Vascular resistance indices are higher in the superior than inferior optic nerve head and retina.

Retinal vascular resistance is of interest in glaucoma research, as a potential link between retinal ganglion cell loss and observed phenomena including disrupted vascular autoregulation, altered biomechanical stiffness, and impaired neurovascular coupling. It can now be assessed in vivo, using laser speckle flowgraphy. However, continued progress in the field requires better understanding of its physiology. In this study, we test the hypothesis of homogeneity of vascular resistance indices between regions of the retina: specifically, between superior and inferior hemifields. The resistivity index (maximum flow minus minimum flow, as a proportion of the maximum) and pulsatility index (maximum minus minimum, as a proportion of the mean) were measured in major vessels within the optic nerve head, in the remaining tissue within the optic nerve head, and in peripapillary branch retinal arteries, separated in each case into superior and inferior quadrants. This was performed in 378 eyes of 189 participants with suspected, early or moderate glaucoma; and in 99 eyes of 50 participants without any ocular pathology. In the glaucoma cohort, the resistivity index was on average 9% higher superiorly than inferiorly in vessels within the optic nerve head; 8% higher superiorly in remaining tissue; and 8% higher superiorly in peripapillary vessels (all p < 0.001). The pulsatility index was on average 11% higher superiorly in all three locations (all p < 0.001). Average flow was slightly higher superiorly in major vessels in the nerve head, but higher inferiorly elsewhere. In the healthy control cohort, resistivity index was higher superiorly by 10% in vessels and 8% in tissue within the optic nerve head; pulsatility index was 12% and 10% higher superiorly respectively (all p < 0.001). The fact that these differences were similar between the two cohorts suggests that they are not caused by the disease process. However, it is notable that glaucomatous loss most frequently occurs first in the superior visual field, corresponding with the inferior retina. The finding that vascular resistance indices are consistently higher in the superior retina warrants further investigation, both for its causes and consequences.

Strain by virtual extensometers and video-imaging optical coherence tomography as a repeatable metric for IOP-Induced optic nerve head deformations.

PURPOSE: To determine if in vivo strain response of the Optic Nerve Head (ONH) to IOP elevation visualized using Optical Coherence Tomography (OCT) video imaging and quantified using novel virtual extensometers was able to be provided repeatable measurements of tissue specific deformations. METHODS: The ONHs of 5 eyes from 5 non-human primates (NHPs) were imaged by Spectralis OCT. A vertical and a horizontal B-scan of the ONH were continuously recorded for 60 s at 6 Hz (video imaging mode) during IOP elevation from 10 to 30 mmHg. Imaging was repeated over three imaging sessions. The 2D normal strain was computed by template-matching digital image correlation using virtual extensometers. ANOVA F-test (F) was used to compare inter-eye, inter-session, and inter-tissue variability for the prelaminar, Bruch's membrane opening (BMO), lamina cribrosa (LC) and choroidal regions (against variance the error term). F-test of the ratio between inter-eye to inter-session variability was used to test for strain repeatability across imaging sessions (FIS). RESULTS: Variability of strain across imaging session (F = 0.7263, p = 0.4855) and scan orientation was not significant (F = 1.053, p = 0.3066). Inter session variability of strain was significantly lower than inter-eye variability (FIS = 22.63, p = 0.0428) and inter-tissue variability (FIS = 99.33 p = 0.00998). After IOP elevation, strain was highest in the choroid (-18.11%, p < 0.001), followed by prelaminar tissue (-11.0%, p < 0.001), LC (-3.79%, p < 0.001), and relative change in BMO diameter (-0.57%, p = 0.704). CONCLUSIONS: Virtual extensometers applied to video-OCT were sensitive to the eye-specific and tissue-specific mechanical response of the ONH to IOP and were repeatable across imaging sessions.

Histologic validation of optical coherence tomography-based three-dimensional morphometric measurements of the human optic nerve head: Methodology and preliminary results.

PURPOSE: To compare the three-dimensional (3D) morphology of the deep load-bearing structures of the human optic nerve head (ONH) as revealed in vivo by spectral domain optical coherence tomography (SDOCT) with ex vivo quantitative 3D histology. METHODS: SDOCT imaging of the ONH was performed in six eyes from three brain-dead organ donors on life-support equipment awaiting organ procurement (in vivo conditions). Following organ procurement (ex vivo conditions), the eyes were enucleated and underwent a pars plana vitrectomy followed by pressurization to physiologic IOP and immersion fixation. Ex vivo ONH morphology was obtained from high-fidelity episcopic fluorescent 3D reconstruction. Morphologic parameters of the observed ONH canal geometry and peripapillary choroid, as well as the shape, visibility and depth of the lamina cribrosa were compared between ex vivo and in vivo measurements using custom software to align, scale, and manually delineate the different regions of the ONH. RESULTS: There was significant correspondence between in vivo and ex vivo measurements of the depth and shape of the lamina cribrosa, along with the size and shape of Bruch's membrane opening (BMO) and anterior scleral canal opening (ASCO). Weaker correspondence was observed for choroidal thickness; as expected, a thinner choroid was seen ex vivo due to loss of blood volume upon enucleation (-79.9%, p < 0.001). In addition, the lamina was shallower (-32.3%, p = 0.0019) and BMO was smaller ex vivo (-3.38%, p = 0.026), suggesting post mortem shrinkage of the fixed tissue. On average, while highly variable, only 31% of the anterior laminar surface was visible in vivo with SDOCT (p < 0.001). CONCLUSIONS: Morphologic parameters by SDOCT imaging of the deep ONH showed promising correspondence to histology metrics. Small but significant shrinkage artifact, along with large effects of exsanguination of the choroid, was seen in the ex vivo reconstructions of fixed tissues that may impact the quantification of ex vivo histoarchitecture, and this should be considered when developing models and biomarkers based on ex vivo imaging of fixed tissue. Lack of visibly of most of the lamina surface in SDOCT images is an important limitation to metrics and biomarkers based on in vivo images of the ONH deep tissues.

Time to surgery following neoadjuvant chemotherapy for breast cancer impacts residual cancer burden, recurrence, and survival.

BACKGROUND: The impact of length of time to surgery (TTS) on oncologic outcomes following neoadjuvant chemotherapy (NAC) in breast cancer patients is unclear. We investigated the relationship between TTS on residual cancer burden (RCB) score and oncologic outcomes. METHODS: Patients with breast cancer receiving NAC from 2011 to 2017 were identified. The association of TTS with recurrence-free survival (RFS), overall and disease-specific survival (OS, DSS), and RCB score was examined with Kaplan-Meier and Cox proportional hazards analysis, adjusting for relevant clinicopathologic factors. RESULTS: We identified 463 patients. Median TTS was 29 days (range 11-153). Median follow-up was 57 months (range, 2-93 months). Five-year local recurrence-free survival, locoregional RFS, OS, and DSS was 86%, 96%, 89%, and 91%, respectively. On multivariate analysis, TTS >6 weeks was independently associated with worse RFS (HR [hazard ratio] 3.45; p < .001) and DSS (HR 2.82; p < .05), while TTS >6 weeks was independently associated with a positive size of the effect on RCB score of 0.59 (p < .0001). CONCLUSION: Prolonged TTS is a modifiable risk factor for adverse oncologic outcomes following NAC for breast cancer, possibly mediated by increasing RCB score overtime after NAC. In the absence of contraindications, surgery should be performed within 6 weeks following NAC for optimal oncologic outcomes.

Expansions of the neurovascular scleral canal and contained optic nerve occur early in the hypertonic saline rat experimental glaucoma model.

PURPOSE: To characterize early optic nerve head (ONH) structural change in rat experimental glaucoma (EG). METHODS: Unilateral intraocular pressure (IOP) elevation was induced in Brown Norway rats by hypertonic saline injection into the episcleral veins and animals were sacrificed 4 weeks later by perfusion fixation. Optic nerve cross-sections were graded from 1 (normal) to 5 (extensive injury) by 5 masked observers. ONHs with peripapillary retina and sclera were embedded, serial sectioned, 3-D reconstructed, delineated, and quantified. Overall and animal-specific EG versus Control eye ONH parameter differences were assessed globally and regionally by linear mixed effect models with significance criteria adjusted for multiple comparisons. RESULTS: Expansions of the optic nerve and surrounding anterior scleral canal opening achieved statistical significance overall (p < 0.0022), and in 7 of 8 EG eyes (p < 0.005). In at least 5 EG eyes, significant expansions (p < 0.005) in Bruch's membrane opening (BMO) (range 3-10%), the anterior and posterior scleral canal openings (8-21% and 5-21%, respectively), and the optic nerve at the anterior and posterior scleral canal openings (11-30% and 8-41%, respectively) were detected. Optic nerve expansion was greatest within the superior and inferior quadrants. Optic nerve expansion at the posterior scleral canal opening was significantly correlated to optic nerve damage (R = 0.768, p = 0.042). CONCLUSION: In the rat ONH, the optic nerve and surrounding BMO and neurovascular scleral canal expand early in their response to chronic experimental IOP elevation. These findings provide phenotypic landmarks and imaging targets for detecting the development of experimental glaucomatous optic neuropathy in the rat eye.

Rat optic nerve head anatomy within 3D histomorphometric reconstructions of normal control eyes.

The purpose of this study is to three-dimensionally (3D) characterize the principal macroscopic and microscopic relationships within the rat optic nerve head (ONH) and quantify them in normal control eyes. Perfusion-fixed, trephinated ONH from 8 normal control eyes of 8 Brown Norway Rats were 3D histomorphometrically reconstructed, visualized, delineated and parameterized. The rat ONH consists of 2 scleral openings, (a superior neurovascular and inferior arterial) separated by a thin connective tissue strip we have termed the "scleral sling". Within the superior opening, the nerve abuts a prominent extension of Bruch's Membrane (BM) superiorly and is surrounded by a vascular plexus, as it passes through the sclera, that is a continuous from the choroid into and through the dural sheath and contains the central retinal vein (CRV), (inferiorly). The inferior scleral opening contains the central retinal artery and three long posterior ciliary arteries which obliquely pass through the sclera to obtain the choroid. Bruch's Membrane Opening (BMO) is irregular and vertically elongated, enclosing the nerve (superiorly) and CRV and CRA (inferiorly). Overall mean BMO Depth, BMO Area, Choroidal Thickness and peripapillary Scleral Thickness were 29 µm, 56.5 × 10(3) µm(2), 57 µm and 104 µm respectively. Mean anterior scleral canal opening (ASCO) and posterior scleral canal opening (PSCO) radii were 201 ± 15 µm and 204 ± 16 µm, respectively. Mean optic nerve area at the ASCO and PSCO were 46.3 × 10(3)±4.4 × 10(3) µm(2) and 44.1 × 10(3)±4.5 × 10(3) µm(2) respectively. In conclusion, the 3D complexity of the rat ONH and the extent to which it differs from the primate have been under-appreciated within previous 2D studies. Properly understood, these anatomic differences may provide new insights into the relative susceptibilities of the rat and primate ONH to elevated intraocular pressure.

Assessment of the reliability of standard automated perimetry in regions of glaucomatous damage.

PURPOSE: Visual field testing uses high-contrast stimuli in areas of severe visual field loss. However, retinal ganglion cells saturate with high-contrast stimuli, suggesting that the probability of detecting perimetric stimuli may not increase indefinitely as contrast increases. Driven by this concept, this study examines the lower limit of perimetric sensitivity for reliable testing by standard automated perimetry. DESIGN: Evaluation of a diagnostic test. PARTICIPANTS: A total of 34 participants with moderate to severe glaucoma; mean deviation at their last clinic visit averaged -10.90 dB (range, -20.94 to -3.38 dB). A total of 75 of the 136 locations tested had a perimetric sensitivity of ≤ 19 dB. METHODS: Frequency-of-seeing curves were constructed at 4 nonadjacent visual field locations by the Method of Constant Stimuli (MOCS), using 35 stimulus presentations at each of 7 contrasts. Locations were chosen a priori and included at least 2 with glaucomatous damage but a sensitivity of ≥ 6 dB. Cumulative Gaussian curves were fit to the data, first assuming a 5% false-negative rate and subsequently allowing the asymptotic maximum response probability to be a free parameter. MAIN OUTCOME MEASURES: The strength of the relation (R(2)) between perimetric sensitivity (mean of last 2 clinic visits) and MOCS sensitivity (from the experiment) for all locations with perimetric sensitivity within ± 4 dB of each selected value, at 0.5 dB intervals. RESULTS: Bins centered at sensitivities ≥ 19 dB always had R(2) >0.1. All bins centered at sensitivities ≤ 15 dB had R(2) <0.1, an indication that sensitivities are unreliable. No consistent conclusions could be drawn between 15 and 19 dB. At 57 of the 81 locations with perimetric sensitivity <19 dB, including 49 of the 63 locations ≤ 15 dB, the fitted asymptotic maximum response probability was <80%, consistent with the hypothesis of response saturation. At 29 of these locations the asymptotic maximum was <50%, and so contrast sensitivity (50% response rate) is undefined. CONCLUSIONS: Clinical visual field testing may be unreliable when visual field locations have sensitivity below approximately 15 to 19 dB because of a reduction in the asymptotic maximum response probability. Researchers and clinicians may have difficulty detecting worsening sensitivity in these visual field locations, and this difficulty may occur commonly in patients with glaucoma with moderate to severe glaucomatous visual field loss.

Predicting adherence to diabetic eye examinations: development of the compliance withAnnual Diabetic Eye Exams Survey.

OBJECTIVE: To identify variables that predict adherence with annual eye examinations using the Compliance with Annual Diabetic Eye Exams Survey (CADEES), a new questionnaire designed to measure health beliefs related to diabetic retinopathy and annual eye examinations. DESIGN: Questionnaire development. PARTICIPANTS: Three hundred sixteen adults with diabetes. METHODS: We developed the CADEES based on a review of the literature, the framework of the Health Belief Model, expert opinion, and pilot study data. To examine content validity, we analyzed participant responses to an open-ended question asking for reasons why people do not obtain annual eye examinations. We evaluated construct validity with principal components analysis and examined internal consistency with Cronbach's α. To assess predictive validity, we used multivariate logistic regression with self-reported adherence as the dependent variable. MAIN OUTCOME MEASURES: Associations with self-reported adherence (defined as having a dilated eye examination in the past year). RESULTS: The content analysis showed that CADEES items covered 89% of the reasons given by participants for not obtaining an annual eye examination. The principal components analysis identified 3 informative components that made up 32% of the variance. Multivariate logistic regression modeling revealed several significant predictors of adherence, including beliefs concerning whether insurance covered most of the eye examination cost (P < 0.01), whether there were general barriers that make it difficult to obtain an eye examination (P < 0.01), whether obtaining an eye examination was a top priority (P = 0.02), and whether diabetic eye disease can be seen with an examination (P = 0.05). Lower hemoglobin A1c levels (P < 0.01), having insurance (P = 0.01), and a longer duration of diabetes (P = 0.02) also were associated with adherence. A multivariate model containing CADEES items and demographic variables classified cases with 72% accuracy and explained approximately 24% of the variance in adherence. CONCLUSIONS: The CADEES showed good content and predictive validity. Although additional research is needed before finalizing a shorter version of the survey, our findings suggest that researchers and clinicians may be able to improve adherence by (1) counseling newly diagnosed patients, as well as those with uncontrolled blood glucose, on the importance of annual eye examinations and (2) discussing perceived barriers and misconceptions.

The Temporal Relation Between Rates of Retinal Nerve Fiber Layer and Minimum Rim Width Changes in Glaucoma.

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.

Assessment of Time Lag Between Blood Flow, Retinal Nerve Fiber Layer Thickness and Visual Field Sensitivity Changes in Glaucoma.

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.

OCT Segmentation Errors with Bruch's Membrane Opening-Minimum Rim Width as Compared with Retinal Nerve Fiber Layer Thickness.

OBJECTIVE: To compare the magnitude and location of automated segmentation errors of the Bruch's membrane opening-minimum rim width (BMO-MRW) and retinal nerve fiber layer thickness (RNFLT). DESIGN: Cross-sectional study. PARTICIPANTS: We included 162 glaucoma suspect or open-angle glaucoma eyes from 162 participants. METHODS: We used spectral-domain optic coherence tomography (Spectralis 870 nm, Heidelberg Engineering) to image the optic nerve with 24 radial optic nerve head B-scans and a 12-degree peripapillary circle scan, and exported the native "automated segmentation only" results for BMO-MRW and RNFLT. We also exported the results after "manual refinement" of the measurements. MAIN OUTCOME MEASURES: We calculated the absolute and proportional error globally and within the 12 30-degree sectors of the optic disc. We determined whether the glaucoma classifications were different between BMO-MRW and RNFLT as a result of manual and automatic segmentation. RESULTS: The absolute error mean was larger for BMO-MRW than for RNFLT (10.8 µm vs. 3.58 µm, P < 0.001). However, the proportional errors were similar (4.3% vs. 4.4%, P = 0.47). In a multivariable regression model, errors in BMO-MRW were not significantly associated with age, location, magnitude, or severity of glaucoma loss (all P ≥ 0.05). However, larger RNFLT errors were associated with the superior and inferior sector location, thicker nerve fiber layer, and worse visual field (all P < 0.05). Errors in BMO-MRW and RNFLT were not likely to occur in the same sector location (R2 = 0.001; P = 0.15). With manual refinement, the glaucoma classification changed in 7.8% and 6.2% of eyes with BMO-MRW and RNFLT, respectively. CONCLUSIONS: Both BMO-MRW and RNFLT measurements included segmentation errors, which did not seem to have a common location, and may result in differences in glaucoma classification. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Differences in Systemic Pulse Waveform Between Individuals With Glaucoma, Glaucoma Suspects, and Healthy Controls.

Purpose: It has been hypothesized that compromised ocular circulation in glaucoma may be concomitant of systemic changes. The purpose of this study is to test whether systemic blood flow pulse waveform patterns differ between individuals with glaucoma (GL), glaucoma suspects (GLS), and normal healthy controls (HC). Methods: The study included 35 bilateral GL, 67 bilateral GLS, 29 individuals with unilateral GL who were considered GLS in the other eye, and 44 healthy controls. Systemic pulsatile blood pressure waveforms were recorded using a finger cuff. A continuous 200 Hz plethysmography recording is made to obtain a pulse waveform. Waveform parameters were extracted using custom software from an average of eight pulse cycles. These were compared between GL, GLS, and HC groups on a per-eye basis, using generalized estimating equation models to account for intereye correlations; and plotted against disease severity by visual field linearized mean deviation (MDlin) and retinal nerve fiber layer thickness (RNFLT). Results: Averaged blood pressure was significantly lower in the HC group (mean ± standard deviation 91.7 ±11.7 mm Hg) than the GLS (102.4 ± 13.9) or GL (102.8 ± 13.7) groups, with P < 0.0001 (generalized estimating equation regression). Waveform parameters representing vascular resistance were higher in both GLS and GL groups than the HC group; and were correlated with RNFLT and MDlin (P ≤ 0.05). Conclusions: The shape of the systemic pulsatile waveform differs in individuals with GL/GLS suspects, compared to HC eyes. Blood pressure changes more rapidly in individuals with GL, which suggests higher arterial stiffness.

Diagnostic Performance for Detection of Glaucomatous Structural Damage Using Pixelwise Analysis of Retinal Thickness Measurements.

Purpose: To compare the diagnostic accuracy of thickness measurements of individual and combined macular retinal layers to discriminate 188 glaucomatous and 148 glaucoma suspect eyes from 362 healthy control (HC) eyes on a pixel-by-pixel basis. Methods: For this retrospective study, we manually corrected the segmentations of posterior pole optical coherence tomography (OCT) scans to determine the thickness of the nerve fiber layer (NFL), ganglion cell layer (GCL), inner plexiform layer (IPL), the ganglion cell complex (GCC), and the total neural retina (TR). For each eye, the total number of pixels with thickness values less than the fifth percentile of the HC distribution was used to create a receiver operating characteristic (ROC) curve for each layer and for layer combinations. Results: Using total abnormal pixel count criteria to discriminate glaucoma from HC eyes, the individual layers with the highest area under the ROC curve (AUC) were the NFL and GCL; IPL performance was significantly lower (P < 0.05). GCC had a significant higher AUC (94.3%) than individual the AUC of the NFL (92.3%) (P = 0.0231) but not higher than AUC of the GCL (93.4%) (P = 0.3487). The highest AUC (95.4%) and sensitivity (85.1%) at 95% specificity was found for the Boolean combination of NFL or GCL. The highest AUC is not significantly higher (P = 0.0882) than the AUC of the GCC but the highest sensitivity is significantly higher than the sensitivity of the GCC. This pattern was similar for discriminating between suspect and HC eyes (P = 0.0356). Conclusions: Using pixel-based methods, the diagnostic accuracy of NFL and GCL exceeded that of IPL and TR. GCC had equivalent performance as NFL and GCL. The specific spatial locations within the posterior pole that exhibit best performance vary depending on which layer is being assessed. Recognizing this dependency highlights the importance of considering multiple layers independently, as they offer complementary information for effective and comprehensive diagnosis.

Retrolaminar Demyelination of Structurally Intact Axons in Nonhuman Primate Experimental Glaucoma.

Purpose: To determine if structurally intact, retrolaminar optic nerve (RON) axons are demyelinated in nonhuman primate (NHP) experimental glaucoma (EG). Methods: Unilateral EG NHPs (n = 3) were perfusion fixed, EG and control eyes were enucleated, and foveal Bruch's membrane opening (FoBMO) 30° sectoral axon counts were estimated. Optic nerve heads were trephined; serial vibratome sections (VSs) were imaged and colocalized to a fundus photograph establishing their FoBMO location. The peripheral neural canal region within n = 5 EG versus control eye VS comparisons was targeted for scanning block-face electron microscopic reconstruction (SBEMR) using micro-computed tomographic reconstructions (µCTRs) of each VS. Posterior laminar beams within each µCTR were segmented, allowing a best-fit posterior laminar surface (PLS) to be colocalized into its respective SBEMR. Within each SBEMR, up to 300 axons were randomly traced until they ended (nonintact) or left the block (intact). For each intact axon, myelin onset was identified and myelin onset distance (MOD) was measured relative to the PLS. For each EG versus control SBEMR comparison, survival analyses compared EG and control MOD. Results: MOD calculations were successful in three EG and five control eye SBEMRs. Within each SBEMR comparison, EG versus control eye axon loss was -32.9%, -8.3%, and -15.2% (respectively), and MOD was increased in the EG versus control SBEMR (P < 0.0001 for each EG versus control SBEMR comparison). When data from all three EG eye SBEMRs were compared to all five control eye SBEMRs, MOD was increased within the EG eyes. Conclusions: Structurally intact, RON axons are demyelinated in NHP early to moderate EG. Studies to determine their functional status are indicated.

Quality of Life and Primary Open-Angle Glaucoma in the Ocular Hypertension Treatment Study.

Importance: If preperimetric glaucoma reduces patient-reported vision-related quality of life (VRQoL), clinicians might consider earlier and more aggressive treatment of some patients with ocular hypertension and early glaucoma. Objective: To determine the impact of preperimetric glaucoma and early glaucomatous visual field (VF) loss on participants' VRQoL compared with participants who did not develop glaucoma in the Ocular Hypertension Treatment Study (OHTS). Design, Setting, and Participants: This cross-sectional study used data from participants enrolled in the OHTS from 1994 to 1996 who completed 20-year examination follow-up and VRQoL surveys from January 7, 2016, to November 19, 2019. Diagnosis of primary open-angle glaucoma (POAG) required reproducible changes in VFs or optic discs as determined by reading centers and attributed to glaucoma by a masked end point committee. Data analysis was performed from June 27, 2023 to March 7, 2024. Exposure: Ocular hypertension and glaucoma. Main Outcomes and Measures: Cross-sectional analysis of Rasch-calibrated total scores of the National Eye Institute Visual Function Questionnaire (VFQ) and the Glaucoma Quality of Life (GQL) survey was performed. Total scores were standardized from 0 (poor) to 100 (good). The main outcomes were differences in total VRQoL scores between participants who did not develop POAG (control) and 4 mutually exclusive POAG groups: unilateral or bilateral disc POAG with no glaucomatous VF loss in either eye and unilateral or bilateral VF POAG with or without disc changes. Differences in total VRQoL scores were analyzed using univariate and multivariate linear regression models. Results: Of 1636 participants originally enrolled in the OHTS, 679 (42%) completed the 20-year examination and VRQoL surveys. Of those participants completing 20-year follow-up, mean (SD) participant age at follow-up was 73.8 (7.7) years, and 412 of 679 participants (60.7%) self-reported as female. The mean (SD) Rasch-calibrated total VFQ scores were 72.5 (13.4) in the no POAG group (control) vs 72.7 (13.8) in the unilateral disc POAG group (difference, 0.17; 95% CI, -3.17 to 3.41; P = .92), 73.4 (14.0) in the bilateral disc POAG group (difference, 0.92; 95% CI, -2.93 to 4.77; P = .64), 69.2 (14.5) in the unilateral VF POAG group (difference, 3.33; 95% CI, -6.38 to -0.27; P = .03), and 58.5 (16.9) in the bilateral VF POAG group (difference, -13.96; 95% CI, -17.73 to -10.19; P<.001). Similar results were found for the GQL questionnaire. Conclusions and Relevance: In this cross-sectional study, among the surviving participants of OHTS who completed the 20-year follow-up examination, those participants who developed preperimetric POAG but no glaucomatous VF loss did not report lower VFQoL compared with participants who did not develop POAG. This finding should allow clinicians and patients the time to determine the frequency of examinations and whether the initiation of treatment is appropriate.

Optical Coherence Tomographic Optic Nerve Head Morphology in Myopia III: The Exposed Neural Canal Region in Healthy Eyes-Implications for High Myopia.

PURPOSE: To determine the prevalence and magnitude of optical coherence tomography (OCT) exposed neural canal (ENC), externally oblique choroidal border tissue (EOCBT), and exposed scleral flange (ESF) regions in 362 non-highly myopic (spherical equivalent -6.00 to 5.75 diopters) eyes of 362 healthy subjects. DESIGN: Cross-sectional study. METHODS: After OCT optic nerve head (ONH) imaging, Bruch membrane opening (BMO), the anterior scleral canal opening (ASCO), and the scleral flange opening (SFO) were manually segmented. BMO, ASCO, and SFO points were projected to the BMO reference plane. The direction and magnitude of BMO/ASCO offset as well as the magnitude of ENC, EOCBT, and ESF was calculated within 30° sectors relative to the foveal-BMO axis. Hi-ESF eyes demonstrated an ESF ≥100 µm in at least 1 sector. Sectoral peri-neural canal choroidal thickness (pNC-CT) was measured and correlations between the magnitude of sectoral ESF and proportional pNC-CT were assessed. RESULTS: Seventy-three Hi-ESF (20.2%) and 289 non-Hi-ESF eyes (79.8%) were identified. BMO/ASCO offset as well as ENC, EOCBT, and ESF prevalence and magnitude were greatest inferior temporally where the pNC-CT was thinnest. Among Hi-ESF eyes, the magnitude of each ENC region correlated with the BMO/ASCO offset magnitude, and the sectors with the longest ESF correlated with the sectors with proportionally thinnest pNC-CT. CONCLUSIONS: ONH BMO/ASCO offset, either as a cause or result of ONH neural canal remodeling, corresponds with the sectoral location of maximum ESF and minimum pNC-CT in non-highly myopic eyes. Longitudinal studies to characterize the development and clinical implications of ENC Hi-ESF regions in non-highly myopic and highly myopic eyes are indicated.

Seasonal changes in visual field sensitivity and intraocular pressure in the ocular hypertension treatment study.

PURPOSE: Longitudinal testing plays a key role in glaucoma management. Variability between visits hampers the ability to monitor progression. It has previously been shown that average intraocular pressure (IOP) exhibits seasonal fluctuations. This study examines whether visual field sensitivity also exhibits seasonal fluctuations and seeks to determine whether such fluctuations are correlated to seasonal IOP effects. DESIGN: Comparative case series. PARTICIPANTS: A total of 33 873 visits by 1636 participants enrolled in the Ocular Hypertension Treatment Study. Participants were split into 6 geographic zones according to the prevailing climate in their location. TESTING: At each visit, standard automated perimetry was conducted on each eye, and IOP was measured. MAIN OUTCOME MEASURES: Mixed effects regression models were formed to look for sinusoidal periodic effects on the change in perimetric mean deviation since the last visit (ΔMD) and on IOP, both overall and within each zone. RESULTS: When all the data were included, a significant seasonal effect on ΔMD was found with magnitude 0.06 dB, peaking in February (P < 0.001). Five of the 6 geographic zones exhibited significant seasonal effects on ΔMD, peaking between January and April, with magnitudes ranging from 0.04 dB (P = 0.049) to 0.21 dB (P < 0.001). Zones with greater climactic variation showed larger seasonal effects on ΔMD. All 6 zones exhibited a seasonal effect on IOP, peaking in January or February, with magnitudes ranging from 0.14 to 0.39 mmHg (P ≤ 0.02 in all cases). However, there was no evidence of a significant association between the magnitudes or dates of peaks of the 2 seasonal effects. CONCLUSIONS: The mean deviation was significantly higher in winter than in summer. There is no evidence of an association with seasonal IOP fluctuations. The cause of the seasonal effect on visual field sensitivity is unknown. These findings may help shed light on the glaucomatous disease process and aid efforts to reduce test-retest variability.

Correlating perimetric indices with three nerve fiber layer thickness measures.

PURPOSE: To determine which of three estimates of retinal nerve fiber layer thickness (RNFLT) correlate best with visual field sensitivity measured using standard automated perimetry (SAP). METHODS: Data were collected from 400 eyes of 209 participants enrolled in the Portland Progression Project. These individuals ranged from high-risk suspects to having non-end-stage glaucoma. In each eye, three measures of average RNFLT (spectral domain optical coherence tomography [SDOCT], scanning laser polarimetry [SLP], confocal scanning laser tomography [CSLT]) and SAP (Humphrey HFAII) were performed on the same day. Mean deviation (MD), mean sensitivity (MS), and pattern standard deviation (PSD) were linearized using the equations MD(Lin) = 10(MD*0.1), MS(Lin) = 10(MS*0.1), and PSD(Lin) = 10(PSD*-0.1). Correlations between each of the estimates of RNFLT and each of the functional metrics were calculated (nine total). Pearson correlations and generalized estimating equations (GEE) were used to calculate the strength and significance of the correlations. RESULTS: Linearized MS had the strongest correlation with SDOCT (r = 0.57), intermediate with SLP (r = 0.40), and weakest with CSLT (r = 0.13). When multiple RNFLT measures were included in a GEE model to predict MS(Lin), SDOCT was consistently predictive (p < 0.001) whereas CSLT was never predictive in these multivariate models. Similar findings were observed for MD(Lin) and PSD(Lin). CONCLUSIONS: Average RNFLT estimated from SDOCT predicts SAP status significantly better than average RNFLT estimated from SLP or CSLT.

Longitudinal Signal-to-Noise Ratio of Perimetry at Different Severities of Glaucoma.

Purpose: Automated perimetry is relied on for functional assessment of patients with glaucoma, but questions remain about its effective dynamic range and its utility for quantifying rates of progression at different stages of the disease. This study aims to identify the bounds within which estimates of rate are most reliable. Methods: Pointwise longitudinal signal-to-noise ratios (LSNR), defined as the rate of change divided by the standard error of the trend line, were calculated for 542 eyes of 273 patients with glaucoma/suspects. The relations between the mean sensitivity within each series and lower percentiles of the distribution of LSNRs (representing progressing series) were analyzed by quantile regression, with 95% confidence intervals derived by bootstrapping. Results: The 5th and 10th percentiles of LSNRs reached a minimum at sensitivities 17 to 21 dB. Below this, estimates of rate became more variable, making LSNRs of progressing series less negative. A significant step change in these percentiles also occurred at approximately 31 dB, above which LSNRs of progressing locations became less negative. Conclusions: The lower bound of maximum utility for perimetry was ∼17 to 21dB, coinciding with previous results suggesting that below this point, retinal ganglion cell responses saturate and noise overwhelms remaining signal. The upper bound was ∼30 to 31 dB, coinciding with previous results suggesting that above this point, the size III stimulus used is larger than Ricco's area of complete spatial summation. Translational Relevance: These results quantify the impact of these two factors on the ability to monitor progression and provide quantifiable targets for attempts to improve perimetry.

Detectability of Visual Field Defects in Glaucoma Using Moving Versus Static Stimuli for Perimetry.

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.