Visual Acuity
Stable n (%)
Relatively Unstable n (%)
ⱖ20/100 (good VA) ⬍20/100 and ⬎20/200 (medium VA) ⬍20/200 (worst VA)
41 (64) 26 (44) 9 (16)
20 (31) 26 (44) 24 (43)
Fixation Location (179 Eyes)
Unstable n (%)
Predominantly Central n (%)
3 (5) 7 (12) 23 (41)
61 (95) 48 (81) 26 (46)
Poor Central n (%)
Predominantly Eccentric n (%)
Presence of Some Dense Central Scotoma n (%)
2 (3) 7 (12) 18 (32)
1 (2) 4 (7) 12 (21)
4 (6) 13 (22) 33 (59)
VA ⫽ visual acuity.
about lesion thickness in our study group, we observed that the proportion of eyes with fixation pattern deterioration was progressively higher as the lesion size increased. However, it is important to note that the functional variability observed among lesions of the same size was significant, and a retinal viability evaluation based solely on lesion size does not seem to be appropriate (Table 2). Some eyes with predominantly eccentric fixation location presented with relatively stable fixation. This probably occurred due to a learning process of patients with bilateral disease that develop increased ability to use their eccentric preferred fixation location. This phenomenon also supports our rationale for introducing new terminology for describing distinct foveal functions. Current surgical “rescue” procedures such as macular translocation have shown the feasibility to recover visual function by probably restoring a more normal subretinal milieu. In a previous article14 we evaluated the outcomes of eyes with various preoperative microperimetric results. Through these results, we were able to better understand what deficits were possibly reversible changes or not based on SLO findings. Eyes with better fixation patterns and central retinal sensitivity were noted to have better visual outcome after effective macular translocation.14 The findings reported herein support the prevailing notion that any treatment modality aimed at rescuing photoreceptors from the underlying CNV pathologic process will have better potential visual outcome when performed earlier in the course of the disease. However, still a significant number of eyes with a long duration of symptoms and poor visual acuity preserve predominantly central fixation with good fixation stability. In our study group, 14 of 34 eyes (41%) with length of symptoms of more than 6 months and 26 of 56 eyes (46%) with poor vision (ⱕ 20/200) presented with predominantly central fixation. We postulate that individuals with predominantly central fixation despite poor vision may well have a potential for foveal photoreceptor viability. Whereas visual acuity provides very good assessment of eyes with good visual function, fixation evaluation by SLO provide valuable assessment of eyes with poor vision, as another level of evaluation capable of discerning between eyes with good or bad retinal cell viability.14
and the Bruch membrane; relative retinal ischemia/hypoxia secondary to abnormal retinal pigment epitheliumBruch membrane-choriocapillaris complex; development of intraretinal edema and subretinal fluid; and occurrence of intraretinal and subretinal hemorrhages. Although those changes can be at least partially reversed if the causative event is removed, it is probable that the persistence of those morphologic abnormalities result in progressive and permanent retinal damage during the course of the pathologic process. In the subgroup of eyes with symptoms for 3 months or less, 89 (89%) and 58 (58%) of 100 eyes, respectively, presented predominantly central and stable fixation. This finding suggests that a great percentage of patients with less than 3 months of symptoms may have viable foveal photoreceptors. A change in preferential fixation location will usually be noticed latter in the course of the disease and will only occur after the fixation instability becomes more prominent (Figures 4, 5). This change will be characterized by a progressive inability to maintain stable fixation within the foveal center until it is no longer attainable. The fixation eccentricity is associated with profound loss of foveal sensitivity and probably becomes permanent if the causative injury persists. At this point, those patients refer to the central vision as one area of central scotoma and complete loss of central visual perception. Morphologically, loss of central fixation probably reflects injury to central photoreceptors, with eventual loss of photoreceptors in many cases. In the subgroup of eyes with length of symptoms of more than 9 months, only three (25%) and one (8%) of 12 eyes, respectively, had predominantly central and stable fixation. Correspondingly, seven (58%) of those 12 eyes had some central dense scotoma and six (50%) had visual acuity of 20/200 or worse. These findings reflect the nature of the relatively rapid visual deterioration resulting from subfoveal CNV secondary to AMD. The direct relationship between the SLO findings and the corresponding photoreceptor loss remains undetermined. In a histopathologic study reported by Green and Enger,17 the extent of photoreceptor cell atrophy was found to be proportional to the size and thickness of the disciform scars. Although we do not have information 1076
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FIGURE 5. The curve of functional deterioration of fixation pattern in 15 eyes with subfoveal choroidal neovascularization secondary to age-related macular degeneration examined successively over time.(Top) Fixation location over time. (Bottom) Fixation stability over time.
Visual acuity, as expected, was also significantly worse in eyes with longer duration of symptoms. Although 42 of 100 eyes (42%) with length of symptoms of 3 months or less presented with visual acuity of 20/100 or better, only 5 of 34 eyes (15%) with more than 6 months of symptoms presented the same level of vision. When we looked at the characteristics of the lesions we observed that five of eight eyes (62.5%) with more than 9 months of symptoms and predominantly classic CNV lesion on fluorescein angiography had predominantly eccentric fixation, whereas one of four eyes (25%) with more than 9 months of symptoms and predominantly occult lesion had the same fixation pattern. This finding suggests that lesion characteristics play a role in the visual decline and that occult lesions are possibly more likely to preserve good fixation patterns. We acknowledge that the exact determination of length of symptoms is challenging, as symptoms may have not been noted by the onset of the disease, particularly in cases in which the fellow eye maintained good vision. VOL. 136, NO. 6
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One limitation of this study was that, owing to its cross-sectional study design, differences in lesion characteristics among eyes of different subgroups might have impacted the microperimetry outcome and limited the interpretation of our findings. We conclude that the sequence of events leading to visual function deterioration appears to involve an initial mild decrease in central retinal sensitivity and visual acuity followed by progressive decrease in fixation instability, and ultimately development of an absolute central scotoma with totally eccentric fixation. Increased length of disease in eyes with subfoveal CNV is associated with worse fixation patterns and retinal sensitivity deterioration as assessed by SLO microperimetry. A better understanding of the characteristics of visual loss in AMD may help optimize timing, patient selection, and treatment options in eyes with this condition. Given the relationship between our microperimetric findings (for example, fixation stability and fixation location), with other parameters of AGE-RELATED MACULAR DEGENERATION
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disease progression (for example, duration of symptoms, visual acuity, lesion size/characteristic), we are optimistic that the microperimetry with fixation evaluation may play a greater role in determining treatment paradigms for patients with CNV secondary to AMD.
9.
10.
REFERENCES 1. Bressler SB, Bressler NM, Fine SL, et al. Natural course of choroidal neovascular membranes within the foveal avascular zone in senile macular degeneration. Am J Ophthalmol 1982;93:157–163. 2. Macular Photocoagulation Study (MPS) Group. Evaluation of argon green vs krypton red laser for photocoagulation of subfoveal choroidal neovascularization in the macular photocoagulation study. Arch Ophthalmol 1994;112:1176 – 1184. 3. Macular Photocoagulation Study Group. Visual outcome after laser photocoagulation for subfoveal choroidal neovascularization secondary to age-related macular degeneration. The influence of initial lesion size and initial visual acuity. Arch Ophthalmol 1994;112:480 –488. 4. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Arch Ophthalmol 1993;111:1200 –1209. 5. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal recurrent neovascular lesions in agerelated macular degeneration. Results of a randomized clinical trial. Arch Ophthalmol 1991;109:1232–1241. 6. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Arch Ophthalmol 1991;109:1220 –1231. 7. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Arch Ophthalmol 1991;109: 1109 –1114. 8. Rohrschneider K, Becker M, Schumacher N, Fendrich T,
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11.
12.
13.
14.
15.
16.
17.
OF
Volcker HE. Normal values for fundus perimetry with the scanning laser ophthalmoscope. Am J Ophthalmol 1998;126: 52–58. Loewenstein A, Sunness JS, Bressler NM, Marsh MJ, de Juan E Jr. Scanning laser ophthalmoscope fundus perimetry after surgery for choroidal neovascularization. Am J Ophthalmol 1998;125:657–665. Rohrschneider K, Becker M, Fendrich T, Volcker HE. Kinetic fundus controlled perimetry with the scanning laser ophthalmoscope [translation]. Klin Monatsbl Augenheilkd 1995;207:102–110. Sunness JS, Schuchard RA, Shen N, Rubin GS, Dagnelie G, Haselwood DM. Landmark-driven fundus perimetry using the scanning laser ophthalmoscope. Invest Ophthalmol Vis Sci 1995;36:1863–1874. Rohrschneider K, Becker M, Kruse FE, Fendrich T, Volcker HE. Stability of fixation: results of fundus-controlled examination using the scanning laser ophthalmoscope. Ger J Ophthalmol 1995;4:197–202. Sunness JS, Bressler NM, Maguire MG. Scanning laser ophthalmoscopic analysis of the pattern of visual loss in age-related geographic atrophy of the macula. Am J Ophthalmol 1995;119:143–151. Fujii GY, de Juan E Jr, Sunness JS, Humayun MS, Pieramici DJ, Chang TS. Patient selection for macular translocation surgery using scanning laser ophthalmoscope. Ophthalmology 2002;109:1737–1744. Macular Photocoagulation Study Group. Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for evaluation and treatment in the macular photocoagulation study. Arch Ophthalmol 1991;109:1242–1257. Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report. Arch Ophthalmol 1999;117:1329 –1345. Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman lecture. Ophthalmology 1993;100:1519 –1535.
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● PURPOSE:
To evaluate the effects of subfoveal choroidal neovascularization secondary to age-related macular degeneration on functional parameters obtained by scanning laser ophthalmoscope microperimetry. ● DESIGN: Retrospective observational case series and cross-sectional study. ● METHODS: At the Doheny Retina Institute and Wilmer Eye Institute a consecutive series of 179 eyes of 175 patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration was studied. The onset of visual symptoms, best-corrected visual acuity, fluorescein angiography, evaluation of fundus microperimetry and fixation pattern using the Rodenstock scanning laser ophthalmoscope were obtained for each patient. The main outcome measures were central retinal sensitivity and fixation pattern (fixation location and fixation stability) in eyes with subfoveal choroidal neovascularization and their relationship to the length of disease, type and characteristics of choroidal neovascularization, and visual acuity. ● RESULTS: Of 179 eyes, 135 (75%) had central fixation, 27 (15%) had poor central fixation, and 17 (9%)
Accepted for publication June 3, 2003. InternetAdvance publication at ajo.com Oct 8, 2003. From the Doheny Retina Institute, Doheny Eye Institute, University of Southern California, Keck School of Medicine, Los Angeles, California (G.Y.F., E.D.J., M.S.H., T.S.C., J.V.R.), and the Lions Vision Center, Wilmer Ophthalmological Institute, The Johns Hopkins Hospital, Baltimore, Maryland (J.S.S.). This work was supported in part by National Eye Institute Grant EY08552 (J.S.S.), Research to Prevent Blindness James S. Adams Special Scholar 1999 –2000 (J.S.S.), and the Panitch Fund to Stop AMD. Inquiries to Eugene de Juan, Jr, MD, Doheny Eye Institute, University of Southern California, Keck School of Medicine, 1450 San Pablo St, Room 3620, Los Angeles, CA 90033; fax: (323) 442-6519; e-mail: [email protected] 0002-9394/03/$30.00 doi:10.1016/S0002-9394(03)00663-9
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2003 BY
had predominantly eccentric fixation. Seventy-six eyes (42%) had stable fixation, 70 eyes (39%) had relatively unstable fixation, and 33 eyes (18%) had unstable fixation. In 50 eyes (28%) a dense central scotoma was noted. Eighty-nine of 100 eyes (89%) with length of symptoms of less than 3 months had predominantly central fixation and 58 (58%) had stable fixation; 14 of 34 eyes (41%) with length of symptoms of more than 6 months had predominantly central fixation, and 5 eyes (15%) had stable fixation. In 15 eyes of patients who elected not to receive treatment, successive scanning laser ophthalmoscope microperimetry were obtained over time (follow-up of 18 months after onset of symptoms). Three months or less after the onset of symptoms, 13 eyes (87.7%) had predominantly central fixation and 9 eyes (60%) had stable fixation. More than 3 months and 6 months or less after the onset of symptoms, 10 eyes (66.7%) had predominantly central fixation and 7 eyes (46.7%) had stable fixation. This trend was further demonstrated in eyes more than 6 months after the onset of symptoms. ● CONCLUSIONS: We conclude that the sequence of events leading to visual function deterioration appears to involve an initial mild decrease in central retinal sensitivity and visual acuity followed by progressive fixation instability and, ultimately, development of an absolute central scotoma with totally eccentric fixation. Increased length of disease is associated with worse fixation pattern and retinal sensitivity deterioration as assessed by scanning laser ophthalmoscope microperimetry. A better understanding of the characteristics of visual loss assessed by fixation pattern evaluation and microperimetry in age-related macular degeneration may help optimize timing, patient selection, and treatment options in eyes with this condition. (Am J Ophthalmol 2003;136: 1067–1078. © 2003 by Elsevier Inc. All rights reserved.)
ELSEVIER INC. ALL
RIGHTS RESERVED.
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of Age-related Macular Degeneration with Photodynamic Therapy (TAP) study.16 Static fundus perimetry was performed on all patients using the Rodenstock scanning laser ophthalmoscope (G. Rodenstock Instrument GmbH, Munich, Germany). The infrared laser was used for imaging, and the helium-neon red laser was used for stimulus presentation. A stimulus size equivalent to a Goldmann III test spot was used. With SLO microperimetry, the stimulus intensity can vary in 0.1-logarithmic steps from 0 to 35 dB. We used the following stimulus intensity: 0 dB, 6 dB, 11 dB, 16 dB, and 21 dB. We defined a dense scotoma as one in which the stimulated area could not be detected with a 0-dB spot of Goldmann III size and a relative scotoma as one in which the stimulated area could be detected by a 0-dB spot but not by a 21-dB spot. (Normal sensitivity is approximately 24 dB in the macular region.) A fixation cross of 1 degree in size on the retina was used. The Rodenstock scotometry software used allowed for acquiring a fundus image at the time of stimulus presentation, and placing a cursor on a retinal landmark on the frozen image to allow for correction for eye movements when the results are displayed. At the conclusion of testing, the results of perimetry are displayed on the retinal image, with stimulus placement adjusted for changes in retinal landmark location at the time of each stimulus presentation. The SLO represents a dynamic assessment of retinal microperimetry. To accurately determine the location and stability of fixation, eye movements during testing must be measured and accounted for. This is carried out in the following manner. At each point of stimulus presentation, the position of a distinct retinal landmark (that is, arteriovenous crossing) was identified by cursor placement in the method described above. Eye movements (as measured by the changes in the landmark position) reflect the changes in the location of fixation. The amplitude of these eye movements is a reflection of fixation stability. At the conclusion of testing, a scattergraph depiction of fixation is displayed. This was used to quantify fixation pattern. The fixation pattern was graded based on two variables: fixation location (defined as the position of fixation with respect to the center of the foveal avascular zone) and fixation stability (defined as the ability of the eye to maintain fixation in the preferred retinal locus). In assessing the fixation location we defined a standard of central fixation to approximate a 2-degree diameter (approximately 700-m) circle centered on the fovea. Patients with more than 50% of the preferred fixation points located within central fixation were classified as L1, predominantly central fixation. Eyes with more than 25% but less than 50% of the preferred fixation points located within central fixation were classified as L2, poor central fixation. Eyes with less than 25% of the preferred fixation points located within central fixation were classified as L3, predominantly eccentric fixation. For eyes with both predominantly central and poor central fixation, the patients
HE NATURAL HISTORY OF EYES WITH SUBFOVEAL
choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD) is poor. Patients with this condition typically experience a significant decrease in visual acuity in a relatively short time.1 In one series, 70% of eyes with subfoveal CNV related to AMD were noted to have a visual acuity of 20/200 or worse within 2 years of the onset of visual symptoms.1 Several clinical trials have provided additional information regarding visual acuity loss in eyes with untreated neovascular AMD.2–7 In many respects, visual acuity is not a complete measure of the visual function. One test of visual function that may help to better understand the characteristics of visual loss in these patients is scanning laser ophthalmoscope (SLO) microperimetry. This instrument can provide accurate determination of preferential fixation location and fixation stability.8 –13 The SLO is also useful in measuring focal areas of retinal sensitivity with correction for eye movements that are common in patients with central visual loss.11 The information given by this functional test provides valuable information about the location of the retinal sensitivity loss, its magnitude and its potential impact on central fixation. The knowledge of fixation and sensitivity parameters in eyes with subfoveal CNV and their relationship to the length of disease may help to understand the mechanisms of visual loss in this disease. In a previous study, we have found that by evaluating the fixation and retinal sensitivity pattern it was possible to assess the retinal cell viability of the macular region in terms of likelihood of improvement in acuity following macular translocation.14 The main purpose of this study was to evaluate the effects of subfoveal CNV secondary to AMD on functional parameters obtained by SLO microperimetry.
METHODS WE RETROSPECTIVELY STUDIED 179 EYES OF 175 CONSECU-
tive patients with subfoveal CNV secondary to AMD at the Wilmer Ophthalmologic Institute and Doheny Retina Institute with appropriate institutional review board approval. Inclusion criteria for this study were (1) fluorescein angiographic evidence of CNV extending under the center of the foveal avascular zone, (2) evidence of age-related macular degeneration, and (3) absence of coexisting ocular disease. The onset of visual symptoms and best-corrected visual acuity on the standard Snellen chart were obtained in each patient. Slit-lamp and fundus biomicroscopic examination, stereo color fundus photography, and Macular Photocoagulation Study (MPS) protocol fluorescein angiography were performed on each patient.15 The CNV size was evaluated using the MPS guidelines15 and the CNV type was classified according to the guidelines of the Treatment 1068
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FIGURE 1. Classification of location of fixation. Fixation points in green indicate the fixation location during each perceived stimulus presentation. Fixation points in red indicate the fixation location during nonperceived stimulus presentation. The fixation cross seen in each picture indicates only the last fixation point recorded at the end of the testing. (Top) The location of fixation was defined as predominantly central fixation when more than 50% of the preferred fixation points were located within a predetermined limit area of variation of 2-degree diameter circle centered in the fovea. (Middle) The location of fixation was classified as poor central fixation when less than 50% but more than 25% of the preferred fixation points were located within the 2-degree diameter circle. (Bottom) The location of fixation was classified as predominantly eccentric fixation when less than 25% of the preferred fixation points located within the 2-degree diameter circle.
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FIGURE 2. Classification of fixation stability. (Top) The location of fixation was defined as stable fixation when more than 75% of the fixation points were located within a predetermined limit area of variation of a 2-degree diameter circle centered in the gravitational center of all fixation points, regardless of the position of the foveal center. (Middle) The location of fixation was classified as relatively unstable fixation when less than 75% of the fixation points were located within a 2-degree diameter circle but more than 75% of the fixation points were located within a 4-degree diameter circle. (Bottom) The location of fixation was classified as unstable fixation when less than 75% of the fixation points were located within a 4-degree circle.
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were required to confirm their ability to see the fixation target while looking straight at it. In situations where patients were unable to maintain foveal fixation even for a short duration, they would be automatically classified as having predominantly eccentric fixation (Figure 1). For the purpose of evaluating the stability of fixation we suggest two new terms: target fixation and extra-target fixation. Target fixation is defined as a 2-degree diameter circle positioned with respect to the gravitational center of all fixation points. Likewise, extra-target fixation is defined as a 4-degree diameter circle positioned with respect to the gravitational center of all fixation points. Eyes with more than 75% of the fixation points located within the target fixation were classified as S1, or stable. If less than 75% of the fixation points were located within the target fixation but more than 75% of the fixation points within extratarget fixation the eye was classified as having S2, or relatively unstable fixation. If less than 75% of fixation points were located within the extra-target fixation, the pattern was described as being S3, or unstable fixation. The stability of fixation was classified separately from the fixation location because some eyes can present with predominantly eccentric and relatively stable fixation (Figure 2). Eyes were classified as having a dense central scotoma when more than three 0-dB-stimuli were not perceived by the patient in a 3-degree diameter circle centered in the fovea. The microperimetric findings and visual acuity were grouped for each specific SLO evaluation according to length of symptoms and visual acuity. In 15 eyes of patients who elected not to receive treatment, successive SLO microperimetry were obtained over time with one visit each 3 months. All 15 eyes included in this series had onset of symptoms within 3 months of presentation and were followed up to 18 months after initial visual symptoms. The statistical analysis for all tests of association was performed using the 2 test. All P values .05 or less were considered significant.
RESULTS THE BASELINE DESCRIPTIVE DATA OF THE PATIENTS IN-
cluded in this study is shown in Table 1. Patient ages ranged from 54 to 91 years with a mean of 74.5 years. The median and mean lengths of symptoms respectively were 3 and 4.8 months, ranging from 1 week to 96 months. The lesion and choroidal neovascularization characteristics were identified with fluorescein angiography and are also described in Table 1. Choroidal neovascular lesions varied in size, ranging from 1 to 16 MPS disk areas with a median size of 3 MPS disk areas (mean, 3.3 MPS disk areas; range, 1–9 MPS disk areas). One hundred and twenty-six eyes in this study (70%) had classic or predominantly classic VOL. 136, NO. 6
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TABLE 1. Preoperative Data for Study Group (175 Patients, 179 Eyes) Characteristic
Age, years ⬍50 50–59 60–69 70–79 ⱖ80 Sex Male Female Study eye Right Left Duration ⬎1 week and ⱕ3 months ⬎3 months and ⱕ6 months ⬎6 months and ⱕ9 months ⬎9 months and ⱕ12 months CNV Character Predominantly classic Predominantly occult Size of CNV ⱕ1 ⬎1 and ⱕ3 ⱖ3.5 and ⱕ4 ⱖ5 Baseline visual acuity 20/30–20/80 20/100–20/160 20/200–20/320 20/400–20/640 20/800 or worse
N
%
0 10 34 79 52
0 5.7 19.4 45.1 29.7
94 81
53.7 46.3
100 79
55.9 44.1
100 45 22 12
55.9 25.1 12.3 6.7
126 53
70.4 29.6
24 77 30 48
13.4 43 16.7 26.8
40 83 35 17 4
22.3 46.4 19.5 9.5 2.2
CNV ⫽ choroidal neovascularization.
patterns of CNV leakage; 53 eyes (30%) had occult or minimally classic CNV. The median visual acuity was 20/150, ranging from 20/30 to counting fingers. The distribution of lesion characteristics by length of symptoms is described in Table 2. As anticipated, lesion size increased with the length of symptoms. In the study group, the percentage of predominantly classic vs minimally classic CNV was essentially the same for all duration of symptoms. The distribution of visual acuity by length of symptoms is described in Table 3. In general, visual acuity worsened with duration of symptoms (P ⫽ .05). Using the SLO, determination of the macular retinal sensitivity, fixation location, and fixation stability was achieved during fundus perimetry. Of all 179 eyes with CNV, 135 (75%) had predominantly central fixation, 27 (15%) had poor central fixation, and 17 (9%) had predominantly eccentric fixation. Seventy-six eyes (42%) had stable fixation, 70 eyes (39%) had relatively unstable AGE-RELATED MACULAR DEGENERATION
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TABLE 2. Lesion Characteristics by Duration of Symptoms Lesion Size (MPS Disk Areas) (179 Eyes)
CNV Type (179 Eyes)
Duration of Symptoms (Months)
ⱕ1 N (%)
⬎1 and ⱕ3.5 N (%)
ⱖ3.5 and ⱕ5 N (%)
⬎5 N (%)
Predominantly Classic N (%)
Predominantly Occult N (%)
0–3 (least) ⬎3–6 (short) ⬎6–9 (medium) ⬎9 (long)
17 (17) 6 (13) 1 (4) 0 (0)
47 (47) 17 (38) 9 (41) 4 (33)
15 (15) 9 (20) 3 (14) 3 (25)
21 (21) 13 (29) 9 (41) 5 (42)
70 (70) 33 (73) 15 (68) 8 (67)
30 (30) 12 (27) 7 (32) 4 (33)
CNV ⫽ choroidal neovascularization; MPS ⫽ Macular Photocoagulation Study.
were obtained over time. At presentation, 12 eyes (80%) had predominantly classic lesion whereas 3 eyes (20%) had minimally classic lesions. Median lesion size at baseline was 3 MPS disk areas (range, 1– 6 MPS disk areas). After 18 months of follow-up, the composition of the CNV type did not change significantly. Only one eye that was classified as minimally classic lesion at baseline converted to predominantly classic. However, the mean lesion size increased to 4.8 MPS disk areas (range, 2–9 MPS disk areas). Figures 4 and 5 illustrate the line of deterioration of the fixation pattern over time. There was significant association between fixation location and length of symptoms, with more eyes with predominantly eccentric fixation overtime (P ⫽ .003). Similarly, there was significant association between fixation stability and length of symptoms, with more eyes with unstable fixation overtime (P ⫽ .01; Figure 5).
TABLE 3. Visual Acuity by Duration of Symptoms (179 Eyes)
Duration of Symptoms (Months)
ⱖ20/100 (Good VA) N (%)
⬍20/100 and ⬎20/200 (Medium VA) N (%)
ⱕ20/200 (Worst VA) N (%)
0–3 (least) ⬎3–6 (short) ⬎6–9 (medium) ⬎9 (long)
42 (42) 17 (38) 3 (14) 2 (17)
35 (35) 12 (27) 8 (36) 4 (33)
23 (23) 16 (35) 11 (50) 6 (50)
VA ⫽ visual acuity.
fixation, and 33 eyes (18%) had unstable fixation. In 50 eyes (28%) a dense central scotoma was noted. The distribution of SLO findings by length of symptoms and visual acuity are summarized in Table 4 and Figure 3. In general, fixation pattern (fixation location and fixation stability) worsened with increased length of symptoms and with decreased visual acuity. (P ⬍ .0001 and P ⬍ .0001, respectively). The development of retinal sensitivity loss was not always homogeneous and varied significantly in location, size, and intensity throughout the lesion. When located within the fovea, retinal sensitivity loss resulted in further loss of fixation stability and a secondary loss of central fixation. Some eyes with subfoveal CNV presented a profound loss of parafoveal retinal sensitivity to the level of absolute dense scotoma but preserved a small island of foveal sensitivity that accounted for preservation of central fixation. Alternatively, some eyes presented with relatively good parafoveal sensitivity and an absolute foveal scotoma resulting in predominantly eccentric and unstable fixation. However, some eyes with predominantly eccentric fixation location presented with relatively stable fixation. Dense central scotoma was present in four of 64 eyes (6%) in the good acuity group and in 33 of 56 eyes (59%) of eyes in the worst acuity group. In general, dense central scotoma was associated with increased length of symptoms (P ⫽ .0002). In 15 eyes of patients who elected not to receive treatment, successive SLO microperimetry measurements 1072
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DISCUSSION WE FOUND THAT VISUAL IMPAIRMENT IN EYES WITH SUB-
foveal CNV secondary to AMD is associated with progressive visual function deterioration expressed by decreased fixation stability, loss of central fixation, and impaired retinal sensitivity as measured by SLO microperimetry. In eyes with progressive deterioration, the inability to maintain the preferential fixation location within the fovea progresses until complete absence of foveal visual perception is established and the preferential fixation location becomes totally eccentric. This reflects a profound loss of central retinal sensitivity and functionality. By drawing a progression line of visual function deterioration across time, we observed that eyes with subfoveal CNV secondary to AMD initially experience metamorphopsia and blurred vision that is usually associated with progressive loss of central retinal sensitivity, visual acuity, and fixation stability. The early morphologic changes associated with those symptoms are probably related to impaired photoreceptor function secondary to abnormal retinal pigment epithelium function (retinal metabolism); impaired nutrient/waste exchange across the retinal pigment epithelium OF
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FIGURE 3. Distribution of scanning laser ophthalmoscope microperimetry findings by length of symptoms. (Top) Fixation location by length of symptoms. (Middle) Fixation stability by length of symptoms. (Bottom) Presence of dense central scotoma by duration of symptoms.
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FIGURE 4. A sequence of scanning laser ophthalmoscope (SLO) microperimetry shows the progressive functional deterioration in one eye with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). The SLO testing demonstrated that eyes with subfoveal CNV secondary to AMD resulted in a predictable and progressive loss of fixation stability, decreased central retinal sensitivity, and loss of central fixation location. A 65-year-old man presented with 20/150 vision and a 1-month history of decreased vision due to a predominantly classic subfoveal CNV secondary to AMD. (A) The SLO testing done at presentation disclosed a pattern of predominantly central and stable fixation. The balls indicate the areas where the patient could perceive the stimulus; the triangles indicate the areas where the patient could not perceive the stimulus. Each ball and triangle is color-coded to indicate the intensity of the stimulus. (B) The SLO microperimetry also showed a mild decrease in central retinal sensitivity. The patient elected not to receive any treatment and had a follow-up visit 4 months after initial visual symptoms. (C) A SLO test was performed and demonstrated that the fixation pattern became poor central and relatively unstable.
FIGURE 4. (Continued) (D) The microperimetry also showed that retinal sensitivity was marked affected with some central areas of dense scotoma. Best-corrected visual acuity at this visit was 20/200. Twelve months after onset of initial visual symptoms and no treatment, SLO microperimetry was performed and disclosed further functional deterioration. (E) The fixation became predominantly eccentric and unstable. (F) During the retinal sensitivity testing it demonstrated a large central area of dense central scotoma.
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TABLE 4. Scanning Laser Ophthalmoscope Findings by Visual Acuity Fixation Stability (179 Eyes)
Visual Acuity
Stable n (%)
Relatively Unstable n (%)
ⱖ20/100 (good VA) ⬍20/100 and ⬎20/200 (medium VA) ⬍20/200 (worst VA)
41 (64) 26 (44) 9 (16)
20 (31) 26 (44) 24 (43)
Fixation Location (179 Eyes)
Unstable n (%)
Predominantly Central n (%)
3 (5) 7 (12) 23 (41)
61 (95) 48 (81) 26 (46)
Poor Central n (%)
Predominantly Eccentric n (%)
Presence of Some Dense Central Scotoma n (%)
2 (3) 7 (12) 18 (32)
1 (2) 4 (7) 12 (21)
4 (6) 13 (22) 33 (59)
VA ⫽ visual acuity.
about lesion thickness in our study group, we observed that the proportion of eyes with fixation pattern deterioration was progressively higher as the lesion size increased. However, it is important to note that the functional variability observed among lesions of the same size was significant, and a retinal viability evaluation based solely on lesion size does not seem to be appropriate (Table 2). Some eyes with predominantly eccentric fixation location presented with relatively stable fixation. This probably occurred due to a learning process of patients with bilateral disease that develop increased ability to use their eccentric preferred fixation location. This phenomenon also supports our rationale for introducing new terminology for describing distinct foveal functions. Current surgical “rescue” procedures such as macular translocation have shown the feasibility to recover visual function by probably restoring a more normal subretinal milieu. In a previous article14 we evaluated the outcomes of eyes with various preoperative microperimetric results. Through these results, we were able to better understand what deficits were possibly reversible changes or not based on SLO findings. Eyes with better fixation patterns and central retinal sensitivity were noted to have better visual outcome after effective macular translocation.14 The findings reported herein support the prevailing notion that any treatment modality aimed at rescuing photoreceptors from the underlying CNV pathologic process will have better potential visual outcome when performed earlier in the course of the disease. However, still a significant number of eyes with a long duration of symptoms and poor visual acuity preserve predominantly central fixation with good fixation stability. In our study group, 14 of 34 eyes (41%) with length of symptoms of more than 6 months and 26 of 56 eyes (46%) with poor vision (ⱕ 20/200) presented with predominantly central fixation. We postulate that individuals with predominantly central fixation despite poor vision may well have a potential for foveal photoreceptor viability. Whereas visual acuity provides very good assessment of eyes with good visual function, fixation evaluation by SLO provide valuable assessment of eyes with poor vision, as another level of evaluation capable of discerning between eyes with good or bad retinal cell viability.14
and the Bruch membrane; relative retinal ischemia/hypoxia secondary to abnormal retinal pigment epitheliumBruch membrane-choriocapillaris complex; development of intraretinal edema and subretinal fluid; and occurrence of intraretinal and subretinal hemorrhages. Although those changes can be at least partially reversed if the causative event is removed, it is probable that the persistence of those morphologic abnormalities result in progressive and permanent retinal damage during the course of the pathologic process. In the subgroup of eyes with symptoms for 3 months or less, 89 (89%) and 58 (58%) of 100 eyes, respectively, presented predominantly central and stable fixation. This finding suggests that a great percentage of patients with less than 3 months of symptoms may have viable foveal photoreceptors. A change in preferential fixation location will usually be noticed latter in the course of the disease and will only occur after the fixation instability becomes more prominent (Figures 4, 5). This change will be characterized by a progressive inability to maintain stable fixation within the foveal center until it is no longer attainable. The fixation eccentricity is associated with profound loss of foveal sensitivity and probably becomes permanent if the causative injury persists. At this point, those patients refer to the central vision as one area of central scotoma and complete loss of central visual perception. Morphologically, loss of central fixation probably reflects injury to central photoreceptors, with eventual loss of photoreceptors in many cases. In the subgroup of eyes with length of symptoms of more than 9 months, only three (25%) and one (8%) of 12 eyes, respectively, had predominantly central and stable fixation. Correspondingly, seven (58%) of those 12 eyes had some central dense scotoma and six (50%) had visual acuity of 20/200 or worse. These findings reflect the nature of the relatively rapid visual deterioration resulting from subfoveal CNV secondary to AMD. The direct relationship between the SLO findings and the corresponding photoreceptor loss remains undetermined. In a histopathologic study reported by Green and Enger,17 the extent of photoreceptor cell atrophy was found to be proportional to the size and thickness of the disciform scars. Although we do not have information 1076
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FIGURE 5. The curve of functional deterioration of fixation pattern in 15 eyes with subfoveal choroidal neovascularization secondary to age-related macular degeneration examined successively over time.(Top) Fixation location over time. (Bottom) Fixation stability over time.
Visual acuity, as expected, was also significantly worse in eyes with longer duration of symptoms. Although 42 of 100 eyes (42%) with length of symptoms of 3 months or less presented with visual acuity of 20/100 or better, only 5 of 34 eyes (15%) with more than 6 months of symptoms presented the same level of vision. When we looked at the characteristics of the lesions we observed that five of eight eyes (62.5%) with more than 9 months of symptoms and predominantly classic CNV lesion on fluorescein angiography had predominantly eccentric fixation, whereas one of four eyes (25%) with more than 9 months of symptoms and predominantly occult lesion had the same fixation pattern. This finding suggests that lesion characteristics play a role in the visual decline and that occult lesions are possibly more likely to preserve good fixation patterns. We acknowledge that the exact determination of length of symptoms is challenging, as symptoms may have not been noted by the onset of the disease, particularly in cases in which the fellow eye maintained good vision. VOL. 136, NO. 6
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One limitation of this study was that, owing to its cross-sectional study design, differences in lesion characteristics among eyes of different subgroups might have impacted the microperimetry outcome and limited the interpretation of our findings. We conclude that the sequence of events leading to visual function deterioration appears to involve an initial mild decrease in central retinal sensitivity and visual acuity followed by progressive decrease in fixation instability, and ultimately development of an absolute central scotoma with totally eccentric fixation. Increased length of disease in eyes with subfoveal CNV is associated with worse fixation patterns and retinal sensitivity deterioration as assessed by SLO microperimetry. A better understanding of the characteristics of visual loss in AMD may help optimize timing, patient selection, and treatment options in eyes with this condition. Given the relationship between our microperimetric findings (for example, fixation stability and fixation location), with other parameters of AGE-RELATED MACULAR DEGENERATION
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disease progression (for example, duration of symptoms, visual acuity, lesion size/characteristic), we are optimistic that the microperimetry with fixation evaluation may play a greater role in determining treatment paradigms for patients with CNV secondary to AMD.
9.
10.
REFERENCES 1. Bressler SB, Bressler NM, Fine SL, et al. Natural course of choroidal neovascular membranes within the foveal avascular zone in senile macular degeneration. Am J Ophthalmol 1982;93:157–163. 2. Macular Photocoagulation Study (MPS) Group. Evaluation of argon green vs krypton red laser for photocoagulation of subfoveal choroidal neovascularization in the macular photocoagulation study. Arch Ophthalmol 1994;112:1176 – 1184. 3. Macular Photocoagulation Study Group. Visual outcome after laser photocoagulation for subfoveal choroidal neovascularization secondary to age-related macular degeneration. The influence of initial lesion size and initial visual acuity. Arch Ophthalmol 1994;112:480 –488. 4. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions of age-related macular degeneration. Updated findings from two clinical trials. Arch Ophthalmol 1993;111:1200 –1209. 5. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal recurrent neovascular lesions in agerelated macular degeneration. Results of a randomized clinical trial. Arch Ophthalmol 1991;109:1232–1241. 6. Macular Photocoagulation Study Group. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Arch Ophthalmol 1991;109:1220 –1231. 7. Macular Photocoagulation Study Group. Argon laser photocoagulation for neovascular maculopathy. Five-year results from randomized clinical trials. Arch Ophthalmol 1991;109: 1109 –1114. 8. Rohrschneider K, Becker M, Schumacher N, Fendrich T,
1078
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11.
12.
13.
14.
15.
16.
17.
OF
Volcker HE. Normal values for fundus perimetry with the scanning laser ophthalmoscope. Am J Ophthalmol 1998;126: 52–58. Loewenstein A, Sunness JS, Bressler NM, Marsh MJ, de Juan E Jr. Scanning laser ophthalmoscope fundus perimetry after surgery for choroidal neovascularization. Am J Ophthalmol 1998;125:657–665. Rohrschneider K, Becker M, Fendrich T, Volcker HE. Kinetic fundus controlled perimetry with the scanning laser ophthalmoscope [translation]. Klin Monatsbl Augenheilkd 1995;207:102–110. Sunness JS, Schuchard RA, Shen N, Rubin GS, Dagnelie G, Haselwood DM. Landmark-driven fundus perimetry using the scanning laser ophthalmoscope. Invest Ophthalmol Vis Sci 1995;36:1863–1874. Rohrschneider K, Becker M, Kruse FE, Fendrich T, Volcker HE. Stability of fixation: results of fundus-controlled examination using the scanning laser ophthalmoscope. Ger J Ophthalmol 1995;4:197–202. Sunness JS, Bressler NM, Maguire MG. Scanning laser ophthalmoscopic analysis of the pattern of visual loss in age-related geographic atrophy of the macula. Am J Ophthalmol 1995;119:143–151. Fujii GY, de Juan E Jr, Sunness JS, Humayun MS, Pieramici DJ, Chang TS. Patient selection for macular translocation surgery using scanning laser ophthalmoscope. Ophthalmology 2002;109:1737–1744. Macular Photocoagulation Study Group. Subfoveal neovascular lesions in age-related macular degeneration. Guidelines for evaluation and treatment in the macular photocoagulation study. Arch Ophthalmol 1991;109:1242–1257. Treatment of Age-related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in agerelated macular degeneration with verteporfin: one-year results of 2 randomized clinical trials—TAP report. Arch Ophthalmol 1999;117:1329 –1345. Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman lecture. Ophthalmology 1993;100:1519 –1535.
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