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Microperimetry As an Outcome Measure in Choroideremia Trials: Reproducibility and Beyond

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Microperimetry As an Outcome Measure in Choroideremia Trials: Reproducibility and Beyond Visual Psychophysics and Physiological Optics Microperimetry as an Outcome Measure in Choroideremia Trials: Reproducibility and Beyond Ioannis S. Dimopoulos, Calvin Tseng, and Ian M. MacDonald Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Alberta, Canada Correspondence: Ioannis S. Dimo- PURPOSE. To determine test-retest repeatability of microperimetry testing (MP) in choroide- poulos, Clinical Research Fellow, remia (CHM) subjects using standard and personalized stimulus grids. Department of Ophthalmology and Visual Sciences, 7-030 Katz Building, METHODS. Fifteen CHM subjects (28 eyes) underwent consecutive repeat examinations with University of Alberta, Edmonton, the Macular Integrity Assessment (MAIA) microperimeter using a standard (108) and a Alberta, Canada, T6G 2E1; customized macular grid adapted to individual macular pathology. Repeatability of standard- [email protected]. grid mean (MS) and point-wise (PWS) sensitivity was determined and compared with age- Submitted: February 16, 2016 matched controls (seven eyes), with PWS separately analyzed for loci within and outside the Accepted: June 26, 2016 border of degeneration. Interpolated volumetric indices were used to estimate repeatability of customized grids and compare their performance to standard grids. Citation: Dimopoulos IS, Tseng C, MacDonald IM. Microperimetry as an RESULTS. Test-retest measures of standard-grid MS yielded higher coefficients of variation (CV) outcome measure in choroideremia in CHM subjects compared with controls (0.09 vs. 0.02). Volumetric indices from customized trials: reproducibility and beyond. grids improved repeatability by driving CV values to 0.05 and close to 0.02 for region-of- Invest Ophthalmol Vis Sci. interest (ROI) analysis. Variability of PWS was significantly higher in CHM, especially at the 2016;57:4151–4161. DOI:10.1167/ border of degeneration (10.68 vs. 4.74 dB at the central retina, < 0.001). iovs.16-19338 P CONCLUSIONS. Microperimetry testing in CHM shows high test-retest variation at the border of degeneration, which influences repeatability of MS measures. Volumetric measures from customized grids can improve reliability of both global and regional sensitivity assessment. Nevertheless, inherent test-retest variation of individual points needs to be taken into account when assessing potential functional decline and/or disease progression. Keywords: choroideremia, microperimetry, retina, clinical trials, gene therapy horoideremia (CHM) is an X-linked disorder defined by extrafoveal fixation,5 such as ABCA4-associated retinopathies6 C progressive degeneration of the neuroretina, the retinal and age-related macular degeneration (AMD).7 pigment epithelium (RPE), and the choroid. Choroideremia is However, recent studies examining the repeatability of caused by loss-of-function mutations in the CHM gene,1 which perimetric sensitivity measures have suggested a high degree of encodes Rab escort protein 1 (REP1), a protein involved in test-retest variability at the border of pathologic changes8,9 and prenylation of Rabs. Clinically, affected males experience night the edge of deep scotomas.10 For CHM and other conditions blindness in early adulthood followed by progressive peripheral with centripetally advancing degeneration, these findings may visual field loss, with central vision preserved until later in life. hamper reliability of microperimetry testing especially during Current investigational therapeutic approaches aim to modify later disease stages, when macular involvement is noted. At the natural history of the disease through viral-mediated gene these stages, which have been shown to provide the best 2 discriminatory power to determine a potential treatment transfer. Visual acuity remains the most widely used outcome 11–13 measure in these trials, providing functional assessment of benefit, mapping macular sensitivity becomes particularly challenging due to the highly variable retinal morphology. Most foveal integrity; however, psychophysical tests have revealed standard perimetry grids fail to sufficiently sample all areas of significant deficits in macular function of CHM patients, surviving retina within the macular region. The use of including those with normal visual acuity.3 Therefore, more personalized grids could potentially improve sensitivity map- sensitive clinical outcome measures are required to determine ping, but their adoption in clinical trials is currently limited due early efficacy of therapeutic interventions in CHM. to the difficulty in comparing examinations acquired with In recent years, fundus-driven perimetry, also known as different grid arrangements. Recently though, interpolation microperimetry, has emerged as a robust method for assessing methods have enabled the generation of indices that surpass 4 visual function in patients with macular disease. Its compar- these limitations.14 ative advantage to conventional perimetry stems from real-time In studies described herein, we sought to investigate test- fundus imaging combined with eye-tracking technology. retest repeatability of microperimetry testing in CHM, espe- Fundus viewing allows ‘‘locking’’ of stimuli at predefined cially for disease stages targeted by current investigational trials. retinal locations, which enables structural-functional correla- Our focus expanded beyond conventional measures from tions to be explored while adapting perimetry grids to standard grids to include repeatability of indices extracted individual retinal morphology. Eye-tracking provides high- from interpolation of personalized grids. Determining test- accuracy functional measures, even in cases of unstable or retest limits of such indices will allow the adoption of a single iovs.arvojournals.org j ISSN: 1552-5783 4151 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from iovs.arvojournals.org on 09/26/2021 Microperimetry as an Outcome Measure in CHM Trials IOVS j August 2016 j Vol. 57 j No. 10 j 4152 TABLE 1. Characteristics of CHM Subjects Subject Age Mutation Exon Protein Change Eye logMAR BCVA MS, dB FAF Area, mm2 P1 42 c.315-?_1166þ?del 5-8 Deletion of exons 5-8 (in frame); OD 0.40 5.8 1.87 REP-1 absent OS 0.40 8.79 2.74 P2 38 c.1245-521A > G REP-1 negative (Splice defect) OD 0.30 8.08 1.79 OS 0.40 5.94 2.08 P3 30 c.1245-521A > G REP-1 negative (Splice defect) OD 0.17 11.55 7.16 OS 0.30 11.2 6.31 P4 33 c.1218C > A 9 p.Cys406* OD 0 10.21 2.77 OS 0.09 9.56 2.19 P5 28 c.1218C > A 9 p.Cys406* OD 0.09 13.75 2.99 OS 0.09 9.59 2.06 P6 65 c.757C > T 6 p.Arg253* OD 0.09 8.8 3.29 OS 0.17 4.4 2.05 P7 27 c.757C > T 6 p.Arg253* OD 0 15.4 12.05 OS 0.17 8.9 8.87 P8 31 c.1218C > A 9 p.Cys406* OD 0.09 8.24 2.77 OS 0.17 4.91 1.17 P9 53 c.525_526delAG 5 p.Glu177Lysfs*6 OD 0.49 0.17 0.3 OS 0.32 3.91 0.55 P10 31 c.757C > T 6 p.Arg253* OD 0 6.31 3.01 OS 0.20 5.9 2.79 P11 63 c.1218C > A 9 p.Cys406* OD 0.39 NA 0.75 OS 0.30 3.2 1.01 P12 43 c.-29-?_1510þ?del 1-12 Deletion of exons 1-12 (in frame); OD 0 11.50 3.0 REP-1 absent OS 0.20 8.1 2.5 P13 33 c.1218C > A 9 p.Cys406* OD 0 19.3 6.61 OS 0.2 15.1 6.23 P14 33 c.470_473del 5 p.Gln157Leufs*10 OD 0.2 9.28 3.60 OS 0 11.23 4.40 P15 36 c.117-?_940þ?del 3-7 Deletion of exons 3-7; REP-1 absent OD 0.3 6.7 2.23 OS 2 NA NA estimate for all microperimetry examinations used in current testing. A near-infrared (NIR) superluminescent diode (850 and future CHM clinical trials. nm, 1024 3 1024 pixel resolution, 368 field of view) is used to visualize the fundus, with eye-tracking performed at a rate of 25 frames per second using the entire fundus as a reference. To METHODS obtain sensitivity thresholds, Goldmann-type size III stimuli (duration: 200 ms) were presented against a background 1.27 Subjects cd/m2, using a 4-2 staircase strategy. Minimum and maximum 2 The study population consisted of 28 eyes of 15 CHM subjects stimulus luminance achieved was 0 and 318 cd/m , respec- (age 39.1 6 11.7 years [mean 6 SD]; range, 21–65 years). All tively, covering a dynamic range of 36 dB. Reliability was subjects had genetic or molecular confirmation of their evaluated by the frequency of responses to 10-dB stimuli at the diagnosis (Table 1). Inclusion criteria consisted of best- physiological blind spot (false positives). Any examination with corrected visual acuity (BCVA) better than or equal to 20/62 greater than 25% false-positive responses was discarded and (0.50 logMAR), stability of fixation determined with micro- repeated. Fixation stability was assessed using the MAIA P1 perimetry (see the Microperimetry Examination section), and fixation stability index, which measures the proportion of presence of active degeneration within the clinical macula fixation points located within a 28 diameter circle centered on determined with spectal-domain optical coherence tomogra- the fovea. Stable fixation was defined by P1 values greater 75%. phy (SD-OCT) (Heidelberg Engineering, Heidelberg, Germany). None of the subjects had concurrent ocular disease that could Retinal Imaging affect visual performance. Normal data for microperimetry were collected from seven eyes of seven healthy subjects (age Before study enrollment, all CHM subjects had undergone 35.3 6 5.1 years [mean 6 SD]; range, 25–40 years). All central 3083308 blue laser fundus autofluorescence (k ¼ 488 procedures conformed to the Code of Ethics of the World nm) imaging (FAF) and SD-OCT line scans using the Spectralis Medical Association (Declaration of Helsinki) and were done SD-OCT unit (Heidelberg Engineering).
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