Longitudinal Evaluation of Visual Function Impairments in Early and Intermediate Age-Related Macular Degeneration Patients

Abstract

Purpose: To evaluate visual function (VF) changes in early and intermediate age-related macular degeneration (eAMD and iAMD) over 24 months.

Design: Prospective, observational natural history study.

Participants: Participants were enrolled at the Duke Eye Center.

Methods: A total of 101 subjects (33 with eAMD, 47 with iAMD, and 21 normal controls) were recruited. Visual function (VF) tests included best-corrected visual acuity (BCVA), low- luminance visual acuity (LLVA), microperimetry (MP), cone contrast tests (CCTs), and dark adaptation (DA). Mixed-effect model repeated measures based on absolute values and change from baseline identified VF tests differentiating AMD from controls and revealing longitudinal VF decline when controlling for covariates (baseline value, age, coronary artery disease, dry eye, and phakic status). Nine AMD genetic risk variants, combinations of these (genetic burden score), reticular pseudodrusen (RPD), and hyperreflective foci (HRF) were tested as predictors of diagnosis and VF performance.

Main outcome measures: Longitudinal changes in VF metrics over 24 months.

Results: A total of 70 subjects completed the 2-year visit (22 with eAMD, 31 with iAMD, and 17 controls). Percent reduced threshold (PRT) on MP and CCT red significantly distinguished iAMD versus controls after 12 and 24 months, respectively. Cone contrast test red, PRT, and absolute threshold (AT) on MP showed significant longitudinal deterioration of VF in iAMD versus baseline at 12 months and onward, however, with a reduced rate of worsening. The DA data confirmed a preexisting functional deficit in iAMD at baseline and revealed an increasing proportion of poorly performing iAMD subjects in DA over the study period. None of the other VF measures showed consistent significant changes among the normal, early, and intermediate groups or over time. The genetic burden score was significantly associated with AMD diagnosis (relative risk for iAMD = 1.64, P < 0.01) and DA (r = 0.42, P = 0.00005). Reticular pseudodrusen and HRF showed moderate associations with DA and weak to moderate associations with MP variables.

Conclusions: In iAMD, MP variables, CCT red, and DA revealed slow and nonlinear functional decline over 24 months. A structure-function relationship in eAMD and iAMD stages was demonstrated among HRF, RPD, and DA, possibly modified by genetic risk factors. These structural and functional features represent potential end points for clinical trials in iAMD.

Keywords: AMD, age-related macular degeneration; AREDS, Age-Related Eye Disease Study; AT, absolute threshold; BCVA, best-corrected visual acuity; CCT, cone contrast test; CFP, color fundus photography; DA, dark adaptation; Early AMD; HRF, hyperreflective foci; Intermediate AMD; LLD, low-luminance deficit; LLVA; LLVA, low-luminance visual acuity; MMRM, mixed-effect repeated measure; MP, microperimetry; Microperimetry; PRT, percent reduced threshold; RIT, rod intercept time; RPD, reticular pseudodrusen; RPE, retinal pigment epithelium; SD, standard deviation; SD-OCT, spectral domain OCT; SNP, single nucleotide polymorphism; VF, visual function; Visual function; dB, decibels; eAMD, early AMD; iAMD, intermediate AMD.

Figure 1

Longitudinal progression in microperimetry (MP) percent reduced threshold (PRT) (A) and absolute threshold (AT) (B) for the normal control, early age-related macular degeneration (eAMD), and intermediate AMD (iAMD) participants over 24 months. Patients with iAMD who converted to neovascular AMD are marked in red. Individual actual visual function (VF) data from all individuals who completed the respective VF assessments are shown by study time point. Box and whisker plots show 25th, 50th, and 75th percentiles. Lower whisker extends to the 25th percentile minus 1.5 times the interquartile range. Upper whisker extends to the 75th percentile plus 1.5 times the interquartile range. Outliers are points outside range of the whiskers. P values are model based and indicate significance of change from baseline to month 24 within each group.

Figure 2

Longitudinal progression in cone contrast test (CCT) red (A), green (B), and blue (C) for the normal control, early age-related macular degeneration (AMD), and intermediate AMD (iAMD) subjects over 24 months, respectively. Patients with iAMD who converted to neovascular AMD are marked in red. For CCT red, green, and blue, 1 neovascular AMD participant did not have values at month 12. Individual actual visual function (VF) data from all individuals who completed the respective VF assessments are shown by study time point. Box and whisker plots show 25th, 50th, and 75th percentiles. Lower whisker extends to the 25th percentile minus 1.5 times the interquartile range. Upper whisker extends to the 75th percentile plus 1.5 times the interquartile range. Outliers are points outside range of the whiskers. P values are model based and indicate significance of change from baseline to month 24 within each group.

Figure 3

Longitudinal progression in dark adaptation (DA) rod intercept time (RIT) for the normal control, early age-related macular degeneration (AMD), and intermediate AMD (iAMD) subjects over 24 months. Patients with iAMD who converted to neovascular AMD are marked in red. Individual visual function (VF) data from all individuals who completed the respective VF assessments are shown by study time point. One converting patient did not have any values for rod intercept on DA. One patient did not have values and 6 and 12 months, and 1 patient did not have values at baseline and 6 months. Box and whisker plots show 25th, 50th, and 75th percentiles. Lower whisker extends to the 25th percentile minus 1.5 times the interquartile range. Upper whisker extends to the 75th percentile plus 1.5 times the interquartile range. Outliers are points outside range of the whiskers. P values are model based and indicate significance of change from baseline to month 24 within each group.

Figure 4

Association of genetic burden score with disease stage by Age-Related Eye Disease Study (AREDS) stage (Spearman r = 0.35, P = 0.0003). In this analysis, the diagnosis was treated as an ordinal variable according to the AREDS stage 1 (normal, n = 20), 2 (early age-related macular degeneration [AMD], n = 33), and 3 (intermediate AMD, n = 47). The 3 intermediate AMD patients who converted to neovascular AMD are highlighted by red circles and revealed values at the high end of the burden scores (10, 12, and 12, respectively). One subject did not consent to use of genetic material for genetic analysis (total n = 100 instead of 101).

Figure 5

Performance of visual function (VF) variables stratified by presence (Y) or absence (N) of reticular pseudodrusen (RPD) on spectral domain OCT (SD-OCT) images in the study eyes at baseline. A, Dark adaptation rod intercept. B, Microperimetry (MP) percent reduced threshold (PRT). C, MP average threshold (AT). D, Cone contrast test (CCT) red. Red circles indicate the data from the 3 intermediate age-related macular degeneration (AMD) subjects who converted to neovascular AMD. dB = decibels.

Figure 6

Performance of visual function (VF) variables stratified by presence (Y) or absence (N) of hyperreflective foci (HRF) on spectral domain OCT (SD-OCT) images in the study eye at baseline. A, Dark adaptation (DA) rod intercept. B, Microperimetry (MP) percent reduced threshold (PRT). C, MP average threshold (AT). D, Cone contrast test (CCT) red. Red circles indicate the data from the 3 intermediate age-related macular degeneration (AMD) subjects who converted to neovascular AMD. dB = decibels.

Supplemental Figure S1