Rizwan Malik

‘Structure–function relationship’ in glaucoma: past thinking and current concepts

An understanding of the relationship between functional and structural measures in primary open‐angle glaucoma is necessary for both grading the severity of disease and for understanding the natural history of the condition. This article outlines the current evidence for the nature of this relationship and highlights the current mathematical models linking structure and function. Large clinical trials demonstrate that both structural and functional change are apparent in advanced stages of disease, and at an individual level, detectable structural abnormality may precede functional abnormality in some patients, whereas the converse is true in other patients. Although the exact nature of the ‘structure–function’ relationship in primary open‐angle glaucoma is still the topic of scientific debate and the subject of continuing research, this article aims to provide the clinician with an understanding of the past concepts and contemporary thinking in relation to the structure–function relationship in primary open‐angle glaucoma.

The relationship between variability and sensitivity in large-scale longitudinal visual field data.

PURPOSE Evaluation of progressive visual field (VF) damage is often based on pointwise sensitivity data from standard automated perimetry; however, frequency-of seeing and test-retest studies demonstrate that these measurements can be highly variable, especially in areas of damage. The aim of this study was to characterize VF variability by the level of sensitivity using a statistical method to quantify heteroscedasticity. METHODS A total of 14,887 Humphrey 24-2 SITA Standard VFs from 2736 patients (2736 eyes) attending Moorfields Eye Hospital from 1997 to 2009 were studied retrospectively. The VF series of each eye was analyzed using pointwise linear regression of sensitivity over time, with residuals (difference from fitted-value) from each regression pooled according to both observed and fitted sensitivities. RESULTS The median (interquartile range) patient age, follow-up, and series length was 64 (54-71) years, 5.5 (3.9-7.0) years, and 6 (5-7) VFs, respectively. The inferred variability as a function of fitted-sensitivity was in good agreement with previous estimates. Variability was also described as a function of measured sensitivity, which confirmed that variability increased rapidly as the observed sensitivity decreased. CONCLUSIONS This study highlights a new approach for characterizing VF variability by the level of sensitivity. A considerable strength of the method is that inference is based on thousands of clinic patients rather than the tens of subjects in test-retest studies. The results can help distinguish real VF progression from measurement variability and will be used in models for glaucoma progression detection.

Are practical recommendations practiced? A national multi-centre cross-sectional study on frequency of visual field testing in glaucoma

Aim To estimate current clinical practice for frequency of visual field (VF) monitoring in glaucoma in England. Methods A cross-sectional review of all patients with chronic open angle glaucoma (COAG) attending specialist glaucoma clinics at six hospitals in England was performed. The number of VF tests undertaken prior to the study date and during the first 2 years since diagnosis were recorded and compared with European Glaucoma Society (EGS) guidelines for newly-diagnosed patients. Clinician-requested monitoring intervals were compared with intervals from the National Institute of Clinical Excellence (NICE) guidelines, and the relationships with disease severity, intraocular pressure (IOP) and glaucoma progression status were reviewed. Results One-hundred and four patients with COAG were included. 73 patients had at least 2 years of follow-up. Median (IQR) total number of VF tests and in the first 2 years of diagnosis were 4 (2–7) and 2 (2–3), respectively. No patients met EGS guidelines, but 87% of patients had their monitoring intervals requested in accordance with NICE guidelines. These intervals were not related to disease severity or VF stability (Kruskal–Wallis test, p=0.25) but shortened significantly when IOP control was inadequate or when the overall clinical impression was disease progression (p<0.001). Conclusions Most newly-diagnosed COAG patients receive less than three VFs in the first 2 years following diagnosis and an average of 0.7 VF per year over the duration of follow-up.

A survey of attitudes of glaucoma subspecialists in England and Wales to visual field test intervals in relation to NICE guidelines

Objectives To establish the attitudes of glaucoma specialists to the frequency of visual field (VF) testing in the UK, using the NICE recommendations as a standard for ideal practice. Design Interview and postal survey. Setting UK and Eire Glaucoma Society national meeting 2011 in Manchester, UK, with a second round of surveys administered by post. Participants All consultant glaucoma specialists in England and Wales were invited to complete the survey. Primary and secondary outcome measures (1) Compliance of assigned follow-up VF intervals with NICE guidelines for three hypothetical patient scenarios, with satisfactory treated intraocular pressure and (a) no evidence of VF progression; (b) evidence of VF progression and (c) uncertainty about VF progression, and respondents were asked to provide typical follow-up intervals representative of their practice; (2) attitudes to research recommendations for six VF in the first 2 years for newly diagnosed patients with glaucoma. Results 70 glaucoma specialists completed the survey. For each of the clinical scenarios a, b and c, 14 (20%), 33 (47%) and 28 (40%) responses, respectively, fell outside the follow-up interval recommended by NICE. Nearly half of the specialists (46%) agreed that 6 VF tests in the first 2 years was ideal practice, while 16 (28%) said this was practice ‘not possible’, with many giving resources within the NHS setting as a limiting factor. Conclusions The results from this survey suggest that there is a large variation in attitudes to follow-up intervals for patients with glaucoma in the UK, with assigned intervals for VF testing which are, in many cases, inconsistent with the guidelines from NICE.

A novel distribution of visual field test points to improve the correlation between structure-function measurements.

PURPOSE To create a new visual field (VF) test grid centered at the optic disc (disc-centered field [DCF]) and to infer the combination of VF test points (structure-function field [SFF]), taken from the DCF and the conventional fovea-centered 24-2 grid (24-2) of standard automated perimetry, which yields the strongest sectorial correlation between structure-function measurements of retinal nerve fiber layer (RNFL) thickness and VF sensitivity. METHODS In 50 eyes with ocular hypertension or open angle glaucoma, the DCF and 24-2 VF were measured with a humphrey field analyzer II (Full Threshold strategy) and RNFL thickness was measured with Stratus optical coherence tomography. test points from the DCF and 24-2 VF Were combined and divided into 12 sectors according to the spatial distribution of the RNFL. A novel VF for structure-function studies was established using the following criteria: each sector must contain at least one or two test points (depending on the sectors location), and the combination of test points which yields the strongest structure-function correlation is selected. RESULTS The SFF consisted of 40 test points. The structure-function correlation for the SFF was compared with the standard 24-2 VF; a multiple-comparison test for dependent groups was carried out using a percentile bootstrap method, which indicated that the sector correlation coefficients in the SFF were significantly higher than those in the 24-2 VF. CONCLUSIONS The SFF, with fewer test locations, has a stronger structure-function correlation than the 24-2 VF. This improved correlation may help clinicians to better interpret functional measurements in relation to structural measurements.

Beta and Gamma Peripapillary Atrophy in Myopic Eyes With and Without Glaucoma

PURPOSE To determine whether beta and gamma peripapillary atrophy (PPA) areas measured with optical coherence tomography (OCT) enhances glaucoma diagnosis in myopic subjects. METHODS We included 55 myopic glaucoma patients and 74 myopic nonglaucomatous controls. Beta-PPA comprised the area external to the clinical disc margin, with absence of retinal pigment epithelium and presence of Bruchs membrane. Gamma-PPA comprised the area external to the disc margin, with absence of both RPE and Bruchs membrane. OCT scans colocalized to fundus photographs were used to measure PPA, choroidal thickness, border tissue of Elschnig configuration, optic disc area, and optic disc ovality. RESULTS Beta-PPA area was larger in glaucoma patients compared with controls (median [interquartile range], 1.0 [0.66-1.53] mm2 and 0.74 [0.50-1.38] mm2, respectively), whereas gamma-PPA was smaller in glaucoma patients compared with controls (0.28 [0.14-0.50] mm2 and 0.42 [0.17-0.74] mm2, respectively). However, the distributions of both beta- and gamma-PPA in the two groups overlapped widely. The areas under the receiver operating characteristic curve of beta- and gamma-PPA areas were 0.60 and 0.59, respectively. Larger beta-PPA area was associated with larger disc area, thinner choroidal thickness, longer axial length, less oblique border tissue configuration, older age, and greater disc ovality. Larger gamma-PPA area was associated with greater disc ovality, more oblique border tissue configuration, and longer axial length. CONCLUSIONS Subclassifying PPA with OCT into beta and gamma zones reveals association with different covariates, but does not enhance the diagnostic performance for glaucoma in a population of predominantly Caucasians myopic subjects.

Refractory glaucoma--tube or diode?

Background:  The aim of the present study was to assess the relative effectiveness of tube surgery and cyclodiode laser in terms of achieving intraocular pressure control.

Contrast Sensitivity Perimetry and Clinical Measures of Glaucomatous Damage

Purpose To compare conventional structural and functional measures of glaucomatous damage with a new functional measure—contrast sensitivity perimetry (CSP-2). Methods One eye each was tested for 51 patients with glaucoma and 62 age-similar control subjects using CSP-2, size III 24-2 conventional automated perimetry (CAP), 24-2 frequency-doubling perimetry (FDP), and retinal nerve fiber layer (RNFL) thickness. For superior temporal (ST) and inferior temporal (IT) optic disc sectors, defect depth was computed as amount below mean normal, in log units. Bland-Altman analysis was used to assess agreement on defect depth, using limits of agreement and three indices: intercept, slope, and mean difference. A criterion of p < 0.0014 for significance used Bonferroni correction. Results Contrast sensitivity perimetry-2 and FDP were in agreement for both sectors. Normal variability was lower for CSP-2 than for CAP and FDP (F > 1.69, p < 0.02), and Bland-Altman limits of agreement for patient data were consistent with variability of control subjects (mean difference, −0.01 log units; SD, 0.11 log units). Intercepts for IT indicated that CSP-2 and FDP were below mean normal when CAP was at mean normal (t > 4, p < 0.0005). Slopes indicated that, as sector damage became more severe, CAP defects for IT and ST deepened more rapidly than CSP-2 defects (t > 4.3, p < 0.0005) and RNFL defects for ST deepened more slowly than for CSP, FDP, and CAP. Mean differences indicated that FDP defects for ST and IT were on average deeper than RNFL defects, as were CSP-2 defects for ST (t > 4.9, p < 0.0001). Conclusions Contrast sensitivity perimetry-2 and FDP defects were deeper than CAP defects in optic disc sectors with mild damage and revealed greater residual function in sectors with severe damage. The discordance between different measures of glaucomatous damage can be accounted for by variability in people free of disease.

Development and evaluation of a linear staircase strategy for the measurement of perimetric sensitivity

Perimetric sensitivity of patients with glaucoma has traditionally been measured in logarithmic (dB) units, but linear sensitivity correlates better with conventional structural measures of glaucomatous damage. Monte Carlo simulations of perimetric algorithms were used to assess potential effects of logarithmic steps on bias and variability when perimetric sensitivity was represented in linear units, and to assess the potential benefits of algorithms using linear steps. Simulations predicted that linear staircases could reduce the sensitivity-dependence of bias, variability and efficiency. These predictions were supported by a perimetric study of 21 patients with glaucoma and 20 age-similar controls who made repeat visits over several weeks.

Choice of Statistical Method Influences Apparent Association Between Structure and Function in Glaucoma

PURPOSE The aim of this study was to explore how different statistical methods may lead to inconsistent inferences about the association between structure and function in glaucoma. METHODS Two datasets from published studies were selected for their illustrative value. The first consisted of measurements of neuroretinal rim area in the superior-temporal sector paired with the corresponding visual field sensitivity. The second consisted of measurements of average retinal nerve fiber layer thickness over all sectors paired with the corresponding visual field sensitivity. Statistical methods included linear and segmented regression, and a nonparametric local-linear fit known as loess. The analyses were repeated with all measurements expressed as percent of mean normal. RESULTS Slopes from linear fits to the data changed by a factor of 10 depending on the linear regression method applied. Inferences about whether structural abnormality precedes functional abnormality varied with the statistical design and the units of measure used. CONCLUSIONS The apparent association between structure and function in glaucoma, and consequent interpretation, varies with the statistical method and units of measure. Awareness of the limitations of any statistical analysis is necessary to avoid finding spurious results that ultimately may lead to inadequate clinical recommendations.