Circadian Rhythm of Intraocular Pressure and Optical Coherence Tomography Imaging in the Rat Eye
Lozano, Diana C.
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Purpose: Ocular hypertension is a risk factor for developing glaucoma, which is an optic neuropathy characterized by progressive degeneration of retinal ganglion cells and subsequent irreversible vision loss. The goal of this dissertation was to address several challenges needed to interpret the relationship between pressure and in vivo changes to retinal thickness and the optic nerve head in a rat model of glaucoma. Methods: Pressure dynamics were evaluated in three experiments: (1) First, the reliability of two TonoLab rebound tonometers was measured in 18 Brown Norway Rats. (2) The calibrated tonometers were then used to measure the circadian rhythm of intraocular pressure (IOP) in standard light-dark conditions (LD) and in continuous dim light (LL). Specifically, the existence of an IOP rhythm in LL was investigated and whether the IOP rhythm was centrally driven by the suprachiasmatic nucleus. (3) The circadian rhythm of IOP and mean arterial pressure (MAP) were measured in 8 adult Brown Norway rats housed in LD. Structural assessment of disease in a rat model of glaucoma was evaluated in three experiments (4) First, the ability to scan the same retinal location with a clinical spectral domain optical coherence tomography (SD-OCT) system was evaluated by acquiring retinal images from 16 rats. (5) A schematic model eye was developed to compensate for lateral magnification in SD-OCT images of the normal rat eye. Mean total retinal thickness was measured 500 µm away from the optic nerve head (ONH) and ONH diameter was measured from SD-OCT images. These images were scaled using the schematic model eye and the SD-OCT system’s Built-in scaling. (6) IOP was surgically elevated by injecting hypertonic saline into an episcleral vein of the rat eye. Circumpapillary scans were computationally generated to calculate global (mean of circumpapillary scan) and regional (superior, inferior, nasal, and temporal) mean nerve fiber layer/retinal ganglion cell layer (NFL/RGLC), NFL/RGCL plus inner plexiform layer (NFL/RGCL+IPL), and total retinal thicknesses. Results: (1) The 95% limits of agreement (95% LoA) were smaller and better for TonoLab #1 (± 4 mm Hg) than for TonoLab #2 (± 6 mm Hg). (2) IOP in the LD conditions was lowest during the light-phase (16 ± 2 mm Hg), highest during the dark-phase (30 ± 7 mm Hg), and peaked near the middle of the dark phase (16.6 ± 1.2 Zeitgeber Time). The maximum range of IOP measurements was 14 ± 3 mm Hg under LD, and this maximum range dampened to 8 ± 1 mm Hg after 1 week, 8 ± 2 mm Hg after 4 weeks and 6 ± 1 mm Hg after 7 weeks of exposure to LL. (3) MAP during the light phase was 101 ± 3 mm Hg and 94 ± 3 mm Hg during the dark phase. IOP peaked 4.6 hours after the lights turned off and MAP peaked 4 hours before the lights turned off. (4) Thickness differences between imaging sessions for NFL/RGCL was 1 µm (95% LoA: –4 to 3 µm; ICC=0.82; CV=4.7%), for NFL/RGCL+IPL was 0 µm (95% LoA: –4 to 4 µm; ICC=0.88; CV=1.4%), and for total retinal thickness was 1 µm (95% LoA: –3 to 4 µm; ICC=0.97; CV=0.7%). (5) Mean total retinal thickness increased by 21 µm and the standard deviation doubled when images were scaled with the Built-in scaling (222 ± 13µm) compared to scaling images with individual biometric parameters (201 ± 6 µm). ONH diameter was three times larger when images were scaled with the Built-in scaling (925 ± 97 µm) than the individual biometric parameters (300 ± 27 µm). (6) In normal rats, mean temporal NFL/RGCL thickness (39 ± 6 µm) was significantly thicker than inferior (33 ± 5 µm) and superior (31 ± 5 µm) NFL/RGCL thickness. NFL/RGCL thickness in the nasal quadrant (36 ± 8 µm) was not significantly different from all other quadrants. In the rat model of glaucoma, IOP after 5 to 10 weeks after disease induction was significantly higher (95% CI: 21 – 43 mm Hg) than before disease induction IOP measurements (95% CI: 17 – 20 mm Hg; P = .02). Mean global NFL/RGCL+IPL thickness significantly decreased from 83 ± 11 µm to 73 ± 15 µm (P = .003) and mean global total retinal thickness decreased from 201 ± 13 µm to 170 ± 31 µm (P = .001). Conclusions: The persistent circadian rhythm of IOP in continuous dim light and the phase relationship between MAP and IOP may further contribute to morphological changes in the ONH and retinal thickness measurements in rats with experimental glaucoma. The in vivo retinal thickness changes measured in rats with experimental glaucoma correlated well with histological assessment of optic nerve damage (e.g., gliosis and collapsed myelin sheaths).