Measuring Rod- and Cone-Photoreceptor-Specific Vision in Inherited Retinal Diseases Using a Commercial Perimeter

Abstract

Purpose: The primary pathology in most inherited retinal diseases (IRDs) is located within photoreceptors. Standard automatic perimetry (SAP) can measure photoreceptor disease severity but cannot distinguish between rods, long/middle-wavelength (L/M)-sensitive, and short-wavelength (S)-sensitive cones. Herein we developed a protocol that can provide photoreceptor-specific sensitivities.

Methods: A commercial (unmodified) perimeter was used to develop a clinical protocol that includes five profiles along the vertical meridian, utilizing different chromatic stimuli presented in the dark-adapted state or on adapting backgrounds. Data were recorded by the Perimetry for IRD (PERIRD) consortium in control participants and patients with IRDs.

Results: The protocol was developed by evaluating the relationship between chromatic thresholds and adapting backgrounds using a threshold-versus-intensity paradigm. Five conditions were selected: two-color dark-adapted, red-on-blue, and blue-on-yellow tests in addition to white-on-white SAP. Prediction intervals from control eyes were defined, and physiological ranges over which rod-, L/M-, and S-cone-specific results can be obtained were estimated. Testing in complete achromatopsia, blue-cone monochromacy, and enhanced S-cone syndrome confirmed classic patterns expected from cone diseases. Patients with incomplete achromatopsia showed partially retained L/M- or S-cone function. Patients with retinitis pigmentosa demonstrated use of photoreceptor-specific function to interpret different disease subtypes and stages. Total test time for the protocol was usually under 30 minutes.

Conclusions: Photoreceptor-specific function can be measured over a large dynamic range using a turnkey commercial perimeter and a relatively short, practical protocol that may be introduced into the clinic, translational work, and clinical trials.

Figure 1.

Relative spectral output of stimuli and backgrounds. (A) Normalized energy of the four narrowband stimuli (440, 500, 600, and 650 nm). Inset: Locations tested along the vertical meridian with profiles (white squares) and with the tvi paradigm (dark squares). (B) Normalized energy of the blue (455-nm peak) and yellow (591-nm peak) backgrounds.

Figure 2.

Adaptation and mediation of spectral sensitivities under dark-adapted conditions and with varying luminances of a blue background. (A) Thresholds for 440-, 500-, 600-, and 650-nm stimuli were evaluated under dark-adapted conditions and increasing amounts of blue background. Three notable conditions (DA, LA1, LA2) are evaluated further in panel B. Available technical dynamic ranges for low-luminance (L) and high-luminance (H) ranges are depicted with dashed lines. (B) Radiometrically adjusted thresholds under DA, −3.5 log cd⋅m⁻² (LA1), and +1.0 log cd⋅m⁻² (LA2) blue backgrounds plotted with luminosity functions for scotopic (green) and photopic (orange) vision. (C) The tvi curve (green) from thresholds for the 500-nm stimuli that fit the scotopic luminosity function (filled circles). (D) The tvi curve (orange) from thresholds for the 650-nm stimuli that fit photopic luminosity functions (filled squares) plotted together with the scotopic tvi curve (green) vertically shifted. Effective physiological dynamic range and technical dynamic range are shown.

Figure 3.

Adaptation and mediation of spectral sensitivities under dark-adapted conditions and with varying luminances of a yellow background. (A) Thresholds for 440-, 500-, 600-, and 650-nm stimuli were evaluated under dark-adapted conditions and increasing amounts of yellow background. Three notable conditions (DA, LA1, LA2) are evaluated further in panel B. Available technical dynamic ranges for low-luminance (L) and high-luminance (H) ranges are depicted with dashed lines. (B) Radiometrically adjusted thresholds under DA, −1.0 log cd⋅m⁻² (LA1), and +2.0 log cd⋅m⁻² (LA2) yellow backgrounds plotted with luminosity functions for scotopic (green), photopic (orange), and S-cone (purple) vision. (C) The tvi curve (green) from thresholds for 500-nm stimuli that fit the scotopic luminosity function (filled circles). (D) The tvi curve (purple) from thresholds for 440-nm stimuli that fit the S-cone luminosity function (filled triangles) plotted together with the scotopic (green) tvi curve vertically shifted. Effective physiological dynamic range and technical dynamic range are shown.

Figure 4.

Standard and two-color dark-adapted perimetry results of three classic IRDs involving cones: ACHM, BCM, and ESCS. (A, C, E) Standard perimetry with white stimuli on a white background. (B, D, F) Two-color dark-adapted perimetry (upper and middle panels) and two-color differences (lower panels). Each colored trace represents an eye tested; some patients had both eyes tested and some only one eye. Censored data are marked with x. Cone-plateau sensitivities are shown with gray pluses. Normal ranges (gray) and mean normal values (black) are shown.

Figure 5.

Cone-specific perimetry results in patients with ACHM with different phenotypes. (A) The cACHM phenotype corresponding to no detectable sensitivity with 440YB or 650BB beyond what could originate from light-adapted rods. (B) iACHM[S] showing macular evidence of S-cone function. (C) iACHM[L/M] centrally and peripherally. Note that P4 did not have 440YB results but is included here because the pattern of 650BB results is comparable to the two eyes of P5. Censored data are marked with x. Sensitivity expected from normal light-adapted rods is shown with gray squares.

Figure 6.

Cone-specific perimetry results in patients with BCM and ESCS. (A) Patients with BCM showing normal or near-normal 440YB results supporting S-cone function. With 650BB, results are consistent with mediation by light-adapted rods. (B) The patients with ESCS showing normal or hypernormal results on 440YB and normal or reduced results on 650BB. Censored data are marked with x. Sensitivity expected from normal light-adapted rods is shown with gray squares.