Test-Retest Intervisit Variability of Functional and Structural Parameters in X-Linked Retinoschisis

Abstract

Purpose: To examine the variability of four outcome measures that could be used to address safety and efficacy in therapeutic trials with X-linked juvenile retinoschisis.

Methods: Seven men with confirmed mutations in the RS1 gene were evaluated over four visits spanning 6 months. Assessments included visual acuity, full-field electroretinograms (ERG), microperimetric macular sensitivity, and retinal thickness measured by optical coherence tomography (OCT). Eyes were separated into Better or Worse Eye groups based on acuity at baseline. Repeatability coefficients were calculated for each parameter and jackknife resampling used to derive 95% confidence intervals (CIs).

Results: The threshold for statistically significant change in visual acuity ranged from three to eight letters. For ERG a-wave, an amplitude reduction greater than 56% would be considered significant. For other parameters, variabilities were lower in the Worse Eye group, likely a result of floor effects due to collapse of the schisis pockets and/or retinal atrophy. The criteria for significant change (Better/Worse Eye) for three important parameters were: ERG b/a-wave ratio (0.44/0.23), point wise sensitivity (10.4/7.0 dB), and central retinal thickness (31%/18%).

Conclusions: The 95% CI range for visual acuity, ERG, retinal sensitivity, and central retinal thickness relative to baseline are described for this cohort of participants with X-linked juvenile retinoschisis (XLRS).

Translational relevance: A quantitative understanding of the variability of outcome measures is vital to establishing the safety and efficacy limits for therapeutic trials of XLRS patients.

Keywords: MP1; OCT; XLRS; electroretinogram; retinoschisis.

Figure 1.

Visual acuity. Replicate visual acuity measurements by subject for the Better (A) and Worse Eye (B) groups. Change in visual acuity measurements at follow-up visits relative to baseline for Better (C) and Worse Eye (D) groups. Dashed lines indicate the range of variability described by the RCs. The dotted lines show the 95% CIs for the RCs. Symbols are offset in each graph for clarity.

Figure 2.

ERGs. Scotopic full-field ERGs recorded at baseline to an ISCEV standard flash from the Better (A) and Worse Eye (B) groups. Red traces show the ERG response from a representative healthy subject. The blue traces are the average ERG from two subjects with genetically confirmed congenital stationary night blindness type 1 (CSNB1). Vertical dotted lines at 47 msec indicate mean b-wave implicit time for healthy subjects with our ERG system.

Figure 3.

Variation in ERG b/a ratios to scotopic ISCEV maximal flash. Replicate ERG b/a ratios by subject for the Better (A) and Worse Eye (B) groups. Change in ERG b/a ratios at follow-up visits relative to baseline for Better (C) and Worse Eye (D) groups. Dashed lines indicate the range variability described by the RCs. The dotted lines show the 95% CIs for the RCs. Symbols are offset in each graph for clarity.

Figure 4.

MP1 microperimetry maps. Microperimetry measured at baseline (A) and 6 months later (B) from the Worse Eye of subject 3. The arrows highlight slight changes in the location of test points relative to nearby blood vessels. The bivariate contour ellipses in each graph describe the variation in the fixation (blue dots) during testing.

Figure 5.

Variation in central retinal thickness. SD-OCT images through the fovea from the Worse Eye of subject 4 at baseline and then subsequently at 3 and 6 months post baseline visit. Insets: Color coded contour maps of retinal thickness (μm) superimposed on ETDRS grids.