With America's population aging and with growing awareness of normal-tension glaucoma, patients who progress with an intraocular pressure of 12 mmHg are no longer rare. However, systemic risk factors play a far greater role in NTG than in high-pressure glaucoma. For that reason, when a patient appears to be progressing despite an IOP as low as 12 mmHg, it's important to proceed cautiously.

Asking the Right Questions

Before assuming that the patient really does have NTG, and that traditional steps to reduce IOP are the appropriate treatment, consider other possible explanations for the patient's signs and symptoms. For example:
Is the IOP really 12 mmHg? Check corneal thickness; a thin cornea could be masking elevated IOP. (Be sure to ask the patient about previous refractive surgery.) Also, remember that high-pressure glaucoma can be camouflaged by systemic beta-blocker use.
• Is the disease truly progressing? Be sure to have a minimum of two visual fields showing significant change before diagnosing progression. (We still can't rely upon computerized imaging to consistently detect change.)
• Does the patient have an abnormal diurnal IOP fluctuation that could account for the progression? Studies have suggested that evenness of IOP control may be more important than average IOP.1,2 The average diurnal pressure fluctuation of a non-medicated patient with glaucoma is 11 mmHg, with a range up to 30 mmHg. Some patients drop 18 mmHg in the first half hour after rising in the morning.

Use of medications can exacerbate the diurnal curve. For example, prostaglandins are excellent at lowering IOP evenly, but using t.i.d. drugs b.i.d., especially if combined with a prostaglandin that encourages washout of the drug from the posterior chamber, may result in wider swings of IOP than using prostaglandins alone. Large IOP swings could also be caused by frequent dialysis, or an extraordinary response to assuming a supine position.

 • Are other factors exacerbating progression? Systemic risk factors that may allow progression of glaucoma at low normal readings can be exacerbated by topical or systemic medications. For example, vascular dysregulation may be improved or worsened by topical beta-blockers; calcium channel blockers may be helpful if the underlying etiology is vasospasm, or hurtful if a patient has systemic hypotension.
• Does the patient really have glaucoma? Many diseases and anatomical anomalies result in pathologic-appearing discs and visual fields; it's important to rule these out.

Glaucoma Signs: Alternate Possible Explanations

Misleading Ocular Conditions

Etiologies that can
result in visual field loss

Etiologies that can predispose to glaucoma progression at normal IOPs

• A large physiologic cup. (HRT and GDx scans can be helpful in these patients.)
• An old branch vein occlusion. (The patient may not have noticed the visual field loss because of the location.)

 • An anomalous optic nerve with congenital pit, coloboma, or severe tilt resulting in visual field loss

 • Retinal hemorrhage or nevus, tumor, chorioretinitis, retinal detachment or retinoschisis

• Optic nerve drusen

• Orbital/intracranial optic nerve compression

• Previous secondary glaucoma (traumatic, steroid-induced,
 inflammatory or ghost-cell) now resolved

• Subacute angle-closure glaucoma

• Burnt-out glaucoma
• Shock-induced neuropathy

• Multiple sclerosis

•Anterior ischemic optic neuropathy (AION). This chronic condition is often associated with arteriosclerotic cardiovascular or carotid artery disease, episodic systemic hypotension, or diabetes. Splinter hemorrhages are common, and glaucomatous cupping and visual defects are frequent.

• Cardiac arrhythmia

• Blood dyscrasias

• Severe anemia

• Polycythemia vera

• Hyperviscosity syndromes
• Increased platelet adhesiveness

• Vascular dysregulation
(inappropriate vasoconstriction or vasodilation, or defective vasodilation in the face of increased local metabolism. This can be seen with systemic hypotension, nocturnal hypotension or vasospastic syndrome.)

• Sleep apnea. (This is present in one-third of POAG patients and one-half of NTG patients; progression seems to be related to hypoxia rather than elevated IOP.)

• Autoimmune problems. (Patients with NTG have increased incidence of autoantibodies to proteins in the retina and/or optic nerve.)

The Patient-Compliance Factor

If the patient really is suffering from progressive glaucoma with an IOP of 12 mmHg, there are other factors which should be pursued before medical or surgical intervention. Foremost among them is the issue of how patients who are already on medications are using them.

For example, a study by Michael Kass, MD, showed that many patients not only grossly over-report their drop usage—they're also likely to go out of their way to use their drops the day before and the morning of their office visit.3 As a result, you could find disease progression in these patients even though their IOPs appear to be nicely controlled. We don't want to resort to drastic measures to reduce IOP further if this is the explanation—although finding a way to circumvent the compliance issue would certainly be appropriate.
How common are compliance problems? A 1995 study found that only 49 percent of single-medication patients were using the medication correctly.4 The percentage dropped to 32 percent if more than one medication was involved.

In the Kass study, patients claimed to take 97.1 percent of prescribed drops, but a hidden microchip in pilocarpine bottles showed only 76 (±24.3) percent of prescribed drops were taken. Fifteen percent of the subjects used less than half of the prescribed amount, and 6 percent used less than a quarter of it.

Compliance is also affected by physical ability. Dr. Kass found that 20 percent of patients rely on a family member to put in drops, and 57 percent admit to difficulty putting them in. Only 20 percent put in a drop correctly the first time. (You can uncover this problem by handing the patient a sample of artificial tears and asking him to show you how he uses his drops. If his hand holding the bottle circles over his eye like a vulture over a carcass and the drop lands on his cheek, the patient is a candidate for a drop guide.)

Studies have found that increasing the number and frequency of meds has a negative effect on compliance,5,6 but Dr. Kass noted that defaulting was not eliminated by prescribing a more convenient medication with fewer side effects. And in addition to all these concerns, treatment of POAG is preventive; without symptoms, noncompliant patients aren't aware that they're hurting themselves.

The bottom line is that physicians are usually unable to determine the extent of patient compliance—and poor compliance, except on the day of the office visit, can create the illusion that the patient is suffering from NTG.
IOP Lowering: How Far?

If you've determined that the patient really does have glaucoma progression with an IOP of 12 mmHg, and all treatable systemic and compliance issues have been addressed, then average IOP is the main risk factor that you can address.

The Collaborative Normal Tension Glaucoma Trial showed that lowering IOP at least 30 percent reduces further visual field loss.7,8 However, 20 percent of patients who achieved that 30-percent drop with an IOP as low as 11 mmHg still suffered further visual field loss. For that reason, I believe the target IOP needs to be 40 percent lower, between 7 and 8 mmHg.

Producing an IOP lower than episcleral venous pressure is rarely possible with present medications, but it can be done with filtering surgery augmented with antifibrosis regimens. Usually, however, I begin by prescribing drops. If this doesn't produce close to my target of a 40-percent drop in IOP, I move to selective or argon laser trabeculoplasty, and then to trabeculectomy. (In 1991 I reported a study of trabeculectomy with 5-FU in normal-tension glaucoma patients that resulted in a 6.9-mmHg average IOP, right on target for these patients.9)

If the IOP does end up close to the target with medical and laser therapy, I generally follow the visual fields every six months and operate only if further damage becomes apparent.

Doing the Right Thing

To summarize: When your patient appears to have NTG, make sure your assessments of IOP and progression are accurate; then look for factors that could disguise high-tension glaucoma (e.g., compliance problems, thin corneas) and factors that could be causing excessive fluctuations of IOP.10 Also check for other possible etiologies and anatomical anomalies that could be responsible for the observed signs and symptoms (some of which may be treatable).

Workup Guidelines

To help determine whether a patient has normal-tension glaucoma or a different physical or neurological problem, I recommend the following:

• Check the visual field. Normal-tension glaucoma often has a characteristic dense paracentral loss impinging on fixation (superiorly more than inferiorly).

•  Examine stereo disc photos, and/or HRT/GDx scans. Eyes with the same amount of total visual field loss as a POAG patient will have a thinner neuroretinal rim, especially superiorly and inferiorly. They are also more likely to have peripapillary atrophy.

•  Check corneal pachymetry. Rule out an IOP error caused by a thin cornea.

•  Perform gonioscopy. This can rule out subacute angle closure.

•  Review the big picture. Go over the history of any present illnesses and conduct a Review of Systems. Consider having an autoimmune workup done if the Review of Systems is positive.

•  Have an internist perform a comprehensive physical examination. The focus should be on neurological and circulatory concerns.

•  Consider other tests. These could include an electrocardiogram, a complete blood count, and a serologic test for syphilis.

•  If appropriate, order 24-hour blood-pressure monitoring. This may reveal blood-pressure related problems.

•  If appropriate, perform neuroimaging. This is useful if the Review of Systems is positive, or the disc and/or visual field are not characteristic of glaucoma. Cupping occurs with neurologic disease at the following rates: arteritic ischemic optic neuropathy—50 percent; non-arteritic ischemic optic neuropathy—10 percent; compressive lesions—5 percent; and optic neuritis—less than 5 percent.

Some general guidelines: 1) With early loss of color vision or central vision, or if a visual field defect obeys the midline, odds are good that the problem is neurologic. 2) Remember that glaucoma is a chronic disease—be suspicious of rapid visual acuity loss. 3) When the problem is neurologic, both vision and pallor tend to be worse than the cupping. Conversely, when the problem is glaucoma, the cupping tends to be worse than the vision problems or pallor. 4) Generally, if the problem is glaucoma, you should be able to predict the visual field results by looking at the disc.         — R.P.W.

Finally, if it's clear that your patient really does have NTG, aim to reduce pressure by 40 percent, with surgery as a viable option. 

Dr. Wilson is professor of ophthalmology at Jefferson Medical College in Philadelphia and co-director of the Glaucoma Service at Wills Eye Hospital. He is the outgoing president of the American Glaucoma Society.

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3. Kass MA, Meltzer DW, Gordon M, Cooper D, Goldberg J. Compliance with topical pilocarpine treatment. Am J Ophthalmol 1986;101:515-523.
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6. Bigger JF. A comparison of patient compliance in treated vs untreated ocular hypertension.
7. Collaborative Normal-Tension Glaucoma Study Group. The effectiveness of intraocular pressure reduction in the treatment of normal-tension glaucoma. Am J Ophthalmol 1998;126:498-505.
8. 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 1998;126:487-497.
9. Wilson RP, Steinmann WC. Use of trabeculectomy with postoperative 5-fluorouracil in patients requiring extremely low intraocular pressure levels to limit further glaucoma progression. Ophthalmology 1991;98:1047.
10. Nouri-Mahdavi K, Hoffman D, et al. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology 2004;111:9:1627-35.