Neil O'Leary

The Functional Consequences of Glaucoma for Eye–Hand Coordination

PURPOSE To examine whether patients with glaucoma exhibit differences in visually guided reaching-and-grasping (prehension) behavior compared with normally sighted control subjects. METHODS Sixteen patients with glaucoma and 16 control subjects with no ocular disease participated. Participants were required to reach out and precision grasp one of two cylindrical objects placed on a table top in front of them in laboratory conditions in three viewing conditions (binocular, right eye alone, left eye alone). Lightweight reflective markers were placed on the subjects preferred hand for recording its movement in three-dimensional space. Three motion capture units recorded the motion of these markers as the subjects reached out and precision grasped household objects. Various indices of prehension planning, execution, and control were quantified. Visual fields (VF) were measured using standard automated perimetry generating monocular mean deviation (MD) scores. Binocular VF sensitivity was estimated by using the integrated visual field (IVF). Stereoacuity was measured with the Frisby stereoacuity test. Significant differences in prehension movement between patients and control subjects in each viewing condition were investigated, and associations between prehension kinematics and VF sensitivity were examined. RESULTS The patients and control subjects were of a similar age (median [range]: patient group, 72.2 years [62.5-86.9]; control group, 69.0 years [64.3-78.3]). The patient group had asymmetrical disease and relatively minor binocular overlapping defects (better eye MD, -5.7 dB [-16.7 to +0.45 dB]; worse eye MD, -11.8 dB [-29.3 to -1.5 dB]; IVF score, 3 [0-36]). They exhibited slightly poorer stereoacuity levels than did the control subjects (patient group, 55 sec arc [40-110]; control group, 40 sec arc [20-80; Mann-Whitney U test, P < 0.05]). They also showed statistically significant delays in average movement onset (MO: approximately 100 ms delay, Mann-Whitney U test P < 0.0001) and overall movement time (OMD: approximately 140 ms delay; Mann-Whitney U test P < 0.05), suggesting impairments in initial movement planning and control. Deficits were exhibited in the reaching component, with data suggesting that glaucomatous patients made more tentative movements when reaching for the object. These deficits correlated with both increasing severity of VF defect and impaired stereoacuity. There were no differences in grasping characteristics between patients and control subjects in this sample. CONCLUSIONS This study provides evidence that patients with glaucoma exhibit deficits in eye-hand coordination compared with the age-matched normally sighted control. Further study is needed to assess the specific effect of field loss location on prehension kinematics.

Laminar Displacement and Prelaminar Tissue Thickness Change after Glaucoma Surgery Imaged with Optical Coherence Tomography

PURPOSE To study changes in lamina cribrosa position and prelaminar tissue thickness (PTT) after surgical IOP reduction in glaucoma patients. METHODS Twenty-two patients (mean age, 71.4 years) were imaged with spectral domain optical coherence tomography (SD-OCT; 24 radial B-scans centered on the optic nerve head [ONH]) before trabeculectomy or tube shunt implantation. Follow up images were acquired 1 week, 1 month, 3 months, and 6 months postsurgery. Bruchs membrane opening (BMO), the internal limiting membrane (ILM) and the anterior laminar surface (ALS) were segmented in each radial scan with custom software. Surfaces were fitted to the ILM and ALS with the extracted three-dimesional coordinates. PTT was the distance between the ILM and ALS, perpendicular to a BMO reference plane. Serial postsurgical laminar displacement (LD), relative to the BMO reference plane, and changes in PTT were measured. Positive values indicated anterior LD. RESULTS Mean (SD) presurgery IOP was 18.1 (6.5) mm Hg, and reduced by 4.7 (5.5), 2.4 (7.7), 7.0 (6.2), and 6.8 (7.5) mm Hg at 1 week, 1 month, 3 months, and 6 months postsurgery, respectively. At the four postsurgery time points, there was significant anterior LD (1.8 [9.5], -1.1 [8.9], 8.8 [20.2], and 17.9 [25.8] μm) and PTT increase (1.7 [13.3], 2.4 [11.9], 17.4 [13.7], and 13.9 [18.6] μm). LD was greater in ONHs with larger BMO area (P = 0.01) and deeper ALS (P = 0.04); however, PTT was not associated with any of the tested independent variables. CONCLUSIONS Both anterior LD and thickening of prelaminar tissue occur after surgical IOP reduction in patients with glaucoma.

Longitudinal In Vivo Imaging of Retinal Ganglion Cells and Retinal Thickness Changes Following Optic Nerve Injury in Mice

Background Retinal ganglion cells (RGCs) die in sight-threatening eye diseases. Imaging RGCs in humans is not currently possible and proof of principle in experimental models is fundamental for future development. Our objective was to quantify RGC density and retinal thickness following optic nerve transection in transgenic mice expressing cyan fluorescent protein (CFP) under control of the Thy1 promoter, expressed by RGCs and other neurons. Methodology/Principal Findings A modified confocal scanning laser ophthalmoscopy (CSLO)/spectral-domain optical coherence tomography (SD-OCT) camera was used to image and quantify CFP+ cells in mice from the B6.Cg-Tg(Thy1-CFP)23Jrs/J line. SD-OCT circle (1 B-scan), raster (37 B-scans) and radial (24 B-scans) scans of the retina were also obtained. CSLO was performed at baseline (n = 11) and 3 (n = 11), 5 (n = 4), 7 (n = 10), 10 (n = 6), 14 (n = 7) and 21 (n = 5) days post-transection, while SD-OCT was performed at baseline and 7, 14 and 35 days (n = 9) post-transection. Longitudinal change in CFP+ cell density and retinal thickness were computed. Compared to baseline, the mean (SD) percentage CFP+ cells remaining at 3, 5, 7, 10, 14 and 21 days post-transection was 86 (9)%, 63 (11)%, 45 (11)%, 31 (9)%, 20 (9)% and 8 (4)%, respectively. Compared to baseline, the mean (SD) retinal thickness at 7 days post-transection was 97 (3)%, 98 (2)% and 97 (4)% for the circle, raster and radial scans, respectively. The corresponding figures at 14 and 35 days post-transection were 96 (3)%, 97 (2)% and 95 (3)%; and 93 (3)%, 94 (3)% and 92 (3)%. Conclusions/Significance Longitudinal imaging showed an exponential decline in CFP+ cell density and a small (≤8%) reduction in SD-OCT measured retinal thickness post-transection. SD-OCT is a promising tool for detecting structural changes in experimental optic neuropathy. These results represent an important step towards translation for clinical use.

Visual Field Progression in Glaucoma: Estimating the Overall Significance of Deterioration with Permutation Analyses of Pointwise Linear Regression (PoPLR)

PURPOSE To establish a method for estimating the overall statistical significance of visual field deterioration from an individual patients data, and to compare its performance to pointwise linear regression. METHODS The Truncated Product Method was used to calculate a statistic S that combines evidence of deterioration from individual test locations in the visual field. The overall statistical significance (P value) of visual field deterioration was inferred by comparing S with its permutation distribution, derived from repeated reordering of the visual field series. Permutation of pointwise linear regression (PoPLR) and pointwise linear regression were evaluated in data from patients with glaucoma (944 eyes, median mean deviation -2.9 dB, interquartile range: -6.3, -1.2 dB) followed for more than 4 years (median 10 examinations over 8 years). False-positive rates were estimated from randomly reordered series of this dataset, and hit rates (proportion of eyes with significant deterioration) were estimated from the original series. RESULTS The false-positive rates of PoPLR were indistinguishable from the corresponding nominal significance levels and were independent of baseline visual field damage and length of follow-up. At P < 0.05, the hit rates of PoPLR were 12, 29, and 42%, at the fifth, eighth, and final examinations, respectively, and at matching specificities they were consistently higher than those of pointwise linear regression. CONCLUSIONS In contrast to population-based progression analyses, PoPLR provides a continuous estimate of statistical significance for visual field deterioration individualized to a particular patients data. This allows close control over specificity, essential for monitoring patients in clinical practice and in clinical trials.

A study comparing videocapillaroscopy and dermoscopy in the assessment of nailfold capillaries in patients with systemic sclerosis–spectrum disorders

OBJECTIVES Nailfold videocapillaroscopy (NVC), the current gold standard for detection of capillary abnormalities suggestive of an SSc-spectrum disorder, is not widely available: a key question is whether lower-magnification, easy-to-use dermoscopy compares favourably. This is especially relevant given the inclusion of capillaroscopic abnormality within the 2013 classification criteria for SSc. Our objectives were to examine the ability to classify capillaries and to evaluate abnormality (severity), by both NVC and dermoscopy, to determine whether these differ between general and specialist rheumatologists, and to compare intra- and interrater reliability of both techniques. METHODS NVC and dermoscopy images were acquired from all 10 nailbeds of 32 subjects with a range of capillary abnormalities. Images were graded (using a web-based interface) on a 0-3 scale of severity: normal (0), mildly (1), definitely (2) and grossly abnormal (3), and an unclassifiable category. Raters graded images from four subjects (40 nailbeds) using each technique, with five repeated images to estimate intrarater reliability. RESULTS Forty-eight rheumatologists from 12 countries participated in the study (22 generalists, 26 specialists). While most images could be graded by both techniques, more were graded by NVC (84% vs 70%) and were systematically scored higher by NVC (mean difference 0.43 between the ratings). Agreement between the techniques was moderate. Intra- and interrater reliability were comparable for the two techniques in the classifiability of images and the grading of severity. CONCLUSION Our results suggest that dermoscopy is comparable to NVC, although NVC images were more likely to be classifiable and were graded more severely.

Clinical evaluation of the proper orthogonal decomposition framework for detecting glaucomatous changes in human subjects.

PURPOSE To evaluate the new proper orthogonal decomposition (POD) framework for detecting glaucomatous progression from HRT topographies of human subjects and compare it with HRT topographic change analysis (TCA). METHODS Of 267 eyes of 187 participants with > or =4 retinal tomographic examinations in the University of California, San Diego Diagnostic Innovations in Glaucoma Study (DIGS), 21 eyes were of longitudinally normal subjects and 36 eyes progressed by stereophotographs or visual field-guided progression analysis (progressors). All others were considered nonprogressing (nonprogressors; n = 210 eyes). POD parameters of Euclidean distance (L(2) norm), image Euclidean distance, and correlation were computed, and their area under receiver operating characteristic curves (AUC) in differentiating progressors from nonprogressors and normal subjects were compared to the TCA parameters of the number of superpixels with significant decrease in retinal height (red pixels), size of the largest cluster of red pixels (CSIZE), and CSIZE% of disc size, all within the optic disc margin. RESULTS AUCs of the best performing POD L(2) norm and TCA red pixel parameters in differentiating progressors from normal subjects were both 0.86 and in differentiating progressors from nonprogressors were 0.68 and 0.64, respectively; the AUC differences were not statistically significant. CONCLUSIONS The POD framework, which can detect and confirm glaucomatous changes in a single follow-up visit, provides a performance similar to that of TCA in differentiating progressors from normal subjects and nonprogressors.

Automated Segmentation of Optic Nerve Head Structures With Optical Coherence Tomography

PURPOSE To quantify and characterize the difference between automated and manual segmentation of optic nerve head structures with spectral-domain optical coherence tomography (SD-OCT). METHODS Optic nerve head radial scans in 107 glaucoma patients and 48 healthy controls were conducted with SD-OCT. Independent segmentations of the internal limiting membrane (ILM) and Bruchs membrane opening (BMO) were performed manually with custom software and with an automated algorithm in each radial scan. The minimum distance between BMO and ILM, termed BMO-minimum rim width (BMO-MRW) was calculated with each segmentation method. Absolute differences between automated and manual segmentations of ILM (ΔILM) and BMO (ΔBMO), and the resulting computation of BMO-MRW (ΔBMO-MRW) were computed. Finally, the relationship between image quality score and ΔILM and ΔBMO was explored. RESULTS The median (interquartile range, IQR) ΔILM was 8.9 (6.5, 13.4) μm in patients and 7.3 (5.3, 9.9) μm in controls. The corresponding values for ΔBMO were 11.5 (6.6, 22.1) μm and 12.4 (6.8, 25.4) μm. Subject-averaged ΔILM was higher in patients than controls (P < 0.01); however, mean ΔBMO was not (P = 0.09). The median (IQR) subject-averaged absolute ΔBMO-MRW was 13.4 (10.6, 16.8) μm in patients and 12.1 (10.0, 16.8) μm in controls and not statistically different (P = 0.21). Mean image quality score was statistically higher in controls than patients (P = 0.03) but not related to subject-averaged ΔILM or ΔBMO. CONCLUSIONS In individual scans, the median difference in ILM and BMO segmentations was <2 and <3 image pixels, respectively. There were no differences between patients and controls in ΔBMO-MRW.

Rates of retinal nerve fibre layer thickness change in glaucoma patients and control subjects

PurposeTo examine the rates of retinal nerve fibre layer thickness (RNFLT) change in glaucoma patients and healthy, age-similar control subjects with three techniques: scanning laser polarimetry with variable corneal compensation (VCC) and enhanced corneal compensation (ECC), and time-domain optical coherence tomography (OCT).MethodsSixty-one patients and thirty-three controls were examined with each technique and with standard automated perimetry (SAP) every 6 months. Rates of global RNFLT change and SAP mean deviation (MD) change were estimated with linear mixed-effects models.ResultsThe median (interquartile range) baseline age was 64.4 (58.2, 71.0) years for patients and 62.4 (56.3, 70.1) years for controls (P=0.56). There was a median of seven examinations over 3.1 years for patients and six examinations in 3.0 years for controls. Baseline visual field MD and RNFLT for all imaging modalities were significantly lower (P<0.01) in patients compared with controls. Rates of RNFLT change were not significantly different between patients and controls (P≥0.19). Mean rates of VCC-measured RNFLT change were −0.18 and −0.37 μm per year in patients and controls, whereas the respective figures for ECC and OCT were −0.13 and −0.31 μm per year, and 0.04 and 0.61 μm per year. Mean rates of MD change were −0.20 and 0.03 dB per year in patients and controls, respectively (P=0.01).ConclusionRates of RNFLT change in glaucoma patients were not statistically different from control subjects for any modality. A significantly negative rate of MD change in patients suggests a genuine, continued deterioration in these patients not reflected by RNFLT changes.

Assessing the impact of a Carer Support Needs Assessment Tool (CSNAT) intervention in palliative home care: a stepped wedge cluster trial

Objectives To test the impact on family carers of a Carer Support Needs Assessment Tool (CSNAT) intervention to facilitate carer-led assessment and support during end of life care. Method Mixed method, part-randomised, stepped wedge cluster trial with 6 palliative home care services comparing carers receiving the intervention with those receiving standard care. Postal survey with carers 4–5 months postbereavement measured adequacy of end of life support, current mental and physical health (Short Form 12 Health Survey SF-12), level of grief (Texas Revised Inventory of Grief, TRIG) and distress (Distress Thermometer, DT), place of death and carer satisfaction with place of death. Results Surveys were sent to 3260 (76%) carers of 4311 deceased patients; 681 (21%) were returned (N=333 control, N=348 intervention). Compared with controls, intervention carers had significantly lower levels of early grief, better psychological and physical health, were more likely to feel the place of death was right, and patients were more likely to die at home. However, differences were small and process measures showed low level of implementation, indicating differences may partially relate to increased awareness of carer issues rather than a direct impact of the intervention. Conclusions Carers had better outcomes in the intervention condition, albeit modest. If this can be achieved through low level implementation and awareness raising of carers’ needs from implementation activities, substantial impact should be possible if the CSNAT intervention can be fully implemented with a majority of carers. The study illustrates challenges of implementing and testing a complex intervention in real-life practice and of achieving comprehensive carer assessment and support in line with government recommendations.

An In Silico Model of Scanning Laser Tomography Image Series: An Alternative Benchmark for the Specificity of Progression Algorithms

PURPOSE There is no gold-standard measurement of glaucomatous structural progression against which to validate software progression algorithms. A computer model was developed and validated to simulate stable series of Heidelberg Retina Tomograph II (HRT; Heidelberg Engineering, Heidelberg, Germany) images, with realistic topographic variability, suitable for benchmarking false-positive rates of progression algorithms. METHODS Three confocal image stacks were selected from each of five sets of HRT II scans, obtained within 6 weeks in 127 eyes of 66 patients. For each eye, a simulated series was propagated from one baseline confocal stack by adding fixational eye movements, photon-counting, and electronic measurement noise. Simulated confocal stacks were imported into the HRT software to generate topography images. Real and simulated image comparisons were quantified with the mean pixel height standard deviation (MPHSD), image cross-correlation (CC) of pixel-wise variability maps, and the rim area (RA) coefficient of variation (CV). RESULTS The mean difference (95% limits of agreement; LoA) in MPHSD between real and simulated images was 3.5 μm (-20.9 to 28.8 μm) within mean topographies and 2.0 μm (-5.4 to 9.3 μm) between mean topographies. The mean CC between real and simulated spatial variability maps was 0.58 within mean topographies and 0.54 between mean topographies. The mean difference (95% LoA) between real and simulated mean topography RA CV was -2.1% (-17.6% to +13.4%). Variability about anatomic features was well reproduced. CONCLUSIONS Simulation realistically reproduces variability in real, stable images acquired over a short period. Stability in clinical datasets is uncertain, whereas in these modeled series, it is certain. This method provides benchmark datasets on which the specificity of progression algorithms can be tested.