(IGR: 1-3) | International Glaucoma Review #

Is normal pressure glaucoma different from primary open-angle glaucoma?

Caroline Geijssen

Is normal pressure glaucoma different from primary open-angle glaucoma?

By: H. Caroline Geijssen and Erik L. Greve

Abstract

Normal pressure glaucoma (NPG) or normal tension glaucoma (NTG) is a confusing non-entity. This terminology may lead to erroneous interpretation of pathogenesis and treatment. Confusion arises from separating so-called NPG from primary open-angle-high pressure glaucoma by a magic intraocular pressure (IOP) number. Secondly, confusion comes from lumping all glaucomas with statistically normal IOP under one heading. A uniform NPG patient does not exist. Several types of glaucoma with statistically normal IOP can be differentiated with different pathogenesis, rate of progression and possibly treatment. The main question is whether the cause of primary open-angle glaucoma (POAG) is IOP (related) or not. In fact, in virtually all glaucomas, IOP plays a role in the form of the perfusion pressure formula. However, in some POAG patients, a raised IOP is the predominant cause of the damage, whereas in others IOP unrelated factors seem to play a decisive role. The question is not so much whether we can distinguish POAG below and above 21 mmHg, as whether we can identify pressure related glaucoma (PRG) and pressure unrelated glaucoma (PUG). It is probable that some 40% of so-called NPG patients are IOP-dependent glaucomas similar to POAG. The remainder may be caused by any of the other factors, while the most important ones are vascular factors and myopia. Treatment may be more efficiently directed to the cause(s) if we use a descriptive classification. It may be sensible to: (1) adopt a causative approach; (2) expect IOP reduction to be beneficial in PRG; (3) expect some effect from other forms of treatment: improve systemic circulation; Ca+ channel blockers and others; neuroprotection. In conclusion, it is difficult to distinguish NPG from POAG because of the large pathogenic overlap. It may be easier and more practical to distinguish PRG from PUG.

Introduction
Are normal pressure glaucoma (NPG) and primary open-angle glaucoma (POAG) different? In fact, the separation of NPG and POAG is a good example of misleading statistics. Yes, we can separate the two on the basis of an intraocular pressure (IOP) level, but very badly. As we will see clinically, the IOP level hides the real differences. That is where the 'No' comes from.

What do we know about intraocular pressure?
The present definition used for NPG creates a confusing non-entity. It almost suggests that a raised IOP will not be the cause of this type of glaucoma. For a long time, ophthalmologists have thought that there is not much to be done when the IOP is so-called normal. However, we do not know whether the IOP is normal or not; it is only normal in a statistical sense, not in a pathogenic sense. An IOP of 18 mmHg may be normal for one patient, while it may be considerably increased for another. There is no way that we can separate so-called NPG from raised pressure glaucoma by a magic number. The higher the IOP, the higher the likelihood that the IOP is involved in the glaucomatous process. However, there is still a considerable likelihood that an IOP of 18 mmHg is a raised IOP and the cause of glaucoma. This type of NPG is indistinguishable from POAG with an IOP of over 21 mmHg (or wherever you should choose your statistical limits to be). On the one hand, the IOP may play an important role as a risk factor in some NPG patients and, on the other, non-IOP related risk factors may be involved in other so-called POAG patients. Indeed, in statistical terms, there are differences between NPG and high pressure glaucoma (HPG), as we shall indicate. However, the two cannot be separated by a single IOP level; the actual IOP level may not be ideal to lead us to the cause of glaucomatous disease in the individual patient, unless it is above 26 mmHg.

Pressure related glaucoma and pressure unrelated glaucoma: relative frequency
Are there other ways in which we can get an indication of the involvement of IOP as a causative factor in glaucomatous disease? If so, can we identify pressure related glaucoma (PRG) and pressure unrelated glaucoma (PUG)? This is not only interesting from a theoretical point of view, but also from a practical point of view.

In the Collaborative Normal Tension Glaucoma Study^1,2, the aim was to compare the impact of at least a 30% reduction of IOP with no treatment. From the overall survival analysis (Fig. 1) of this study, we learn that, in the treated group, some 20% of patients progressed anyway, notwithstanding the sizeable IOP reduction. Some 80% of patients survived in the treated group. In the untreated group, the survival was 40%, which is 40% less than in the treated group. This means that, in both groups, whether treated or untreated, 40% of the so-called normal tension glaucoma patients did not progress. In these patients, we have no information as to the cause of the disease. In the 40% who progressed untreated, but did not progress treated (although we are not talking about the same patients), we may assume that IOP was involved in the cause of progression, because IOP reduction did stop progression. In the 20% who progressed in the treated group, we may assume that progression took place unrelated to the level of IOP. It could be reasoned that the IOP reduction was not enough. For instance, an IOP reduction of 30% at a level of 20 mmHg would have reduced the IOP to some 13 mmHg, whereas 9 mmHg was needed. For the sake of this discussion, let us assume that at least 40% in this particular study were IOP related, 20% were IOP unrelated, and for 40% we do not yet know. IOP-related patients are an important part of NPG. Interestingly, this same percentage, now of the type with concentric enlargement of the disc, was also found in our own study⁶.

Fig. 1. Overall survival analysis in the Collaborative Normal Tension Glaucoma Study in the treated and untreated groups².
Designed by the present authors on the basis of CNTGS results.

Pressure related glaucoma and pressure unrelated glaucoma: how to distinguish clinically?
How can we distinguish these PRGs from the PUGs? Spaeth³ and ourselves^4-6, have demonstrated that several types of discs can be found in patients with NPG and also in patients with so-called POAG. Differentiation on the basis of disc morphology may be one approach for distinguishing several types of glaucoma⁷. Nowadays, most ophthalmologists are aware of the four major types of optic disc excavation that can be found in the early stages of glaucoma^6,10: concentric enlargement, focal notch, senile sclerotic type and the myopic type (Table 1).

Table 1.

Focal Myopic Senile sclerotic Concentric Gender F > M M > F M = F M = F Age (years) 60-65 50-55 70-75 55-60
IOP
n or 20s n or 20s n or 20s > 26
Local vascular risk factor
          hemorrhage +++ ++ +++ rare           PPA focal myopic all around rare
Systemic vascular risk factor
vasospasm cardiovascular cardiovascular rare Visual field local/fix local/fix/cc relatively widespread widespread
Modified from Geijssen⁶ and Broadway et al.¹⁰PPA: peripapillary atrophy; fix: threat to fixation; cc: centrocoecal visual field defect

We all know that young patients with POAG usually have a concentric enlargement (Fig. 2a) of the excavation. They usually have high IOP, few disc hemorrhages, little peripapillary atrophy, and no systemic vascular risk factors^6,8-10. This is also true of many of our secondary open-angle glaucoma (OAG) patients, such as pigmentary glaucoma and pseudo-exfoliation glaucoma, all purely IOP-related glaucomas. In these young patients with OAG and high IOP, the focal type of excavation is rare, and senile sclerotic type is not found. It seems probable that the concentrically enlarged discs are associated with raised IOP. Apart from anecdotal clinical evidence, several studies have indeed suggested that, in patients with similar sized visual field defects, the concentric enlargement of the excavation is associated with higher IOP. As we have seen, IOP-related NPG with concentric enlargement may be about 50% of our total NPG group.

Patients with a focal notch (Fig. 2b) of their disc are more frequently female, aged between 60 and 65 years, with an IOP in the statistical normal range or in the low twenties. Disc hemorrhages are seen in 30-40% of eyes and local peripapillary atrophy frequently coincides with localization of the notch. This type of disc has been associated with vasospastic disease¹¹. The visual field defects are usually local dense nerve fiber bundle defects which can extend into to the central area, causing a threat of fixation^6,12. We estimate that this type occurs in about 20% of NPG.

The myopic type (Fig. 2c) of glaucoma, which has sloping and thin rims on the temporal side of the disc, occurs more frequently in males than in females. They are usually between aged between 50 and 55 years, although younger patients are not rare. The IOP is within the statistical normal range or in the low twenties. Disc hemorrhages can be seen in about 30% of eyes, and peripapillary atrophy is most often present as the typical myopic crescent on the temporal side of the disc. Systemic cardio- and/or cerebrovascular disease is found in the majority of patients. The visual field shows local visual field defects frequently occurring in the centrocoecal area, threatening visual acuity in the rather early stages of the disease¹³. We estimate that this type occurs in about 25% of NPG.

Senile sclerotic glaucomas (Fig. 2d) are seen in elderly (70-75 years of age) males and females with normal IOP or IOP in the low twenties. Forty-five percent of eyes have disc hemorrhages, while extensive all around peripapillary atrophy is seen in virtually all eyes. Over 60% have systemic vascular disease. Relative visual field defects are more equally divided over the upper and lower half of the visual field. We estimate that this type occurs in about 5% of NPG.

It seems probable that the concentrically enlarged disc is associated with raised IOP, while the other three types of discs are associated with lower and probably not even raised IOP levels, and with non-IOP risk factors.

The limitations of the use of the appearance of the excavation for distinguishing between PRG and PUG lie in the fact that all glaucoma will end up with a total excavation; and furthermore, mixed types of excavations may occur.

2A: Concentrically enlarged excavation

2C: Myopic type of excavation



2B: Focal notch type of excavation

2D: Senile Sclerotic type of excavation

Non-intraocular-pressure-related risk factors
If IOP is not the cause, or not the major cause, of glaucomatous damage, what other risk factors can be involved? In our experience, vascular risk factors and myopia are the two major IOP-unrelated risk factors, or at least are those that we can identify and that play a role in a sizeable number of glaucoma patients.

If we are talking about myopia, it is not so much the very high myopes with extensive myopic chorioretinal changes as those many intermediate myopes with the typical obliquely-implanted myopic disc and typical myopic conus. The type of disc is often a better separator than the actual dioptric value.

Vascular risk factors: clinical importance
Is it more difficult to recognize vascular risk factors than IOP risk factors? Given the fact that we know very little about the actual rise of IOP in the individual patient at levels ranging between 15 and 26 mmHg - levels that are found in the vast majority of our glaucoma patients - we may wonder whether vascular risk factors are not as predictive as IOP risk factors. Again, a patient with an IOP of 25 mmHg may never progress because we are dealing with a higher corneoscleral rigidity¹⁴, other measurement variations, or an IOP-resistant optic nerve. We may be relatively good at measuring IOP levels (with a variability of some 4 mmHg), but we are hardly capable of measuring a raised IOP - and that is what we need to know - if we do not have the patient's original normal individual IOP at our disposal.

Vascular factors can be subdivided into systemic and local vascular risk factors. Systemic vascular factors include: nocturnal hypotension^15,16, systemic hypertension, vasospasm^17,18, cardiovascular disease, cerebrovascular disease, biochemical and hematological changes^19,20, etc. These systemic vascular risk factors are more frequently found in elderly so-called NPG patients^6,10. The relative importance, in terms of cause of the disease and progression, is unknown. However, their presence can easily be identified and taken into account.

The situation is much easier with local vascular risk factors, such as: peripapillary atrophy, disc hemorrhages, choroidal sclerosis, and narrow retinal arterioles. Here, we have an abundance of literature at our disposal which shows us that, particularly disc hemorrhages and peripapillary atrophy, are related to progression^6,21,22. We also know that disc hemorrhages and peripapillary atrophy occur more frequently in OAG with IOP in the lower range than in those with high IOPs^23,24. It is therefore very unlikely that they are caused by IOP. Their presence indicates the likelihood that a vascular factor is involved in the pathogenesis of the glaucomatous damage in this particular patient. The correlation between disc hemorrhages and progression is most evident, however, disc hemorrhages are by no mean always present. They come and go. On the other hand, peripapillary atrophy is always present and can easily be seen on ophthalmoscopy. These local manifestations of primary vascular disease seem to be most indicative of the presence of vascular disease, and thus of PUG. We know that they are related to progression. In a sense, they can be compared to a certain level of IOP that is associated with the same chance of progression.

Blood flow
Of course it is possible to measure blood flow-related parameters. Several methods have been proposed, but none actually measures blood flow. Correlations between methods have been disappointing. Such methods may measure quite different aspects of blood flow-related factors, different vascular systems, and different regions of the vascular supply to the eye. Nevertheless, it has been repeatedly demonstrated that local reductions of blood flow-related parameters do exist in POAG and more so in the group

with relatively low IOP, the so-called NPG. To our knowledge, there is only one study that claims a correlation between disturbed blood flow-related factors and progression of glaucomatous disease²⁵. Such methodology is not usually available in the general ophthalmology practice.

Pressure related glaucoma and pressure unrelated glaucoma
On the one hand, it seems to be almost impossible to distinguish between so-called NPG and POAG on the basis of IOP level, except at levels over 26 mmHg. On the other, there are several other factors that may help us to differentiate PRG from PUG, as can be seen in Table 2, in which we have illustrated the factors that may help in this differentiation in a practical clinical setting. The fourth column gives the relative clinical importance that we feel could be attributed to a particular risk factor. The relative importance is derived from the available literature and from personal experience. This does not necessarily mean that their recognition has great discriminative power. We have tried to approach the relative clinical importance of non-pressure-related risk factors without going into details of sensitivity and specificity.

On the one hand, we see the typical POAG patient who presents at the age of 55 years with an IOP of 35 mmHg, a concentrically enlarged disc, infrequent cardiovascular or cerebrovascular disease, infrequent disc hemorrhages and peripapillary atrophy, and more widespread visual field damage. On the other, there is the typical elderly patient with an IOP of 18 mmHg, focal damage to the optic nerve head or a myopic excavation, focal damage to the visual field, treated cardiovascular disease or even signs of vasospasm, peripapillary atrophy, and a disc hemorrhage and reduced blood flow-related parameters on qualitative measurements, or less frequently, the elderly patient with a senile sclerotic disc which, in itself, already points to vascular involvement. If a patient with glaucoma is examined, the presence of one of the factors in Table 2 may help in differentiating PUG from PRG. The three plus factors are the most helpful.

Table 2
Possible multifactorial approach to differentiate between pressure related glaucoma (PRG) and pressure unrelated glaucoma (PUG)

PRG

PUG
Relative importance Age (Years) 55-60
50-75
+ IOP > 26 mmHG + - +++ Disc type      Concentric enlarged + - +++      focal - + +++      myopic - + ++      senile sclerotic - + +++ CCV disease - + +      nocturnal hypotension - + +      vasospasm - + ++ Disc hemorrhage - + +++ PPA - + ++ Blood flow - + ++ Blood flow retinal* + - +? Blood flow choroidal* - + +? Visual field widespread + - + Visual field focal/fix - + ++

CCV: cardio-cerebro vascular; PPA: peripapillary atrophy; fix: threat to fixation
* Duijm HFA et al. A comparison of retinal and choroidal hemodynamics in patients with primary open angle glaucoma and normal pressure glaucoma. 1997; 123 (5): 644-6

Treatment of pressure related glaucoma and pressure unrelated glaucoma
In terms of treatment, we would expect the first patient to do very well on IOP reduction, and the second patient to do relatively well on IOP reduction, but he or she may also benefit from an improvement of blood flow and/or neuroprotection.

Now that we are talking about treatment, let us realize that, apart from the NTG study, there are several studies available in which one eye of a patient with so-called NPG has been operated on, while the other eye has not^26-28. All studies concluded that the operated eye at the lower IOP level did better than the non-operated eye, implying that IOP is indeed a major player in the cause of glaucomatous damage. On the other hand, while we may derive some evidence for IOP involvement from the effect of treatment, there are also several studies suggesting that improving blood flow may also have a beneficial effect on the progression of NPG.

References

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

2. Collaborative Normal Tension Glaucoma Study Group: The effectiveness of intraocular pressure reduction in the treatment of normal tension glaucoma. Am J Ophthalmol 126:498-505, 1998

3. Spaeth GL: Low tension glaucoma: its diagnosis and management. Doc Ophthalmol Proc Ser 22:263-287, 1980

4. Greve EL, Geijssen HC: The relation between excavation and visual field in glaucoma patients with high and low intraocular pressures. Doc Ophthalmol Proc Ser 35:35-42, 1983

5. Greve EL, Geijssen HC: Comparison of glaucomatous visual field defects in patients with high and with low intraocular pressures. Doc Ophthalmol Proc Ser 35:101-105, 1983

6. Geijssen HC: Studies on Normal Pressure Glaucoma. Amsterdam: Kugler Publ 1991

7. Jonas JB, Gusek GC, Naumann GO: Optic disk morphometry in chronic primary open angle glaucoma. I. Morphometric intrapapillary characteristics. Graefe's Arch Clin Exp Ophthalmol 192:693-698, 1988

8. Caprioli J, Spaeth GL: Comparison of the optic nerve head in high and low tension glaucoma. Arch Ophthalmol 103:1145-1149, 1985

9. Pederson JE, Anderson DR: The mode of progressive disc cupping in ocular hypertension and glaucoma. Arch Ophthalmol 98:490-495, 1980

10. Broadway DC, Nicolela MT, Drance SM: Optic disk appearances in primary open angle glaucoma. Surv Ophthalmol 43(Suppl 1):S223-S243, 1999

11. Broadway DC, Drance SM: Glaucoma and vasospasm. Br J Ophthalmol 82:862-870, 1998

12. Spaeth GL: A new classification of glaucoma including focal glaucoma. Surv Ophthalmol 38:S9-S17, 1994

13. Greve EL, Furuno F: Myopia and glaucoma. Graefe's Arch Clin Exp Ophthalmol 213:33-41, 1980

14. Morad Y, Sharon E, Hefetz L et al: Corneal thickness and curvature in normal tension glaucoma. Am J Ophthalmol 125:164-168, 1998

15. Hayreh SS, Zimmerman MB, Podhajski P et al: Nocturnal arterial hypotension and its role in optic nerve head and ocular ischaemic disorders. Am J Ophthalmol 117:603-624, 1994

16. Graham SL, Drance SM, Wijsman K et al: Ambulatory blood pressure monitoring in glaucoma: the nocturnal dip. Ophthalmology 102:61-69, 1995

17. Gasser P, Flammer J: Bloodcell velocity in the nailfold capillaries of patients with normal tension and high tension glaucoma. Am J Ophthalmol 111:585-588, 1991

18. Nicolela MT, Drance SM: Various glaucomatous optic nerve appearances: clinical correlations. Ophthalmology 103:640-649, 1996

19. Sugiyama T, Moriya S, Oku H et al: Association of endothelin-I with normal tension glaucoma: clinical and fundamental studies. Surv Ophthalmol (Suppl) 39:49-56, 1995

20. Wax MB, Tezel G, Saito I et al: Anti-Ro/SS-A positivity and heat shock protein antibodies in patients with normal pressure glaucoma. Am J Ophthalmol 125:145-157, 1998

21. Araie M, Sekine M, Suzuki Y et al: Factors contributing to the progression of visual field damage in eyes with normal tension glaucoma. Ophthalmology 101:1440-1444, 1996

22. Airaksinen PJ, Alanko HI: Optic disc hemorrhage precedes retinal nerve fibre layer defects in ocular hypertension. Acta Ophthalmol (Kbh) 59:627-641, 1981

23. Airaksinen PJ, Mustonen E, Alanko HI: Optic disk hemorrhages. Arch Ophthalmol 99:1795-1801, 1981

24. Kitazawa Y, Shirato S, Yamamoto T: Optic disc hemorrhage in low tension glaucoma. Ophthalmology 93:853-857, 1986

25. Galassi F, Sodi A, Rossi MG et al: Results of color doppler imaging in various types of glaucoma: In: Pillunat LE et al (eds) Current Concepts on Ocular Blood Flow in Glaucoma, pp 119-127. The Hague: Kugler Publ 1999

26. De Jong N, Greve EL, Hoyng PFJ et al: Results of a filtering procedure in low tension glaucoma. Int Ophthalmol 13:131-139, 1989

27. Bhandari A, Crabb DP, Poinosawmy D et al: Effect of surgery on visual field progression in normal tension glaucoma. Ophthalmology 104(7):1131-1137, 1997

28. Daugeliene L, Yamamoto T, Kitazawa Y: Effect of trabeculectomy on visual field in progressive normal tension glaucoma. Jpn J Ophthalmol 42(4):286-292, 1998

Issue 1-3

Table of Contents Editor's Selection

Change Issue

advertisement

contact · Back to top

© 1999-2025 International Glaucoma Review · Privacy · Terms of Use