Progress and Lack of Progress in Glaucoma (2010)

We have come to the end of the first decade of the third millennium. And this issue of Acta Ophthalmologica contains mainly contributions dealing with glaucoma directly or indirectly. It is interesting to look at these contributions and reflect for a moment on glaucoma research. Are we making real progress or are we not? Should we do things differently? Glaucoma used to be identical to elevated IOP. This of course is not true true any more. Yet, glaucoma has a lot do do with IOP. IOP is what we treat and it is the centre of interest for us a lot of the time, and also in many (or perhaps most?) papers about glaucoma. A review paper in this issue by Peeters and co-workers emphasizes the large effects of IOP reduction. The authors performed a meta-analysis of papers on studies of patients in ocular hypertension and found that the risk of conversion to glaucoma decreased by 14% for every mm Hg of IOP reduction. They could not perform a meta-analysis of OAG patients, because they found only one study. This, of course, is new and solid knowledge. Peeters’ meta-analysis paper on the effects of IOP reduction on glaucoma progression pin-points one of the areas where the most important firm knowledge has occurred in the last decade. We now all know the very large effects of IOP lowering, and that pressure lowering is of benefit in progressing glaucoma eyes also if IOP levels are normal. It would now be useful and interesting to find out if the effect of IOP lowering increases with lower IOP levels. It seems reasonable to assume that an eye progressing at 15 mm Hg would have more benefit from 2 mm Hg extra lowering than an eye with an IOP of 22. And how can we determine or even guess if extra IOP lowering will slow progression or whether the observed worsening of a glaucoma eye with low pressures is actually do to factors other than IOP? Many papers in this issue address surgical issues. Ollikainen et al conclude after a 1 year prospective study that the mitomycin-augmented deep sclerectomy seems to have the same effect in POAG and exfoliation glaucoma –encouraging outcomes with low post-op IOP values and no serious complications. Another group from Finland found the same procedure effective in normal tension glaucoma, also with the same short follow-up of only one year. Surgery reduced mean IOP from 15.1 to 10.5 mm Hg. That is very valuable information considering how much more difficult it is to lower IOP in NTG patients at such pressure levels with medication and laser (cf. the paper by Heijl et al in this issue). Anand and Pilling reviewed laser goniopuncture after deep sclerectomy. Just as Ollikainen, they found that goniopuncture was used in the majority of patients. This makes me reflect on whether we ought to use the term non-penetrating surgery at all… There is a small study that I particularly like in the current issue. Papaconstantinou and co-workers performed a rather small, but prospective and randomized glaucoma surgery trial. We do not have a lot of those. Usage of the OloGen implant did not seem to influence the results of trabeculectomy. There are issues of statistical power with all negative studies, and the authors correctly conclude that their results need confirmation in other studies. Nevertheless, I feel that it is particularly important that negative results are published - also if the power is not very high. Positive publication bias is strong, and many therapeutic and diagnostic procedures are uncritically accepted by the ophthalmic community, often because of effective marketing. It is important that inventions with questionable value are identified as early as possible. A whole group of papers in the current issue address management of “difficult” glaucomas – those relatively unusual patients who always present us with challenges. Vuori from Finland reports very positive long-term results with Molteno shunts in uveitic glaucoma, 85% qualified success rate after 4 years. A consecutive case series of refractory glaucoma eyes treated with diode transscleral cyclophotocoagulation is reported from Italy with relatively good success. Two papers studied effects of bevacizumab in neovascular glaucoma. The study by Saito and co-workers is at least partly controlled involving 2 series of consecutive operations, first 32 eyes with neovascular glaucoma that underwent trabeculectomy without bevacizumab, and then 20 eyes undergoing the same procedure and also received intravitreal bevacizumab before the glaucoma procedure. There were large differences between the groups with the bevacizumab group having the better results. In a un-controlled German study of 20 eyes with neovascular glaucoma bevacizumab was given intravitreally – often repeatedly - and combined different other treatment modalites. Mean post-op IOP was satisfactory. A rather large American retrospective study reports IOP reductions after conventional cataract phacoemulsification – in non-glaucoma eyes. The results confirm that IOP goes down after such surgery and that the reduction persists of 2 years. My own group analyzed IOP reduction on a fixed treatment protocol in the Early Manifest Glaucoma Trial. We found that IOP reduction was extremely dependent on untreated IOP levels, with larger reductions both in mm Hg and expressed as percentages in eyes with higer baseline pressures. Actually each mm Hg higher untreated IOP was associated with an average of 0.6 mm Hg additional IOP lowering. The results indicate that discussing differences in IOP lowering potency among drugs becomes rather meaningless unless untreated IOP levels are taken into account. Three contributions in the current have are related to blood flow. Siesky and co-workers found reduced IOP and improvement of some parameters in retinal blood flow when dorzolamide was added to timolol in healthy subjects and patients with glaucoma. In a study using flowmetry Fadini et al. found evidence of increased levels of indicators of endothelial vascular dysfunction in patients with glaucoma and ocular hypertension as compared to control subjects. Ritch and co-workers noticed pseudoexfoliation material in many eyes with central retinal vein occlusion, even when pseudoexfoliation could not be seen at the clinical examination. Bozkurt and co-workers describes the diagnostic performance of the HRT in a Turkish population comparing analyses with the Moorefields algorithm and the Glaucoma Probability Score. The diagnostic accuracies of both methods were only moderate, with the Moorefields regression coming out somewhat better than GPS. In this issue we also see a description of a something entirely new. The tight orbit syndrome. Six patients from two centres are described. Time will tell if this is a new valuable notion. Well, looking at these articles as examples and as indicators of research areas within the glaucoma field: are we making progress ? have we made significant progress within the last decade? what should we do now or more of? The large number of papers on glaucoma surgery show that we have actually made progress. Some of the newer techniques show very promising results. Anti-VEGF seems valuable in neovascular glaucoma (in small controlled(!)trials) In many papers a lack of controls make conclusions difficult or non-convincing, however. This issue demonstrates what we all know: There is a need for more prospective, randomized and controlled studies on glaucoma surgery. This is not an ethical problem; several of the large prospective glaucoma trials starting in the 90’ies managed these problems well. This is a challenge that glaucoma surgeons should accept! The blood-flow related contributions in this issue are also in agreement with the general impression from this research area. Lots of research, but conflicting results, probably no really convincing clinical progress. The researchers themselves often point out how difficult it is to measure ocular blood flow relevant for glaucoma, and that there many techniques available, partially a sign of a lack of ideal techniques. Blood flow in glaucoma is thus similar to neuroprotection: a lot of optimism, largely unsupported claims from industry, positive publication bias. We still need to see long-term, randomized, prospective clinical studies of agents influencing ocular blood flow where visual function and possibly quality of life are the outcomes. The HRT paper also reminds us of the considerable progress that has been made in glaucoma imaging in the last 10–15 years. Again: no diagnostic methods are perfect. Diagnostic accuracies are only moderate – but at the same time we know that they are on par with glaucoma expert, which is quite impressive in itself! All these diagnostic papers remind me that we again we need long-term, longitudinal studies comparing several different methods for follow-up, always including visual function, and preferably assessment of quality of life. Preserving visual function and QoL after all is what glaucoma treatment is all about. In the great majority of glaucoma patients it is much more difficult to make management decisions during follow-up, than to make a diagnosis of glaucoma – often a very easy task the very first time that the patient comes for an examination. So: Yes we are making progress. We now stand on a much firmer ground in many areas, than what we did the end of the last millennium. And we have new therapeutic and treatment modalities with promising results. But there is a lot of work to do for those who want to contribute: in clinical glaucoma research many long-term, controlled studies are needed. They take time, but they can improve glaucoma care.