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Andrew Zheng, Stephen H Tsang; Comparing functional and structural measures of disease progression in retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3813.
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© ARVO (1962-2015); The Authors (2016-present)
To determine whether degeneration in retinal structure correlates with the decline in retinal function in both human patients and preclinical mouse models with retinitis pigmentosa (RP)
3 patients and 1 normal relative in a family with autosomal dominant RP due to a rhodopsin mutation were examined on 4 visits over an 8-year period. To assess structural integrity of the retina, the length of the ellipsoid zone (inner/outer segment junction) was segmented in an optical coherence tomography (OCT) section thru the fovea, and the horizontal diameter of the hyperautofluorescent rings was measured using fundus autofluorescence (AF). Retinal function was measured using electroretinography (ERG), and visual fields were assessed by microperimetry. In transgenic mice harboring an analogous rhodopsin mutation, OCT images were taken at 2, 5, and 8 months of age to evaluate the thickness of the outer nuclear layer (ONL), corresponding to photoreceptor nuclei. ERG measurements were also made at these time points (n = 2 - 4 mice per time point per experiment). For each experiment, Wild-type littermates were used as a control.
As predicted by previous reports,  the length of the ellipsoid zone in our RP patients declined with age at an exponential rate (k = .037; r^2 = .9878), with only 1000 - 2000 microns remaining in the affected father (Fig 1A). The diameter of the hyperautofluorescent ring contracted in a similar manner (not shown). 30-Hz flicker ERG also declined steeply in early-stage disease in the affected children, but had much greater variance (Fig 1B). Contrarily, the microperimetry results were stable throughout early disease and declined precipitously only at late stages (as seen in the father, Fig 1C). In mutant mice, ERG amplitudes decline at a slow but steady rate over the first third of the lifespan; the scotopic maximal b-wave declines from 603 microvolts at 2mo. to 442 uv at 8mo. (Fig 2A). ONL thickness in mutant mice declines in a similar fashion, from 49 microns at 2mo. to 30 um at 8mo. (Fig 2B).
In both mice and humans, retina structural degeneration correlates with functional decline. However, subjective tests such as visual fields and microperimetry become abnormal only as patients approach advanced stages of disease, likely due to compensatory behaviors, and thus are not ideal clinical markers for RP progression.  Clarke et al. (2001). HMG 10(20): 2269.
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