Should clinical automated perimetry be considered for routine functional assessment of early/intermediate age‐related macular degeneration (AMD)? A systematic review of current literature

Selection of studies

The electronic database searches yielded 2223 studies and 1740 unique studies, with 1683 studies excluded after being screened by title/abstract and 33 studies excluded after being assessed by full text (Figure 1). The primary reasons for exclusion by full text are provided in Supplementary Table S5. No additional studies were identified through the Imaging and Perimetry Society articles. Two additional studies were identified through reference lists of selected studies or relevant review studies. Thus, a total of 26 unique studies were eligible for inclusion. The number of eligible studies per search query are provided in Supplementary Table S1. Reviewers MT and LNS were in agreement for all included and excluded studies, with three of the 26 final included studies requiring brief discussion and resolution as relevant data were not immediately obvious.

image Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram29 for the selection of studies. iAMD, intermediate age-related macular degeneration; MD, mean deviation; MS, mean sensitivity; SAP, standard automated perimetry; WoS, Web of Science Core Collection Quality assessment and study characteristics

Quality assessment details and study characteristics for the 26 included studies can be seen in Supplementary Table S4. All studies were observational studies, with the majority being case-control studies (n = 19/26),15, 49, 82-98 followed by cohort studies (n = 5/26),48, 99-102 and cross-sectional studies (comparison between groups that did not involve a control or baseline group, but instead defined groups by AMD severity or phenotype; (n = 2/26).103, 104 Feher et al.102 had their study type re-classified from a randomised controlled trial to a cohort design, as for the purposes of this review, only longitudinal data from the treatment-naïve (placebo) early/iAMD eyes were extracted.

Studies were conducted in Australia (n = 11/26),15, 48, 49, 83, 84, 87-89, 97, 100, 101 USA (n = 6/26),85, 94, 95, 98, 99, 103 Italy, (n = 3/26),92, 93, 96 China,86 Hungary,102 India,104 Korea,91 Sweden90 and the UK82 (n = 1/26 for each remaining country). The majority of studies included funding source(s) (n = 19/26)15, 48, 49, 82, 84, 85, 87, 88, 90, 92-95, 97-100, 103, 104 and conflict of interest statements (n = 15/26),15, 48, 49, 82, 85, 88, 91, 93-95, 97-100, 104 provided in Supplementary Table S6. Four studies48, 49, 88, 100 had funding or conflict of interest associated with clinical automated perimetry.

Over one-third of included studies used an uncommon or outdated classification scheme for AMD such as ‘age-related maculopathy’ (n = 9/26),83, 84, 86, 87, 90-93, 103 which was expected as all but one91 of these studies were published prior to the Beckman Initiative classification.61 The remainder used the Age-Related Eye Disease Study classification105 (AREDS; n = 9/26)85, 89, 94-97, 99, 101, 104; the International Classification and Grading System106 (ICGS; n = 5/26)15, 48, 49, 100, 102; the Beckman Initiative classification61 (n = 2/26)88, 98 and the Rotterdam study classification107 (n = 1/26).82 Study sample sizes varied from four to 827 eyes with early and/or iAMD and four to 1007 normal eyes. Age as a significant co-variable affecting global visual field indices were controlled or adjusted for in 23/26 studies.15, 48, 49, 82-85, 87-101, 103

Testing conditions, i.e., visual field testing device/protocol, radius, threshold strategy, stimulus size, background luminance, etc. also varied across all studies. The most commonly used testing device was the Humphrey Field Analyser (n = 19/26),82, 84, 85, 87-95, 97-99, 101-104 followed by the Medmont automated perimeter (n = 5/26),15, 48, 49, 83, 100 the Octopus static automated perimeter (n = 2/26)86, 96 and the first-generation Humphrey FDT (n = 1/26).83 Testing protocols included: SAP under photopic conditions (10 cd/m2; n = 21/26)49, 82, 84-99, 101-104; SAP under low-photopic conditions (3.2 cd/m2; n = 3/26)48, 49, 83; SAP under scotopic conditions (0 cd/m2; n = 1/26)86; flicker perimetry under low-photopic conditions (3.2 cd/m2; n = 5/26)15, 48, 49, 83, 100 and FDT under photopic conditions (100 cd/m2108; n = 1/26).83 Some studies used more than one test device/protocol. Additional testing conditions were included if mentioned: inclusion of practice exam; prior perimetry experience; pupil status; background lighting adaptation; spatial area analysed (if different to the testing radius); study groups (if sub-divided beyond early and/or iAMD and normal eyes) and follow-up time. Further details of testing conditions are seen in Supplementary Table S4.

All studies measured outcomes in the same way between the groups being compared. In the five cohort studies,48, 99-102 follow-up times ranged from one to three years and was not sufficiently long considering the protracted natural history of AMD.109 Eight studies48, 82, 87, 92, 93, 97, 103, 104 explored a potential dose-response gradient.

Risk of bias

Risk of bias assessment for the 26 included studies can be seen in Supplementary Table S7. Regarding patient selection, almost all studies (n = 25/26)15, 48, 49, 82-101, 103, 104 had a high risk of bias while one study102 had a low risk of bias. Regarding comparability of study groups, few studies (n = 4/26)86, 94, 102, 104 had a high risk of bias while most studies (n = 22/26)15, 48, 49, 82-85, 87-93, 95-101, 103 had a low risk of bias. No studies had unclear risk of bias. All studies had at least one domain with a high risk of bias.

Primary outcome – global visual field indices Decreased mean deviation (MD) in early/intermediate age-related macular degeneration (iAMD) versus normal eyes Photopic conditions

Three studies [#ID 1, 13, 26]82, 91, 97 reported MD of early/iAMD eyes in comparison to normal eyes using SAP under photopic conditions (Supplementary Table S4). These studies all controlled or adjusted for age between groups. The studies however used different sample sizes (20–76 early/iAMD eyes and 22–100 normal eyes), different classifications of early/iAMD and different testing conditions, potentially contributing to heterogeneous outcomes.

Data from the three studies [#ID 1, 13, 26]82, 91, 97 were collated for meta-analysis, including assessment of heterogeneity to determine if the above study design differences may have significantly varied the study results (Figure 2). The combined sample size was 162 early/iAMD eyes and 198 normal eyes. The total MD mean difference between early/iAMD and normal eyes was −1.52dB [95% CI −2.27, −0.78 dB], i.e., worsened, with a large and significant effect size (Z = 4, p < 0.0001). The estimates may have represented moderate-to-substantial heterogeneity not reaching statistical significance (I2 = 60%, Chi2p = 0.08). As I2 was ≥50%, individual study results were further investigated. There were two notable differences between the three studies [#ID 1, 13, 26].82, 91, 97 First, different classifications of early/iAMD were used including the Rotterdam study,107 ‘dry AMD’,91 and AREDS classifications respectively, with a further sub-group defined as the ‘better eye’ and ‘worse eye’ in Wood et al.[#ID 26].97 Second, each study also used varying visual field testing protocols including radii of 10°, 30° and 24–2, respectively. These differences likely contributed to the moderate-to-substantial heterogeneity of meta-analysis results, although all three studies commonly reported statistically significant decreased MD in early/iAMD (ranging from −0.8dB [−1.6, 0 dB] to −2.23dB [−3.37, −1.09 dB]).

image

Forest plot of mean deviation (MD) mean differences between early/intermediate age-related macular degeneration (iAMD) and normal eyes using standard automated perimetry (SAP) under photopic conditions. Negative values indicate worsened mean deviation (MD) in early/intermediate age-related macular degeneration (iAMD) versus normal eyes

Low-photopic conditions

Phipps et al. [#ID 22]49 reported a similar index ‘mean defect’ mean difference using SAP (Medmont automated perimeter, 10° radius) and flicker perimetry (10° radius) under low-photopic conditions. Twenty-five AMD eyes (modified ICGS classification)106 were compared to 34 normal eyes with age accounted for. Mean defect was increased (worsened) in AMD eyes using both SAP (mean ± SD, 1.8 ± 0.6 dB) and flicker perimetry (4.3 ± 0.6 dB). No studies explored MD (or equivalent) under scotopic conditions.

Increased pattern standard deviation (PSD) in early/intermediate age-related macular degeneration (iAMD) versus normal eyes Photopic conditions

Two studies [#ID 1, 13]82, 91 reported PSD of early/iAMD eyes in comparison to normal eyes using SAP under photopic conditions (Supplementary Table S4). These studies had differing sample sizes (20 and 76 early/iAMD eyes, 22 and 76 normal eyes, respectively) and both controlled or adjusted for age between groups. Classification of early/iAMD used the Rotterdam study107 and ‘dry AMD’91 classifications, respectively. Both studies also used differing testing radii of 10° and 30°, respectively. These differences likely contributed to the dissimilar results, whereby Acton et al. [#ID 1]82 showed no significant difference and Lee et al. [#ID 13]91 showed significantly increased (worsened) PSD (2.38dB [2.16, 2.6 dB]) in their respective comparisons of early/iAMD to normal eyes.

Low-photopic conditions

Phipps et al. [#ID 22]49 reported a similar index ‘pattern defect’ mean difference using SAP (Medmont automated perimeter, 10° radius) and flicker perimetry (10° radius) under low-photopic conditions. Comparing 25 AMD eyes (modified ICGS classification)106 to 34 normal eyes with age accounted for, resulted in increased (worsened) pattern defect using both SAP (5.2 ± 0.4 dB) and flicker perimetry (7.6 ± 0.5) excluding non-zero values. No studies explored PSD (or equivalent) under scotopic conditions.

Decreased mean sensitivity (MS) in early/intermediate age-related macular degeneration (iAMD) versus normal eyes Photopic conditions

Fourteen studies [#ID 1, 2, 5–7, 9–11, 13, 16–19, 24]82, 84, 86-95, 98, 101 reported MS of early/iAMD eyes in comparison to normal eyes using SAP under photopic conditions (Supplementary Table S4). Varying sample sizes (11–253 early/iAMD eyes and 8–1007 normal eyes), classifications of early/iAMD, and different testing conditions potentially contributed to heterogeneous outcomes. Chen et al. [#ID 5]86 did not control or adjust for age between groups and was subsequently excluded from meta-analysis. Neely et al. [#ID 18]94 was also excluded from meta-analysis, as although age was adjusted for between eyes with sub-retinal drusenoid deposits (SDDs) versus without SDDs, age was not controlled or adjusted for between AMD and normal eyes. Owsley et al. [#ID 19]95 was excluded from meta-analysis as their control group was AREDS stage 1 eyes, which overlaps with AMD classification in other studies. A further three studies [#ID 2, 7, 11]84, 88, 90 were excluded from meta-analysis as data were not available to calculate MS mean differences between early/iAMD and normal eyes.

The eight remaining studies [#ID 1, 6, 9, 10, 13, 16, 17, 24]82, 87, 89, 91-93, 98, 101 were collated for meta-analysis including assessment of heterogeneity (Figure 3). The iAMD (but not early AMD) group from Sevilla et al. [#ID 24]98 were older than comparative groups and hence excluded from meta-analysis. The combined sample size was 234 early/iAMD eyes and 221 normal eyes. The total MS mean difference was −1.47dB [−2, −0.94 dB], i.e., worsened, with a large and significant effect size (Z = 5.48, p < 0.00001). The estimates may have represented moderate to substantial heterogeneity and this was borderline statistically significant (I2 = 55%, Chi2p = 0.03). As I2 was ≥50%, individual study results were further investigated. Notable differences between the eight studies included different classifications of early/iAMD in almost every study and different testing radii and spatial areas analysed, likely contributing to the moderate-to-substantial heterogeneity. While all studies commonly reported decreased MS in early/iAMD (ranging from −0.5dB [−1.56, 0.56 dB] to −2.73dB [−4.62, −0.84 dB]), only three studies [#ID 13, 16, 17]91-93 reported statistically significant results.

image

Forest plot of mean sensitivity (MS) mean differences between early/intermediate age-related macular degeneration (iAMD) and normal eyes using standard automated perimetry (SAP) under photopic conditions. Negative values indicate worsened MS in early/iAMD versus normal eyes

Low-photopic and scotopic

Luu et al. [#ID 15]48 reported decreased MS which varied by AMD sub-group, using SAP (Medmont automated perimeter, 10° radius) under low-photopic conditions. The study compared 266 eyes with ‘early AMD’ (ICGS classification)106 vs. 24 normal eyes and accounted for age. Three studies [#ID 12, 14, 15]15, 48, 100 also reported decreased MS using flicker perimetry (common 10° radius) under low-photopic conditions. These studies had varying sample sizes (15–266 early/iAMD eyes, 14 or 24 normal eyes), although ages were accounted for and AMD eyes were commonly defined by the ICGS classification.106 Decreased MS were similar for the former two studies [#ID 12, 14]15, 100 (−3.28dB [−3.82, −2.74 dB] and −4.09dB [−6.09, −2.09 dB], respectively), while the latter study [#ID 15]48 reported varying results by AMD sub-group.

Chen et al. [#ID 5]86 reported decreased MS (−2.73dB [−10.48, 5.02 dB]) using SAP (Octopus static automated perimeter, 25° radius and GV stimulus) under scotopic conditions using a Wratten blue filter (commercially available). Twenty-four eyes with ‘dry-form age-related macular degeneration’ were compared against normal eyes albeit without accounting for age differences.

Frequency of defects in early/intermediate age-related macular degeneration (iAMD) versus normal eyes Photopic conditions

Two studies [#ID 1, 3]82, 85 reported frequency of defects of early/iAMD eyes in comparison to normal eyes using SAP under photopic conditions (Supplementary Table S4). Sample sizes were slightly different (20 and 59 early/iAMD eyes, 22 and 15 normal eyes, respectively), both controlled or adjusted for age between groups, and testing conditions (10° radius) were similar. Both studies reported no significant mean difference in the frequency of defects.

Low-photopic conditions

Phipps et al. [#ID 22]49 reported significantly increased frequency of defects in early/iAMD eyes in comparison to normal eyes using SAP (Medmont automated perimeter, 10° radius) and flicker perimetry (10° radius) under low-photopic conditions. Twenty-five AMD eyes (modified ICGS classification)106 were compared to 34 normal eyes with age accounted for. No studies explored frequency of defects under scotopic conditions.

Dose-response gradient of visual field indices in early/intermediate age-related macular degeneration (iAMD) eyes

Several studies explored a potential dose-response gradient of visual field indices in early/iAMD eyes, i.e., whether indices worsened with increasing AMD severity. For MD (or equivalent), two studies [#ID 1, 26]82, 97 using SAP under photopic conditions revealed no significant MD mean differences between different AMD stages, or between the ‘worse eye’ and ‘better eye’ of early/iAMD eyes, respectively. The former study compared 20 AMD eyes (Rotterdam study classification)105 with 22 normal eyes using a 10° radius protocol, while the latter compared 66 AMD eyes (AREDS classification)110 with 100 normal eyes using a 24–2 protocol. Both studies accounted for age between groups. No studies explored a dose-response gradient of MD (or equivalent) using low-photopic or scotopic conditions.

For PSD (or equivalent), Acton et al. [#ID 1]82 using SAP under photopic conditions found no significant PSD mean differences between different AMD stages. Study characteristics were as described above. No studies explored a dose-response gradient of PSD (or equivalent) using low-photopic or scotopic conditions.

For MS, four studies [#ID 1, 6, 16, 17]82, 87, 92, 93 using SAP under photopic conditions reported varying dose-response relationships. The four studies had similar sample sizes (20 to 47 early/iAMD, 8 to 36 normal eyes) and testing protocol (common 10° radius). However, meta-analysis was not feasible due to the varying classifications of AMD, i.e., Rotterdam study,107 ‘PARM’ and ‘early ARM’,87 ‘macular drusen’92 and ‘early AMD

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