Quantifying rod photoreceptor-mediated vision in retinal degenerations: Dark-adapted thresholds as outcome measures

Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Experimental Eye Research (Impact Factor: 2.71). 03/2005; 80(2):259-72. DOI: 10.1016/j.exer.2004.09.008
Source: PubMed


Pre-clinical trials of treatment in retinal degenerations have shown progress toward preventing loss or restoring function of rod photoreceptors. In anticipation of human clinical trials, we assessed two psychophysical methods of quantifying rod photoreceptor-mediated function as potential outcome measures. Modified automated perimeters were used to deliver focal or full-field light stimuli and dark-adapted thresholds were measured. Patients with retinal degeneration were studied in two experimental protocols. Experiment 1 (n = 35 patients) studied dark-adapted focal chromatic stimuli in central retinal locations along the horizontal meridian. Experiment 2 (n = 146 patients) studied dark-adapted responses to a full-field stimulus test (FST) using white and chromatic stimuli. Patients in both experimental groups had testing on two different visits to determine inter-visit variability. In Experiment 1, two subgroups of patients were identified: a group with a majority of test loci detected by rod photoreceptors and a group with only cone-mediated detection. Inter-visit variability (95% confidence interval) was +/-3.1 dB for normals, +/-3.0 dB for patients with rod-mediated function and +/-2.8 dB for patients with only cone-mediated function. In Experiment 2, the dynamic range of the FST using white stimuli was sufficient to quantify sensitivity in all patients studied, including those with severe retinal degenerations. Chromatic stimuli in the FST were detectable by 85% of patients and rod- or cone-mediation could be determined. Regional retinal sources of FST were explored by comparing FST and dark-adapted perimetry in the same patients; there was a strong correlation between FST level and the loci with highest sensitivity by perimetry. Inter-visit variability (95% confidence interval) in the patients was +/-3.9 dB compared to +/-3.5 dB in normals. Dark-adapted focal threshold measurements with an abbreviated protocol in retinal degeneration patients with stable fixation may be useful as an outcome measure for therapies that can affect rod vision. FST measurements were feasible and reproducible in a large spectrum of retinal degenerative diseases and will be most applicable as a psychophysical outcome measure for treatment trials of very severe disorders in which fixation is lost and there is need for a large dynamic range of stimulus intensity.

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    • "Tests such as chromatic FST which was used in the most recent clinical characterization (Jacobson et al., 2013) and in the clinical trial for RPE65-LCA2 (Jacobson et al., 2012) could be used to measure localized improvements in rod function. The limits of variability for this assay have already been defined in patients with various retinal degenerations, including LCA (Roman et al., 2005; Roman et al., 2007; Jacobson et al., 2009a). OCT should be performed to monitor the safety of injections performed under the fovea or para/peri- fovea, with emphasis placed on the former given the slow return of cone outer segment structure observed in LCA2 patients treated subfoveally (Jacobson et al., 2012). "
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    • "Kinetic visual fields and dark-and light-adapted chromatic static threshold perimetry (200-msec duration, 650-and 500-nm stimuli, dark-adapted, and 600 nm, light-adapted; 1.7° diameter target) were performed with a modified HFA-750i analyzer (Zeiss-Humphrey, Dublin , CA). Our methods for data collection and analyses have been published ( Jacobson et al., 1986, 2010; Roman et al., 2005). Reflectance imaging and reduced-illuminance autofluorescence imaging (RAFI) were performed with nearinfrared (NIR) and short-wavelength (SW) lights with a confocal scanning laser ophthalmoscope (SLO) (HRA2; Heidelberg Engineering, Heidelberg, Germany) as described (Cideciyan et al., 2007, 2011; Jacobson et al., 2011). "
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