Donna M. Hutchison

Laminar and Prelaminar Tissue Displacement During Intraocular Pressure Elevation in Glaucoma Patients and Healthy Controls

OBJECTIVE To determine the response of the anterior lamina cribrosa and prelaminar tissue to acute elevation of intraocular pressure (IOP) in glaucoma patients and healthy subjects. DESIGN Prospective case-control series. PARTICIPANTS AND CONTROLS Patients with open-angle glaucoma (n = 12; mean age ± standard deviation [SD], 66.8 ± 6.0 years), age-matched healthy controls (n = 12; mean age ± SD, 67.1 ± 6.2 years), and young controls (n = 12; mean age ± SD, 36.1 ± 11.7 years). METHODS One eye was imaged with spectral-domain optical coherence tomography to obtain 12 high-resolution radial scans centered on the optic disc. Imaging was repeated at precisely the same locations with an ophthalmodynamometer held perpendicular to the globe via the inferior lid to raise the IOP. A line joining Bruchs membrane opening in 4 radial scans was used as reference in the baseline and elevated IOP images. The vertical distance from the reference line to the anterior prelaminar tissue surface and anterior laminar surface was measured at equidistant points along the reference line in the 2 sets of images. The difference between the 2 sets of corresponding measurements were used to determine laminar displacement (LD) and prelaminar tissue displacement (PTD). MAIN OUTCOME MEASURES Laminar displacement and PTD. RESULTS Intraocular pressure elevation among patients, age-matched controls, and young controls was similar (mean ± SD, 12.4 ± 3.2 mmHg). The mean ± SD LD and PTD were 0.5 ± 3.3 μm and 15.7 ± 15.5 μm, respectively. The LD was not statistically different from 0 (P = 0.366), but PTD was (P < 0.001). The mean ± SD LD was similar among the groups (-0.5 ± 3.7 μm, 0.2 ± 2.0 μm, and 2.0 ± 3.6 μm, respectively; P = 0.366), whereas the mean ± SD PTD was different (6.8 ± 13.7 μm, 20.8 ± 17.5 μm, and 19.6 ± 11.8 μm, respectively; P = 0.045). In all subjects, the PTD was greater than LD. In multivariate regression analyses, LD was negatively associated with optic disc size (P = 0.007), whereas PTD was positively associated with the degree of IOP elevation (P = 0.013). CONCLUSIONS In glaucoma patients and controls, the anterior laminar surface is noncompliant to acute IOP elevation. Acute optic disc surface changes represent compression of prelaminar tissue and not laminar displacement.

Enhanced Structure–Function Relationship in Glaucoma With an Anatomically and Geometrically Accurate Neuroretinal Rim Measurement

PURPOSE To evaluate the structure-function relationship between disc margin-based rim area (DM-RA) obtained with confocal scanning laser tomography (CSLT), Bruchs membrane opening-based horizontal rim width (BMO-HRW), minimum rim width (BMO-MRW), peripapillary retinal nerve fiber layer thickness (RNFLT) obtained with spectral-domain optical coherence tomography (SD-OCT), and visual field sensitivity. METHODS We examined 151 glaucoma patients with CSLT, SD-OCT, and standard automated perimetry on the same day. Optic nerve head (ONH) and RNFL with SD-OCT were acquired relative to a fixed coordinate system (acquired image frame [AIF]) and to the eye-specific fovea-BMO center (FoBMO) axis. Visual field locations were mapped to ONH and RNFL sectors with fixed Garway-Heath (VF(GH)) and patient-specific (VF(PS)) maps customized for various biometric parameters. RESULTS Globally and sectorally, the structure-function relationships between DM-RA and VF(GH), BMO-HRW(AIF) and VF(GH), and BMO-HRW(FoBMO) and VF(PS) were equally weak. The R(2) for the relationship between DM-RA and VF(GH) ranged from 0.1% (inferonasal) to 11% (superotemporal) whereas that between BMO-HRW(AIF) and VF(GH) ranged from 0.1% (nasal) to 10% (superotemporal). Relatively stronger global and sectoral structure-function relationships with BMO-MRW(AIF) and with BMO-MRW(FoBMO) were obtained. The R(2) between BMO-MRW(AIF) and VF(GH) ranged from 5% (nasal) to 30% (superotemporal), whereas that between BMO-MRW(FoBMO) and VF(PS) ranged from 5% (nasal) to 25% (inferotemporal). The structure-function relationship with RNFLT was not significantly different from that with BMO-MRW, regardless of image acquisition method. CONCLUSIONS The structure-function relationship was enhanced with BMO-MRW compared with the other neuroretinal rim measurements, due mainly to its geometrically accurate properties.

Optic disc progression in glaucoma: comparison of confocal scanning laser tomography to optic disc photographs in a prospective study.

PURPOSE To compare confocal scanning laser tomography (CSLT) to optic disc photography for detecting progressive glaucomatous disc changes. METHODS Four expert observers first examined a training set of 40 pairs of monoscopic disc photographs to help set a criterion for change. They then classified 44 pairs of monoscopic photographs of patients followed prospectively as having either definitely no change, probably no change, probably change, or definitely change (score, 0, 1, 2, or 3, respectively). Observers were unaware that 10 pairs were photographs of fellow eyes obtained the same day to measure specificity. These patients were imaged with the Heidelberg Retina Tomograph every 6 months. Topographic change analysis (TCA) software with three criteria (yielding specificity of 81%, 94%, or 97%) was used. Comparisons between the TCA results and those of observers were made for a range of liberal to conservative criteria and for individual and combined observer scores. RESULTS The median follow-up was 9.0 years with 18 CSLT images. Observer specificity varied from 50% to 90% (using score 0) and 60% to 100% (using score 0 or 1). Interobserver kappa ranged from 0.22 to 0.38 from the most liberal to conservative criterion and was generally higher than corresponding TCA-observer agreement. For most criteria, observers had either a high hit rate with low specificity or high specificity with a low hit rate compared with the TCA. Similar results were obtained when observer scores were combined to derive a broader range of criteria. CONCLUSIONS The results indicate that the TCA performs at least as well as either the individual or best combination of observer classifications of disc photographs.

Central corneal thickness and progression of the visual field and optic disc in glaucoma

Aims: To determine whether central corneal thickness (CCT) is a significant predictor of visual field and optic disc progression in open angle glaucoma. Methods: Data were obtained from a prospective study of glaucoma patients tested with static automated perimetry and confocal scanning laser tomography every 6 months. Progression was determined using a trend based approach called evidence of change (EOC) analysis in which sectoral ordinal scores based on the significance of regression coefficients of visual field pattern deviation and neuroretinal rim area over time are summed. Visual field progression was also determined using the event based glaucoma change probability (GCP) analysis using both total and pattern deviation. Results: The sample contained 101 eyes of 54 patients (mean (SD) age 56.5 (9.8) years) with a mean follow up of 9.2 (0.7) years and 20.7 (2.3) sets of examinations every 6 months. Lower CCT was associated with worse baseline visual fields and lower mean IOP in the follow up. In the longitudinal analysis CCT was not correlated with the EOC scores for visual field or optic disc change. In the GCP analyses, there was a tendency for groups classified as progressing to have lower CCT compared to non-progressing groups. In a multivariate analyses accounting for IOP, the opposite was found, whereby higher CCT was associated with visual field progression. None of the independent factors were predictive of optic disc progression. Conclusions: In this cohort of patients with established glaucoma, CCT was not a useful index in the risk assessment of visual field and optic disc progression.

Importance of Normal Aging in Estimating the Rate of Glaucomatous Neuroretinal Rim and Retinal Nerve Fiber Layer Loss

PURPOSE To describe longitudinal rates of change of neuroretinal parameters in patients with glaucoma and healthy controls, and to evaluate the influence of covariates. DESIGN Prospective longitudinal study. PARTICIPANTS Treated patients with glaucoma (n = 192) and healthy controls (n = 37). METHODS Global disc margin-based neuroretinal rim area (DMRA) was measured with confocal scanning laser tomography, while Bruchs membrane opening-minimum rim width (BMO-MRW), BMO area (BMOA), and peripapillary retinal nerve fiber layer thickness (RNFLT) were measured with optical coherence tomography at 6-month intervals. Individual rates of change were estimated with ordinary least-squares regression, and linear mixed effects modeling was used to estimate the average rate of change and differences between the groups, and to evaluate the effects of baseline measurement and baseline age on rates of change. MAIN OUTCOME MEASURES Rates of change for each parameter. RESULTS Subjects were followed for a median (range) of 4 (2-6) years. The proportion of controls who had significant reduction of neuroretinal parameters was 35% for BMO-MRW, 31% for RNFLT, and 11% for DMRA. The corresponding figures for patients with glaucoma were not statistically different (42%, P = 0.45; 31%, P = 0.99; 14%, P = 0.99, respectively). Controls had a significant reduction of BMO-MRW (mean: -1.92 μm/year, P < 0.01) and RNFLT (mean: -0.44 μm/year, P = 0.01), but not DMRA (mean: -0.22×10(-2) mm(2)/year, P = 0.41). After adjusting for covariates, patients with glaucoma had faster, but not statistically different, rates of deterioration compared with controls, by -1.26 μm/year (P = 0.07) for BMO-MRW, -0.40 μm/year (P = 0.11) for RNFLT, and -0.38×10(-2) mm(2)/year (P = 0.23) for DMRA. Baseline BMO-MRW and RNFLT significantly influenced the respective rates of change, with higher baseline values relating to faster reductions. Older age at baseline was associated with a slower reduction in rates of BMO-MRW. Reductions in intraocular pressure were related to increases in BMO-MRW and DMRA. There was a tendency for BMOA to decrease over time (-0.38×10(-2) mm(2)/year; P = 0.04). CONCLUSIONS Age-related loss of neuroretinal parameters may explain a large proportion of the deterioration observed in treated patients with glaucoma and should be carefully considered in estimating rates of change.

Metabolism of primary bile acids by Clostridium perfringens

Abstract C. perfringens degraded chenodeoxycholic acid (CDC) into two major products: 7α-hydroxy-3-oxo-5β-cholanoic acid and 3β,7α-dihydroxy-5β-cholanoic acid, the latter appearing very quickly and the former very slowly in whole cell cultures. Yields of about 60 and 16% were obtained for the respective products. Both products, as substrates in C. perfringens cultures, were quickly transformed back to CDC (about 84%) and 3β,7α-dihydroxy-5β-cholanoic acid (about 16%), whereas 7α-hydroxy-3-oxo-5β-cholanoic acid was formed slowly (4–5 days). In contrast to CDC, cholic acid was not epimerized at 3α-OH position; however, 7α, 12α-dihydroxy-3-oxo-cholanoic acid was formed slowly. When 7α,12α-dihydroxy-3-oxo cholanoic acid was substrate, rapid quantitative reduction, back to cholic acid then slow oxidation back to the 3-oxo product was observed. Thirty-six strains of C. perfringens (18 from a culture collection and 18 isolated from human feces) were screened for 3α-OH epimerization and oxidation of the primary bile acids. All but three strains epimerized CDC (yields 14–20%), while none epimerized cholic acid. Oxidation at the 3 position varied from 0–30% for CDC and 0–90% for cholic acid. Cell-free preparations of C. perfringens in the presence of NADP produced both 3-oxo and 3β-hydroxyl products with CDC, but only the 3-oxo product with cholic acid; these activities were non-inducible. The authors propose that 3α-OH isomerization takes place early in log phase via a 3α- and 3β-hydroxysteroid dehydrogenase (HSDH) system. Accumulation of 3-oxo product occurs late in stationary phase as the Redox (Eh) value rises above —100 mV.

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.

Visual Field Progression With Frequency-Doubling Matrix Perimetry and Standard Automated Perimetry in Patients With Glaucoma and in Healthy Controls

IMPORTANCE A new analysis method called permutation of pointwise linear regression measures the significance of deterioration over time at each visual field location, combines the significance values into an overall statistic, and then determines the likelihood of change in the visual field. Because the outcome is a single P value, individualized to that specific visual field and independent of the scale of the original measurement, the method is well suited for comparing techniques with different stimuli and scales. OBJECTIVE To test the hypothesis that frequency-doubling matrix perimetry (FDT2) is more sensitive than standard automated perimetry (SAP) in identifying visual field progression in glaucoma. DESIGN, SETTING, AND PARTICIPANTS Patients with open-angle glaucoma and healthy controls were examined by FDT2 and SAP, both with the 24-2 test pattern, on the same day at 6-month intervals in a longitudinal prospective study conducted in a hospital-based setting. Only participants with at least 5 examinations were included. INTERVENTION Data were analyzed with permutation of pointwise linear regression. MAIN OUTCOME AND MEASURE Permutation of pointwise linear regression is individualized to each participant, in contrast to current analyses in which the statistical significance is inferred from population-based approaches. Analyses were performed with both total deviation and pattern deviation. RESULTS Sixty-four patients and 36 controls were included in the study. The median age, SAP mean deviation, and follow-up period were 65 years, -2.6 dB, and 5.4 years, respectively, in patients and 62 years, +0.4 dB, and 5.2 years, respectively, in controls. Using total deviation analyses, statistically significant deterioration was identified in 17% of patients with FDT2, in 34% of patients with SAP, and in 14% of patients with both techniques; in controls these percentages were 8% with FDT2, 31% with SAP, and 8% with both. Using pattern deviation analyses, statistically significant deterioration was identified in 16% of patients with FDT2, in 17% of patients with SAP, and in 3% of patients with both techniques; in controls these values were 3% with FDT2 and none with SAP. CONCLUSIONS AND RELEVANCE No evidence was found that FDT2 is more sensitive than SAP in identifying visual field deterioration. In about one-third of healthy controls, age-related deterioration with SAP reached statistical significance.

Epimerization versus dehydroxylation of the 7α-hydroxyl- group of primary bile acids: Competitive studies with Clostridium absonum and 7α-dehydroxylating bacteria (Eubacterium SP.)

Abstract Primary bile acids, chenodeoxycholic (3α,7α-dihydroxy-5β-cholan-24-oic) and cholic (3α,7α,12α-trihydroxy-5β-cholan-24-oic) were included in cultures of (a) Clostridium absonum alone (b) a mixture of C . absonum and a 7-dehydroxylating organism, Eubacterium sp. (c) a mixture of C. absonum and fecal bacteria, and (d) fecal bacteria alone. C. absonum , when added to Eubacterium sp. cultures totally prevented lithocholic acid formation when the substrate was chenodeoxycholic acid and halved deoxycholic acid formation when the substrate was cholic acid. As expected, formation of 7β-hydroxy- and 7-keto-bile acids took precedence over formation of 7α-dehydroxylated bile acids. However, the addition of C. absonum to mixed fecal cultures containing chenodeoxycholic acid did not alter production of lithocholic (3α-hydroxy-5β-cholan-24-oic) acid; instead it enhanced formation of ursodeoxycholic acid (3α,7β-dihydroxy-5β-cholan-24-oic acid) at the expense of 7-keto-lithocholic acid (3α-hydroxyl-7-oxo-5β-cholan-24-oic acid). Similarly, the addition of C. absonum to mixed fecal cultures containing cholic acid promoted production of ursocholic acid (3α,7β,12α-trihydroxy-5β-cholan-24-oic acid) which did not take place when C. absonum was not added. Surprisingly, deoxycholic acid formation was somewhat enhanced when C. absonum was added to fecal cultures. These studies suggest that successful introduction of “foreign” 7α-epimerizing organisms into animal or human intestines may influence bile acid metabolism in vivo .

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.