Exploring Scotopic Microperimetry as an Outcome Measure in Choroideremia

Abstract

Purpose: Choroideremia is an X-linked outer retinal degeneration. Early symptoms include nyctalopia and progressive visual field loss, but visual acuity is preserved until late disease stages. Dark-adapted two-color fundus-controlled perimetry (also known as scotopic microperimetry) has been developed to enable spatial assessment of rod and cone photoreceptor function. This study explores the use of scotopic microperimetry in patients with choroideremia.

Methods: Twenty patients with choroideremia and 21 age-matched healthy controls completed visual acuity and scotopic microperimetry testing, which used the Scotopic Macular Integrity Assessment (S-MAIA) microperimeter. A subset of participants completed repeat scotopic testing to enable Bland-Altman repeatability analyses. Test reliability was assessed using fixation stability, fixation losses, and assessment of the rod-free zones. Pointwise sensitivity, mean sensitivity, and volume sensitivity indices were analyzed.

Results: False positive responses were the main source of poor test reliability, indicated by stimuli responses in the physiological blind spot and lack of rod-free mapping. Scotopic cyan and red sensitivities were significantly reduced in choroideremia participants (n = 17) compared to healthy controls (n = 16) (P < 0.01, Mann-Whitney U test). Scotopic cyan sensitivity was statistically lower than scotopic red sensitivity in both healthy controls and choroideremia (P < 0.01, Wilcoxon signed rank test). Interpretation of scotopic cyan-red differences should be used with caution due to high test-retest variability.

Conclusions: Scotopic microperimetry could be a useful outcome measure in patients with early choroideremia. Careful selection of test grid design and sensitivity indices is required.

Translational relevance: Scotopic microperimetry may be a useful outcome measure in clinical trials for patients with early stage choroideremia.

Figure 1.

Pointwise scotopic microperimetry outputs including standard mean sensitivity (MS) and fixation loss (FL) indices. (A–C) The top row details the cyan, red, and cyan–red difference outputs for a participant with choroideremia. This participant had many tested loci with undetectable sensitivities, indicated by black test points (<0.0 dB). Four cyan-colored loci depicting greater cyan than red sensitivity suggest red (cone) dysfunction, whereas the three red points indicate reduced cyan sensitivity relative to red sensitivity, suggested cyan (rod) dysfunction. The olive-green points indicate equal cyan–red differences (within ±4.0 dB). (D–F) The lower row details cyan, red, and cyan–red difference pointwise sensitivity outputs for a healthy control participant. All points have equal differences (within ±4.0 dB), as indicated by the olive-green points, with only the central point showing reduced cyan sensitivity versus red sensitivity, which is characteristic of the rod-free fovea.

Figure 2.

(A) Frequency distribution of pointwise sensitivity values for cyan stimuli. (B) Frequency distribution of pointwise sensitivity values for red stimuli. (C, D) Shown are the cyan and red mean sensitivity (C) and volume sensitivity (D) values for both healthy controls (n = 17) and choroideremia participants (n = 16), as well as the cyan–red volume difference.

Figure 3.

Scotopic microperimetry correlation analyses in choroideremia. (A) Mesopic microperimetry volumetric sensitivity correlated significantly with cyan volume sensitivity (ρ = 0.56; P = 0.05) and red volume sensitivity (ρ = 0.95; P < 0.01). (B) There was no correlation between cyan volumetric sensitivity and red volumetric sensitivity (ρ = 0.26; P = 0.30). (C) The areas of preserved seeing islands identified with fundus autofluorescence in choroideremia correlated significantly with red volume sensitivity (ρ = 0.89; P < 0.01) but not with cyan volume sensitivity (ρ = 0.36; P = 0.17). (D) Cyan–red difference correlated significantly (ρ = −0.56; P = 0.02).

Figure 4.

The variation in cyan–red difference plots for a single patient after accounting for different degrees of pointwise test–retest variability (TRTV). Standard output cyan pointwise plot (A) and red pointwise plot (B), with mean sensitivity (MS) and fixation loss (FL) indices noted, for a single choroideremia participant with well-preserved central visual function. (C–E) Remodeled cyan–red difference pointwise plots after accounting for different degrees of test–retest variability. Gray points lie within the set test–retest variability, blue points indicate cyan dysfunction, and red points indicate red dysfunction. Cyan–red differences are shown with no test–retest variability accounted for (C). Cyan versus red dysfunctional differences are highlighted after accounting for ±4.0-dB variation, which corresponds to the arbitrary cut-off used by the S-MAIA difference output plot (D). The cyan–red difference plot was remodeled to account for the ±13.0-dB combined pointwise test–retest variability (E).