Low tension glaucoma: A bad concept that just won’t die. So how do you deal with it?

Harry A. Quigley

Glaucoma Service and Dana Center for Preventive Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

Drive a stake in its heart? Will that be the only way to kill the myth of Low Tension or Normal Tension Glaucoma? One of the great mistakes of ophthalmic history is the idea that those with open-angle glaucoma (OAG) who have normal intraocular pressure (IOP) are somehow different, have a different course, or really are not the same as other OAG patients. How did we get into this mess?

For many decades, in the era prior to disc photography, quantitative visual field testing, and epidemiological studies, the idea arose that OAG was the disease of ‘elevated’ IOP. Clearly, then, anyone who had something that looked like OAG, but had normal IOP was weird and should undergo neurological evaluation, imaging, and be told that they were going blind and there was nothing we could do for them.

Then, a series of population-based studies of persons with typical disc and field damage for OAG was performed. The investigators were surprised to find that half of those with OAG damage at the optic nerve had IOP measurements that were within the normal range. As the most modern studies have been done of those developing OAG under observation in populations, over half develop OAG without benefit of an IOP above the former magic number1,2 (which will not be mentioned in this paper). It is true that, on average, OAG patients have higher IOP than the non-glaucoma population. But, many of them never have ‘elevated’ IOP. We must simply rid ourselves of the prejudice that OAG must be associated with high IOP.

The new definition of OAG describes the disease as an abnormality of the optic nerve with typical cup and field findings. It has no level of IOP that defines the disease.1 The optic disc excavation that differentiates OAG from other optic nerve diseases has been repeatedly shown to involve a deepening of the lamina cribrosa opening at the disc that differs dramatically from neurological injury to the optic nerve, including that seen in disorders such as ischemic optic neuropathy.2 Simple loss of retinal ganglion cells, as seen in primary optic atrophies, causes the surface

Address for correspondence: Glaucoma Service, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA

Eye on the Bayou, New Concepts in Glaucoma, Cataract and Neuro-Ophthalmology, pp. 75–77 Transactions of the 54th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, February 18-20, 2005

edited by Jonathan D. Nussdorf

© 2006 Kugler Publications, The Hague, The Netherlands

of the disc to subside backward somewhat, and the whole disc becomes pale. In OAG, the central portion of the cup is deeply placed, but the remaining rim is pink.

It is actually quite rare to find a clinical example of conditions that look like OAG but are due to some other disorder. The clues to this situation are that those that are not OAG have:

•Pallor of the disc rim out of proportion to the degree of cup enlargement

•Field defects that do not match the asymmetry of the disc rim loss

•Central visual defects (acuity and color vision loss) prior to end-stage field loss

•Field findings that are homonymous or respect the vertical midline

•Rapidly progressive course

So, if low tension glaucoma is so common, why do people consider it to be rare? We clinicians live in an insulated world, seeing what is referred or self-referred to us. Those with higher IOP come from many sources, due to pressure screening systems. Those with normal pressures only come to attention when someone notes their disc is excavated, or the patient complains bitterly about losing central vision. Once we begin to count up the times we see OAG at normal IOP, we realize that it is quite common and commonplace to deal with.

Should we do cerebral imaging on those with normal tension OAG? This question, which I have been asked at every meeting at which OAG is discussed for twenty years, is a very important one. The answer is: if you are going to image normal tension glaucoma, then image high tension glaucoma. You have the same chance to find a brain tumor in both groups. Because they have the same disease. But, if the picture fits one of the non-glaucoma criteria listed above (the disc and field do not fit, the central vision is affected) then do the imaging. But, be aware that the patient who is sent for brain imaging will never forget the terror of being told he/she may have a brain tumor. And, an extraordinary number of imaging studies are read as showing ‘minimal atrophy due to vascular disease’ or ‘lucencies compatible with multiple sclerosis’. Over-reading of imaging studies is a cottage industry and is a permanent memory for any patient. We should not affect the quality of life of persons with a treatable disorder in the mistaken search for something they do not have.

Should studies that examine OAG divide patients into those with ‘low tension’? By dichotomizing OAG into two ‘groups’, researchers degrade the quality of their projects, and actually make it less likely that they will derive useful information. It has been often reported that there are ‘vascular’ abnormalities in low tension patients. But, it is equally likely (perhaps more so) that vascular phenomena are important as risk factors in higher pressure OAG as well. Studies that examine this issue should not cut the sample size of the study in half by looking only at those with normal IOP. The evaluation should be done by including all OAG patients and treating IOP as a continuous variable, which maximizes the determination of an IOP-dependent association with the factor of interest.

Al Sommer wrote: “If there is no such thing as an abnormal pressure, only pressures at which the risk of glaucomatous optic nerve damage is higher or lower than average, then there is no basis for the term low-tension glaucoma.”3 M. Roy Wilson wrote: “With respect to normal tension glaucoma, there is no such disease entity – distinct from primary open angle glaucoma – and it serves no useful purpose to continue to perpetuate this term.”4 How long will it be before

the correct concept of OAG and its relation to IOP is translated from the known scientific facts into appropriate clinical behavior?

References

1.Foster PJ, Buhrmann R, Quigley HA, Johnson GJ: The definition and classification of glaucoma in prevalence surveys. Br J Ophthalmol 86: 238-242, 2002

2.Danesh-Meyer HV, Savino PJ, Sergott RC: The prevalence of cupping in end-stage arteritic and nonarteritic anterior ischemic optic neuropathy. Ophthalmology 108:593-598, 2001

3.Sommer A: Intraocular pressure and glaucoma. Am J Ophthalmol 107:186-188, 1989

4.Wilson MR: The myth of “21”. J Glaucoma 6:75-77, 1997

Neuroprotection strategies from the research lab (‘cause there aren’t any ready for prime time yet)

Harry A. Quigley

Glaucoma Service and Dana Center for Preventive Ophthalmology, Wilmer Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA

We now know that open-angle glaucoma (OAG) happens at all intraocular pressure (IOP) levels. Thus, it is irrational to believe that the treatment should be to ‘normalize’ the IOP or to lower IOP below 21 as the goal of treatment.1 If we operationalize the concept that glaucoma happens at any IOP, then we should determine in each patient an average baseline untreated IOP. From this level, IOPlowering will occur. There is good evidence from recent clinical trials2,3 that lowering of IOP by 20-30% decreases progressive worsening in OAG by 50-60%. So, we have already got a means of neuroprotection, namely, lowering IOP.

It is logical that the target pressure should be lower when there is substantial damage already present in the visual field.4 But, how much should IOP go down? Some advocate decreasing it to 12 mmHg or less based on some clinical trials data. But, there must surely be a risk/benefit ratio associated with such lowered IOP and the treatments needed to get there. Furthermore, it makes no more sense to lower everyone to 12 than it did to use 21 as a magic number. So, the next steps in needed research are to determine the relative efficacy of various levels of IOP lowering adjusted for the variety of clinical pictures that present themselves in clinical practice. To some degree, this could be approached by new clinical trials in which two or more levels of target pressure are randomly assigned to the treated OAG patients – for example, 20% versus 40% lowering.

However, the ideal approach would be to tailor the target to the risk level of the individual patient. To do so, we would need risk calculations based on the known factors of each patient, and recalculated over time as new IOP, disc, field and other information revealed itself during follow-up. This should be a goal for us all.

Some portion of glaucoma injury is surely independent of the prevailing IOP and its fluctuations. To attack this area requires a different approach. If we examine the process of retinal ganglion cell (RGC) injury and death in glaucoma, there are clues about how new preventive strategies might be developed to preserve the

Address for correspondence: Glaucoma Service, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD 21287, USA

Eye on the Bayou, New Concepts in Glaucoma, Cataract and Neuro-Ophthalmology, pp. 79–82 Transactions of the 54th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, February 18-20, 2005

edited by Jonathan D. Nussdorf

© 2006 Kugler Publications, The Hague, The Netherlands

80 Harry A. Quigley

maximum visual function and quality of life for OAG patients. In both experimental models and human eyes with glaucoma, RGC axons at the optic nerve head show anatomic and physiologic injury.5 The death of RGC was found to occur through apoptosis, the reactivation of a programmed sequence of cell suicide.6,7 A logical link between these two facts would be to suppose that axonal transport blockade from the injury to RGC fibers at the nerve head produced an obstruction in a vital messenger molecule that would normally arrive back at the cell body in the retina by retrograde movement. This fall in messenger would initiate apoptosis. In embryological life, RGC know that they are properly paired with their brain center partners by receiving the appropriate messenger molecules from the brain. When they are misdirected and fail to reach the right target, the fall in messenger level leads to cell death. We proposed that this process repeats itself in adult life by the injury of glaucoma – in effect, pathology recapitulates ontogeny.

Indeed, the important messenger protein, brain-derived neurotrophic factor, is blocked from coming from the brain to the eye at the nerve head in experimental glaucoma.8 When it is provided to RGC by gene therapy in experimental glaucoma, a substantially lower number of RGC die, without lowering of IOP.9 This, then, is a potential neuroprotective therapy area. Whether the neurotrophin would be delivered by gene insertion, by injected cells carrying the gene and chronically expressing it, or by pharmacological delivery remains for further research.

In such clinical trials, non-IOP treatments that will be tested in humans will be entered in protocols that consist of large numbers of patients, all of whom will have some IOP lowering, and the neuroprotective agent will be tested in half of the sample for its additional benefit in slowing structural or functional loss.

Another gene therapy success was reported by McKinnon et al., when they inserted a gene that blocks a late stage of enzyme activation in the apoptosis process, again in the rat glaucoma model.10 Any method that prevents RGC death and preserves their function would be a welcome addition to our armamentarium. However, it makes sense to attempt to interrupt the process as early as possible in the cascade of pathological events.

Some early events occur at the interface between the RGC axon and its supportive and nutritional tissues in the nerve head. The level of IOP is transmitted to RGC by the corneoscleral shell, most critically the collagen and elastin containing connective tissues of the nerve head. Failure to retain normal elasticity could be an initial link between IOP and RGC injury.11 In order to recognize that axonal shape is being altered by external forces, pressure sensitive channels (TRAAK channels) may be the operative pathway.12 RGC axons might be made less sensitive to compression through manipulation of TRAAK channel sensitivity.

A molecule that deserves study is the motor protein that carries messenger proteins on their receptors is dynein, a huge complex riding along the axonal microtubules. It requires substantial ATP-provided energy to bring messengers back to the RGC body, and may be the nexus for action of failure in nutritional blood flow to the axons. Each of these ‘upstream’ areas deserves intense investigation for protective interventions.

Finally, there are a variety of other pieces of evidence linking various processes to RGC death in glaucoma. Free radical damage mediated either through nitric oxide synthesis13 or glutamate excitotoxicity14 has been suggested as events that may serve as therapeutic avenues.

Stimulation of immune-mediated phenomena by glatiramer has also been suggested to improve outcomes in experimental glaucoma.15 It is not clear how nitric oxide or glutamate toxicity relate to the other risk factors for glaucoma, or how they fit into the pathway from initial events to RGC death.

It is possible that some RGC die from primary injury and that others are killed by secondary events initiated by the primary deaths.16 We may, then, be looking for neuroprotective approaches that block events in the IOP-initiated pathway or events that result from the disturbed environment produced in the retina and optic nerve by initial glaucoma damage that are IOP-independent.

Future of glaucoma therapy will come from our new ideas and research, if we are prescient enough to ask the right questions and test them rigorously.

References

1.Wilson MR: The myth of “21”. J Glaucoma 6:75-77, 1997

2.Heijl A, Leske MC, Bengtsson B, Hyman L, Bengtsson B, Hussein M; Early Manifest Glaucoma Trial Group: Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 120:1268-1279, 2002

3.Collaborative Normal-Tension Glaucoma Study Group: Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol 126:487-497, 1998

4.Jampel HD: Target pressure in glaucoma therapy. J Glaucoma 6:133-138, 1997

5.Quigley HA, Addicks EM, Green WR, Maumenee AE: Optic nerve damage in human glaucoma. II. The site of injury and susceptibility to damage. Arch Ophthalmol 99:635-649, 1981

6.Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ: Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 36:774-786, 1995

7.Kerrigan LA, Zack DJ, Quigley HA, Smith SD, Pease ME: TUNEL-positive ganglion cells in human primary open angle glaucoma. Arch Ophthalmol 115:1031-1035, 1997

8.Pease ME, McKinnon SJ.,Quigley HA, Kerrigan-Baumrind LA, Zack DJ: Obstructed axonal transport of the neurotrophin receptor TrkB in experimental glaucoma. Invest Ophthalmol Vis Sci 41:764-774, 2000

9.Martin KRG, Quigley HA, Zack DJ, Levkovitch-Verbin H, Kielczewski J, Valenta D, Baumrind L, Pease ME, Klein RL, Hauswirth WW : Gene therapy with brain-derived neurotrophic factor protects retinal ganglion cells in a rat glaucoma model. Invest Ophthalmol Vis Sci 44:4357-4365 2003

10.McKinnon SJ, Lehman DM, Tahzib NG, Ransom NL, Reitsamer HA, Liston P, LaCasse E, Li Q, Korneluk RG, Hauswirth WW : Baculoviral IAP repeat-containing-4 protects optic nerve axons in a rat glaucoma model. Mol Ther 5:780-787, 2002

11.Quigley HA, Brown A, Dorman-Pease ME: Alterations in elastin of the optic nerve head in human and experimental glaucoma. Br J Ophthalmol 75:552-557, 1991

12.Maingret F, Fosset M, Lesage F, Laxdunski, Honore E: TRAAK is a mammalian neuronal mechano-gated K+ channel. J Biol Chem 274:1381-1387, 1999

13.Neufeld AH, Sawada A, Becker B: Inhibition of nitric-oxide synthase 2 by aminoguanidine provides neuroprotection of retinal ganglion cells in a rat model of chronic glaucoma. Proc Natl Acad Sci USA 96:9944-9948, 1999

14.Hare W, WoldeMussie E, Lai R, Ton H, Ruiz G, Feldmann B, Wijono M, Chun T, Wheeler L: Efficacy and safety of memantine, an NMDA-type open-channel blocker, for reduction of retinal injury associated with experimental glaucoma in rat and monkey. Surv Ophthalmol 45 Suppl 3:S284-289, 2001

15.Schwartz M: Neurodegeneration and neuroprotection in glaucoma: development of a thera-

peutic neuroprotective vaccine: the Friedenwald lecture. Invest Ophthalmol Vis Sci 44:14071411, 2003

16.Levkovitch-Verbin H, Quigley HA, Kerrigan-Baumrind LA, D’Anna S, Kerrigan DF, Pease ME: Optic nerve transection in monkeys may result in secondary degeneration of retinal ganglion cells. Invest Ophthalmol Vis Sci 42:975-982, 2001