Characterizing the Natural History of Visual Function in Choroideremia Using Microperimetry and Multimodal Retinal Imaging

Abstract

Purpose: Centripetal retinal degeneration in choroideremia (CHM) leads to early visual field restriction and late central vision loss. The latter marks an acute decline in quality of life but visual prognostication remains challenging. We investigated visual function in CHM by correlating best-corrected visual acuity (BCVA), microperimetry and multimodal imaging.

Methods: Fifty-six consecutive CHM patients attending Oxford Eye Hospital were examined with BCVA, 10-2 microperimetry, optical coherence tomography, and fundus autofluorescence (AF). Microperimetry was repeated in 21 eyes and analyzed with Bland-Altman. Kaplan-Meier survival plots of eyes retaining 20/20 BCVA were created. Intereye symmetry was assessed.

Results: Microperimetry coefficient of repeatability was 1.45 dB. Survival analysis showed an indistinguishable pattern between eyes (median survival 39 years). Macular sensitivity showed a similar decline in right and left eyes, with half-lives of 13.6 years. Zonal analysis showed faster decline nasal to the fovea. Intereye symmetry was more consistent for microperimetry sensitivity (r = 0.95, P < 0.001) than BCVA (r = 0.42, P = 0.0006). Near normal foveal sensitivity was maintained when the fovea was at least 2500 μm from the advancing edge of AF.

Conclusions: BCVA is a marker of central degeneration and can provide valuable information about the position of the remaining retina as well as a measure of the impact on daily living. Microperimetry represents the global macular region. Both visual functions showed a high degree of intereye symmetry, particularly in early stages, indicating the fellow eye can provide a suitable control for assessing interventions to one eye. The findings may help to tailor visual prognosis and interpret outcomes of trials.

Figure 1

Macular threshold sensitivity and AF imaging in the left eye of a typical 27-year-old patient with choroideremia. (A) A 30° fundus AF image captured using the Heidelberg Spectralis BluePeak module showing a central “island” of residual functional retina with hyperfluorescence surround by areas of degeneration. (B–E) MAIA microperimetry was performed using the 10–2 grid centered on the fovea. The threshold sensitivity value at each retinal location is color-coded and shown as overlay on the infrared SLO image either as annotated dots (B) or as heat-map (C): green for normal sensitivity (maximum 36 dB), yellow to red for reduced sensitivity, purple for 0 dB, and black for absolute scotoma. (D) A histogram of threshold frequencies plotted against normative population data (green bell curve). The positions of actual patient fixation detected during the test are shown as fine cyan dots (B) and eye movements (fixation) is plotted against test time (E).

Figure 2

Intereye symmetry of VA and macular threshold sensitivity in patients with CHM. Intereye symmetry of BCVA (A) and mean threshold sensitivity of the central 10 degrees of the macula measured by MAIA microperimetry (B) was assessed in a cohort of 56 patients with confirmed CHM. Linear regression lines (solid lines) are shown with correlation coefficient (r) and flanked by 95% CI (two dotted lines). For reference, the line of intereye equality is shown (dashed line). The decimal VA of 2.0 represents hand movements/counting fingers acuity, which is not truly quantifiable.

Figure 3

Rate of decline in VA and threshold macular sensitivity with age in CHM. (A) BCVA was measured in a cohort of 56 patients with CHM. A Kaplan-Meier survival plot was used to illustrate the proportion of eyes retaining BCVA of 20/20 with advancing age (years). The survival plots for the right and left eyes are shown in dashed and solid lines, respectively. (B) Rate of decline of macular sensitivity (dB) with age in CHM. Fifty-six patients with CHM underwent automated MAIA microperimetry in each eye to measure threshold sensitivity of the central 10 degrees of the macula (10–2 setting). Regression analysis of the data for the right eyes (OD) and left eyes (OS) separately showed near-identical trend of exponential decline with age: OD half-life = 13.56 (df = 51, R² = 0.6332) and OS half-life = 13.60 (df = 51, R² = 0.5523). (C) Kaplan-Meier survival curve to assess the proportion of eyes retaining microperimetry symmetry as defined by mean sensitivity threshold difference ≤1.5 dB.

Figure 4

Repeatability of MAIA microperimetry in CHM patients. (A) MAIA 10–2 microperimetry was performed twice in the same eye (right eye) at the same sitting in a subcohort of 21 CHM patients over a spectrum of disease severity. Bland-Altman repeatability analysis showed a CR of 1.45 (95% limits of agreement +1.24 to −1.62). (B) Further repeatability analysis on a subset of 11 patients over 2 days at the same time of day, show a CR of 1.05 (95% limits of agreement +0.62 to −1.22). (C) Repeatability analysis on the same subset of 11 CHM patients who undertook microperimetry in the morning and afternoon of the same day, showing a CR of 1.67 (95% limits of agreement +1.05 to −1.95).

Figure 5

The area covered by 95% of the fixation points during the test time was plotted against mean threshold sensitivity. Fixation stability appeared to deteriorate once the mean threshold sensitivity falls below 6 dB.

Figure 6

Decline in visual functions as the degeneration approaches the fovea in choroideremia. (A) Correlation between microperimetry mean threshold sensitivity and the distance between the fovea and the nearest edge of autofluorescence (D_f). Negative D_f values indicate that the fovea was outside the edge of the AF island, whereas positive D_f indicate fovea within the island. (B) Relationship between fixation stability, as represented by the 63% (±1 SD) and 95% (±2 SD) areas of fixation during microperimetry testing, and D_f. (C) Correlation between BCVA and D_f. It was noted that BCVA was particularly variable between +500 and −500 μm D_f (red dashed box) between CHM patients with similar foveal anatomical configurations.

Figure 7

Zonal analyses of the decline in macular sensitivity in CHM. The right eye is displayed on the left and the left eye is displayed on the right as per clinical convention. (A). Composite heat-map of MAIA microperimetry threshold sensitivities within the central 10 degrees of the macula for a cohort of 56 CHM patients. Value in the color key represents the mean threshold in each subzone square. (B) Point ID assignment of the MAIA test grid (from 0 to 69, note 0 = blind spot) to enable statistical comparisons of retinal sensitivities between the central (C), nasal (N) and temporal (T) macula of both eyes using ANOVA test with Bonferroni correction.