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Reports SOE, Stockholm, Sweden, June 1999
Non Perforating Filtering Surgery
Chairman: E.L.Greve
Speakers: R. Carassa, T. Kozlova, A. Mermoud & P. Palmberg
This report summarizes a discussion symposium that was held at the SOE with Roberto Carassa, Erik Greve (chair), Tatiana Kozlova, Andre Mermoud and Paul Palmberg.
The technique of Non Perforating Filtering Surgery (NPFS) that was already subject of several presentations at the Vth Congress of the EGS in Paris 1996 has received increasing interest. Its major claim is reduced complication rate.
The technique involves a large scleral flap (after conjunctival opening) of about one third scleral thickness, a second scleral excision inside the first flap up to a thin scleral layer covering the choroid, preparation of this flap into the roof of Schlemm (unroofing) and into the cornea, thus creating a "descemets" window, suturing of the first scleral flap.
In deep sclerectomy a collagen gel may be left, in viscocanalostomy a visco-elastic is injected in Schlemm's canal and under the scleral flap. These are not easy techniques, everyone agrees.
Postoperative IOP
Reported mean IOP's post-operatively are in the 16-17 mmHg range (Stegmann, Kozlova, others) with the notable exception of Mermoud who claimes lower IOP. Mermoud reported in the B.J.O. that 40% of his patients need additional medication after 3 years. Kozlova after 15 years of experience with her technique reports success values of 87.5 % including medication; Stegmann 82.7 % with / without medication.Kozlova with by far the longest experience after 5 years still has IOP between 16 and 20 mmHg. She stresses that she has the same results after trabeculectomy.
In 20% to 60% of cases later YAG goniopuncture is necessary to perforate Descemets membrane and further reduce IOP. This may happen up to three years post-operatively.
Carassa suggested that there is a trend for IOP's to increase over time. Mermoud said that he obtained lower post-operative IOP's in NPG with a larger scleral lake and use of mitomycine (MMC). He did not have sufficient data on each modification (scleral lake, MMC) separately.
As for the visual field only Kozlova described some results with 26 % of advanced visual field defects deteriorating and 8 % of early or moderate fields. Similar results were found by her after trabeculectomy.
Palmberg compared her results with 5% deterioration with post-operative IOP's of around 11 mmHg after trabeculectomy with antimetabolites. He said that in the AGIS study the results for trabeculectomy without antimetabolites at 5 years were 15.5 mmHg with 20% suffering visual field progression (half of the patients were black). In Palmberg's own series with antimetabolites 2% of eyes were blind after 5 years versus 7% in the AGIS study. Based on IOP results and Mermouds lifetable analysis Palmberg feels that NPFS may show a progression rate of 30% at 5 years. It may be that most patients require reoperation in their lifetime. Palmberg warned that IOP's of between 16 and 20 mmHg on additional medication may not be sufficient to save the visual field.
Outflow and blebs
As options for post-operative outflow pathways the subconjunctival space, intrascleral lake and aqueous veins, suprachoroidal space and Schlemms canal were suggested. Most outflow goes through the anterior meshwork and descemets window according to Mermoud. It is not known how much flow proportionately goes through each of the four options.Both Kozlova and Carassa have used UBM for finding outflow routes. Kozlova confirms subconjuntival and suprachoroidal exits. The role of Schlemms canal and aqueous veins in the long term post-operative period remains to be established. Mermoud found blebs in 60% of cases. Carassa describes blebs in 34 %.
Complications
The complication-rate is less in NPFS compared to standard TE both in comparative and historical studies. In a different symposium Lachkar(Paris) reported that after one week postoperatively he could not find a difference in complications after NPFS and trabeculectomy. There may be two reasons for the reported early differences in complications: 1. Reduced inflammation. 2. Reduced bulk outflow in the immediately post-operative period. The panelists agreed that the reduced inflammation was mainly related to not doing the peripheral iridectomy. Thus a TE without peripheral iridectomy may be comparable in this respect. The question then remains whether outflow can be better controlled by the non-perforated Descemets and trabecular membrane than by a scleral flap. Mermoud felt that that the membrane was much more reliable in this respect, whereas Palmberg said that with his TE technique he can adequately control post-operative IOP. The answer will have to come from a comparative study by. It remains to be shown that NPFS is superior to TE without peripheral iridectomy and a well sutured and suture released scleral flap.We do not know what the effect of fibrosis inhibitors on NPFS will be although Mermoud suggests the expected outcome of lower IOP.
The major advantage of NPFS seems to be the type of bleb: mainly intrascleral. This applies to the non-MMC supported NPFS.
Neither Stegmann nor Carassa use collagen gels. They use visco-elastics. A comparative study on the use of implants by Mermoud claim better IOP's with the implant. Such studies for visco-elastics are not available. Hamard et al have suggested that the effect of collagen gel is similar to that of 5FU.
There is little doubt that NPFS deserves the increased attention. The most exciting aspect is that intra-scleral filtration may avoid some of the late complications of modern filtering surgery.
Our present day TE technique may be improved. An alternative TE without peripheral iridectomy, with post-operative pilocarpine and scleral lake and well sutured scleral flap may be a technique available to many surgeons. What then is the place of NPFS in glaucoma surgery and what additional evidence do we need to establish that place?
1. We need long-term randomized studies on the effect of NPFS on visual function compared to TE with MMC.
2. We need more knowledge on the separate aspects of the technique and their relative value: non-peripheral iridectomy, non-perforation, scleral lake, role Schlemm's canal.
3. We need to know more about the relative contribution of the four possible outflow pathways.
4. We need to know the effect of fibrosis inhibition.
So far it is concluded that the NPFS technique, and each of its parts, deserves extensive further study. Its role in advanced glaucoma and any other glaucoma that needs relatively low IOP's needs confirmation.
Erik L. Greve
From a comment by David Epstein on Glaucoma-net, re: non-perforating filtering surgery
First, let's be clear: you can cure (outflow pathway) glaucoma by making three tiny perforations into Schlemm's canal (SC) (e.g., with a YAG laser) evenly spaced around the circumference of SC. This bypasses the abnormal resistance to outflow, probably allows an intraocular pressure (IOP) in the low teens due to the remaining distal resistance, no bleb, and allows circumferential flow in SC unless the canal has collapsed. This is very simple and deserves more attempts to be made at creating new methods. However, what happens is that these perforations heal (except sometimes in juvenile glaucoma). If there were a method to keep these perforations into SC open, either ab interno or ab externo (see below), the glaucoma field could be moved much further.
For those who would like to have further details and citation with regard to the various questions:
1. Using an ab interno approach, Grant first identified the site of normal and abnormal resistance to be at/just proximal to the inner wall of SC. This behaved in a segmental manner, in that the entire circumference of the angle needed to have the internal wall of SC incised to eliminate all this resistance (R). This is because of the very limited circumferential flow in SC (and this has implications for those of you who believe your new surgery works by exposing the cut ends of SC, which in fact usually collapse regardless). Also, this explains why, in appositional angle closure, you get a proportionate effect depending on the extent of closure: if there were true circumferential flow in SC, then as long as part of the angle were open, the IOP would not rise. So outflow is segmental. (If you bypass the TM with a filter type operation, then none of this matters, but if you believe that, in your surgery, you are only eliminating the R in the operated segment, then you should not expect a large IOP effect from one clock hour of the circumference!)
On the other hand, there is some limited circumferential flow in SC such that above three evenly spaced holes into SC would work. This was thoroughly studied by Van Buskirk who, interestingly, found that simulated ciliary muscle contraction (by analogy pilocarpine which you are also discussing) can increase circumferential flow in SC.
Another important point is that Grant had to cleanly incise the inner wall of SC in order to get these effects. When he had previously tried just to strip TM away (as you might do in curettage), he got variably negative results, which at first misled him.
2. No-one talks about it, but there is normally some important resistance to outflow distal to the outer wall of SC (see Rosenquist et al., Current Eye Research 1989;8:1233. Note: 'major' journals did not think that it was an important subject!). In Grant's study, he eliminated 75% of the R with internal goniotomy, which left 25%, but he conducted his experiments at elevated IOP = 35 mmHg. When Rosenquist did this at normal IOP, 40-50% of the R was distal! When is this locus? No-one knows! Glaucoma grant applications to study this further were turned down! However, this normal distal R is why, if you eliminate proximal R, you will not get very low IOP or bleb problems.
3. Sinusotomy: the original concept from Nesterov was that there were glaucomas with abnormally high distal R (this was not found in Grant's studies). However, the surgery worked (for a time). However, when studied experimentally by Ellingsen and Grant (and perhaps also later by M. Johnstone, and possibly Mike Van B), it was found that, when you unroofed SC, you lost support for more proximal tissue, so what happened was that the inner wall now herniated/ruptured into the external gap, and so, in a sense, similar to the above, you were also violating the inner wall and JCT. Also, very frequently by now bypassing through this hole through the outflow pathway tissue, a filter was being created. This all sound familiar to the current NPFS discussion in which, if you are disrupting Descemet's, I think that you are probably creating a bypass of the normal outflow pathway and a form of filtration surgery perhaps into an intrascleral lake, which I think might be an important new wrinkle in terms of 'deep filter'.
What would make sense to me for NPFS is the same as for the above sinusotomy consideration, that directly or indirectly (through herniation of the inner wall/SC into the gap), the outflow pathway is actually being bypassed and a form (perhaps a new important form with an internal lake) of filtration surgery is being created. Only eliminating the R of the intact outflow pathway in the operated segment part of the circumference could not be expected to produce such a large IOP effect. On the other hand, it is always possible that the old observations above, while accurate, have some other explanation, and so there is reason to pursue this further both clinically and experimentally. We still know so little about both normal and abnormal R in glaucoma, so all this might help us with important new information!
(The Rosenquist article mentioned above contains many of the classic references for this discussion.)
David Epstein
Chairman: J. Jonas
Speakers: E. Garway-Heath, R. Burk, R. Ramrattan & R. Weinreb
The optic disc symposium included five presentations. T. Garway-Heath and R. Hitchings reported on problems in detecting progression in imaging of the optic disc. They described the Heidelberg Retina Tomograph (HRT) as an example of a confocal laser scanning tomograph, and concluded that the ability to detect progression, functional or structural, depends on the reproducibility of the measurement method employed. The reproducibility of the newer forms of fundus imaging was compared to that of visual field testing, and the advantages and disadvantages of the various methods were discussed. Different approaches to the statistical analysis of measurement data to detect progression were outlined, and the clinical significance of detectable changes was considered. One approach to analysis was illustrated with an example to show how measurement data of optic nerve head structure can influence patient management.
R. Burk described patterns of optic disc change in the follow-up of glaucoma analyzed by scanning laser tomography. An upcoming new software version of the HRT showed very promising results in the early detection of progression.
R. Ramrattan and P. de Jong reported on the optic disc data found in the Rotterdam study, which is a large epidemiological study. Using
an image analyzer to measure the disc characteristics on stereoscopic simultaneous optic disc transparencies, de Jong, Ramrattan and colleagues found a mean optic disc area of 2.42 mm² and a mean neuroretinal rim area of 1.85 mm². Age was not a determinant of size and shape of the optic disc, optic cup, or neuroretinal rim. Disc and rim areas were slightly (3.2%) larger in males than in females, and for each diopter increase toward myopia, the disc area increased by 0.033 mm². The disc area increased by 0.02 mm² for each 10-cm increase in height. Beta zone of parapapillary atrophy was associated with increasing myopic refractive error.
R. Weinreb described the evaluation of the retinal nerve fiber layer, using different techniques including clinical ophthalmoscopy, retinal nerve fiber layer polarimetry, confocal laser scanning tomography, and retinal nerve fiber layer photography. He emphasized the importance of examining the retinal nerve fiber layer in all subjects at risk for optic nerve damage and in all patients with already proven loss of optic nerve fibers.
Finally, J. Jonas described the simple ophthalmoscopic approach for assessing the appearance of the optic nerve head in normal subjects, glaucoma patients, and patients with nonglaucomatous optic nerve damage.
Jost B. Jonas
Anders Heijl
Glaucoma management against a background of epidemiology, quality of life and cost
Chairman: A. Heijl
Speakers: B. Calissendorff, A. Tuulonen, Ü.-B. Bramdahl & P. Roos
Dr Calissendorff discussed blindness and glaucoma. She reported results from a survey of all patients known at low vision centers in the Stockholm area, and emphasized that the risk of blindness in glaucoma is small. Glaucoma is not the main reason for blindness or seriously impaired vision in patients who have glaucoma. Other diseases, particularly ARMD, are more frequently the cause.
Ms Bramdahl discussed glaucoma from the perspective of patients with the disease. The patient has to take the final responsibility for himself and his disease, but this requires complete and relevant information on the disease, the prognosis, and the reasonable treatment alternatives. Patients today often experience difficulty in obtaining enough relevant information from their ophthalmologists. Ms Bramdahl advocated increased cooperation between patients with glaucoma and all categories of personnel, who take part in the care of these patients. Enough time must be spent with the patient to provide a proper perspective. Correct information will more often alleviate excessive anxiety than create unnecessary concerns.
Dr Tuulonen also stressed that there is a constant need for better patient education on the implications of glaucoma. The coordination of care between different health professionals is essential for high quality services. A mutual understanding of the importance of glaucoma care between professionals and patients can improve the health-related quality outcomes of this disease. It would also be possible to improve the efficacy of glaucoma health care systems by developing the care processes. In addition to clinical and quality aspects, economic assessment should be incorporated into future treatment guidelines.
Dr Heijl looked at the disease from an epidemiological point of view. Half of all patients with glaucoma remain undetected, and a very large percentage of these patients have normal tension glaucoma. Ocular hypertension is common and does not usually lead to glaucoma. The value of our conventional pressure-lowering treatment in glaucoma is unknown, and a meta-analysis of three studies addressing pressure reduction in ocular hypertension has shown that we do not know whether such treatment can reduce the incidence of glaucoma damage. Important ongoing trials will provide us with extremely important information, both on the effects of intraocular pressure reduction and on risk factors for glaucoma. The results of these studies may change ophthalmic practice within the coming decade, and may, for example, precipitate increased screening for patients with undetected glaucoma.
Dr Roos discussed the costs of glaucoma health care, comparing the costs of detection and of various types of follow-up in patients with glaucoma and ocular hypertension. In the management of glaucoma, cost minimization and output maximization are two objectives which may or may not be achieved by the producer. The reported study indicated that overall efficiency could be improved by the better allocation of costs between detection, control and treatment.
The discussion and the reactions from the audience confirmed that it may be fruitful sometimes to look at the management of glaucoma from a broader perspective than just our conventional ophthalmologists' view. We must remember that our first duty is to serve our patients and society. Both need high-quality information and advice, and the cost effectiveness or lack of such effectiveness in our medical care is of importance to both patients and health care providers.
Anders Heijl
Juhani Airaksinen
New options in the medical management of glaucoma
Chairman: J.P. Airaksinen
Speakers: W. Stewart, C. Migdal, S. Miglior, R. Allen & M. Wand
The first speaker was William Stewart who reviewed factors influencing noncompliance in glaucoma. He reported that a number of factors may influence compliance, including those related to the disease itself, the medicines prescribed, patient-physician communication, and the patient's own circumstances. He thought that fixed combination glaucoma drops will be one of the factors to reduce noncompliance.
Clive Migdal presented a review on target intraocular pressure (IOP) that is perhaps between 10 and 12 mmHg in some patients and 18 and 20 mmHg in others. He reported that target IOP will need to be adjusted during the course of the disease according to the severity of the glaucomatous changes, such as optic disc damage and the status of the visual fields. He also pointed out that a large proportion of all glaucomatous optic nerve damage occurs at lower IOPs, since these comprise the bulk of the population. Patients with higher mean IOP levels tend to show progression, while patients with lower IOP levels tend to be more stable. He concluded by pointing out the importance of assessing each patient individually.
Stefano Miglior reported on the ongoing European glaucoma prevention study. This study is being carried out in four European countries: Italy, Belgium, Germany and Portugal. The centers have now collected 1100 patients, and the recruitment period is over. The aim of the study is to determine whether, in patients with ocular hypertension, the reduction of IOP will lower the incidence of POGO.
Robert Allen gave an overview of published clinical trials on fixed combination dorzolamide-timolol in terms of efficacy and safety profiles. Patient acceptance of fixed combination dorzolamide-timolol is similar to results obtained in clinical trials. Also, the fixed combination was more efficacious than monotherapy.
Finally, Martin Wand reported on a study of dorzolamide-timolol fixed combination therapy compared to the concomitant administration of a topical beta-blocker and dorzolamide. He found that the fixed combination therapy achieved superior IOP control compared to concomitant administration of a beta-blocker and dorzolamide. He concluded that the likely explanation for this is improved compliance and elimination of a washout effect.
Juhani P. Airaksinen
Albert Alm
Targeting the neuroscleral outflow: the new approach to intraocular pressure reduction
Chairman: A. Alm
Speakers: M. Diestelhorst, R. Weinreb, C. Migdal & P. Kaufman
Diestelhorst gave an update on clinical studies on latanoprost. A number of studies by different investigators have verified the efficacy of the drug observed in the phase III studies.
Weinreb presented data from his laboratory on the mechanism of action of latanoprost. Studies on cell cultures and in vivo studies on monkey eyes have shown that latanoprost, as well as the natural prostaglandin F2a, induces changes in the extracellular matrix of the ciliary muscle, with a reduction in the amounts of collagens. The reorganization of the extracellular matrix would explain the decreased resistance to flow through the muscle.
Alm presented the concept of 'target pressure' which is partly set by the level of the untreated intraocular pressure (IOP). In consequence, data from clinical studies on the pressure lowering effect of drugs, laser or surgery, should permit the clinician to find the likelihood of reaching any predetermined target pressure from the level of the IOP in the individual eye to be treated.
Migdal discussed the new situation of six different classes of topical drugs for reducing IOP from the perspective of both clinicians and patients.
Kaufman presented ongoing research on future candidates for increasing outflow, both through the uveoscleral and conventional routes. This includes drugs acting on the cytoskeleton as well as cholinergic drugs without a miotic effect.
Albert Alm
Steve Obstbaum
Glaucoma surgery into the next Millennium
Chairman: S.A. Obstbaum
Speakers: R. Carassa, P. Palmberg, A. Mermoud, R. Stegmann, L. Buratto & G. Baerveldt
Roberto Carassa presented the current concepts of surgical glaucoma management. Trabeculectomy with or without the use of antimetabolites is presently the accepted surgical treatment for primary open-angle glaucoma. The results with these procedures are favorable with regard to the reduction of intraocular pressure (IOP), although the absolute effects on visual function and quality of life remain only partially addressed. A major concern with the aggressive use of mitomycin-C intraoperatively is early wound leakage and the late appearance of bleb defects and endophthalmitis. There is a strong possibility that these complications are underreported. Trabeculectomy, however, is a successful procedure in the majority of cases, and is associated with satisfactory pressure reduction. There is a loss of effectiveness with this procedure with the passage of time.
Paul Palmberg discussed the problems related to postoperative hypotony and bleb defects associated with the use of antimetabolites in filtration surgery. He emphasized the beneficial effect on pressure reduction with the use of antimetabolites, and suggested that techniques are available to minimize these potential complications. He discussed the use of low concentration/short duration application of mitomycin-C and the creation of a corneal valve-like incision into the anterior chamber when fashioning the trabeculectomy. Once again, there is a question regarding the general ophthalmic experience with antimetabolites and how complications associated with their use are managed by general ophthalmologists.
André Mermoud discussed the technique of deep sclerectomy with a collagen implant (DSCI). The key step to this procedure is to create a dissection sufficiently deep to permit aqueous humor to percolate through the trabeculo-Descemet's membrane. Once this is accomplished, a cylindrical collagen implant is sutured into the scleral bed and then covered with the loosely sutured superficial scleral flap. Aqueous humor passes from the anterior chamber through the trabeculo-Descemet's membrane to the scleral bed and then to the subconjunctival space. If the IOP is not sufficiently reduced, Nd:YAG laser goniopunctures are performed. Eyes undergoing this procedure were compared with standard trabeculectomy. DSCI was slightly more effective than trabeculectomy, but there were fewer complications associated with the deep sclerectomy procedure. Almost one of four of the DSCI eyes required Nd:YAG laser goniopuncture.
Robert Stegmann presented his technique of viscocanalostomy. This procedure has been successful in reducing IOP in a black African population in whom conventional filtration surgery, even with the use of antimetabolites, had failed. A parabolic superficial scleral flap of approximately one-third the scleral thickness is initially created. A deeper parabolic dissection about 0.5 mm within the margin of the superficial dissection is generated so that the choroid is visible through the remaining scleral tissue. A paracentesis with removal of aqueous permits reflux into Schlemm's canal to make its identification easier. The deep dissection is carried forward into clear cornea and unroofs the canal. High viscosity sodium hyaluronate is injected into the ostia of Schlemm's canal to widen it and permit passage of the specially designed cannula a short distance into the canal on each side. The deeper scleral flap is then elevated while gentle pressure is applied at the base of the flap with a cellulose sponge. This maneuver creates the Descemet's window through which aqueous percolates. The deep flap is then excised and the superficial scleral flap secured with interrupted sutures. High viscosity sodium hyaluronate is injected beneath the scleral flap to fill the scleral lake, and the conjunctiva is closed. The proposed benefit of this procedure is that it reduces IOP without the complications attendant on conventional filtration procedures.
Lucio Buratto presented the current trends in combined surgery for glaucoma and cataract. These techniques take advantages of the advances in small incision cataract surgery with intraocular lens (IOL) implantation and the newer methods of glaucoma surgery. He discussed one site and separate site surgery, pupil management, the use of viscoelastic agents, implantation of a single-piece PMMA and foldable IOL, and the combination of either trabeculectomy or viscocanalostomy with the cataract procedure. The benefit of this combined surgery from the patient's perspective is that it is a single surgical event with little additional morbidity. However, whether combined surgery is performed, or cataract alone or with trabeculectomy at another time, depends on the severity of the glaucomatous process.
George Baerveldt discussed the evolution of the tube shunt used in glaucoma surgery. The principle of the implant is to shunt aqueous from the anterior chamber to a more posterior site where the plate portion of the implant is encapsulated. The use of these devices has generally been reserved for refractory glaucomas, particularly neovascular glaucoma. Newer designs and techniques of implantation have obviated some of the earlier problems associated with their use, yet the issue of early hypotony remains a challenge. Modifications of the presently used tube shunt implant permits its introduction into the vitreous cavity in eyes in which there is insufficient space in the anterior chamber angle. As the designs of these implants make them easier to implant, it is anticipated that their use will be expanded.
Steve A. Obstbaum
Cell death and neuroprotection
Neville Osborne and co-workers wrote - amongst others - two reviews: one on ganglion cell death in glaucoma and one on neuroprotection.
We have published here in IGR I/2 a short "birds-eye" view of the reviews and the authors summary of a symposium on the subject at the SOE, June 1999 in Stockholm.
This staccato and incomplete abstract highlights certain issues discussed by the authors and is meant to stimulate reading of the original article in the British Journal of Ophthalmology.
Ganglion Cell Death in glaucoma: what do we really know?
1. What are the apparent characteristics of ganglion cells in glaucoma?
· Optic nerve axons and retinal ganglion cell somata do not die at same time
· Glaucomatous optic neuropathy may be a series of acute losses of individual, or groups, of ganglion cells.
· Only some ganglion cells are dead, whereas others may range from being "unhealthy" to being "slightly sick" while others are "perfectly normal".
2. Are certain retinal ganglion cells particularly susceptible?
· The evidence to suggest that certain ganglion cells in the retina are inherently more vulnerable than others is not overwhelming.
· The view that large ganglion cells of a type which is related to the magnocellular pathway are particularly susceptible is based on histology with all its problems.
· Somata size of the same ganglion cell will appear, in pathological tissues of glaucoma patients, to be smaller than in normal retina.
· Data from psychophysical tests do not support the histological data.
· It is a perception only that there is a preferential loss of larger diameter ganglion cells.
3. What initiates ganglion cell death in glaucoma?
· We need to concern ourselves with issues such as why individual subsets of ganglion cells are initiated to die in the first place, what initiates subsequent subsets to die, and whether the process of death initiation for different subsets of ganglion cells varies.
· A further possibility to consider is the concept of secondary degeneration.
4. Damage to ganglion cell axons.
· Excavation of the optic disc may indicate that ganglion cells die because of an insult to their axons.
· Blockage of axonal transport has been demonstrated.
· Any malfunction of the vascular supply to the optic nerve head may cause ischaemic/hypoxic insults to the ganglion cell axons.
· It is possible that in the acute monkey model for glaucoma the blockage of ganglion cell axonal transport mechanisms is due to ischaemia/hypoxia.
5. Insufficient trophic factor(s).
· Axonal injury results in retrograde neuronal degeneration.
· The cell body is deprived of a growth factor.
· Ganglion cell degeneration can be partially prevented by intravitreal administration of large doses of growth factors.
· The suggestion has been made that ganglion cells die in glaucoma because of lack of specific growth factors.
6. Overexcitement of the ganglion cells.
· The types of receptors associated with ganglion cells may be the most important reason to explain not only why ganglion cells die but also why they die at different rates.
· This information suggests that the death of ganglion cells in glaucoma is because of overactivation of ionotropic (NMDA and kainate/AMPA) glutamate receptors and that hypoxia causes extracellular glutamate to rise.
· Definite proof remains elusive.
· It is therefore possible that the variable complement of receptor types associated with different ganglion cells do not die at the same time in glaucoma.
· All neurotransmitters are released in excessive amounts in hypoxia.
· Evidence exists to support the view that at least some of the characteristic arcuate visual field loss in glaucoma could well be the result of changes at the level of the optic disc.
· The cause of the selective death of ganglion cells in glaucoma may ultimately prove to be a combination of factors.
7. Elevated glutamate in the vitreous humour of glaucoma patients: significance.
· Our present knowledge on the subject is restricted to a single study; the elevated glutamate could have originated from ischaemia, a malfunction in the way Muller cells metabolise glutamate, and / or a malfunction in the inactivation of released glutamate by two active transport processes.
· It is postulated that the combined effects of the extracellular neurotransmitters on a neuron will result in death if excessive overexcitement occurs.
8. How good is the evidence for ganglion cells dying by apoptosis in glaucoma?
· There is a problem in determining how a cell may have died in histological sections of pathological tissues.
· It is possible that in reality apoptosis and necrosis form a continuum at the extremes of a biochemically overlapping death pathway.
· The basis for suggesting that ganglion cell death in glaucoma is by apoptosis is not because of any conclusive evidence but more because of a lack of any firm demonstration of cell necrosis.
· The combined evidence for ganglion cells dying by apoptosis in glaucoma is not compelling.
9. So what is really known about ganglion cell death in glaucoma?
· It is clear that there remains a lack of definitive data as to why, how, and when ganglion cells die in true glaucoma. While some of our speculations and predictions stem from clinical observations, most come from data derived from animal studies. However, recognising the significance of data derived from animal models in relation to true glaucoma remains a problem. It is known that optic nerve crush, ocular ischaemia, and ocular hypertension will result in ganglion cell death but whether such data are of relevance, limited relevance, or of no relevance to true glaucoma cannot be judged with any degree of certainty. It could be argued that detailed answers to the questions posed about ganglion cell death in glaucoma can only be obtained by a series of studies on an animal model which precisely stimulates true glaucoma. Unfortunately, we are long way from achieving this goal. Realistic interpretation of data derived from studies on animal models may nevertheless yield data which, when viewed unbiasedly, may be of relevance to glaucoma, particularly in relation to the treatment of the disease.
Neuroprotection
The second review comes with an abstract of the author, which is reproduced here. Some of it is also covered in the paper on cell death. Like in the first review we have extracted some interesting statements, exclusively those that were in the cell death review.Abstract (736): Visual field loss in glaucoma is due to death of retinal ganglion cells. Reducing or slowing down the loss of ganglion cells in glaucoma, a concept known as neuroprotection, would appear to be the only way forward. This does not imply that treatment of risk factors, such as elevated intraocular pressure, must not be continuously implemented. In this paper we point out that very little is known about the mechanisms of ganglion cell death in glaucoma and that data derived from studies on the 'ideal animal model for glaucoma' must not be overemphasized. We also propose that the death processes of neurones in various diseases are fundamentally the same but vary in cause. Experimental data show that the death rate of neuronal populations is dependent on the impact of the insult and that neuroprotectants are more likely to benefit a patient in diseases in which the neurones die slowly, as in glaucoma, than in a disease in which the death of a set of neurones is rapid. We conclude that if a putative neuroprotectant can be administered in such a way that it reaches the retina in appropriate amounts and has insignificant side effects, it is likely to attenuate ganglion cel death and thus benefit the glaucoma patient.
Animal models and the development of neuroprotectants for glaucoma.
· An embarassing number of substances can be used to attenuate ganglion cell death when given just prior to or at the onset of the insult.· Because, by definition, no animal model can simulate what truly occurs in human glaucoma, the time spent producing "the best animal model to study glaucoma" may not necessarily be the west way of progressing.
· Although the hypertensive model may mimic human glaucoma in a closer way than the High IOP model, its usefulness for studies related to the neuroprotection of ganglion cells appears inferior.
· It seems reasonable from present evidence to propose that substances that protect against ganglion cell death in situ, irrespective of the model used, may potentially attenuate damage to these neurones in human glaucoma.
Potential use of neuroprotectants to treat ganglion cell death in glaucoma.
· The ideal characteristics for a drug to attenuate ganglion cell death in glaucoma include the ability to reach the retina in significant amounts following administration by an appropriate route and the elicitation of minimal side effects. Because it is known that moderate amounts of aspirin, melatonin, and vitamin E can be taken orally as a prophylactic by most patients without significant side effects, it would appear that their use as neuroprotectants in glaucoma is a possibility.· Drugs that reduce the release or stimulate the removal of glutamate would therefore theoretically act as neuroprotectants. Because the release and removal of glutamate are generally thought to be energy-dependent processes, the effectiveness of such putative neuroprotectants may be questionable. Using ionotropic glutamate receptor antagonists as neuroprotectants would probably be more successful.
· Antagonists such as memantine that have a low affinity for the glutamate site on the NMDA receptor may find a clinical use because they appear to be equally effective ameliorative agents and yet produce less side effects.
· Substances that act as non-competitive inhibitors of the NMDA receptor may also find a clinical use as neuroprotectants e.g. flupirtine, nitric oxide and ifenprodil.
· Substances that act further downstream than the receptor which include calcium channel blockers, scavengers of free radicals, chloride channel blockers, neurotrophins, and substances that prevent lipid peroxidation, apoptosis, or inflammation may be particularly worthy of consideration because treatment will be implemented after diagnosis.
· Whether any of the other substances can be taken orally or by some systemic route and fulfill these criteria is not known. It seems likely that the side effects of the majority of the substances will be too great.
· Alternative delivery routes of the neuroprotectant to the retina will have to be developed.
E.L.G
Neville Osborne
Neuroprotection to ganglion cell death: relevance to glaucoma
Chairman: N.N. Osborne
Speakers: J. Kitazawa, R.W. Nickels, M. Schwartz, L. Wheeler
Visual field loss in glaucoma is due to ganglion cell death. The main task in the treatment of the disease is to reduce or slow down the loss of ganglion cells. Treatment to date has concentrated on reducing raised intraocular pressure (IOP), but this only occurs in some patients. Additional therapies are urgently needed. One other possibility is for a drug to reach the retina and directly reduce the effect of whatever insult is causing ganglion cell death. This is generally known as 'neuroprotection'.
In order to develop suitable drugs for neuroprotection, it is desirable to have information on the mode of ganglion cell death in glaucoma. Only theories exist about how this may occur. For example, glutamate is elevated in the vitreous humor of glaucoma patients and one possibility is that it originates from anoxia/hypoxia to kill ganglion cells at variable rates depending on the cells' receptor profiles (Osborne). It then accumulates in the vitreous humor because the inactivation process for glutamate (re-uptake into neurones and glial cells) does not function adequately in anoxia/hypoxia. Another possibility is that glutamate may be 'released' from a sub-set of dead ganglion cells due to damage of their axons (Schwartz). The release glutamate then kills (secondary degeneration) other ganglion cells. If this is the case, then it is difficult to understand what glutamate accumulates in the vitreous humor because the normal inactivation process will still work.
The death of ganglion cells in glaucoma is more likely to be by apoptosis than necrosis. However, there is a lack of knowledge about the steps involved in the death of ganglion cells in true glaucoma, as opposed to what occurs in animal models or in cell culture experiments. The only evidence for ganglion cells dying by apoptosis in true glaucoma comes from histology. Now studies on animal tissues suggest that certain gene products are only activated in apoptosis when neurones are given a defined insult (Nickells). It follows that any two cells that appear to have died by apoptosis from histological analysis may, in fact, have died by different biochemical processes.
It is apparent from laboratory studies that there are various ways of attenuating ganglion cell death, despite the lack of clear biochemical information on the cascade of events leading to cell death. Two substances that are used to treat patients for raised IOP are betaxolol and bromonidine. Both these have now been shown to nullify ganglion cell death in animal studies (Kitazawa and Wheeler). This suggests that patients on such drugs may have had additional benefits, assuming they reached the retina. In the case of betaxolol, there is some weak evidence that this may be the case.
Although a case for neuroprotection in true glaucoma remains a theory, sufficient laboratory studies exist to give hope for the future. Better methods need to be developed to detect minute changes in visual field loss in glaucoma patients in order to prove a case for neuroprotection.
Comment by IGR editor: any neuroprotective agent will have to substantiate its claim by showing its effect on visual field survival.
Neville N. Osborne
