Longitudinal changes in the visual field and optic disc in glaucoma

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Abstract

The nature and mode of functional and structural progression in open-angle glaucoma is a subject of considerable debate in the literature. While there is a traditionally held viewpoint that optic disc and/or nerve fibre layer changes precede visual field changes, there is surprisingly little published evidence from well-controlled prospective studies in this area, specifically with modern perimetric and imaging techniques. In this paper, we report on clinical data from both glaucoma patients and normal controls collected prospectively over several years, to address the relationship between visual field and optic disc changes in glaucoma using standard automated perimetry (SAP), high-pass resolution perimetry (HRP) and confocal scanning laser tomography (CSLT). We use several methods of analysis of longitudinal data and describe a new technique called “evidence of change” analysis which facilitates comparison between different tests. We demonstrate that current clinical indicators of visual function (SAP and HRP) and measures of optic disc structure (CSLT) provide largely independent measures of progression. We discuss the reasons for these findings as well as several methodological issues that pose challenges to elucidating the true structure–function relationship in glaucoma.

Introduction

Open-angle glaucoma is an age-related optic neuropathy that causes loss of retinal ganglion cells (RGCs). The pathogenesis of glaucoma has been linked to the action of intraocular pressure (IOP) on the optic disc causing glaucomatous optic disc cupping and visual field defects (Hoskins and Kass, 1989; Epstein, 2004). There is no universally accepted definition of glaucoma, however, it is likely to represent a series of syndromes that precipitate in glaucomatous damage. A diagnosis of glaucoma is made after careful assessment of the optic disc, visual field, a measurement of IOP and in consideration of ocular, systemic and demographic factors. The choices and degree of treatment depend on the initial level of field and disc damage as well as on factors such as the patient's lifestyle and life expectancy.

Clinically the visual field is measured most often using conventional static automated perimetry (SAP), though other techniques such as high-pass resolution perimetry (HRP) (Frisen, 1987), frequency doubling technology (FDT) perimetry (Johnson and Samuels, 1997) and short-wavelength automated perimetry (SWAP) (Sample and Weinreb, 1989; Johnson et al., 1989) are also used. The optic disc is examined clinically with ophthalmoscopy and can be documented using conventional photography or one of the newer imaging techniques such as confocal scanning laser tomography (CSLT) (Zinser et al., 1989). While the pattern and mode of progression of the visual field and optic disc have been studied and described by many authors using techniques from kinetic perimetry to SAP (Hart Jr. and Becker, 1982; Mikelberg and Drance, 1984; Mikelberg et al., 1986; Chauhan et al., 1990; Spry and Johnson, 2002; Nicolela et al., 2003) and from ophthalmoscopic examinations and disc photography (Pederson and Anderson, 1980; Tuulonen and Airaksinen, 1991; Airaksinen et al., 1992; Zeyen and Caprioli, 1993) to CSLT (Kamal et al., 1999; Chauhan et al., 2001), determining whether the visual field or the optic disc have changed in individual patients remains one of the most challenging aspects of glaucoma management.

Central to the task of determining glaucomatous progression is the distinction of true change from variability. Variability of measurements with SAP and CSLT has been studied extensively. Knowledge of the biological variability of measurements in a healthy population allows the clinician to determine the likelihood that the visual field or optic disc show signs of damage. While this approach is logical, the diagnostic accuracy of a technique will depend on the overlap in a measurement of the visual field or optic disc between groups of unselected glaucoma patients and healthy subjects. The diagnostic accuracy also depends on the criteria by which subjects were selected into the study. If, for example, the criteria include an abnormal visual field, it is not surprising that a measure of the visual field will yield high diagnostic accuracy. Likewise, if optic disc appearance is part of the inclusion criteria, then it is not surprising that a measure of the optic disc will appear to provide good separation between the populations. Because the definition of glaucoma invariably includes the appearance of the optic disc and/or visual field, independent assessments of the diagnostic accuracy of these tests is difficult.

Traditionally it is thought that the task of making a diagnosis of glaucoma based on the visual field and/or the optic disc (i.e., based on the probability of the observed values being within normal limits) is distinct from determining the presence of progression. However, an alternative approach is to regard any change of the visual field or the optic disc that exceeds normal ageing as a diagnostic sign, irrespective of whether the measurements are within or outside the statistically defined normal limits. For example, the optic disc in a patient suspected of glaucoma may change, yet still remain within the large range of physiological between-subject variability. In such cases, the evidence of change can be used a diagnostic sign. Likewise, detectable change over time in the visual field can be highly suggestive of disease, even though the various visual field indices may appear well within normal limits.

Glaucoma is likely a disease that is modulated by many factors. This may be related to the fact that there is a wide range of optic disc appearances and visual field defects which can be classified as glaucomatous. As discussed above, in many cases the appearance of the visual field or optic disc alone may not be sufficient for accurate diagnosis. In such cases, the clinical evidence is stronger if the optic disc appearance can be corroborated with the visual field and vice-versa. Similarly, when optic disc change is suspected over time, corresponding changes in the visual field may strengthen the level of clinical information. Whether visual field and optic disc changes in longitudinal studies occur in tandem is one of the subjects of this paper.

Elucidating the relationship between a functional and structural test, or indeed two functional tests, is also important to determine the relative utility of the tests at the different stages of disease. For example, it is frequently thought that optic disc examination or quantification has more utility during the earlier stages of the disease than SAP, while psychophysical tests may have greater utility during the later stages of the disease. It is also thought that SWAP may have more utility than SAP in early glaucoma, but less so in the advanced stages, owing to the limited dynamic range of SWAP (Demirel and Johnson, 2000).

Finally, elucidating the structure–function relationship in glaucoma is scientifically important in determining the order of changes during the disease process. Determining this information in different sub-types of glaucoma, for example based on optic disc appearance (Nicolela et al., 2003), may shed light on the nature of progression and may eventually allow a more tailored approach to treatment.

Section snippets

Types of structure–function relationships

Correlating visual function to a structural parameter derived from the optic disc, or nerve fibre layer appearance, and visual function in a population describes the strength of such a relationship at one point in time. An often-made assumption is that this cross-sectional relationship is a useful ‘first approximation’ for the longitudinal relationship between function and structure in individual patients. For example, the slope of the relationship between, say, the visual field mean deviation

Purpose

The paper describes a comprehensive investigation on progression in glaucoma in a group of patients with open-angle glaucoma who were followed in a prospective study for several years. We also report data from a cohort of healthy controls followed identically. We have developed a new method of analysing progression called evidence of change (EOC) to facilitate the comparison between different tests and describe the use of this metric as well as of others to elucidate the relationship between

Glaucoma patients and healthy controls

This paper reports on data from 84 patients with a clinical diagnosis of open-angle glaucoma, and 41 healthy controls, followed in a prospective longitudinal study. Patients were recruited consecutively from the glaucoma clinics of the Eye Care Centre at the Queen Elizabeth II Health Sciences Centre while the controls were enrolled from a local telephone company, seniors’ groups and local church organizations in Halifax, Nova Scotia. The study was approved by the institutional Research Ethics

Event-based analyses

Fig. 6 shows the Kaplan-Meier survival curves for change in the glaucoma patients, based on the three criteria (from least conservative to most conservative) that led to similar numbers of patients classified as progressing over the follow-up period.

The least conservative set of criteria classified progression in approximately 42% of the glaucoma patients, while the respective figures for the intermediate and most conservative criteria were 25% and 17%, respectively.

With all criteria, the

Case examples

To illustrate the large variability in the relationship between visual field and optic disc changes found in these studies, three case examples are presented. In the first (Fig. 18), there is evidence of visual field change, but there appears to be no change in the optic disc. In the second example (Fig. 19), there was unequivocal concentric enlargement of the optic cup while the visual field at appeared stable. In the final example (Fig. 20), the visual field and optic disc changes occurred in

Visual field and optic disc changes: findings from these studies

Assessing glaucomatous progression is one of the most important challenges that face clinicians and scientists. Important patient management decisions, such as to modify therapy, depend on good evidence of whether the disease, as measured by visual field and optic disc changes, is stable or progressing. Clinical studies comparing therapeutic modalities also require reliable and robust measures of change.

Correlating functional and structural changes in glaucoma has both clinical and scientific

Future directions

Our laboratory will continue to investigate the nature of glaucomatous progression with current as well as newer tools for measuring function (such as frequency doubling perimetry) and structure (such as optical coherence tomography and scanning laser polarimetry). Ultimately we feel that measures of progression should be test-specific and that understanding the similarities and dissimilarities between these techniques may allow us to determine which biological aspects of progression are best

Acknowledgements

We are grateful to our colleagues, Drs. Marcelo Nicolela, Raymond LeBlanc and Paul Rafuse for their close collaboration and discussions. Subject testing, data collation and organization was done by Ms. Terry McCormick and Ms. Donna Hutchison. Dr. Ted Garway-Heath provided critical and constructive comments on the initial submission. This work was supported by grants from the Canadian Institutes of Health Research (MOP-11357) to BCC and from the Nova Scotia Health Research Foundation (MED-727)

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