Glaucoma Concepts – Rate of Progressionglaucomanow.com/media/5367/gn no2.pdf · Glaucoma Now – No2. 3 can be intensified to prevent too much extra damage. To do this within a

Glaucoma Now – No2. www.glaucomanow.com 1

i s s u e 22 0 1 0

Main topic issue No 2: Glaucoma Concepts – Rate of Progression

TARGET AUDIENCEThis educational activity is aimed at general ophthalmologists, glaucoma specialists and ophthalmo logy residents.

Glaucoma Now is published and adminis-tered by the editorial board and supported by an unrestricted educational grant from Allergan, inc. Copyright 2010 Editorial Board. All rights reserved. No responsibility as-sumed for injury or damage to persons or property arising from the use of information or ideas contained in this publication.

LEARNING OBJECTIVES• Special Focus: Concept, importance, measurement of visual fields versus disc, evidence from clinical trials.• What’s New: New technologies, software, guidance from clinical trial outcome.• Clinical Issues: Treatment strategies for prevention, the concept of target pressure.Practical Tips: Frequency of visual fields/disc imaging, available indices.

Special Focus: Concept and importance of Visual Field Measure-ments to detect Glau-coma Progression

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Clinical Issues: Treatment strategies to help prevent Progression

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What’s New: New Technologies to measure Glaucoma Progression

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Practical Tips: Frequency of Visual Field and Disc imaging

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inside this issue:

EDITORIAL BOARDClive Migdal MD, FRCs, FRCOphth Western eye Hospital, London, uK.Ivan Goldberg MD, FRANZCO, FRACs sydney eye Hospital, sydney, NsW, Australia.Remo Susanna MD, Professor and Head of Department of Ophthalmology, university of são Paulo, Brazil.

Glaucoma Now is a continuing medical education publication.Distributed worldwide to approximately 40,000 ophthalmologists, our goal is to educate and update general ophthalmologists, glaucoma specialists and ophthalmology residents.

international leaders in the field of glaucoma are invited to contribute to this journal, sharing their most recent insights.

supported by an unrestricted educational grant, the publication is non-promotional and has a fully independent editorial Board.Glaucoma Now is in the process of gaining accreditation for Continuing Medical education (CMe) by the european Accredita-tion Council for Continuing Medical Accreditation.

Executive officer:Patricia Buchholz RPh, PhD Karlsruhe, Germany [email protected] Production by Phosworks www.phosworks.se

2 Glaucoma Now – No2. www.glaucomanow.com

special Focus: Concept and importance of Visual Field Measurements to detect Glaucoma Progression. Author: Anders Heijl, MD, PhD1. Department of Ophthalmology, Lund university, Malmö university Hospital, se-20502 Malmö, sweden

Rate of Progression Concept“Rate of progression” can be misunder-stood. “Rate” in English means both the speed at which something happens and the frequency of instances (a frac-tion or a percentage) or number of times that something has happened. Rate of progression has been used both ways in glaucoma, e.g. as the number/percent-age/fraction of patients who have pro-gressed (failure rate) , and as the speed of progression. 3, 4, 5, 6.

In this text rate of progression will refer to speed of progression. Whereas eyes with higher rates of progression are

Core Concepts• Rate of progression is defined as the amount of progression over time, which is used to project the in-crease of glaucoma damage.• The goal of treatment is to prevent loss of visual function and ultimately quality of life.• A progression rate of – 2dB per year is rapid and corresponds to go-ing from a full normal field to peri-metric blindness in about 15 years.• Risk factors that may be associ-ated with progression include older age, greater glaucoma damage, pseudoexfoliation syndrome and disc hemorrhages.• Perimetrically measured visual function has been adopted by all eyecare professionals, but it is the global summation of visual function at all locations, that best helps to understand how patients are doing now and predicts their prognosis.• From natural history data, patients with pseudoexfoliation syndrome progress most rapidly, followed by high-tension glaucoma patients and ultimately normal tension glaucoma patients.

deteriorating more rapidly, lower rates mean slower worsening.

Thinking of rate of progression as speed of progression rather than risk of progression or observed fraction of pro-gressed eyes/patients is something that has been much more common in recent years. This may be a shift in paradigm. We hoped our treated glaucoma patients would not worsen at all, with every con-vincing sign of progression seen as a rea-son to step up treatment. Now, the large trials and other studies (cf Evidence from clinical trials below) have revealed the progressive nature of glaucoma, that most glaucoma patients will suffer some progression if monitored for long enough with reasonably sensitive methods.

Assessing and using rate of progression clinically projects the observed change, i.e. increase, of glaucoma damage for-ward. We aim to see if disease progres-sion during the period of management is safe, or whether the disease is progress-ing at such a rate that the patient’s visual function and Quality of Life is threat-ened in their likely life-span. The goal of glaucoma treatment, as formulated by the European Glaucoma Society, is: To prevent loss of visual function and loss of Quality of Life (QoL). Assessing rate of progression is a necessary part of modern individualized glaucoma management.

We do not know how much visual damage is necessary before Quality of Life is jeopardized, but if less than half of the visual field remains in the better eye, most questionnaires will find mea-surable loss of QoL .

When rate of progression of visual function damage is measured we most commonly follow changes of mean de-viation (MD) in decibels (dB) per year. Slow progression rate could be, e.g., 0.2 dB/year – which corresponds to go-ing from a full normal field to perimetric blindness in about 150 years, while a rate of progression of 2 dB/year is rapid pro-

gression, corresponding to going from a full normal field to perimetric blindness in about 15 years. MD in dBs is avail-able both in the Humphrey and the Oc-topus perimeters. The new visual field index (VFI) of the Glaucoma Progres-sion Analysis II (GPA2) program of the Humphrey perimeter instead expresses rate of progression as a percentage of a full field per year.

When measured in perimetric loga-rithmic units, glaucoma visual field pro-gression is usually linear if observation time is long and the number of obser-vations is large (cf Measurement of field versus disc below). With fewer observa-tions, variation in results often obscures the picture. Theoretically, progression should accelerate – at least over very long time periods – since the risk of progres-sion increases both with older age and with increasing field loss. 8, 9

ImportanceRate of progression is really important for the patient. Over a long – and par-ticularly a life – perspective it is rate of progression that will determine whether the patient can live a normal life with normal or near normal QoL, or whether she/he will suffer from visual disability and loss of QoL. Look at the 2 examples in Fig. 1. Both patients start out with small or limited damage and no subjec-tive problems. Patient (A) with a low rate of progression fares well also over a long time perspective, while the more unfortunate patient with the high rate of progression (B) ends up with serious problems (Fig. 1).

Rate of progression is also really im-portant for the physician. By identify-ing the large minority of patients, who progress rapidly (often despite ocular pressure (IOP) readings always within the statistically normal range), the phy-sician realizes these patients have great risk of visual impairment; treatment


can be intensified to prevent too much extra damage. To do this within a few years requires more frequent field testing initially after diagnosis, than has been common in the past. From the large ran-domized clinical trials 11, 12, 13, 14 we know every mmHg of extra IOP reduction is associated with a significant reduction of the risk of progression, we have both incentive and duty to identify early those patients with rapid disease progression (cf below).

The most important factors for fast-er disease progression include higher IOP, older age, more glaucoma damage, pseudoexfoliation syndrome and disc haemorrhages 15, 16, 17 18. These factors are useful, e.g. when first setting target pres-

sures after diagnosis. Risk factors have limited value, however, since rate of pro-gression varies so very much even among patients with the same risk factors.

Once we have followed a patient long enough and measured damage enough times, we are able to calculate rate of progression; then we ignore most of the risk factors, and base clinical manage-ment on the observed rate of progres-sion. Since progression tends to be linear over time as long as the management (and the IOP levels) are approximately the same, we can improve predictions by using data gathered from the patient, rather than on group data, which is on what the risk factors are based. 19

By using rate of progression for clini-cal decision-making during long-term glaucoma follow-up, we replace the guess-work of group risk factors with patient-specific evidence of disease de-velopment that the patient’s observed rate of progression represents.

Measurement of field versus discGlaucoma progression is approxima tely linear in most cases if measured in the common global MD index. MD is a measure of the mean deviation from the age-corrected normal threshold sensi-tivity values, which are logarithmic. The linear decay of MD over time seems to be a rule in most patients also if we look over long time perspectives – 10 years or more. If we plot structure-function rela-tionships with perimetric measures like MD on one axis and retinal nerve fiber layer (RNFL) thickness on the other axis in a cross-sectional study involv-ing many glaucomatous eyes, we find typically a curvilinear relationship with little change in MD in early stages of structural change and small changes in structure in moderate or severe disease.20

If we were to measure progression with a non-logarithmic unit, e.g. RNFL thickness, it is most likely that rate-of-progression would not be linear over long time periods (but probably over short period of 2–4 years). This and the fact that we are trying to prevent dis-ease progression to a severe functional stage are good reasons not to use disc or RNFL measures to define rate of progression. In the future we might get tables translating structural measure-ments to functional units, and we could

then base rate of progression measures on structural measures, after translation of the structural findings to functional units. Probably at least in moderate or severe stages of the disease these transla-tions from structure will not work well, since rather large changes of changes in MD or VFI will correspond to very small structural changes. The rate of progression expressed in structural/anatomic measures might be interest-ing, but difficult to use in management. A statistically significant worsening of a structural parameter probably means the patient is deteriorating, but is uncertain clinically, since we cannot translate the structural measurements to the visual function domain. Clinical management requires the present visual field and the rate of progression of visual field defects (Fig. 2).

Improvement of glaucoma care needs perimetrically measured visual func-tion. Progression rates will vary greatly among test point locations; blind points will not progress, and also many normal points will be stable, while a subset of test point locations often surrounding existing deep field defects will show rapid progression. Global summation of the visual function at all locations indi-cates the overall trend that best helps us to understand how the patient is doing and how the patients visual function will develop in the future.

Fig.1 Examples of two eyes, one with a very slow rate of progression (≈0.1 dB/year) (A), and one with a rapid and dangerous rate of progression (≈ 2 dB/year)

Fig. 2 Judging the clinical relevance of progression is much easier with ac-cess to field data. If we cover the fields on the right side of the picture, the disk photographs show us that the eye has very clear glaucoma, and that it is pro-gressing over time. But if we look at the field series we immediately also recog-nize that progression is large a threat-ening and that the eye has advanced visual field loss.


Evidence from clinical trialsWe now have information of the natu-ral history of visual field progression in glaucoma. The Collaborative Normal Tension Glaucoma Study (CNTGS) reported a low mean rate of progression of 0.43 dB/year in patients with normal tension glaucoma.21 Recently, natural history progression rates were reported from the Early Manifest Glaucoma Trial22. Patients with normal tension glaucoma were included in EMGT, and the mean rate of progression was simi-lar in EMGT (0.36 dB/year) to that in CNTGS, thus confirming the results from the latter study. Just as in CNTGS inter-patient rate of progression variabil-ity was very large in EMGT, also among patients with similar IOP levels.

EMGT results further showed that the mean rate of progression in POAG with elevated pressures, were consider-ably and significantly higher than in NTG, at 1.31 dB/year, while on the average eyes with exfoliation glaucoma progressed very rapidly at more than 3dB/year corresponding to going from a normal field to perimetric blindness in less than 10 years (Fig. 3). These rates are similar to those calculated from cross-sectional data.22

While other large randomized trials have not published as detailed results on rate of progression, progression was frequent and early in several of them. In Advanced Glaucoma Intervention Study (AGIS) the mean field loss after 7 years

was 1.6 AGIS units, which corresponds to about 2.3 dB i.e. over 0.3 dB/year. Progression rates depended very much on IOP levels during follow-up.24

In a large retrospective study of clini-cally managed glaucoma patients, mean rates of progression were smaller but of similar magnitude to those of the natu-ral history studies; inter-patient variabil-ity was huge.25

However, there is a lack of data on typically encountered rates of progres-sion in clinical care and from prospective studies. We need a better understanding of patients’ performance as a benchmark for clinical glaucoma care, and to assess the met and un-met needs of glaucoma patients.

REFERENCES1 Fayers T, NG strouthidis & DF Garway-Heath: Monitoring glaucomatous progression us-ing a novel Heidelberg Retina Tomograph event analysis. Ophthalmology 2007; 114: 1973-80.2 Threlkeld AB, e Hertzmark, RT sturm, DL ep-stein & RR Allingham: Comparative study of the efficacy of argon laser trabeculoplasty for exfoli-ation and primary open-angle glaucoma. J Glau-coma 1996; 5: 311-6.3 Bengtsson B & A Heijl: A visual field index for calculation of glaucoma rate of progression. Am J Ophthalmol 2008; 145: 343-53.4 Broman AT, HA Quigley, sK West, J Katz, B Munoz, K Bandeen-Roche, JM Tielsch, Ds Friedman, J Crowston, HR Taylor, R Varma, MC Leske, B Bengtsson, A Heijl, M He & PJ Foster: estimating the rate of progressive visual field damage in those with open-angle glaucoma, from cross-sectional data. invest Ophthalmol Vis sci 2008; 49: 66-76.5 Chauhan BC, MT Nicolela & PH Artes : inci-dence and rates of visual field progression after longitudinally measured optic disc change in glaucoma. Ophthalmology 2009; 116: 2110-8.6 Heijl A, B Bengtsson, L Hyman & MC Leske : Natural history of open-angle glaucoma. Oph-thalmology 2009; 116: 2271-6.7 Bengtsson B & A Heijl: A visual field index for calculation of glaucoma rate of progression. Am J Ophthalmol 2008; 145: 343-53.8 Lichter PR, DC Musch, BW Gillespie, Ke Guire, NK Janz, PA Wren & RP Mills: interim clini-cal outcomes in the Collaborative initial Glauco-ma Treatment study comparing initial treatment randomized to medications or surgery. Ophthal-mology 2001; 108: 1943-53.9 Leske MC, A Heijl, L Hyman, B Bengtsson, L Dong & Z Yang: Predictors of long-term pro-gression in the early manifest glaucoma trial. Ophthalmology 2007; 114: 1965-72.10 Chauhan BC, DF Garway-Heath, FJ Goni, L Rossetti, B Bengtsson, AC Viswanathan & A Heijl: Practical recommendations for measur-ing rates of visual field change in glaucoma. Br J Ophthalmol 2008; 92: 569-73.11 Gordon MO, JA Beiser, JD Brandt, DK Heuer, eJ Higginbotham, CA Johnson, JL Kelt-

ner, JP Miller, RK Parrish, 2nd, MR Wilson & MA Kass: The Ocular Hypertension Treatment study: baseline factors that predict the onset of primary open-angle glaucoma. Arch Ophthalmol 2002; 120: 714-20; discussion 829-30.12 Leske MC, A Heijl, M Hussein, B Bengtsson, L Hyman & e Komaroff : Factors for glaucoma progression and the effect of treatment: the early manifest glaucoma trial. Arch Ophthalmol 2003; 121: 48-56.13 Miglior s, N Pfeiffer, V Torri, T Zeyen, J Cunha-Vaz & i Adamsons : Predictive factors for open-angle glaucoma among patients with ocu-lar hypertension in the european Glaucoma Pre-vention study. Ophthalmology 2007; 114: 3-9.14 Chauhan BC, Fs Mikelberg, AG Balaszi, RP LeBlanc, MR Lesk & Ge Trope: Canadian Glaucoma study: 2. risk factors for the progres-sion of open-angle glaucoma. Arch Ophthalmol 2008; 126: 1030-6.15 Lichter PR, DC Musch, BW Gillespie, Ke Guire, NK Janz, PA Wren & RP Mills: inter-im clinical outcomes in the Collaborative initial Glaucoma Treatment study comparing initial treatment randomized to medications or surgery. Ophthalmology 2001; 108: 1943-53.16 Grodum K, A Heijl & B Bengtsson : Risk of glaucoma in ocular hypertension with and with-out pseudoexfoliation. Ophthalmology 2005; 112: 386-90.17 Leske MC, A Heijl, L Hyman, B Bengtsson, L Dong & Z Yang: Predictors of long-term pro-gression in the early manifest glaucoma trial. Ophthalmology 2007; 114: 1965-72.18 Bengtsson B, MC Leske, Z Yang & A Heijl: Disc hemorrhages and treatment in the early manifest glaucoma trial. Ophthalmology 2008; 115: 2044-8.19 Bengtsson B, VM Patella & A Heijl: Prediction of glaucomatous visual field loss by extrapola-tion of linear trends. Arch Ophthalmol 2009; 127: 1610-5.20 schlottmann PG, s De Cilla, Ds Greenfield, J Caprioli & DF Garway-Heath: Relationship between visual field sensitivity and retinal nerve fiber layer thickness as measured by scanning laser polarimetry. invest Ophthalmol Vis sci 2004; 45: 1823-9.21 Anderson DR, sM Drance & M schulzer: Nat-ural history of normal-tension glaucoma. Oph-thalmology 2001; 108: 247-53.22 Heijl A, B Bengtsson, L Hyman & MC Leske: Natural history of open-angle glaucoma. Oph-thalmology 2009; 116: 2271-6.23 Broman AT, HA Quigley, sK West, J Katz, B Munoz, K Bandeen-Roche, JM Tielsch, Ds Friedman, J Crowston, HR Taylor, R Varma, MC Leske, B Bengtsson, A Heijl, M He & PJ Fos-ter: estimating the rate of progressive visual field damage in those with open-angle glaucoma, from cross-sectional data. invest Ophthalmol Vis sci 2008; 49: 66-76.24 The Advanced Glaucoma intervention study (AGis): 7. The relationship between control of in-traocular pressure and visual field deterioration.The AGis investigators. Am J Ophthalmol 2000; 130: 429-40.25 Heijl A et al. Rates of visual field progression in glaucoma care. ARVO Abstract 1155; 2008.

Fig.3 Natural history of glaucomatous visual field damage. Untreated rates of progression for POAG with high base-line IOP - HTG(≥21 mmHg), with low baseline IOP (NTG) and with pseudo-exfoliation glaucoma (PEXG). The to-tal inter-patient range of progression rates (between the red and greed dot-ted lines) is huge. Data from(Heijl et al. 2009).


1) IntroductionGlaucoma is a multifactorial neurode-generative disorder characterized by progressive structural and functional injury of the optic nerve complex (optic nerve + parapapillary region) for which intraocular pressure (IOP) remains the only proven modifiable risk factor. As-sessments of both structure and func-tion of the optic nerve are indispensible aspects of the glaucoma examination and disease detection, monitoring, and management. [1] Since the main goal of treatment is to either halt or slow dis-ease progression, clinicians must be able to indentify patients at increased risk of progression and, most importantly, be able to detect and measure progression when it occurs.

Glaucomatous progression can be de-tected clinically either by structural or functional tests, with change detected by either event-based or trend-based analysis.

2) New Technologies/ SoftwareA. Functional TestsStandard automated perimetry (SAP) is the most widely used method to assess visual function in glaucoma and corre-lates well with patient quality of life and vision. SAP has also been used in the major randomized clinical trials (RCT) to determine glaucoma functional change or progression endpoints.

Different types of event-based VF progression criteria were used by each of these trials. However, a widely used sta-tistical package of event-based analysis is automatically provided by the Hum-phrey Field Analyzer (HFA, Carl Zeiss Meditec, Inc., Dublin, CA) and is called Guided Progression Analysis™ (GPA) (Carl Zeiss Meditec, Inc., Dublin, CA). The Humphrey Field Analyzer II-i with the new GPA software additionally pro-vides a trend-based analysis using the Visual Field Index™ (VFI) (Carl Zeiss Meditec, Inc., Dublin, CA) described by Bengtsson and Heijl, along with the

more familiar event-based analysis.[2] The VFI is an age-adjusted index that summarizes the global VF status for each test of the VF series. Briefly, the VFI calculation is based on the pattern stan-dard deviation (PSD) probability maps with a greater weighting for more central points. Therefore, the final index which ranges from 0 (blind) to 100% (normal) has a greater weight of the central points relative to the paracentral and peripheral points. (Figure 1). A minimum of five exams over at least three years must be included in GPA 2 for the linear regres-sion results to be presented.

Another option to perform trend-analysis with HFA data is the Progres-sor™ software (Version 3.3, Medisoft, Inc., London, UK). (Figure 2). In 1996,

Fitzke et al. described a graphical meth-od of measuring rates of VF change us-ing pointwise linear regression (PLR) analysis which was further employed to build the Progressor™ software pack-age.[3] At least five tests are necessary for the analysis to provide the global rates of change (dB/yr) and p values. The software also allows one to define differ-ent progression criteria (Figure 2 B). If any of the tested points meets the chosen criteria a graphical display shows the lo-

What’s NewNew Technologies to measure Glaucoma ProgressionCarlos Gustavo V. De Moraes, M.D.1,2, Jeffrey M. Liebmann, M.D.1,2

1einhorn Clinical Research Center, New York eye and ear infirmary, New York, NY. 2New York university school of Medicine, New York, NY

Figure 1: Guided Progression Analysis, Humphrey Visual Field Analyzer (Carl Zeiss Meditec, Inc., Dublin, CA). Both event- and trend-based analyses are provided by the software printout.

Figure 2: Pointwise linear regression analysis, Progressor™ software (Medi-soft, Inc., London, UK). A) Selection of visual field test dates to be analyzed. B) Definition of progression criteria. C) Graphic output showing pointwise rates of change and their significance. D) Display showing number of points reaching the predefined progression criteria, global and localized rates of change (dB/yr).


cation of the progressing point (s) on the VF, as well as the level of significance of the slope (p) (Figure 2 C and D).

For those who use the Octopus Perim-eter (Haag Streit, Berne, Switzerland), the PeriTrend™ provides a trend-anal-ysis ; this is part of the device’s standard statistical package. Similar to GPA 2, this is a form of trend-analysis based on global indices and therefore has the limi-tation of not detecting focal change.

B. structural testsStereo disc photographsReview of simultaneous or non-simul-taneous stereophotographs of the optic disc and retinal nerve fiber layer (RNFL) remains the most widely used method to detect structural change in glaucoma. Masked photograph review was used by some of the major RCTs to determine structural progression.[4-6]

HRTNew imaging technologies have been de-veloped to evaluate objectively the optic

disc and retinal nerve fiber layer and to enhance identification of structural pro-gression. (Figure 3). Confocal Scanning Laser Ophthalmoscopy (Heidelberg Retina Tomograph, [HRT], Heidel-berg Engineering, GmbH, Heidelberg, Germany) was among the first devices designed to do this. The Topographic Change Analysis™ (TCA) program was developed to allow objective mea-surements of topographic change in a series of HRT examinations. Due to its stable platform, data from the older version of HRT (HRT II) can also be analyzed using the current version of the software (HRT III). (Figure 4). TCA currently also provides objective, trend-based measurements of rates of changes (mm2/yr). Moreover, a regression line is provided both globally as well as for each stereometric parameter on the printout. Recent reports have applied linear re-gression to HRT longitudinal data sug-gesting that this method may be useful to quantify rates of progression using the HRT. [7,8]

GDXScanning Laser Polarimetry (GDx-VCC and GDx-ECC, Carl Zeiss Meditec, Inc., Dublin, CA, USA) is an additional technology used to detect structural pro-gression. The new Guided Progression Analysis™ (GPA) software provides both an event- and trend-based analy-sis of longitudinal change of the RNFL thickness. A colored map with a classifi-cation system resembling the HFA GPA is also provided: yellow, possible progres-sion; red, likely progression; and purple, possible increase (RNFL “thickening”). Graphical images of the linear regression (microns/yr) of values for the average RNFL thickness as well as for the vari-ous RNFL sectors are also shown along with its extrapolation over time, assum-ing the rate remains constant (Figure 5). There is a good correlation between RNFL thickness change shown on GDx and conventional progression endpoints (SAP and photograph review).[9]

OCTTime-domain optical coherence tomog-raphy (Stratus OCT, Carl Zeiss Meditec, Inc., Dublin, CA, USA) has also been reported to be able to assess structural progression. The new version of the soft-ware, the GPA Advanced Serial Analy-sis, provides the rates of RNFL thick-ness change (microns/yr) and their level of significance (p) both globally and by clock-hours (Figure 6). This feature may

Figure 3: PeriTrend™ progression ana lysis, Octopus Perimeter (Haag Streit, Berne, Switzerland).

Figure 4: The Topographic Change Analysis™ (TCA), Confocal Scanning Laser Ophthalmoscope (HRT, Heidelberg Engineering, GmbH, Heidelberg, Germany).

Figure 5: Guided Progression Analy-sis™, Scanning Laser Polarimetry (GDx, Carl Zeiss Meditec, Inc., Dublin, CA).


allow topographic correlations between localized RNFL loss and VF progres-sion. Detection of structural progression using time-domain OCT has been dem-onstrated using both topographic and RNFL parameters of the device. [10]

Improvements in the OCT technolo-gy (Fourier-domain OCT) are available and due to their rapid image acquisi-tion with high-resolution, may improve performance of the devices fromseveral companies, to detect structural change.

3) Guidance from clinical trial outcomesMost glaucoma clinical trials have evalu-ated progression by means of event-anal-ysis using SAP and photographic review. In a post-hoc analysis, Nouri-Madahvi et al. employed pointwise linear regres-sion (PLR) to determine VF progression

in a subset of the Advanced Glaucoma Intervention Study (AGIS) population and found results consistent with the pre-existing literature regarding the pre-viously documented importance of risk factors for progression (e.g. intraocular pressure [IOP] and age).[11] In the Di-agnostic Innovations in Glaucoma Study (DIGS), rates of structural loss using different technologies can be measured in glaucoma patents and suspects; these values correlate well with the follow-up IOP and SAP/optic disc endpoints.[9,10] Large studies involving real-world patients have shown that trend-analysis may be an effective method to determine progression with results consistent with the major clinical trials.

4) ConclusionThese functional and structural methods to determine rates of progression ought to be tested in populations enrolled in the major clinical trials in order to as-sess their performance and consistency with previously reported risk factors. New, more accurate, and improved soft-ware algorithms should continue to be developed to allow clinicians to detect better structural and functional changes in glaucoma so that treatment paradigms can be modified to prevent visual dis-ability.

References1. Weinreb RN, Greve eL. in international Glau-coma Review. Glaucoma Diagnosis. structure and Function. 2004, Kugler Publications, The Hague, The Netherlands.2. Bengtsson B, Heijl A. A visual field index for calculation of glaucoma rate of progression. Am J Ophthalmol. 2008;145:343-53.3. Fitzke FW, Hitchings RA, Poinoosawmy D, McNaught Ai, Crabb DP. Analysis of visual field progression in glaucoma. Br J Ophthalmol. 1996;80:40-84. Kass MA, Heuer DK, Higginbotham eJ, et al. The Ocular Hypertension Treatment study: a randomized trial determines that topical ocu-lar hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002;120:701–13.5. Parrish RK 2nd, Feuer WJ, schiffman JC, Lichter PR, Musch DC; CiGTs Optic Disc study Group. Five-year follow-up optic disc findings of the Collaborative initial Glaucoma Treatment study. Am J Ophthalmol. 2009;147:717-7246. Heijl A, Leske MC, Bengtsson B, et al. early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120:1268–79.7. strouthidis NG, Gardiner sK, Owen VM, Zuni-ga C, Garway-Heath DF. Predicting Progression to Glaucoma in Ocular Hypertensive Patients. J Glaucoma. 2009.[epub ahead of print]8. Kotecha A, spratt A, Bunce C, Garway-Heath DF, Khaw PT, Viswanathan A; MoreFlow study Group. Optic disc and visual field changes af-ter trabeculectomy. invest Ophthalmol Vis sci. 2009;50:4693-9.9. Medeiros FA, Alencar LM, Zangwill LM, sam-ple PA, Weinreb RN.The Relationship between intraocular pressure and progressive retinal nerve fiber layer loss in glaucoma. Ophthalmo-logy. 2009;116:1125-33.10. Medeiros FA, Zangwill LM, Alencar LM, Bowd C, sample PA, susanna R Jr, Weinreb RN. De-tection of glaucoma progression with stratus OCT retinal nerve fiber layer, optic nerve head, and macular thickness measurements. invest Ophthalmol Vis sci. 2009;50:5741-8.11. Nouri-Mahdavi K, Hoffman D, Coleman AL, Liu G, Li G, Gaasterland D, Caprioli J; Advanced Glaucoma intervention study. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma intervention study. Oph-thalmology. 2004;111:1627-35.

Core Concepts• Progression can be detected ei-ther by structural or functional tests with change detected by either us-ing event-based or trend-based analyses.• standard automated perimetry is currently the most widely used method to assess visual function• The Humphrey Visual Field Ana-lyzer with the new GPA software provides a trend based analysis us-ing the Visual Field index• The Visual field index ranges from 0 (blind) to 100% (normal)• structural tests are stereo disc photographs, HRT (Heidelberg Retina Tomograph), GDX (scanning Laser Polarimetry) and OCT (optical coherence tomography)• HRT and topographic change analysis enables an objective mea-surement of topographic change in HRT examinations• GDX and OCT can both be used with the new Guided Progression Analysis (GPA) to provide both event- and trend-based analysis of longitudinal change of the RNFL thickness.• All methods described should be tested in populations enrolled in ma-jor clinical trials• New, more accurate and improved software algorithms should continue to be developed.

Figure 6: Guided Progression Analy-sis™, Advanced Serial Analysis, Time-domain Optical Coherence Tomog-raphy (OCT, Carl Zeiss Meditec, Inc., Dublin, CA).


Rate of progression: Clinical FocusGlaucoma is a chronic optic neuropathy in which progressive neurodegenerative loss of retinal ganglion cells results in increasing damage to the visual field, potentially leading to blindness. From the natural history of glaucoma, pro-gression is very common without treat-ment: more than 60% of untreated pa-tients in the Early Manifest Glaucoma Trial(EMGT) experienced progression of visual field damage in 5 years .

Even though progression to blindness is relatively rare, a cohort study follow-ing glaucoma patients for more than 20 years found that, despite treatment, almost 20% of patients went blind. Re-sults from the same study highlighted the wide variation in damaging intra-ocular pressure (IOP) levels between individuals;some patients went blind at IOP values that other patients could tol-erate without progression.

This introduces the concept of Target Pressure: the IOP (or range of IOP val-ues) that the treating ophthalmologist aims to achieve to try to preserve optic nerve head health Just as progression

rates vary between different patients, target IOP also vary. As stated in the European Glaucoma Society Guide-lines, target IOP depends on the level of untreated IOP at baseline, the patient’s age and life expectancy, the level of glau-coma damage and the progression rate of that damage (Figure 1). There is no mag-ic number that will be safe in all patients, but the choice of the target IOP should be individualized and the accuracy of our choice should be verified by check-ing visual function during follow-up.

Assessment of the rate of progression is particularly important to verify the choice of target IOP: if the new slope (after target IOP is reached) of the line of MD changes (or Visual Field Index (VFI)) improves over time so that visual function will not be affected significant-ly during the patient`s lifetime, then the target IOP has been chosen correctly. However, if the new rate of progression is still risky for the patient, a lower target IOP should be selected.

The concept of target IOP is not evi-dence-based although data coming from the large National Institute of Health trials helps us with a starting point. For

Clinical issues:Treatment strategies to help prevent ProgressionLuca Rossetti, Ospedale San Paolo, University Milano, Milano, Italy

Core Concepts• Natural history data indicates that progression is very common without iOP lowering treatment• Damaging iOP levels vary widely among patients• Target Pressure is the iOP (or rather a range of iOP values) that the treating ophthalmologist wants to achieve to try to preserve visual health. it depends on the level of untreated iOP, the patient’s age and life expectancy, the level of glau-coma damage and the progression rate.• Visual Field values need to be monitored carefully and treatment should be adjusted if speed of pro-gression threatens visual disability.• even a small (1 mmHg) reduction in iOP could reduce significantly (around 10%) glaucoma progres-sion• Monotherapy is indicated as an initial treatment approach, which may then lead to combination treat-ment or non medical therapies

Figure 1. The choice of the target IOP according to the EGS guidelines

HIGHERTARGET

IOP

LOWERTARGET

IOP

EARLY SHORT HIGH SLOW

ADVANCED LONG LOW FAST

THE ABOVE FACTORS NEED TO BE CONSIDERED AS A WHOLE IN DECIDING THE INDIVIDUAL TARGET PRESSURE REQUIRED

GLAUCOMA DAMAGE LIFE EXPECTANCY UNTREATED IOP RATE OFPROGRESSION


relatively early glaucomas (cf. Collabora-tive Initial Glaucoma Treatment Study (CITGS)) an IOP reduction of about 35% will control the disease in the vast majority of cases, while for more ad-vanced disease (cf Advanced Glaucoma Intervention Study (AGIS)) an IOP constantly below 18 mmHg would be a reasonable target (Figure 2). From these trials (e.g. Ocular Hypertensive Treat-ment Study (OHTS) , EMGT), is even a small amount (1 mmHg) of reduction in IOP could reduce (around 10%) glau-coma progression significantly. Every single mmHg counts and, for progress-ing patients it might make a difference.

Development of a therapeutic strategy must keep this in mind. Monotherapy is always preferable initially to reach the target. However, as reported in the CIGTS, the majority of glaucoma pa-tients (75%) need more than one drug to reach target IOP.

Remember to judge the adequacy of the target IOP according to the effect

on visual function (rate of progression). If medical therapy alone is not enough, then other options (e.g. laser and/or sur-gery) should be considered without de-lay.

References:1 Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M. Reduction of intraocular pressure and glaucoma progression: results from the early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120:1268–79.2 Oliver Je et al. Blindness and glaucoma: A com-parison of patients progressing to blindness from glaucoma with patients maintaining vision. Am Journal Ophthalmol 2002;133:764-723 european Glaucoma society: Terminology and guidelines for glaucoma. Dogma savona italy, 20084 Lichter PR, Musch DC, Gillespie BW, et al.: in-terim clinical outcomes in the Collaborative ini-tial Glaucoma Treatment study comparing initial treatment randomized to medications or surgery. Ophthalmology 2001, 108:1943–19535 The AGis investigators: The advanced glau-coma intervention study (AGis): 7: The relation-ship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 2000, 130:429–440.6 Kass MA, Heuer DK, Higginbotham eJ, et al.: The Ocular Hypertension Treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol 2002, 120:701–713.

Figure 2. Potential target IOP derived from large clinical trials

Target IOP• OHTs - Ocular hypertensives

- 20 % iOP reduction = 54% reduction of progression vs the untreated group (4.4% vs 9.5%).

• CNTGs - Normal tension glaucoma - 30% iOP reduc-tion - 3 times less progres-sion (from 60% to 20%).

• eMGT – early glau-coma – 25% iOP reduc-tion - 45% progression.

• CiGTs - early glaucoma – 35% to 48% iOP reduction (target iOP). No progression.

• AGis - Advanced glau-coma – mean iOP of 12.3 mmHg and iOP always <18mmHg. No progression.


B. Older patient (70 yrs) with moderately advanced loss and a rapid rate of progression can be expected to have visual disability by age 80 years. With a long life expectancy and a slower rate (-0.2 dB/yr), the patient may experience borderline visual disability.

Visual field assessment remains the cor-nerstone of glaucoma practice; it pro-vides key diagnostic information on the progression of the disease. Knowing the visual field, and whether and how much it is changing helps the clinician to op-timize management and follow-up of the individual patient with the aim of achieving the best functional outcomes.

Together with age and stage (or se-verity) of visual field loss at diagnosis, the rate of visual field change is vital to gauge the likelihood of visual disability (Fig. 1). Rate estimates usually cannot be made with few examinations and gener-ally, the frequency of visual field exami-nations falls below recommended levels.1

Several indices can be used for mea-suring rates of visual field progression: global indices such as Mean Sensitiv-ity (MS), Deviation (MD) or the Vi-sual Field Index (VFI),2 and visual field sectors or individual point-wise values.

Practical Tips:Frequency of Visual Field and Disc imagingBalwantray C. Chauhan, Ph.D.Department of Ophthalmology and Visual sciences, Dalhousie university, Halifax, Nova scotia, Canada

Core concepts• several indices can be used for measuring rates of visual field pro-gression: Mean sensitivity (Ms), Mean Deviation (MD) and the Visual Field index (VFi).• Clinicians are most familiar with measuring MD.• More examinations are required with a lower MD progression rate and a higher MD variability.• A relatively slow change of 0.5 dB/year over only 2 years will require 7 examinations per year to detect progression.• To identify rapidly progressing patients (MD rates of -2 dB/year or worse), 6 examinations in the first 2 years of follow-up are recom-mended.• Clinical decisions based on visual field progression require more than a formulaic approach; aspects of the visual field as well as the overall clinical picture need to be taken into account.

FIGURE LEGENDSFig. 1: A. Young patient (55 yrs) with early visual field loss and a rapid rate of progression (-2 dB/yr) can be expected to have visual disability by age 70 years, but with a slower progression rate (-0.2 dB/yr), he or she may not experience lifetime visual disability.


Table 1. The frequency of visual field examinations required over 2, 3 and 5 years to detect various progression rates.*

Number of examinations/year

Progression rate 2 years 3 years 5 years

-0.5 dB/yr 7 5 3

-1.0 dB/yr 5 3 2

-2.0 dB/yr 3 2 1

*assuming moderate visual field variability

REFERENCES1. Friedman Ds, Nordstrom B, Mozaffari e, Quigley HA. Glaucoma management among indi-viduals enrolled in a single comprehensive insur-ance plan. Ophthalmology 2005;112:1500-1504.2. Bengtsson B, Heijl A. A visual field index for calculation of glaucoma rate of progression. Am J Ophthalmol 2008;145:343-353.3. Chauhan BC, Garway-Heath DF, Goni FJ, et al. Practical recommendations for measuring rates of visual field change in glaucoma. Br J Ophthalmol 2008;92:569-573.

While the VFI corrects the degree of visual field loss for a diffuse reduction in sensitivity and therefore is less sensitive to effects of cataract, to date, clinicians are most familiar with MD. Sectoral and point-wise analyses can be very helpful, but this article will discuss only MD.

Rates of visual field change in glau-coma vary considerably. The ability to detect statistical change depends on (i) the rate (the amount of MD change over time); and (ii) the variability of MD measurements. Generally, to detect rate of change, the number of examinations required increases with a decreasing MD rate and higher MD variability: to detect a slowly progressing visual field with highly variable examinations re-quires more examinations while to de-tect a faster progressing visual field with less variable examinations requires fewer examinations.

A recent publication provided the number of examinations required to de-tect various rates of visual field change with different levels of visual field vari-ability.3 Table 1 summarizes this key information assuming moderate visual field variability and illustrates the fre-quency of examinations required to de-tect various rates of change over 2, 3 and 5 years. To detect a relatively slow rate of change (-0.50 dB/yr) over only 2 years requires 7 examinations per year; over 5 years, this decreases to 3 examinations per year. To identify rapidly progress-ing patients (those with MD rates of -2 dB/yr or worse), 6 examinations in the first two years of follow-up are recom-mended.

This approach also helps clinicians to decide on the frequency of examinations required to detect a rate of visual field

loss that could potentially lead to visual disability, for example after an interven-tion to reduce the rate of progression.

Finally, clinical decisions based on vi-sual field progression require more than a formulaic approach as any summary index, such as MD, is not sensitive to the topography of visual field defects. Hence MD derived from a small paracentral vi-sual field defect close to fixation merits very different consideration to the same MD derived from a more peripheral vi-sual field defect. Therefore recommend-ed frequencies of visual field examina-tions are only a guide to be considered together along with aspects of the visual field in the context of the overall clinical picture.


CME credits can be obtained via the questions on the website very soon.

The process of obtaining CME accreditation for the journal is currently ongoing.

STATEMENT OF NEED AND PROGRAM DESCRIPTIONRecent months and years have seen significant advances in our under-standing of glaucoma. Much has been learned, not only about damage mecha-nisms and pathogenesis, but also about diagnosis and management. Treatment options – both medical and surgical – continue to expand. This program will review this new knowledge with an em-phasis on incorporating recent insights into day-to-day practice.

DATE OF ORIGINAL RELEASEJuly 2010. Approved for a period of 12 months

DISCLAIMERParticipants have an implied responsibil-ity to use newly acquired information to enhance patient outcomes and profes-sional development. The information presented in this activity is not meant to serve as a guideline for patient care. Any procedures, medications, or other courses of diagnosis or treatment

discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications or dan-gers in use, applicable manufacturer’s product information, and comparison with recommendations of other authori-ties.

CONTRIBUTORS• Anders Heijl MD is Professor and

Chairman of the Department of Ophthalmology at Lund university Hospital, Malmö, sweden.

• Carlos Gustavo V. De Moraes MD is an Ophthalmology special-ist and Jeffrey M. Liebmann MD is Professor of Ophthalmology at the einhorn Clinical Research Centre, New York eye and ear infimary , and at the New York university school of Medicine, New York, usA.

• Luca Rossetti MD is a Professor of Ophthalmology at the Osped-

ale san Paolo, university Milano, Milano, italy

• Bal Chauhan PhD is a Professor at the Department of Ophthalmology and Visual sciences, Dalhousie university, Halifax, Nova scotia, Canada

DISCLOSURE STATEMENT EDITORIAL BOARDClive Migdal serves on the Faculty and Advisory Boards of the following compa-nies: Alcon, Allergan, Merck, Pfizer and santen. Ivan Goldberg serves on the Faculty and Advisory Boards of the following companies: Alcon, Allergan, Merck and Pfizer.Remo Susanna serves on the Faculty and Advisory Boards of the following companies: Alcon, Allergan, Merck and Pfizer.

Documents

Glaucoma Concepts – Rate of Progressionglaucomanow.com/media/5367/gn no2.pdf · Glaucoma Now – No2. 3 can be intensified to prevent too much extra damage. To do this within a