Stuart K. Gardiner

Précis: This study shows that GCC thickness is most sensitive for detecting progression at the onset of glaucoma, but less sensitive than cpRNFL thickness. These findings suggest no clear additional value of GCC thickness over cpRNFL overall, although further evaluation in larger cohorts with advanced glaucoma is warranted. Purpose: To compare the sensitivity of ganglion cell complex (GCC) thickness in the macula to circumpapillary retinal nerve fiber layer (cpRNFL) thickness from OCT, and Mean Deviation (MD) and Visual Field Index (VFI) from Standard Automated Perimetry (SAP), for detecting glaucomatous progression across glaucoma stages. Methods: Using longitudinal data from 205 eyes (125 participants), contrast-to-noise ratios (CNRs) were calculated for GCC, cpRNFL, MD and VFI. Glaucoma stage was defined by MD. Contrast was the parameter difference between two stages; noise was the variability from linear regression residuals from five consecutive OCT scans and HFA 24-2 tests per eye. Higher CNR indicates greater sensitive for detecting progression between stages. Results: CNRs ranged from 3.7 to 13.2. In the transition from suspect to mild glaucoma, cpRNFL (13.2) and GCC (8.7) had significantly higher CNRs than MD (4.5) and VFI CNR (4.8); cpRNFL was also significantly higher than GCC. No significant CNR differences were found between structural and functional measures in later stages. Conclusions: GCC thickness is more sensitive than functional measures, but less than cpRNFL thickness, for detecting progression at glaucoma onset. In later stages, structural and functional parameters showed comparable sensitivity within the limits of the available data.

Glaucomatous pathophysiology may impair retinal vasodilation, leading to increased upstream pulsatility. We sought to quantify pulsatility at multiple locations, concurrently, and identify changes that correlate with the rate of disease progression. One hundred eighty-one eyes of 139 participants were tested twice annually for six or more visits. Vessels within the optic nerve head (ONH) and peripapillary region were identified and classified as arteries versus veins using deep learning models applied to optical coherence tomography angiography scans. Vessels were then colocalized to high temporal resolution scans from laser speckle flowgraphy to quantify pulsatility and average flow at each location. These were compared against the rates of functional loss (mean deviation from automated perimetry) and structural loss (retinal nerve fiber layer thickness from optical coherence tomography) over time, using linear generalized estimating equation models. More severe functional and structural loss were correlated with lower blood flow within ONH major vessels (Pearson correlation r = 0.406, P < 0.001 and r = 0.466, P < 0.001, respectively) and tissue (r = 0.432, P < 0.001 and r = 0.466, P < 0.001), and with lower pulsatility in ONH tissue only (r = 0.293, P = 0.001 and r = 0.279, P < 0.001). Higher pulsatility in the peripapillary arteries was correlated with more rapid functional loss (r = -0.220, P = 0.004) and structural loss (r = -0.220, P = 0.006), and remained a significant predictor when adjusting for current severity, age, or IOP. Faster glaucomatous progression was associated with increased pulsatility in peripapillary arteries, suggesting impaired downstream retinal vasodilation beyond the ONH and neuroretinal rim.

Purpose: This study aims to determine whether OCT-derived rates of change in minimum rim width (MRW) are associated with and can potentially predict corresponding alterations in retinal nerve fiber layer thickness (RNFLT) in people with glaucoma. Methods: The rates of change between six-monthly visits were taken from 568 eyes of 278 participants in the P3 Study. Structural equation models (SEM) assessed whether one parameter was predicted by the concurrent or previous rate of the other parameter, after adjusting for its own rate in the previous time interval. Root mean square error of approximation (RMSEA, with 90% confidence intervals [CI]), Tucker Lewis index (TLI) and the comparative fit index (CFI) assessed goodness of fit. Results: Models without a time lag provided a better fit for the data (RMSEA = 0.101 [CI, 0.089, 0.113]), compared to a model featuring a time lag in RNFLT (RMSEA = 0.114 [CI, 0.102, 0.126]) or MRW (RMSEA = 0.114 [CI, 0.102, 0.127]). The SEMs indicated that rates for both MRW and RNFLT were predicted by their own rate in the previous time interval and by the other measure's change in the concurrent time interval (P > 0.001 for all). No evidence of a clinically significant time lag for either parameter was determined. Conclusions: MRW and RNFLT exhibit concurrent changes over time in patients with glaucoma, with no clinically significant time lag determined. Translational Relevance: RNFLT may be more useful than MRW in early glaucoma assessment because of its previously reported lower variability and reduced sensitivity to intraocular pressure changes.

Purpose: This study investigates the temporal relationship between blood flow changes and alterations in retinal nerve fiber layer thickness (RNFLT) and mean deviation (MD) in individuals with glaucoma. Methods: Blood flow, measured by mean blur rate in optic nerve head vessels (MBRv) and tissues (MBRt) using laser speckle flowgraphy (LSFG)-NAVI, was analyzed using structural equation models (SEMs). SEMs assessed whether the previous rate of one parameter predicted the current rate of the other parameter, adjusted for its own rate in the previous time interval. Data from 345 eyes of 174 participants were gathered from visits every six months. Results: Rates of change of both MBRv and MBRt were significantly predicted by their own rate in the previous time interval and by the rate of change of MD in the previous time interval (P < 0.001 and P = 0.043, respectively), but not by the rate of MD in the concurrent interval (P = 0.947 and P = 0.549), implying that changes in MD precede changes in blood flow. Rates of change of RNFLT were predicted by their own previous rate and the rate of change of MBRv and MBRt in either the previous interval (P = 0.002 and P = 0.008) or the concurrent interval (P = 0.001 and P = 0.018), suggesting that MBR may change before RNFLT. Conclusions: The evidence supports a temporal sequence where MD changes precede blood flow changes, which, in turn, may precede alterations in RNFLT.

Purpose: We have previously shown that using moving, instead of static, stimuli extends the effective dynamic range of automated perimetry in glaucoma. In this study, we further investigate the effect of using moving stimuli on the detectability of functional loss. Methods: We used two experimental perimetry paradigms to test 155 subjects with a diagnosis of glaucoma or glaucoma suspect, and 34 healthy control subjects. One test used stimuli moving parallel to the average nerve fiber bundle orientation at each location; the other used static stimuli. Algorithms were otherwise identical. Sensitivities to moving stimuli were transformed to the equivalent values for static stimuli based on a Bland–Altman plot. The proportions of locations outside age-corrected normative limits were compared, and test–retest variability was compared against defect depth for each stimulus type. Results: More tested locations were below the fifth percentile of the normative range for that location using static stimuli. However, among locations abnormal according to standard clinical perimetry on the same day, 19.2% were abnormal using static stimuli, versus 20.5% using moving stimuli (P = 0.372). Test–retest variability was 44% lower for moving stimuli across the range of defect depths. Conclusions: When compared with static automated perimetry and expressed on a common scale, moving stimuli extend the effective dynamic range and decrease variability, without decreasing the detectability of known functional defects. Translational Relevance: Moving stimuli provide a method to improve known problems of current clinical perimetry.

Purpose: Tissue stiffening and alterations in retinal blood flow have both been suggested as causative mechanisms of glaucomatous damage. We tested the hypothesis that retinal blood vessels also stiffen, using laser speckle flowgraphy (LSFG) to characterize vascular resistance. Methods: In the longitudinal Portland Progression Project, 231 eyes of 124 subjects received LSFG scans of the optic nerve head (ONH) and automated perimetry every 6 months for six visits. Eyes were classified as either “glaucoma suspect” or “glaucoma” eyes based on the presence of functional loss on the first visit. Vascular resistance was quantified using the mean values of several instrument-defined parameterizations of the pulsatile waveform measured by LSFG, either in major vessels within the ONH (serving the retina) or in capillaries within ONH tissue, and age-adjusted using a separate group of 127 healthy eyes of 63 individuals. Parameters were compared against the severity and rate of change of functional loss using mean deviation (MD) over the six visits, within the two groups. Results: Among 118 “glaucoma suspect” eyes (average MD, −0.4 dB; rate, −0.45 dB/y), higher vascular resistance was related to faster functional loss, but not current severity of loss. Parameters measured in major vessels were stronger predictors of rate than parameters measured in tissue. Among 113 “glaucoma” eyes (average MD, −4.3 dB; rate, −0.53 dB/y), higher vascular resistance was related to more severe current loss but not rate of loss. Conclusions: Higher retinal vascular resistance and, by likely implication, stiffer retinal vessels were associated with more rapid functional loss in eyes without significant existing loss at baseline.