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Chapter 221 – Normal-Tension Glaucoma

Chapter 221 – Normal-Tension Glaucoma

 

ROGER HITCHINGS

 

 

 

 

 

DEFINITION

• Variety of primary open-angle glaucoma that features an intraocular pressure within the normal range.

 

KEY FEATURES

• Intraocular pressure within the normal range.

• Progressive glaucomatous cupping.

• Retinal nerve fiber type of visual field loss.

• Open angles on gonioscopic examination.

• No history of eye disease with raised intraocular pressure.

 

ASSOCIATED FEATURES

• Peripheral vasospasm, as in Raynaud’s phenomenon.

• Migraine.

• Optic disc hemorrhage.

 

 

 

INTRODUCTION

Chronic open-angle glaucoma typically is associated with an elevated intraocular pressure (IOP). Total population surveys show that 10–30% of patients newly diagnosed with glaucoma have IOPs that are and remain normal. Although the relative risk for the development of glaucomatous optic neuropathy increases with an increase in IOP, the numerical majority of normotensive individuals ensures that the small percentage who have open-angle glaucoma constitute a significant proportion of the whole open-angle glaucoma population. The traditional therapy for primary open-angle glaucoma is to lower IOP to within the normal range, but this approach becomes more difficult when the initial IOP is “normal.”

EPIDEMIOLOGY AND PATHOGENESIS

Total population surveys in Europe, North America, and Australia reveal open-angle glaucoma with normal IOPs in 15–25% of the population surveyed. Only a small proportion of these patients have elevated IOPs on repeat testing. Patients with normal-tension glaucoma (NTG) constitute a significant proportion of patients with glaucoma in any clinic. Interestingly, in Japan, where the upper limit of normal IOP is approximately 18?mmHg (2.4?kPa), 50–60% of patients affected by open-angle glaucoma have baseline IOPs below this level.

The pathogenesis of the condition remains unclear. Progressive optic neuropathy with a normal IOP suggests an underlying vascular insufficiency. The association with peripheral vasospasm, migraine, and recurrent optic disc hemorrhages supports this hypothesis. The association with myopia and peripapillary atrophy also indicates a deficiency in the short, posterior ciliary circulation.[1] [2] For some patients (and normal individuals) in whom ambulatory blood pressure has been monitored, the nocturnal blood pressure falls dramatically (80/40?mmHg [10.6/5.3?kPa] being not uncommon).[1] [3] Such nocturnal “dips” may lower pulse pressure at the optic disc if no commensurate fall in IOP occurs.

The most effective management has been to lower IOP. Color Doppler imaging has demonstrated an increase in blood velocity in the ophthalmic artery after filtration surgery,[4] which suggests a mechanical hypothesis in which the IOP is “too high for the eye,” and the optic nerve is less able to withstand an IOP in the normal range. The mechanical support given by the lamina cribrosa may be insufficient, and the quality (type) of the collagen may be deficient.[5] [6] Finally, and speculatively, the lamina cribrosa may have an abnormal pressure gradient across it, not because the IOP is too high, but because the intracranial pressure is lower than normal.

OCULAR MANIFESTATIONS

No characteristic features exist, other than level of IOP that consistently differentiates high-tension glaucoma from NTG. The appearance of the optic disc and the visual field defect can be identical. However, some differences can occur. Patients who have NTG are, on average, 10 years older than those who have high-tension glaucoma, and their optic discs are more likely to show focal notching and optic disc hemorrhages. Optic discs in patients who have NTG have been categorized into different subtypes based on appearance—myopic, focal ischemic, senile sclerotic, and so on ( Fig. 221-1 ). [7] [8] Such descriptions are not, as yet, indicative of different causes or clinical courses. The visual field is more likely to show defects close to fixation.[8] In addition, the outflow resistance may be normal or extremely high, and the rate of aqueous flow may be normal or extremely low.[9] Familial tendency occurs, and it has been reported that women are affected twice as frequently as men.[10] There is evidence to suggest that the left eye is 2.5 times more likely to be affected first although, with increasing age, NTG tends to become a bilateral disease. The IOP is usually slightly higher in the more severely affected eye, although the difference may only be 1–2?mmHg (0.1–0.3?kPa).[11] [12]

 

 

Figure 221-1 Optic disc of a patient who has normal-tension glaucoma. Note disc hemorrhage (H).

 

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Long-term follow-up suggests that, although most patients maintain the same IOP over many years, approximately 8% show a trend toward higher IOPs. In such eyes the IOP may rise above the upper limit of normal, in which case the patient would be considered to have high-tension glaucoma. [13] Repeated “splinter” hemorrhages at the optic disc are common, and such eyes are likely to show progressive visual field loss.

Two reviews of the untreated condition exist. Both suggest that over a period of 4–5 years, a significant minority will not show demonstrable progression.[14] This needs to be remembered when considering management options for the elderly patient.

DIAGNOSIS

Confirmation of the diagnosis requires:

• Repetitive IOP measurements to rule out occult hypertension

• Confirmation of glaucomatous cupping, rather than a “suspicious” appearance to the optic disc

• Exclusion of other causes of optic disc changes and previous ocular hypertension

• Confirmation that the visual field defect is of the retinal nerve fiber layer type and corresponds with the location of changes at the neuroretinal rim

The following are helpful in the identification of a causative vascular factor:

• Measure the response of the nail fold capillaries to cold

• Monitor ambulatory blood pressure to identify nocturnal dips

• Obtain color Doppler imaging of the common carotid artery to establish the presence of lumen reduction.

Any retro-ocular lesion must be ruled out, also. A brain scan and other neurological investigation is indicated if any disparity arises between the optic disc appearance and the visual field defect. In glaucoma, a close association is found between glaucomatous cupping and the visual field defect. Atrophy greater than the field loss suggests a previous anterior ischemic optic neuropathy. Visual field defects that respect a vertical meridian and central (rather than paracentral and arcuate) field defects indicate the need for neurological investigation.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of NTG is summarized in Box 221-1 .

High-tension, primary open-angle glaucoma that has episodic normal IOP is a theoretical concept in which wide diurnal fluctuations “hide” elevated IOPs that induce damage.

In secondary open-angle glaucoma, a normal IOP is present after a previous hypertensive episode sufficient to produce glaucomatous cupping (e.g., corticosteroid-induced glaucoma, hypertensive uveitis). Any young patient who has glaucoma and a history of external eye disease or contact lens wear must be questioned closely about topical corticosteroid medication use.

In non-glaucomatous optic neuropathy, the IOP, visual field, and the age of the patient are similar to those in the patient with glaucoma. The optic disc does not show glaucomatous cupping, but rather a flat optic atrophy in which the area of atrophy exceeds the extent of the visual field defect (disc–field disparity). When extensive neuronal loss has occurred, the optic disc may develop a massive enlargement of the optic cup with pallor of the remaining rim. The condition does not progress.

 

 

 

Differential Diagnosis of Normal-Tension Glaucoma

High-tension primary open-angle glaucoma with episodic “normal intra-ocular pressure”

 

Secondary open-angle glaucoma from previous elevated intraocular pressure

 

Nonglaucomatous optic neuropathy

 

Other lesions that affect the visual pathways

 

 

 

 

Other lesions that affect the visual pathways include lesions of the optic chiasm and visual pathways, back to the occipital cortex, which produce visual field defects that respect the vertical meridian. In time, such lesions also produce optic atrophy without glaucomatous cupping.

SYSTEMIC ASSOCIATIONS

No systemic diseases are associated with NTG. However, both the female-to-male ratio and the occasional familial nature of the disease suggest a systemic component. More speculatively, the left eye over right eye also suggests a systemic component. The association with peripheral and perhaps central (ocular) vasospasm, migraine, and Raynaud’s phenomenon suggests a vascular predisposition to the condition.[15] [16]

TREATMENT

Treatment is indicated for patients with progressive disease. Few patients become legally blind from this disease. Many patients are elderly at diagnosis and have a sufficiently slow rate of change that, even without treatment, clinically significant loss of vision does not occur. Significant visual loss may cause social restriction, such as the loss of a driving license. Trend or event analysis that uses commercially available software will identify progression. Cluster or point-wise analysis is more likely to identify progression than analyses that rely on the identification of a global change. Care must be taken to differentiate between long-term fluctuations and true change before any therapeutic decisions are made. Management is directed toward the implementation of a lower IOP or to the correction of reversible circulatory deficiencies at the optic nerve or both.

Lower Intraocular Pressure

Studies suggest that a reduction in IOP may exert a beneficial effect on the course of the disease.[17] [18] [19] [20] A 25–30% fall is required, best achieved by the perioperative use of 5-fluorouracil. If surgery does not achieve this 25–30% fall, the rate of change is likely to remain unaltered.[21] Current medical therapy may not maintain this pressure reduction for the lifetime of the patient, although the recent introduction of latanoprost may help a proportion of these patients.[22]

Reversal of Circulatory Deficiencies at the Optic Nerve Head

VASOSPASM.

Central vasospasm may be indicated by an abnormal (vasoconstrictive) response of finger circulation to cold, which may be reversed by calcium channel blockers and carbon dioxide rebreathing.[23] [24] [25] Theoretically, a carbonic anhydrase inhibitor also should have a beneficial effect.

NOCTURNAL HYPOTENSION.

Patients who take drugs to lower blood pressure and some patients who have NTG exhibit an excessive fall in systolic and diastolic blood pressures while asleep (dips). Such changes may reduce ocular perfusion pressure unless the IOP also falls. All patients must be questioned about systemic hypotensive (antihypertensive) medication, and any patient who uses such medication must be checked for such falls in blood pressure.

CAROTID INSUFFICIENCY.

Patients who have asymmetrical NTG may show significant (>50%) lumen reduction in the common carotid artery, which results in reduction of turbulence and reduction of volume flow. The end arteries of the ophthalmic artery (and particularly those in the laminar region of the optic nerve) may suffer as a result of reduced flow.

To date, the best hope for those patients who have progressive disease is to reduce IOP by 25% or more, to reverse vasospasm using a calcium channel blocker, and to correct any drug-induced nocturnal dips.

 

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Monitoring for Progression

The younger the patients at diagnosis, the greater is the possibility of clinically significant visual loss in their lifetime. It is important for these patients to be “trained” early in the management of their disease to become reliable performers with threshold perimetry. All patients require repeat visual field testing to identify progression and, within reason, the more frequently the field test is repeated, the better. Perimetry 3–4 times a year gives a better chance of identifying change, and will do so considerably earlier, than field testing once or twice a year.

Therapeutic Intervention

Medical management to lower IOP that fails to maintain a 25% reduction is unlikely to affect the course of the disease. A trial of medical management may be justified in patients with progressive disease, but failure to achieve this reduction should mean a recommendation for fistulizing surgery, rather than waiting for further progression to occur.

Glaucoma surgery designed to lower IOP by 30% from a starting level of, say, 17?mmHg runs significant risk of postoperative hypotony.[26] This will convert the frequently asymptomatic patient into one with symptoms of fluctuating and progressively deteriorating sight. It is essential, therefore, to have identified progressive disease correctly and to have discussed with patients the effect of their rate of visual loss on their vision before asking them to undergo fistulizing surgery. Most patients with NTG are elderly and their disease progresses slowly, so that the surgical option is not resorted to frequently.

Neuroprotection

Apoptosis (programmed cell death) occurs both in the experimental primate glaucoma model and in human glaucoma, which has stimulated research into neuroprotective agents.[27] [28] Trials of calcium channel blockers have been shown to exert some neuroprotection in selected cohorts of patients with NTG. Other potential neuroprotective agents include antiparkinsonian drugs and brimonidine. Trials of such agents are under way.

COURSE AND OUTCOMES

Many patients are in their seventh and eighth decade of life at diagnosis and, with slow disease progression, they do not notice any visual change. Progression for other patients is more rapid, and they suffer severe visual loss. No progression has been seen in some patients monitored for 10 years or more by the author, while other patients have demonstrated rates of loss at individual retinal locations of up to and exceeding 5?db per year. Similarly, patients who have one normal visual field initially may show no signs of visual field loss in the second eye for more than 10 years, even though the appearance of the optic disc suggests glaucoma. The identification of change, either by the patient’s symptoms or by visual performance, is an indication that IOP must be lowered by 25% or more. To maintain this reduction in IOP for the necessary decades may be difficult, but if this is not carried out the visual loss may be slowed only and not halted. Finally, neuroprotective agents, such as calcium channel blockers, may come to play a pivotal role in the management of this condition. To date, the only two approaches shown to affect the course of the disease are the lowering of IOP and the use of calcium channel blockers.

 

 

REFERENCES

 

1. Graham SL, Drance SM, Wijsman K, et al. Ambulatory blood pressure monitoring in glaucoma. The nocturnal dip. Ophthalmology. 1995;102:61–9.

 

2. Nicolela MT, Drance SM, Rankin SJ, et al. Color Doppler imaging in patients with asymmetric glaucoma and unilateral visual field loss. Am J Ophthalmol. 1996;121:502–10.

 

3. Hayreh SS, Zimmerman MB, Podhajsky P, Alward WL. Nocturnal arterial hypotension and its role in optic nerve head and ocular ischemic disorders. Am J Ophthalmol. 1994;117:603–24.

 

4. James CB. Effect of trabeculectomy on pulsatile ocular blood flow. Br J Ophthalmol. 1994;78:818–22.

 

5. Dandona L, Quigley HA, Brown AE, Enger C. Quantitative regional structure of the normal human lamina cribrosa. A racial comparison. Arch Ophthalmol. 1990;108:393–8.

 

6. Quigley H, Pease ME, Thibault D. Change in the appearance of elastin in the lamina cribrosa of glaucomatous optic nerve heads. Graefes Arch Klin Exp Ophthalmol. 1994;232:257–61.

 

7. Geijssen HC, Greve EL. Focal ischaemic normal pressure glaucoma versus high pressure glaucoma. Doc Ophthalmol. 1990;75:291–301.

 

8. Geijssen HC. Studies on normal pressure glaucoma, ed 1. Amsterdam: Kugler Publications; 1991.

 

9. Larsson LI, Rettig ES, Sheridan PT, Brubaker RF. Aqueous humor dynamics in low-tension glaucoma. Am J Ophthalmol. 1993;116:590–3.

 

10. Poinoosawmy D, Fontana L, Hitchings RA. Asymmetric field defects in normal tension glaucoma. Ophthalmology. 1998;105(6):988–91.

 

11. Haefliger IO, Hitchings RA. Relationship between asymmetry of visual field defects and intraocular pressure difference in an untreated normal (low) tension glaucoma population. Acta Ophthalmol (Copenh). 1990;68:564–7.

 

12. Crichton A, Drance SM, Douglas GR, Schulzer M. Unequal intraocular pressure and its relation to asymmetric visual field defects in low-tension glaucoma. Ophthalmology. 1989;96:1312–4.

 

13. Membrey WL, Poinoosawmy DP, Bunce C, et al. Comparison of visual field progression in patients with normal pressure glaucoma between eyes with and without visual field loss that threatens fixation. Br J Ophthalmol. 2000;84(10):1154–8.

 

14. Drance S, Anderson DR, Schulzer M. Risk factors for progression of visual field abnormalities in normal-tension glaucoma. Am J Ophthalmol. 2001;131(6):699–708.

 

15. Corbett JJ, Phelps CD, Eslinger P, Montague PR. The neurologic evaluation of patients with low-tension glaucoma. Invest Ophthalmol Vis Sci. 1985;26:1101–4.

 

16. Phelps CD, Corbett JJ. Migraine and low-tension glaucoma. A case-control study. Invest Ophthalmol Vis Sci. 1985;26:1105–8.

 

17. Bhandari A, Crabb DP, Poinoosawmy D, et al. Effect of surgery on visual field progression in normal-tension glaucoma. Ophthalmology. 1997;104:1131–7.

 

18. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol. 1998;126(4):498–505.

 

19. 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. 1998;126(4):487–97.

 

20. Koseki N, Araie M, Shirato S, Yamamoto S. Effect of trabeculectomy on visual field performance in central 30 degrees field in progressive normal-tension glaucoma. Ophthalmology. 1997;104:197–201.

 

21. Membrey WL, Poinoosawmy DP, Bunce C, et al. Comparison of visual field progression in patients with normal pressure glaucoma between eyes with and without visual field loss that threatens fixation. Br J Ophthalmol. 2000;84(10):1154–8.

 

22. Greve EL, Rulo AH, Drance SM, et al. Reduced intraocular pressure and increased ocular perfusion pressure in normal tension glaucoma: a review of short-term studies with three dose regimens of latanoprost treatment. Surv Ophthalmol. 1997;41(Suppl 2):S89–S92.

 

23. Sawada A, Kitazawa Y, Yamamoto T, et al. Prevention of visual field defect progression with brovincamine in eyes with normal-tension glaucoma. Ophthalmology. 1996;103:283–8.

 

24. Pilunat LE, Lang GK, Harris A. Effect of nimodipine on visual function in normal pressure glaucoma. Ophthalmology. 1994;101(Suppl):108.

 

25. Pillunat LE, Lang GK, Harris A. The visual response to increased ocular blood flow in normal pressure glaucoma. Surv Ophthalmol. 1994;38:139–48.

 

26. Membrey WL, Poinoosawmy DP, Bunce C, Hitchings RA. Glaucoma surgery with or without adjunctive antiproliferatives in normal tension glaucoma: 1 intraocular pressure control and complications. Br J Ophthalmol. 2000;84(6):586–90.

 

27. Quigley HA, Nickells RW, Kerrigan LA, et al. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36:774–86.

 

28. Kerrigan LA, Zack DJ, Quigley HA, et al. Tunnel positive ganglion cells in human primary open angle glaucoma. Arch Ophthalmol. 1997;115:1031–5.

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