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change over time (Fig. 5C). A global assessment is also provided in terms of ‘‘possible’’ or ‘‘likely’’ progression (Fig. 5D).

Optical coherence tomography (OCT) has been traditionally used in the past strictly for vitreoretinal diseases; however, over the past several years, it has also been useful in glaucoma thanks to built-in software that is able to analyze optic nerve head and RNFL measurements (Jaffe and Caprioli, 2004; Nouri-Mahdavi et al., 2004). The axial resolution available with this technology has progressively gotten better from prior versions (OCT, OCT 2, OCT 3, Stratus OCT) to the latest Cirrus HD-OCT version, which uses high definition spectral domain to provide retinal tissue images of high detail. The most frequently used testing protocols in glaucoma are Fast RNFL Thickness 3.46 and Fast Optical Disc, which have both been proven to be useful in the early diagnosis of glaucoma (Brusini et al., 2006; Hougaard et al., 2007).

Studies have reported that OCT can be useful in monitoring patients over time (Wollstein et al., 2005), however, there is no specific OCT software available to date that can statistical assess progression. A new software, called GPA for Stratus OCT, has recently been proposed and is currently under evaluation. Progression assessment with this method involves comparisons between the latest test results with previously obtained RNFL scans, which is all summarized in a single-paged report. The summary shows color-coded TSNIT plots at each time on the same graph, RNFL thickness linear regression analysis, and the statistical significance of change over time (Fig. 6). This new GPA for OCT appears promising, however, studies are obviously needed to determine the clinical usefulness of it.

Monitoring functional damage progression

Albeit modern imaging technological advances, VF assessment is still considered to be the best method to monitor glaucomatous progression in patients with evident functional damage.

White-on-white standard automated perimetry (SAP) is still considered as the gold standard for

VF testing in glaucoma, for both diagnosing and monitoring VF progression over time. Functional defect progression is most commonly seen as a deepening of a scotoma, followed by defect enlargement, and less commonly by the formation of new scotomas (Mikelberg and Drance, 1984). Progressive diffuse sensitivity depression is usually related to cataract and hardly ever due to strictly glaucoma. Threshold tests (i.e. Zeiss-Humphrey 30-2/24-2 or Octopus G1/G2) should always be the preferred method of choice, using either full threshold or SITA standard testing strategies. It is of utmost importance in monitoring glaucomatous patients to have an accurate and reliable VF baseline, thus taking into account possible artifacts, learning and fatigue effects, and long-term fluctuation (Zulauf and Caprioli, 1992; Anderson et al., 2000). The trend of progression should always include the assessment of several VFs (at least 5 to 7) over time. Tests that show significant variations from previous results should always be repeated for confirmation within a short period of time.

Different methods can be used to monitor functional glaucomatous progression over time

Fig. 7. Regression analysis of MD showing significant worsening in follow-up VFs.

(Spry and Johnson, 2002), which include: (1) clinical judgment; (2) classification systems; (3) trend analysis; and, (4) event analysis.

Clinical judgment is based on the simple observation of a sequential series of VF tests. It is easy to perform, is highly flexible, and takes clinical reasoning and know-how into account. It is, however, subjective and strictly based on the clinician’s experience, thus interobserver variability tends to be quite high. Overview programs can be used to automatically group test results in chronological order to simplify the assessment.

Defect classification systems have often been utilized in multicenter clinical studies like AGIS and CIGTS (The Advanced Glaucoma Intervention Study Investigators, 1998; Musch et al., 1999). A score (generally ranging from 0 to 20), which is usually calculated from the total deviation plot values, is used to monitor VF defect progression. ‘‘Progression’’ is defined as a worsening in score (at least four units for AGIS and three for CIGTS), which must be confirmed on two

consecutive tests. The classification systems are standardized and reproducible, but tend to be rigid, time-consuming, and lacking in information on VF defect spatial location and characteristics. Moreover, progression can be classified differently for the same case, considering that the score calculation methods are not identical (Katz, 1999).

Trend analysis methods are based on the change of a single VF parameter (i.e. mean deviation or MD index) over time. This approach is used in some Zeiss–Humphrey Statpac 2 statistical programs (glaucoma change analysis, glaucoma change probability, glaucoma progression analysis) and in Octopus Peritrend trend (which also considers the loss variance index). If five or more tests are available, a regression analysis is automatically provided, supplying pertinent information regarding VF change over time (Fig. 7).

A pointwise linear regression analysis is also available in software like Progressor (Fitzke et al., 1996), which uses different color bars on a single figure to show both the amount of sensitivity loss

and the level of significance in VF sensitivity variation for each test location over time (Fig. 8).

The glaucoma staging system (GSS) and currently updated version GSS 2, are simple X–Y coordinate diagrams that have been created to classify functional defects according to severity (stages) and type (generalized, localized, and mixed) (Brusini, 1996; Brusini and Filacorda, 2006). Although GSS does not provide statistical information on progression, it can be used to graphically follow the trend of both MD and CPSD/PSD/CLV/LV indices simultaneously over time (Kocak et al., 1997) (Fig. 9).

Event analysis methods usually compare the latest VF result with a reference baseline and highlight test points that show significant worsening or improvements in sensitivity that are greater than the test–retest variability found in a stable glaucoma patient population. The variations are respectively shown as black and white triangles in the total deviation plot found in the glaucoma change probability program (Zeiss–Humphrey Statpac 2). GPA utilizes a similar assessment on the pattern deviation plot, thus reducing the confounding effect of cataract and other nonspecific causes of diffuse sensitivity depression. Moreover, this program provides a ‘‘GPA alert,’’ flagging results as ‘‘possible’’ or ‘‘likely progression’’ when at least three points show a significant sensitivity deterioration in two and three consecutive tests, respectively (Fig. 10).

GPA is based on the early manifest glaucoma trial (EMGT) study (Heijl et al., 2003), and can be used to assess test results obtained with different strategies, including full threshold, SITA standard, and SITA fast strategies. The release of an enhanced version of GPA is expected in 2008. The enhancements in this new version include: a new printout format; graytone and pattern deviation plots of both the baseline and most current exam on a single printout; and, a new parameter to express VF loss — the visual field index (VFI) — which is assessed with regression analysis of the pattern deviation instead of the mean deviation. The regression line is extrapolated 5 years in the future to show the possible impact of glaucoma progression on the patient’s vision loss, assuming that the rate of progression remains the same. A VFI bar is

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Fig. 10. Glaucoma progression analysis of a glaucoma patient (in Fig. 10) showing four test points (solid black triangles) with sensitivity worsening in three consecutive tests. GPA Alert indicates that progression is probable.

also provided, to graphically show this index in time. Like most VF parameters, VFI is normalized for age and is reported as % of vision (Fig. 11).

The European Glaucoma Society (2003) guidelines recommend the method proposed by Hodapp et al. (1993) to monitor progression over time. The EGS criteria for VF defect progression are the following:

(1)For a new defect in a previous normal area:

(a)a cluster of three or more nonedge points, each of which declines Z5 dB compared to baseline on two consecutive fields; (b) a single nonedge point that declines Z10 dB compared to baseline on two

consecutive fields; (c) a cluster of three or more nonedge points, each of which declines at a po5% compared to baseline on two consecutive fields.

(2)For deepening of a preexisting defect: (a) a cluster of three nonedge points, each of which declines Z10 dB compared to baseline on two consecutive fields. The confirming points may differ if they are part of a contiguous cluster; or,

(b)a cluster of three nonedge points that are part of the same scotoma, each of which worsens at

least 5 dB and is depressed compared to baseline at a po5% level on two consecutive fields. The confirming points may differ if they are part of a