| Summary: | (1) Background: The aim of our study was to investigate the relationship between retinal metabolic alterations (retinal vessel oximetry, RO) and structural findings (retinal vessel diameter, central retinal thickness and retinal nerve fiber layer thickness, RNFL) in patients with inherited retinal diseases (IRDs). (2) Methods: A total of 181 eyes of 92 subjects were examined: 121 eyes of 62 patients with IRDs were compared to 60 eyes of 30 healthy age-matched controls. The retinal vessel oximetry was performed with the oxygen saturation measurement tool of the Retinal Vessel Analyser (RVA; IMEDOS Systems UG, Jena, Germany). The oxygen saturation in all four major peripapillary retinal arterioles (A-SO<sub>2</sub>; %) and venules (V-SO<sub>2</sub>; %) were measured and their difference (A-V SO<sub>2</sub>; %) was calculated. Additionally, retinal vessel diameters of the corresponding arterioles (D-A; µm) and venules (D-V; µm) were determined. The peripapillary central retinal thickness and the RNFL thickness were measured using spectral domain optical coherence tomography (SD-OCT) (Carl Zeiss Meditec, Dublin, CA, USA). Moreover, we calculated the mean central retinal oxygen exposure (cO<sub>2</sub>-E; %/µm) and the mean peripapillary oxygen exposure (pO<sub>2</sub>-E; %/µm) per micron of central retinal thickness and nerve fiber layer thickness by dividing the mean central retinal thickness (CRT) and the RNFL thickness with the mean A-V SO<sub>2</sub>. (3) Results: Rod-cone dystrophy patients had the highest V-SO<sub>2</sub> and A-SO<sub>2</sub>, the lowest A-V SO<sub>2</sub>, the narrowest D-A and D-V and the thickest RNFL, when compared not only to controls (<i>p</i> ≤ 0.040), but also to patients with other IRDs. Furthermore, in rod-cone dystrophies the cO<sub>2</sub>-E and the pO<sub>2</sub>-E were higher in comparison to controls and to patients with other IRDs (<i>p</i> ≤ 0.005). Cone-rod dystrophy patients had the lowest cO<sub>2</sub>-E compared to controls and patients with other IRDs (<i>p</i> ≤ 0.035). Evaluated in central zones, the cO<sub>2</sub>-E was significantly different when comparing cone-rod dystrophy (CRD) against rod-cone dystrophy (RCD) patients in all zones (<i>p</i> < 0.001), whereas compared with controls and patients with inherited macular dystrophy this was observed only in zones 1 and 2 (<i>p</i> ≤ 0.018). The oxygen exposure was also the highest in the RCD group for both the nasal and the temporal peripapillary area, among all the evaluated groups (<i>p</i> ≤ 0.025). (4) Conclusions: The presented metabolic-structural approach enhances our understanding of inherited photoreceptor degenerations. Clearly demonstrated through the O<sub>2</sub>-E comparisons, the central and the peripapillary retina in rod-cone dystrophy eyes consume less oxygen than the control-eyes and eyes with other IRDs. Rod-cone dystrophy eyes seem to be proportionally more exposed to oxygen, the later presumably leading to more pronounced oxidative damage-related remodeling.
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