The Unique Challenges of Normal Tension Glaucoma

An expert shares his approach.

By Darrell WuDunn, MD, PhD

Normal tension glaucoma (NTG) can be a challenging condition to diagnose and manage. Although it is similar in many aspects to high tension primary open-angle glaucoma (POAG), several clinical aspects differentiate the two conditions. The most obvious difference is that intraocular pressures tend to run at the lower end of the spectrum in normal tension glaucoma. But other, more subtle differences also may be found in patients with NTG.

Whether NTG is a separate entity from primary openangle glaucoma or part of the spectrum of disorders remains unknown. It is likely that both NTG and POAG represent groups of disorders that share common clinical features such as a characteristic progressive optic nerve appearance and pattern of retinal nerve fiber loss. However, until the pathophysiology of glaucoma is better characterized or distinct genes are identified that account for most NTG and POAG cases, I will still tend to think of NTG as a subset of POAG.

Diagnosis of NTG

Because the intraocular pressure is usually normal in persons with NTG, making the diagnosis of NTG requires more attention to other details, especially the optic nerve examination. When the intraocular pressure is elevated, we naturally tune into the possibility of glaucoma. However, with the pressure normal, we need to remain vigilant and look for other clues of glaucoma.

It may be important, but not always possible, to rule out other conditions that mimic NTG. The most common condition that looks like NTG is primary open-angle glaucoma. The intraocular pressure in POAG may be intermittently in the "normal" range (i.e., below 21 mm Hg) and we may have happened to catch the person when the pressure was low. Subsequent measurements at different visits and/or different times of the day may reveal elevated pressures consistent with high tension glaucoma.

We know that corneal elasticity can affect Goldmann applanation measurements. Persons with thin central corneal thickness or low corneal hysteresis tend to have Goldmann applanation pressures that are lower than their true intraocular pressures. Persons with NTG tend to have thinner central corneal thickness than normal or high tension glaucoma patients, so it may be that some NTG patients truly do have elevated intraocular pressures.¹

Because a hallmark of NTG is its progressive nature, we are frequently unable to make a definitive diagnosis of NTG at the initial visit. This is technically true for POAG as well; however, when I see a person with elevated intraocular pressure, optic nerve cupping and characteristic visual field loss, I usually make the diagnosis of POAG even without documented progression.

In the absence of elevated intraocular pressure, I feel more comfortable with the initial diagnosis of NTG suspect and I look for other possible causes of optic nerve cupping. Optic nerve cupping may have been caused by a prior history of elevated pressure, due to iritis, pigmentary dispersion, steroid usage or intermittent angle closure. Other optic neuropathies can cause shallow cupping, so I inquire about past history of sudden vision loss, perhaps due to optic neuritis or anterior ischemic optic neuropathy. Acute or severe blood loss or anemia can result in an optic neuropathy that resembles cupping, so I ask about major surgeries or trauma or blood transfusions. I have very rarely requested brain imaging in a NTG suspect and only for unilateral cupping. In the absence of other neurologic signs, I do not think the yield of an MRI or CT scan is very high.

After a detailed history and review of systems has eliminated or lessened the likelihood of another cause, I then look for exam findings that may suggest NTG. If one eye has consistently higher intraocular pressure than the fellow eye then I would expect that eye to have worse cupping in NTG. Gonioscopy to rule out intermittent angle closure or pigment accumulation due to pigmentary dispersion or pseudo exfoliation is critical but often must be done during a return visit if the pupil is already dilated when the suspicion for glaucoma is raised. In my experience, the optic nerve cupping in NTG patients tends to be shallower than in high tension glaucoma.

Peripapillary atrophy and disc hemorrhages are common in normal tension glaucoma and so the presence of either or both is suggestive of NTG. As with POAG, the extent of optic nerve changes in NTG may be asymmetric between the two eyes but severe asymmetry (>0.2 difference in cup-to-disc ratio), especially in the absence of IOP asymmetry, makes me concerned about other causes.

Visual field defects in normotensive are similar to those found in primary open-angle glaucoma. Some reports in the literature suggest that NTG visual field defects are more often "deep and steep" and nearer to fixation. Nerve fiber layer analysis should confirm glaucomatous pattern loss with localized thinning primarily at the inferior and superior sectors. Corneal pachymetry is often helpful. Thin central corneas increase my concern because Goldmann applanation measurements may underestimate the true intraocular pressures.

Management of NTG

We have learned from the Collaborative Normal Tension Glaucoma Study that the natural course of NTG is highly variable, with some patients suffering continued optic nerve damage within a few months, while others show no change at all over five years.² Factors that were found to be risks for progression were being female, having a history of migraines, and having disc hemorrhages.³ We also learned that lowering intraocular pressure by at least 30% slows the progression of the disease but that some patients will still progress despite treatment.

For the most part, I treat patients with NTG in the same manner as I treat patients with high-tension glaucoma: namely, I initiate medical therapy and aim for a significant drop in intraocular pressure. A 30% decrease in intraocular pressure was used as the target in the Collaborative Normal Tension Glaucoma Study, and I think that is a reasonable starting aim. However, depending on the individual patient's age and degree of optic nerve damage or visual field loss, I will adjust my target. I may settle for a less dramatic intraocular pressure decrease (say, 20%) if the patient has a short life expectancy or only mild optic nerve damage or visual field loss.

To reach my target pressure, I usually start with a prostaglandin analogue and then switch to or add a topical carbonic anhydrase inhibitor, then brimonidine or a beta blocker. Although beta-adrenergic blockers and alphaadrenergic agonists may have systemic cardiovascular effects that could affect optic nerve circulation (ocular perfusion pressure),⁴ the evidence is insufficient for me to avoid using them to treat NTG.

I advance medication treatment until we have achieved target IOP or until we have reached the maximal number of medications that the patient can tolerate. If we have still not reached target IOP after all medication combinations have been tried, I will reconsider the target IOP and decide whether to recommend surgical intervention or to settle for a more modest target IOP.

I monitor my patients with NTG in much the same way I monitor my patients with other forms of glaucoma, with serial visual field testing and optic nerve evaluations/ imaging. Visual field testing is quite variable in NTG, and multiple fields are needed to confirm true progression. In the Collaborative Normal Tension Glaucoma Study, three confirmatory visual fields were used before progression was declared.⁵ More recent visual field testing algorithms, such as SITA-standard, may be less variable but I still want to see at least two confirmatory fields before I am convinced that progression has occurred. Even the recently developed Glaucoma Progression Analysis probability plots and the Visual Field Index linear regression analysis require multiple (three or more) tests to demonstrate likely progression.

Figure 1. A 65-year-old woman with normal tension glaucoma. Prior to treatment, her IOP typically measured in the 15-18 mm Hg range (highest 20 mm Hg). On dorzolamide-timolol, her pressures run 10-15 mm Hg in each eye. She has been intolerant of latanoprost and brimonidine. Optic nerves have shallow cups and thinning of the inferior neuroretinal rim in each eye. Right optic nerve showed a disc hemorrhage inferotemporally before treatment was initiated. Visual fields consistently show severe superior arcuate and nasal step defects in each eye, but have been stable since treatment began five years ago. Corneal pachymetry was 490-500 microns in each eye.

I rely on serial retinal nerve fiber layer analysis/imaging to monitor optic nerve structure. Since criteria for progression with imaging technologies is not well established for the newer technologies such as OCT or GDx, I want to see structure-function correlation with the visual fields. Seeing disc hemorrhages raises my suspicion that progression is occurring but I still want to see corroborating evidence on visual field testing or optic nerve imaging.

The decision to recommend surgery comes down to whether the benefits of surgery (potentially lower IOP) outweigh the risks of surgery (vision loss due to cataract formation, bleb-related complications, etc.). To appreciate the benefit of lowering IOP with surgery, I need to know if the disease is progressing on maximal tolerated medications. Thus, as in the management of high-tension glaucoma, moni toring of NTG is critical. I also consider the rate of progression, the visual functioning in the fellow eye, the patient's visual needs and any co-existing ophthalmic and systemic conditions.

I have not found laser trabeculoplasty to be very effective in lowering IOP in NTG. It has been shown that the higher the IOP, the greater the pressure lowering one gets with laser trabeculoplasty.⁶ Likewise, I have not found much IOP lowering from cataract surgery in patients with NTG. In my experience, the pressure-reducing effects of laser trabeculoplasty and of cataract surgery are very similar, and I suspect the two procedures share a common mechanism of action on outflow facility.

Managing our patients with normal tension glaucoma remains a challenging endeavor. Because IOP is already relatively low, we do not achieve the dramatic drops in IOP with treatment as we do in high tension glaucoma. In addition, factors other than IOP probably play a more important role in NTG than in high-tension glaucoma, but lowering IOP is still our only proven treatment. Thus, we may be more limited in our ability to mitigate the natural course of disease with NTG compared to high tension glaucoma. Diagnosing and managing patients with NTG requires diligence and persistence, but with proper care most patients with NTG maintain good visual functioning. OM

References

1. Morad Y, Sharon E, Hefetz L, Nemet P. Corneal thickness and curvature in normal-tension glaucoma. Am J Ophthalmol. 1998;125:164-8.
2. Anderson DR, Drance SM, Schulzer M; Collaborative Normal-Tension Glaucoma Study Group. Natural history of normal-tension glaucoma. Ophthalmology. 2001;108:247-53.
3. Drance S, Anderson DR, Schulzer M; Collaborative Normal-Tension Glaucoma Study Group. Risk factors for progression of visual field abnormalities in normaltension glaucoma. Am J Ophthalmol. 2001;131:699-708.
4. Quaranta L, Gandolfo F, Turano R, Rovida F, Pizzolante T, Musig A, Gandolfo E. Effects of topical hypotensive drugs on circadian IOP, blood pressure, and calculated diastolic ocular perfusion pressure in patients with glaucoma. Invest Ophthalmol Vis Sci. 2006;47:2917-23.
5. Schulzer M. Errors in the diagnosis of visual field progression in normal-tension glaucoma. Ophthalmology. 1994;101:1589-94.
6. Hodge WG, Damji KF, Rock W, Buhrmann R, Bovell AM, Pan Y. Baseline IOP predicts selective laser trabeculoplasty success at 1 year post-treatment: results from a randomised clinical trial. Br J Ophthalmol. 2005;89:1157-60.