How do we kill the idea of low-tension glaucoma?

How do we kill the idea of low-tension glaucoma?

Harry A. Quigley

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

Half the glaucoma in the USA is undiagnosed.

Half the glaucoma patients have an IOP of less than 21.

Undiagnosed glaucoma patients have lower IOP.

The tyranny of technology

How did we get into this mess? At the start of the 20th century, the only persons who were called glaucoma patients had what we now call symptomatic angleclosure glaucoma. Using rudimentary tonometers, poor ophthalmoscopy, and no field tests, doctors recognized those who presented to them as ‘glaucoma’ when they had pain, blurred vision, red eyes, and very high intraocular pressure (IOP). However, in an amazingly prescient paper in 1930, Bengt Rosengren documented the depth of the anterior chamber in glaucoma, showing that subjects with the more common form, glaucoma irritativum (angle closure), had shallow chambers, but that those with ‘glaucoma simplex’ had normal chamber depths.1 He may have been one of the few who recognized that there were two major forms of glaucoma, differing in this measurement as well as in clinical picture. Barkan subsequently used the gonioscope to differentiate angle-closure from open-angle glaucoma. And so, a pattern began in which the latest technology separated diseases from each other. Some technological advances (such as gonioscopy) were real advances. But, as Rosengren wrote so wisely: “It must be borne in mind that (differentiation among glaucoma cases is) related to the system of classification employed. ...the boundaries between different forms of glaucoma are by no means clearly defined.” By trying to set boundaries that were too clear, based on IOP, we later fell into a trap.

We have to sympathize with ophthalmologists in the early 20th century. It was logical to conclude that an IOP that felt hard to the fingers could blind someone. However, subjects with ‘glaucoma simplex’, who had no symptoms, and by the tonometry of the day often seemed not to have ‘high’ IOP, were a puzzle. Even the sharpest clinicians thought that open-angle glaucoma did not happen very

Address for correspondence: Harry A. Quigley, MD, Wilmer 122, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA. e-mail: hquigley@jhmi.edu

Glaucoma in the New Millennium, pp. 13–19

Proceedings of the 50th Annual Symposium of the New Orleans Academy of Ophthalmology, New Orleans, LA, USA, April 6-8, 2001

edited by Jonathan Nussdorf

© 2003 Kugler Publications, The Hague, The Netherlands

often. Curran is given appropriate credit for the concept that pupil block is important in angle closure. Yet, he denied the existence of open-angle glaucoma: “These classes of cases (open-angle glaucoma),... notwithstanding any prevailing opinion to the contrary, I have found to be very few.”2 (p 135). Why was he so sure? I suspect that open-angle glaucoma patients did not present themselves to him with symptoms and when they did, he failed to recognize it as having a relationship with angle-closure, the prevailing concept of glaucoma. But, that would not happen to us in modern times, or would it?

By 1948, the Schiøtz tonometer’s new calibration made ophthalmologists think that they had another new solution. Any eye with an IOP of 28-30 mmHg by the tonometry of the day was considered abnormal enough to treat. The findings at the optic disc were recognized as important in glaucoma, but there were few who used the rudimentary visual field measuring approaches (such as those of Bjerrum and Traquair). Even into the 1960s, it took a pretty high IOP to be classified as glaucoma. Despite the gonioscopic separation of open-angle and angle-closure glaucomas, the association of this disorder with a high IOP replaced the association with pain, blurred vision, and shallow chambers.

Then, Sloan, Aulhorn, and Goldmann began doing visual fields in a careful way. They found people with visual field defects who looked just like ‘real’ glaucoma at high IOP, but they had normal IOP. Even their optic discs were similar to glaucoma. IOP was ‘normal’ because by then Leydecker, Armaly, and Graham and Hollows had delineated the values present in population-based samples (in Germany, Iowa, and Wales). In European-derived persons, the IOP had a mean around 15 mmHg, and only 2.5% of the population exceeded 21 mmHg by applanation tonometry. Abnormal began to be defined by the upper limits of ‘normality’, and the tyranny of 21 was born.

Trouble in paradise

But, quite soon contradictions began to pile up. Firstly, a large number of subjects who had ‘abnormal’ IOP and were followed without therapy in the Collaborative Glaucoma Study, showed no visual field abnormalities year after year.3 Only about 1% per year of those followed up developed some detectable defect. Paradox #1: how can you be abnormal (with regard to IOP) without developing a disease? In fact, we now know that the majority of those with IOP above the normal number will never develop a disease.

Secondly, Drance wrote eloquently about persons with typical open-angle glaucoma damage to the optic nerve and visual field who had levels of IOP that were considered normal by population standards.4 Paradox #2: if glaucoma is a disease of high IOP, how can it happen at normal IOP? There were many who had explanations for this.

First of all, there were those who thought that if you just measure the IOP enough times, you will ‘catch’ those with glaucoma at normal IOP ‘spiking’ to an abnormal number. Doing tonometry at home,5 or around the clock, or in various body positions have each enjoyed popularity as explanations for how the IOP can seem normal at the 10 a.m. office visit, but ‘really’ be high enough to explain the glaucoma damage.

Then, some said that these eyes did not have glaucoma at all, but had some neurological disorder masquerading as glaucoma. Prior to MRI scanning, this

approach led to truly medieval torture, including arteriography, pneumoencephalography, and plunging the victim’s hands into freezing water. Even now, the most frequent unnecessary diagnostic testing in ophthalmology is neurological evaluation of glaucoma patients with normal IOP. The vast majority of those with glaucoma at normal IOP have field defects that do not respect the vertical midline, and their discs are excavated, not pale. They simply do not look sufficiently ‘neurological’ to merit this testing.

Thirdly, some viewed the glaucoma patient at normal IOP as having glaucoma, but stated that it had nothing to do with the IOP. In fact, some suggested that IOP really had no causative role in any person with glaucoma, and that the IOP increased because of glaucoma damage, instead of the other way around.6 This led to investigations of blood pressure, sedimentation rate, migraine, and other risk factors. Detailed comparisons were made of eyes with glaucoma at lower and higher IOP, to try to find the difference. Since these risk factors are important in glaucoma, this research contributed significantly to the field. Indeed, some modest differences were thought to be characteristic of lower IOP glaucoma eyes, such as larger diameter discs, disc hemorrhages, focal disc damage, and deep, central field defects. But, data from population-based glaucoma surveys for glaucoma brought light to the end of this tunnel (vision).

The population perspective

In Sweden, Wales, and Baltimore,7-9 surveys were conducted on how many had glaucoma in the general population, not just those who presented to an eye doctor’s office. These studies sought to discover who had glaucoma (diagnosed or not), and what it looked like. In order to define glaucoma, we have to decide whether to include IOP in the definition. Each prevalence survey found that subjects with the defined visual field defects, and whose optic discs met glaucoma criteria, were seen to have eyes with IOP higher and lower than the magic number 21 mmHg. This forced a decision: whether to include them all as glaucoma and eliminate IOP from the definition of open-angle glaucoma; or to report, separately, the detection of persons with high-pressure glaucoma and those with low-pressure glaucoma. While some studies split and others lumped, the similarity of the glaucoma eyes above and below the divide was increasingly apparent. In 1985, I was involved with the Baltimore Eye Survey, separating those who had glaucoma and those who did not during a definitive examination. We found that half those with disc and field defects typical for glaucoma had normal IOP. We brought a number of them back for examination on additional days, and about 25% never had an abnormal IOP. This led us and others to begin to define glaucoma without an IOP criterion.

So what?

What have we learned about glaucoma in the last ten years, and what are the practical consequences of that knowledge? Firstly, the relationship between IOP and glaucoma has been found to be real. In study after study, IOP level is the risk factor as closely linked to glaucoma as age.10 If IOP is high enough, it will damage any eye. Elevated IOP damages an animal optic nerve indistinguishably from

human glaucoma.11 In fact, increasing the IOP is the only experimental model approach that has ever simulated glaucoma. In every population study, the higher the IOP the more likely the person is to have glaucoma.12 Not only is IOP associated with the presence of glaucoma, but also the higher it is, the more severe the glaucoma is likely to be, even in the normal pressure range.13 Past and recent studies show that the level of IOP during the follow-up of glaucoma is highly correlated with outcome – the lower the IOP, the slower the damage.14 In addition, in a recent clinical trial, therapy that lowered IOP improved the outcome compared to no treatment, even in those whose IOP was on average below 21 at baseline.15 In rats, as in humans, while higher IOP will damage the optic nerve, lowering it is protective.16

So, it has been established that the level of IOP is an important determining factor in who gets glaucoma and how fast it progresses. But, notice that it is the level of IOP, not high IOP, not elevated IOP, and not some particular level of IOP. In fact, if we estimate the risk of developing initial glaucoma damage as a function of IOP,17 the risk increases exponentially from low to high, without any particular break point. In many of our heads, we have conceptualized glaucoma as a disease in which there is no substantial chance of its happening until the IOP is over (the magic) 21. Then, we are energized to wake up, do a field, photograph/image the disc, and start eyedrops. But, in fact, the true situation is a continuous (exponential) increase in risk related to IOP that is never really zero. There is no place to hide, and glaucoma can occur at an IOP of 11. The chance someone will have glaucoma at an IOP of 30 is much higher than the chance at 15 – but, there are so many more people with an IOP of 15 that the absolute number of those with glaucoma at this IOP is really rather large.

If this is true, then why do we not see them? Why did Curran think that openangle glaucoma was rare? First of all, they do not present to our offices as often as those with higher IOP. Those with higher IOP get screened into our examination rooms from air puff machines and army discharge physicals. Secondly, they are in our offices and we do not recognize them. Population-based surveys show that those with undiagnosed glaucoma (50% of the US total) are more likely to have lower IOP. Whatever type of eye care professional you are, there are persons with glaucoma, more often with normal IOP, not being identified.18

A recently recognized anomaly related to this issue is the reportedly higher rate of ‘normal-tension glaucoma’ among Asians. Shiose probably first recognized that Japanese persons have lower measured IOP than Europeans.19 But, in reporting the prevalence of open-angle glaucoma, he used the European normal IOP distribution to compare his patients, leading to the amazing conclusion that 80% of open-angle glaucoma in Japanese persons is ‘normal tension’. IOP was indeed lower than 21, the cutoff for European-derived persons, but the 97.5th percentile for Japanese is 18 mmHg. If we wish to make the same mistake in Asians that we have in European/Americans, we should define normal-tension glaucoma in Asia by an IOP of less than 18. It is possible that applanation tonometry underestimates the true pressure in the eyes of Asians, making this an artifact.20 In either case, the absolute level of IOP is irrelevant in a person with glaucoma damage. It does not matter if they have a thick cornea that reads artificially high or a post-LASIK cornea that reads artificially low. The take-home-message of epidemiology is that the actual level of IOP in a newly diagnosed glaucoma patient is irrelevant, except as a baseline for determining the treatment target. The frequency of glaucoma in

Asians is related to their (measured) IOP distribution in nearly an identical fashion to the same relationship in Europeans; just shifted down 2 mmHg. If this is a tonometric artifact, then we are all susceptible to glaucoma damage at the same hydrostatic forces. If Asians really have lower absolute IOP, they develop openangle glaucoma at the same rate that Europeans do, but at lower IOP. This would mean that their IOP susceptibility is higher, or that other risk factors supplement the risk related to IOP. Clearly, many factors other than IOP are important in causing glaucoma (see Pathogenesis paper in this symposium).

Baseline-target

If you cannot trust 21 mmHg, what can you trust? Jampel wrote a summary of the new approach to glaucoma therapy, the use of baseline and target IOP.21 In past research, the measure of success was often the frequency with which the IOP was reduced to less than 21. If the risk of disease and the risk of progression is a continuous function of IOP with no break point, then this is an erroneous choice for success. For the glaucoma patient who suffers damage at IOP = 19, lowering the IOP to 19 is not success. Rather, we must define the treatment target using IOP that prevails at the time we recognize the glaucoma damage. This may not really be the IOP that caused the damage – that could have been different in the past (higher or lower). But, pragmatically, we can only measure it now, so that is what must be done, and it must be done more than once in order to get a decent estimate. In a given patient, baseline can be anywhere, and it may be different for the two eyes of one person.

But, how much below the baseline should we set the target? This concept is new enough that there is insufficient evidence to decide. The practical range is between 20 and 50% lower. Jampel set out a large number of variables for consideration, but there are really only two in most cases – what percentage to lower it from baseline, and should we take the amount of existing field loss into account. As we get the results of more and more clinical trials over the next five years, we will have better data to judge the efficacy of target goals. The Normal Tension Glaucoma Study goal of 30% lowering slowed the progression of glaucoma to half the untreated rate. What is clear is that no longer can we equate good therapy with ‘normalizing the pressure’. Normal IOP is meaningless in setting a target. We must get used to writing down a target (or at least a target range) and assessing therapy by this standard. While we should not be slaves to each decimal point of IOP near the target, neither can we set a target and then ignore it. Congress may do this with budget guidelines, but their deficits do not blind people. We should take the level of injury into account when setting the target, making it lower when there is more field loss. This is logical and is supported by the anecdotal experience of experts like Morton Grant.22

Who cares what the IOP is?

Does it ever really matter to know the absolute IOP? It does for the person with no optic nerve damage of the disc or field and who has an abnormal IOP for his/ her ethnicity. In some persons, this may be an artifact of tonometry and routine

ocular follow-up will show no disease in the long term. Recent efforts have evaluated corneal thickness as an explanation for some of these eyes. But, if the IOP is to be credited as above normal, the ocular hypertensive is at greater risk for lifetime damage, and the person merits more detailed examination than others in the population. The degree to which IOP-lowering therapy is beneficial to this group is the subject of the Ocular Hypertension Treatment Study.

I would go so far as to say that there is no such disorder as low-tension or normal-tension glaucoma. Since there is no meaningful dividing line among glaucoma patients by their IOP level, these definitions are patently arbitrary. Schulzer et al. found that glaucoma subjects can be divided into two groups by their clinical features, but that IOP level was not one of the distinguishing features.23

What harm does it do to keep using the term low-tension glaucoma? It is a legitimate research technique arbitrarily to separate glaucoma subjects into stratified groups by IOP level, though IOP data on subjects can be more effectively used as a continuous variable. But, for many ophthalmologists and the patients who listen to them, this ‘diagnosis’ is interpreted to mean that IOP-lowering therapy will be useless or less effective. I encounter many patients who have been told that those with glaucoma at lower IOP will go blind more often. This is simply not supported by any evidence. Secondly, the continued use of the low-tension concept probably perpetuates the mindset that we do not have to look for glaucoma until the IOP is over 21. The undiagnosed 50% will continue to be overpopulated by those with glaucoma at lower IOP. Thirdly, the use of this pseudo-diagnosis is a cause of expensive and terror-provoking neurological evaluations. Patients never get over the fear that a brain tumor may be lurking up there that was somehow missed by the first two imaging studies. Fourthly, arbitrary separation of glaucoma patients into IOP dichotomies frustrates the use of baseline and target pressure approaches.

The ultimate irony of dividing glaucoma into two groups by IOP level is that those who study non-IOP-related risk factors in glaucoma decrease their ability to do so by using the low-tension glaucoma concept. Many studies of ocular blood flow in glaucoma patients only look at those with ‘low tension’. As a result, the study fails to evaluate half or more of those with glaucoma. Is it not possible that poor blood flow autoregulation is a contributor in those with higher IOP? I would even argue that this is more likely. By not studying those with IOP over 21, the power of a study to find risk factors is decreased. Some reports do include the higher IOP cases, dividing glaucoma into two groups. Since IOP is a continuous variable, the power to determine whether a risk factor other than IOP is important will be enhanced if IOP is treated continuously or in stratified groups of 5-mm increments.

What does it take to change popular beliefs in medicine? How much more data do we need to see that the normal-tension concept is as Neanderthal as ‘glaucoma simplex’ was in the 1930s? There is a lot more to learn about glaucoma, but we should use what we know, now.

References

1.Rosengren B: Reprinted from the original 1930 German version as: Studies in depth of the anterior chamber of the eye in primary glaucoma. Arch Ophthalmol 44:523-538, 1950

2.Curran EJ: A new operation for glaucoma involving a new principle in the aetiology and treatment of chronic primary glaucoma. Arch Ophthalmol 49:131-155, 1920

3.Armaly MF, Krueger DE, Maunder L, Becker B, Hetherington J, Kolker AE, Levene RZ, Maumenee AE, Pollack IP, Shaffer RN: Biostatistical analysis of the collaborative glaucoma study. I. Summary report of the risk factors for glaucomatous visual field defects. Arch Ophthalmol 98:2163-2171, 1980

4.Drance SM: Some factors in the production of low tension glaucoma. Br J Ophthalmol 56:229242, 1972

5.Jensen AD, Maumenee AE: Home tonometry. Am J Ophthalmol 76:929-932, 1973

6.Krakau CE, Bengtsson B, Holmin C: The glaucoma theory updated. Acta Ophthalmol (Kbh) 61:737-741, 1983

7.Bengtsson B, Krakau CE: Automatic perimetry in a population survey. Acta Ophthalmol (Kbh) 57:929-937, 1979

8.Hollows FC, Graham PA: Intra-ocular pressure, glaucoma, and glaucoma suspects in a defined population. Br J Ophthalmol 50:570-586, 1966

9.Sommer A, Tielsch JM, Quigley HA, Gottsch JD, Javitt J, Singh K: Relationship between intraocular pressure and primary open angle glaucoma among white and black Americans: the Baltimore Eye Survey. Arch Ophthalmol 109:1090-1095, 1991

10.Tielsch JM: The epidemiology and control of open angle glaucoma: a population-based perspective. Ann Rev Publ Hlth 17:121-136, 1996

11.Quigley HA, Addicks EM: Chronic experimental glaucoma in primates. II. Effect of extended intraocular pressure on optic nerve head and axonal transport. Invest Ophthalmol Vis Sci 19:137-152, 1980

12.Leske MC, Connell AM, Wu SY, Hyman LB, Schachat AP: Risk factors for open-angle glaucoma. The Barbados Eye Study. Arch Ophthalmol 113:918-924, 1995

13.Cartwright MJ, Anderson DR: Correlation of asymmetric damage with asymmetric intraocular pressure in normal-tension glaucoma (low-tension glaucoma). Arch Ophthalmol 106:898900, 1988

14.The AGIS Investigators: The advanced glaucoma intervention study (AGIS). 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol 130:429-440, 2000

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

16.Morrison JC, Nylander KB, Lauer AK, Cepurna WO, Johnson E: Glaucoma drops control intraocular pressure and protect optic nerves in a rat model of glaucoma. Invest Ophthalmol Vis Sci 39:526-531, 1998

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

18.Wang F, Ford D, Tielsch JM, Quigley HA, Whelton PK: Undetected eye disease in a primary care clinic population. Arch Intern Med 154:1821-1828, 1994

19.Shiose Y, Kitazawa Y, Tsukahara S, Akamatsu T, Mizokami K, Futa R, Katsushima H, Kosaki H: Epidemiology of glaucoma in Japan: a nationwide glaucoma survey. Jpn J Ophthalmol 35:133-155, 1991

20.Foster PJ, Wong JS, Wong E, Chen FG, Machin D, Chew PT: Accuracy of clinical estimates of intraocular pressure in Chinese eyes. Ophthalmology 107:1816-1821, 2000

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

22.Grant WM, Burke JF: Why do some people go blind from glaucoma. Ophthalmology 89:991998, 1982

23.Schulzer M, Drance SM, Carter CJ, Brooks DE, Douglas GR, Lau W: Biostatistical evidence for two distinct chronic open angle glaucoma populations. Br J Ophthalmol 74:196-200, 1990