The times they are a‐changin’: time to change glaucoma management

We live in a time with vastly increased and clinically important knowledge of glaucoma. For a long time, glaucoma was somewhat of a stepchild in ophthalmology. Critics stated that glaucoma experts could not agree on how to define the disease, how to treat it, how to follow it and – by the way – maybe treatment made no difference. That led to a climate, where it was hard to give solid information to colleagues and healthcare providers on how glaucoma care could be organized and implemented, and to give evidence-based advice to patients. This in turn sometimes made it difficult to secure enough resources for glaucoma care. Clearly, fundamental clinical research was needed to fill in important knowledge gaps to provide a solid foundation for good glaucoma care. The large randomized glaucoma trials – often referred to as the ‘alphabet soup’ [The Advanced Glaucoma Intervention Study (AGIS 1994), The Collaborative Initial Glaucoma Treatment Study (Musch et al. 1999). The Collaborative Normal Tension Glaucoma Study (CNTGS 1998), The Early Manifest Glaucoma Trial (EMGT) (Leske et al. 1999), The Ocular Hypertension Treatment Study (OHTS) (Gordon & Kass 1999) and The European Glaucoma Prevention Study (EGPS) (Miglior et al. 2002)] – were designed to provide evidence for glaucoma care, and through them, the most important research needs have now been met. Important knowledge has also come from other clinical studies. Many of the important knowledge gaps that existed 10 years ago have thus been filled. This means that it is time to consider whether clinical glaucoma care has taken advantage of the new knowledge, or whether changes are now motivated. What is it that we have learned in the last decade? The most fundamental issue is that we now know that reducing intraocular pressure helps. The Early Manifest Glaucoma Trial and CNTGS have shown that lowering intraocular pressure (IOP) reduces the risk of progression, that is, treatment prolongs time to progression and, therefore, rate of disease progression (Collaborative Normal-Tension Glaucoma Study Group 1998; Heijl et al. 2002). Patients whose eyes pressures are always quite low show only little progression (AGIS Investigators 2000). The Ocular Hypertension Treatment Study clearly showed that pressure reduction in patients with ocular hypertension reduces the incidence of glaucoma damage (Kass et al. 2002). The randomized trials have also shown that treatment effects are surprisingly large. In EMGT, a mean IOP reduction of 5 mmHg reduced the risk of progressing by half (Heijl et al. 2002; Leske et al. 2003). Also in OHTS, the same IOP reduction reduced glaucoma incidence by half (Kass et al. 2002). Actually risk reductions were 10–14% per mmHg in EMGT (Leske et al. 2003), OHTS (Gordon et al. 2002) and EGPS (Miglior et al. 2007). In the more recent Canadian glaucoma Study, which included treated patients with lower IOP levels than the other studies, risk reduction was as high as 19% per mmHg (Chauhan et al. 2008a). These findings are clinically very important, because they show that over a long-time perspective an extra pressure reduction of just a few mmHg might make a meaningful or sometimes even a great difference (cf. below). As the percentages of risk reduction seem to be larger in studies with lower IOP levels, the results also suggest that, for example, 2 mmHg additional pressure reduction might be more important in a patient progressing at lower IOP levels than in a patient with higher pressure. A fundamental piece of knowledge is that IOP reduction leads to decreased risk of progression even in eyes with IOP within the statistically normal range (Collaborative Normal-Tension Glaucoma Study Group 1998; Heijl et al. 2002). Glaucoma is a multifactorial disease, and we must remain hopeful that we in the future may successfully exploit treatment modalities other than IOP lowering, that is, treatment that addresses vascular insufficiency or offers neuroprotection. Yet, even today, we must remember that further reducing IOP may be very helpful in treated eyes that do not do well despite the fact that measured IOP is always ‘normal’. Another important observation is that most patients with glaucoma do progress if monitored for long enough with at least moderately sensitive tools. This is so even if IOP is always measured within the statistically normal range. Thus, for example, in EMGT, 59% of patients randomized to the treatment arm had shown definite progression, a large proportion with all IOP readings within ‘normal’ limits (Leske et al. 2007). Therefore, progression paradigms in glaucoma have changed. It used to be considered that any progression was a reason to step up treatment or at least to consider such a step. Now, it is realized that a change of treatment depends on the magnitude of the progression, and whether the progression rate is high enough to constitute a threat to the quality of life (QoL) of the patient during his remaining lifetime. The trials have also shown that also early progression can be identified with great statistical power using standard automated perimetry, if only field testing is performed often enough, and event analyses are used to identify progression. Thus, definite visual field progression in EMGT was associated with a worsening of mean deviation (MD) by <2 dB (Heijl et al. 2003) with a specificity of at least 99% per test (Heijl et al. 2008). This indicates that at least 15 steps of progression can be identified with perimetry between a normal field and a perimetrically blind field (Fig. 1). Perhaps surprisingly, this is a considerably larger number of steps of progression than with present-day structural imaging techniques. Thus, sensitivity to change, which depend on long-term fluctuation, and dynamic range is still somewhat smaller with optical coherence tomorgraphy (OCT), laser polarimetry and confocal laser tomography where the number of steps between a normal and a glaucoma blind eye, is approximately 6–10 (Jampel et al. 2006; Leung et al. 2008, 2011) at specificities of approximately 95%. One likely reason for this is that event analyses for perimetry have had considerably longer time to develop than those for structure, and available perimetric event analyses for the detection of change exploit data from individual test point locations and can detect local, focal progression (Fitzke et al. 1996; Bengtsson et al. 1997). With frequent perimetry, progression can be ascertained early with high statistical power. In Early Manifest Glaucoma Trial, definite progression was associated with a mean deterioration of mean deviation of <2 dB. The diagram depicts the number of independent progression events that could theoretically be detected with frequent perimetric testing. Presently, structural tests can diagnose glaucoma with high sensitivity and specificity (Bengtsson et al. 2010), but for follow-up, structural tests may best be performed as ancillary tests, but not at the expense of visual field testing (Chauhan et al. 2008b). The trials and other studies have also shown that rates of progression vary tremendously among patients, in clinical glaucoma care, and also in those few studies that have followed glaucoma patients untreated. Thus, some patients progress extremely slowly, while others are fast progressors – often defined as those who show a worsening of MD by 1.5 or 2 dB or more per year. We therefore cannot guess the progression rate of individual patients very well. Today, there is at least some knowledge on commonly encountered rates of progression. In treated glaucoma, mean rates often seem to be perhaps 0.4–0.6 dB/year, but with the very large interindividual variability. Natural history data are available form CNTGS and EMGT. In the latter study, the average rate was a little over 1 dB/year in the whole patient cohort and similar in patients with high-tension glaucoma (IOP ≥21 mmHg) (Heijl et al. 2009) (Fig. 2). This corresponds to going from a normal field to perimetric blindness in approximately 30 years. Progression rates are considerably slower in normal-tension glaucoma (IOP ≤ 20 mmHg) with mean rates of approximately 0.4 dB/year both in CNTGS and in EMGT patients (Anderson et al. 2001; Heijl et al. 2009). Patients with untreated exfoliation glaucoma in EMGT progressed at disturbingly high rates; the mean was over 3 dB/year, which corresponds to going from a normal field to perimetric blindness in approximately 10 years. Progression rates in untreated glaucoma have also been calculated from cross-sectional epidemiological data (Quigley et al. 1996). Rates of progression vary greatly among patients with glaucoma, but also among groups of patients. This graph shows mean rates of progression in untreated glaucoma patients from Early Manifest Glaucoma Trial (Heijl, Bengtsson et al. 2009). The fact that rates of progression cannot be guessed has resulted in new advice on management of patients with newly detected glaucoma. Frequent perimetry is required the first years after diagnosis, if we want to be able to detect rapidly progressing eyes before too much additional damage has occurred. Thus, to detect an eye that progresses by 2 dB/year in 2 years with 80% statistical power, we need to perform three visual field per year, during those first 2 years (Chauhan et al. 2008b). Such frequent perimetry will not only help detect rapid progressors; it will also help to give us measured individual rates of progression. Establishing such rates of progression as a part of standard glaucoma care is now also part of modern management recommendations, for example, by the European Glaucoma Society (2008) and by the Swedish Ophthalmological Society (Heijl et al. 2010). Perimetric progression rates in treated glaucoma tend to be linear if the measurement unit is logarithmic, for example, MD values or mean sensitivites of visual field index (VFI) values (Bengtsson et al. 2009). This means that we can assume with at least some level of confidence that if a glaucoma patient continues with the same treatment as during the period when we measured his rate of progression, or with similar IOP values, it is likely that he will continue to progress at approximately the same rate. This, of course, is of considerable help, when we need to consider future treatment. Glaucoma is still the second most common cause of blindness. Many years ago, Hattenhauer et al. (1998) found in a retrospective chart review in Minnesota that after 20 years of follow-up after diagnosis 22% of patients who were initially diagnosed with manifest glaucoma with field loss were blind in both eyes. In a recent study by Forsman et al. (2007) in a well-defined geographical catchment area in Finland, 15% of patients with glaucoma were blind in both eyes at the last visit before death. One reason is that glaucoma is often diagnosed late with considerable damage (Grødum et al. 2002), increasing the risk for blindness. This is a problem in itself. In ophthalmic care, we can help early detection by always inspecting the optic disc and measure intraocular pressure in patients over 50, who undergo ophthalmic examinations for any reason. This would only be a partial help; however; a screening programme must probably be developed and subjected to large-scale testing in the field to solve the detection problem. But clearly most patients who develop visual impairment or blindness from glaucoma do so while undergoing treatment. Many clinicians have noted that more drastic measures to reduce IOP, for example, surgery, are often not performed until most of the visual function is already lost in the treated eye. The question is why this is so. One reason can be that glaucoma management is based far too much on tonometry alone. This was obvious, for example, in a national questionnaire, reported in a systematic literature review of open-angle glaucoma by the Swedish Board of Health Technology Assessment, which showed that patients with glaucoma were subjected to perimetric testing only approximately every second year (Lindén et al. 2011). There are also data from the US which indicate that in ordinary clinical practice perimetry is performed too rarely to detect rapidly progressing patients or establish rates of progression within just a few years after diagnosis (Quigley et al. 2007). The concept target pressure is certainly valuable, and it makes a lot of sense to base target pressure on the risk of future impairment or loss of QoL. In this way, patients with more damage and younger age should have lower target pressures. We must realize, however, that the initial target pressure is just a guess based on risk factors. After measuring a patient’s individual rate of progression, target pressure should be redefined (cf. below) (European Glaucoma Society 2008; Heijl et al. 2010). Today patients with glaucoma should be followed not only with tonometry – to ensure that the target pressure has been met – but also with repeated measurement of glaucoma damage. It is only by measuring damage that we can assess rate of progression to see whether the initial target pressure was adequate or whether target pressure has to be lowered further and treatment be stepped up. Currently, it is preferable to measure damage with perimetry for two reasons: One is that perimetric results are results of visual function testing. They show how much visual reserve that is available, and we know pretty well where on the visual field scale that QoL is affected in a clear way. Certainly, structural parameters frequently show progression in patients with glaucoma, but the agreement with perimetry is small (Chauhan et al. 2001; Leung et al. 2011). With structural testing, this relationship is presently quite unclear. Further, we still do not have tools to translate structural measurements, like optic disc rim area or retinal nerve fibre layer thickness, to the functional domain. Another reason to presently prefer field testing is the earlier recognition of progression with perimetry than with structural testing (cf. above) and probably a smaller test-retest variability of global visual field measures (MD or VFI) than of global structural measurements (Jampel et al. 2006). Currently, structural testing, particularly with OCT, is very helpful for diagnosis (Bengtsson et al. 2010), but probably considerably less valuable for follow-up of patients with established glaucoma with field loss. This may change in the future with the present fast development of imaging and for statistical of imaging The diagram is very in glaucoma management (Fig. This diagram has age on the and a global index of visual function on the the index is MD that for the mean deviation from the normal deviation is in A normal visual field has an MD of while a perimetrically blind eye has an MD of approximately dB or even in the The MD in the is very similar but has a in MD in the means mean perimetric test results over time in the diagram an and of how a glaucoma eye is The diagram is a and in modern glaucoma is on the and visual function on the with function The unit on the is mean deviation in the or mean in the can be for example, at the level of MD dB or a of quality of life is clearly and reduced in patients who have field loss at this level or in eye. A of glaucoma management is to loss of QoL Glaucoma Society QoL is often not in patients with glaucoma. Patients with glaucoma as a often show no in QoL with when with QoL tools et al. or with tools when analyses are et al. 2008). patients with glaucoma in quality of life even when with QoL et al. 2009). of life is certainly to the of disease and with MD and in patients with glaucoma et al. et al. et al. while to remain until very late disease et al. at least in some studies. Yet, some studies have identified reduction in QoL even with visual field loss et al. 2008). It is therefore difficult to define a target for visual field loss. There is pretty good however, that QoL has certainly been reduced when at least half the visual field has been lost in a patient’s best eye, that is, at an MD of approximately dB or This, of course, not mean that progression at levels is but at least visual function the dB level during the patient’s remaining is an important which is not always to There are similar in most (Fig. but despite the fact that they have been available in all and for more than 20 are to most and much deviation have been available in the and for over 20 years. if they do not have age on the and even if the time of the is not to the time between tests, they are very valuable tools to assess disease clear for clinical tools have been much and do not even know that they have to A modern development of the diagram in the in the glaucoma progression (Fig. The new diagram has been developed to be as as It has also been on the same of as the of the most recent two with the that clinicians will the as a for all patients with glaucoma who are followed up over time, so that the is always in glaucoma care. In this MD has been with – the which is in of in (Bengtsson & Heijl 2008). The time is and shows the patient’s age now and also for the first and for all follow-up The modern of the of the is an rate of progression. data are the will be up to 5 an guess of how the patient will progress if treatment is not or if IOP approximately the of is quite A few years after diagnosis with enough data in the it is quite to see the It is important to at the of the than at the The is often of considerable even if it is statistically are in and in the of the As should the for the patient’s some more to see whether the is associated with great risk of loss of QoL. treatment should be the functional of both eyes is of but in are often made for eye Therefore, while the or the field in the eye, is of we should at the development of eye and treatment After 2 or 3 years of repeated visual field testing, rate of progression can be with some The of the is the for the patient’s remaining the risk of loss of quality of With a and treatment can be while with a very change of target must be In the common should consider lowering IOP further particularly if this can be with little risk of of The diagram may also be at diagnosis or during the first few years after diagnosis, when rate of progression has not been The functional of eye may be in the Initial treatment can be made on the risk of future loss of QoL (Fig. level of functional damage and patient and life are of great if we cannot guess the rate of progression of the individual patient or eye, a as shown in the and may be of some It is of not difficult to that a glaucoma for example, years of has a much larger risk of loss of QoL than a considerably patient with the same level of damage. is it difficult to that between two patients of the same age but with considerably levels of the patient with more damage is at larger or at age and level of damage in an diagram is so and that it might us to treat patients with both lower target pressures and increased and follow-up in patients at higher the diagram can help us not glaucoma management in patients with very little who therefore have a very small risk of of QoL. rate of progression has been this diagram with and could be of some The between the the rate of progression in a large study of clinically treated patients. The two eyes in that have the same of have very to progress to the with more damage. The eye with has a much higher because the younger patient has a longer life in with two eyes of patients of the same the eye a much higher risk of field loss and In where the measured rate of progression is may the diagram to consider other treatment the measured rate is much higher than may that IOP must be reduced quite measured IOP levels have been the new target levels must be very probably which will changes of In where progression rates and are not so but still may the diagram to to the effects of small and reductions of the progression rate. the results on the relationship between risk of progression and IOP from the large trials (cf. a guess is that the rate of progression may be by per mmHg of further IOP Also reductions in which may be by more going to or laser may in considerable over a long-time perspective (Fig. The patient may years large of QoL. a very extra reduction of IOP may make a difference in the long years of good and quality of on glaucoma has increased considerably during the last and glaucoma management can now on a much evidence-based foundation than Treatment and treatment effects are large. IOP levels cannot be great in of and treatment must be to the individual needs of Treatment at of and thus this risk must be part of all management We have learned that progression is the even in patients who always have IOP readings within the statistically normal range. The individual rate of progression is very and to pressure therefore is an guess only and must be on disease that is, progression of glaucoma damage. is not Therefore, a new standard in modern glaucoma management is the need to establish individual rates of progression in the great of patients with manifest glaucoma. This will more frequent perimetric examinations during the first few years after diagnosis, than has been common in the of life is to visual field The diagram therefore is a in modern glaucoma diagnosis, this diagram with the and concept can be used to help the initial target pressure and initial treatment. After a few years when glaucoma damage has been or and rate of progression has been the diagram can help us whether the measured rate is or that it can also be used to help the long-term effects of changes of treatment and to identify those patients who need changes to treatment before too much further visual damage has occurred. The changes needed to standard glaucoma care to a level where we can always a patient’s question on how he is over time, and on the of future are not and the of perimetry are larger to progress than of of glaucoma is not an disease for and healthcare perimetry is not very As an example, increasing the of visual field testing in from an average of field test every second year to every year has a lower for the whole than a on every year. not that it is up to us as a and to patient to to change the Glaucoma management needs to be Treatment and follow-up should be to the needs of based on the risk of future of QoL. In this way, we should be able to the of glaucoma damage and the of impairment by glaucoma.

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